Lung Cancer—Non-Small Cell Metastatic

LUNG CANCER—NON-SMALL CELL METASTATIC

9000 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).

Kazuhiko Nakagawa, Edward B. Garon, Takashi Seto, Makoto Nishio, Santiago Ponce Aix, Chao-Hua Chiu, Keunchil Park, Silvia Novello, Ernest Nadal, Fumio Imamura, Kiyotaka Yoh, Jin-Yuan Shih, Kwok Hung Au, Denis Moro-Sibilot, Sotaro Enatsu, Annamaria H. Zimmermann, Bente Frimodt-Moller, Carla M. Visseren Grul, Martin Reck; Kindai University Hospital, Osaka, Japan; David Geffen School of Medicine, University of California/TRIO-US Network, Los Angeles, CA; National Kyushu Cancer Center, Fukuoka, Japan; Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Hospital 12 de Octubre, Madrid, Spain; Taipei Veterans General Hospital, Taipei, Taiwan; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Oncology, University of Turin, Orbassano, Italy; Institut Catala ` d’Oncologia, L’Hospitalet, Barcelona, Spain; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Queen Elizabeth Hospital, Kowloon, China; Service Hospitalier Universitaire Pneumologie Physiologie Poleˆ Thorax et Vaisseaux Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France; Lilly Research Laboratories Japan, Kobe- shi, Japan; Eli Lilly & Co., Indianapolis, IN; Eli Lilly and Company, Copenhagen, Denmark; Lilly Oncology Europe, Utrecht, Netherlands; LungenClinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany

Background: Dual blockade of EGFR and VEGFR pathways in EGFRm NSCLC augments anti-tumor efficacy versus (v) EGFR inhibition alone. RELAY (NCT02411448) evaluated efficacy and safety of ERL, an EGFR TKI standard-of-care, plus RAM, a human IgG1 VEGFR2 antagonist, or PL in 1L EGFRm metastatic NSCLC. Methods: Eligibility included untreated metastatic NSCLC pts with Exon 19 deletion (del) or L858R and no CNS metastasis. Randomized (1:1) pts received ERL (150 mg/day) + RAM (10 mg/kg q2w) or ERL + PL, stratified by gender, geographic region (East Asia v other), EGFRm type (Ex19del v L858R) and EGFR testing method (Therascreen/Cobas v other). The primary endpoint was Investigator assessed progression free survival (PFS). Other objectives included ORR, DoR, PFS2, OS, safety, and plasma T790M mutation (Guardant NGS). Results: 449 pts were randomized characteristics were balanced between treatment arms: Asian 77%, Females 63%, Ex19del 54%. RAM + ERL significantly prolonged PFS, DoR, and PFS2 (Table). Grade .=3 TEAEs were greater with RAM (72%) v PL (54%), largely driven by hypertension (24 v 5%, no Gr4); with 1 treatment related on study death (hemothorax) in RAM v 0 PL. EGFR T790M+ rates at progression are forthcoming. Conclusion: RAM + ERL led to superior PFS in 1L EGFRm metastatic NSCLC. Safety was consistent with the established safety profiles of the individual compounds. Clinical trial information: NCT02411448.

RAM + ERL (n=224) PL + ERL (n=225) HR (95% CI) p-value PFS 0.591 (0.461 – 0.760) ,0.0001 Median, months (95% CI) 19.4 (15.4 – 21.6) 12.4 (11.0 – 13.5) Censoring rate 46% 30% ORR, % (95% CI) 76.3 (70.8 – 81.9) 74.7 (69.0 – 80.3) 0.7413 Number of responders 171 168 DoR** 0.619 (0.477 – 0.805)* 0.0003* Median, months (95% CI) 18.0 (13.9 – 19.8) 11.1 (9.7 – 12.3) Censoring rate 41% 24% PFS2 0.690 (0.490 – 0.972) 0.0325 Median, months (95% CI) NR NR Censoring rate 73% 65% Interim OS 0.832 (0.532 – 1.303) 0.4209 Median, months (95% CI) NR NR Censoring rate 83% 81%

Median follow-up: 20.7 months NR, not reached * unstratified **Ns are based on number of responders from the ITT population

9001 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C).

Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Anuradha Chougule, Abhishek Mahajan, Amit Janu, Nilendu Purandare, Rajiv Kumar, Sucheta More, Supriya Goud, Nandkumar Kadam, Nilesh Daware, Srushti Shah, Akanksha Yadav, Amit Dutt, Vaishakhi Trivedi, Vichitra Behel, Shripad Dinanath Banavali, Kumar Prabhash; Tata Memorial Centre, Mumbai, India; Tata Memorial Hospital, Mumbai, India; Gunvati J Kapoor Medical Relief Charitable Foundation, Mumbai, India; Tata Memorial Center, Mumbai, India; Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India

Background: Standard first-line therapy for EGFR mutant advanced non-small cell lung cancer (NSCLC) is an EGFR-directed oral TKI. We evaluated whether adding pemetrexed-carboplatin to oral TKI would improve outcomes. Methods: Phase III randomized trial in advanced chemotherapy-na¨ıve NSCLC harboring EGFR sensitizing mutation (exon 19, 21 or 18) with performance status (PS) 0 to 2 planned for palliative therapy. Patients were stratified for PS and EGFR mutation and randomly assigned (computer-generated randomization by independent biostatistician) 1:1 to gefitinib 250 mg orally daily (gef) or gefitinib 250 mg orally daily with pemetrexed 500 mg/m2 IV and carboplatin AUC 5 IV every 3 weeks for 4 cycles, followed by maintenance pemetrexed 500 mg/m2 IVevery3weeks(gef+C). Restaging was every 2 to 3 mths; therapy continued until progression or intolerable toxicity. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), toxicity and response rate. Survival endpoints were assessed in the intention-to-treat population. Results: Between Aug 2016 and Aug 2018, 350 patients were randomly assigned to gef (n = 177) and gef+C (n = 173). Median age was 54 yrs, 48% were females, 84% never-smokers, 21% were PS 2 and 18% had brain metastases. Median follow-up in surviving patients was 17 months (range, 7 to 30). Radiologic response rates were 81% and 69% in gef+C and gef respectively, P = 0.012. 234 patients (67%) have had events for PFS, 98 in gef+C and 136 in gef. Estimated median PFS was significantly longer with gef+C than gef (16 months, [95% CI, 13.7 to 18.3] vs. 8 months [95% CI, 7.1 to 8.9]; hazard ratio for disease progression or death, 0.5; 95% CI, 0.39 to 0.65; P , 0.001). 120 patients (34%) have died, 42 in gef+C and 78 in gef. Estimated median OS was significantly longer with gef+C than gef (not reached vs. 18 months [95% CI, 14.28 to 21.72]; hazard ratio for death, 0.45; 95% CI, 0.31 to 0.66; P , 0.001). Clinically relevant $ grade 3 toxicities occurred in 51% and 25% of patients in gef+C and gef arms respectively, P , 0.001. Conclusion: Adding pemetrexed-carboplatin chemotherapy to gefitinib significantly prolonged progression free and overall survival but also increased toxicity. Pemetrexed-carboplatin-gefitinib represents a new standard first-line therapy for EGFR mutant NSCLC. Clinical trial information: CTRI/ 2016/08/007149.

9002 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

ECOG-ACRIN 5508: Pemetrexed, bevacizumab or the combination as maintenance therapy for advanced non-squamous NSCLC.

Suresh S. Ramalingam, Suzanne Eleanor Dahlberg, Chandra Prakash Belani, Joel N. Saltzman, Gopakumar S. Nambudiri, John McCann, Jerome D. Winegarden, Mohammed Azher Kassem, Mohamed K. Mohamed, Jan M. Rothman, Alan P. Lyss, Leora Horn, Tom Stinchcombe, Joan H. Schiller, ECOG-ACRIN Cancer Research Group; Winship Cancer Institute, Emory University, Atlanta, GA; Dana-Farber Cancer Institute, Boston, MA; Penn State Hershey Cancer Institute, Hershey, PA; University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH; Health East Cancer Care, Woodbury, MN; Baystate Medcl Ctr, Springfield, MA; Ann Arbor Hem Onc Assocs, Ypsilanti, MI; Mt.Sinai Hosp, Chicago, IL; Cone Health Center at Wesley Long, Greensboro, NC; The Regional Cancer Center, Erie, PA; Missouri Baptist Cancer Ctr, St Louis, MO; Vanderbilt University Medical Center, Nashville, TN; Duke Cancer Institute, Durham, NC; The University of Texas Southwestern Medical Center, Dallas, TX

Background: Maintenance therapy is a standard approach for advanced non-squamous NSCLC. Peme- trexed or bevacizumab are considered evidence-based options. The combination of bevacizumab and pemetrexed has been documented to improve progression-free survival (PFS). We conducted a phase 3 study to determine the optimal maintenance therapy for advanced NSCLC. Methods: Patients (pts) with advanced non-squamous NSCLC, no prior systemic therapy, and ECOG performance status 0/1 were treated with carboplatin (AUC = 6), paclitaxel (200 mg/m2) and bevacizumab (15 mg/Kg) every 3 weeks for up to 4 cycles (step 1). Patients with CR/PR/SD after 4 cycles were then randomized 1:1:1 to maintenance therapy with bevacizumab (15 mg/Kg), pemetrexed (500 mg/m2) or the combination of the two agents every 3 weeks until disease progression (step 2). The primary endpoint was overall survival (OS), defined as the time from randomization to death from any cause and censoring defined at the last date of followup. 1495 pts provided 81% power to detect a hazard ratio of 0.75 while controlling the 2- sided type I error at 0.025 for each comparison, assuming approximately 60% of those patients would be randomized. Results: We enrolled 1516 pts to step 1 (male 52%; ECOG PS 1 62%; adenocarcinoma 90%); After induction therapy, 874 (57%) pts were randomized to step 2 (median age 64 yrs; male 49%; ECOG PS 1 55%). Baseline characteristics were balanced across all three groups. The median follow-up in maintenance is 50.6 months. Conclusions: Single agent bevacizumab or pemetrexed is the optimal maintenance therapy for advanced non-squamous NSCLC. The combination of bevacizumab and pemetrexed cannot be recommended due to the lack of survival benefit in this definitive study. (Drs. Ramalingam, Dahlberg and Belani contributed equally to this work). Supported by the NCI: CA180820, CA180794,CA180799, CA180821, CA180838, CA180844, CA180847, CA180853, CA180857, CA180864, CA180867, CA180868, CA180870, CA180882, CA189830, CA189859, CA189863, CA189971. Clinical trial information: NCT01107626.

Bevacizumab Pemetrexed Bevacizumab + Pemetrexed Number of patients 287 294 293 Efficacy (Medians, 97.5% CIs) PFS 4.2 m 5.1 m 7.5 m HR 0.85,(0.69, 1.03) HR 0.67,(0.55, 0.82) p , 0.001 p = 0.06 OS 14.4 m 15.9 m 16.4 m HR 0.86,(0.70, 1.07)p = 0.12 HR 0.90,(0.73, 1.12)p = 0.28 Grade 3/4/5 Toxicity Worst Degree 30% 37% 50% Anemia 2% 7% 6% Neutropenia 1% 7% 11% Thrombocytopenia -3%4% Fatigue 2% 7% 8% Hypertension 16% 5% 19%

9003 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

A randomized phase III study of continuous maintenance bevacizumab with or without pemetrexed after induction therapy with carboplatin (Car), pemetrexed (Pem), and bevacizumab (Bev) for advanced non-squamous non-small cell lung cancer (nSQ-NSCLC) without sensitizing EGFR mutations: The COMPASS study (WJOG5610L).

Takashi Seto, Koichi Azuma, Takeharu Yamanaka, Shunichi Sugawara, Hiroshige Yoshioka, Akira Ono, Shinji Atagi, Yasuo Iwamoto, Hidetoshi Hayashi, Isamu Okamoto, Hideo Saka, Mitsuoka Shigeki, Daichi Fujimoto, Kazumi Nishino, Atsushi Horiike, Haruko Daga, Takashi Sone, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Yoichi Nakanishi; National Kyushu Cancer Center, Fukuoka, Japan; Kurume University School of Medicine, Kurume, Japan; Yokohama City University, Yokohama, Japan; Sendai Kousei Hospital, Sendai, Japan; Kansai Medical University Hospital, Hirakata, Japan; Shizuoka Cancer Center, Shizuoka, Japan; Department of Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan; Hiroshima Citizens Hospital, Hiroshima, Japan; Kindai University Faculty of Medicine, Osaka, Japan; Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; National Hospital Organization, Nagoya Medical Center, Nagoya, Japan; Osaka City University Hospital, Osaka, Japan; Kobe City Medical Center General Hospital, Kobe, Japan; Osaka International Cancer Institute, Osaka, Japan; The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Osaka City General Hospital, Osaka, Japan; Kanazawa University Hospital, Kanazawa, Japan; Wakayama Medical University, Wakayama, Japan; Kindai University Hospital, Osaka, Japan

Background: Two continuous maintenance therapies, “Pem after Pem+Platinum” and “Bev after Bev+Plt- doublet”, demonstrated the prolongation of survival for advanced nSQ-NSCLC. We conducted a randomized trial of Bev versus Bev+Pem as continuation maintenance therapy after Car+Pem+Bev induction therapy. Methods: Patients were eligible if they had previously untreated advanced nSQ-NSCLC whose EGFR status was either wild-type, unknown, or other than Del19 or L858R. They received the induction treatment with Car (AUC6), Pem (500 mg/m2), and Bev (15mg/kg) every 3 weeks for 4 cycles. Those who showed no progression during the induction therapy were randomized to receive maintenance therapy using Bev or Bev+Pem in a 1:1 ratio. The primary endpoint was overall survival (OS) from randomization. The planned sample size was 620 to provide a power of 85% at one-sided significance level of 5%. Violations found at a study site led us to conduct source document verification for 95.4% of patients to assure data quality. (Trial Identifier, UMIN000004194). Results: Between September 2010 and September 2015, 907 patients had the induction therapy. Of those, 621 patients were randomized; five did not receive study treatment and 22 did not meet the eligibility criteria. Among 594 patients for evaluable (299 in the Bev+Pem arm and 295 in the Bev arm), median age was 65 years; Male, 72%; PS 0/1, 60/40%; Stage IV, 83%; EGFR status, wild-type/others, 91/7%. Median OS was 23.3 vs 19.6 months (mo) with a hazard ratio (HR) of 0.87 (95%CI, 0.72-1.04) and one-sided logrank P= 0.069; in patients with wild-type EGFR tumor, HR for OS was 0.82 (0.68-0.99). Median progression-free survival was 5.7 vs 4.0 mo with a HR of 0.67 (0.57-0.79). 87.4% of patients received subsequent therapy. No new safety signals were observed. Conclusions: The primary analysis was not met. However, the incorporation of Pem significantly prolonged OS in patients with wild-type EGFR. Clinical trial information: UMIN000004194.

9004 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Capmatinib (INC280) in METDex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study.

Juergen Wolf, Takashi Seto, Ji-Youn Han, Noemi Reguart, Edward B. Garon, Harry J.M. Groen, Daniel Shao-Weng Tan, Toyoaki Hida, Maja J. De Jonge, Sergey V. Orlov, Egbert F. Smit, Pierre Jean Souquet, Johan F. Vansteenkiste, Monica Giovannini, Sylvie Le Mouhaer, Anna Robeva, Maeve Waldron-Lynch, Rebecca Suk Heist; Lung Cancer Group Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Dept. for Internal Medicine, Cologne, Germany; National Kyushu Cancer Center, Fukuoka, Japan; National Cancer Center, Gyeonggi-Do, South Korea; University Hospital Clinic of Barcelona, Barcelona, Spain; University of California, Los Angeles, Los Angeles, CA; Dept. of Pulmonary Diseases - University of Groningen and University Medical Center Groningen, Groningen, Netherlands; National Cancer Center, Singapore, Singapore; Aichi Cancer Center, Nagoya, Japan; Erasmus MC Cancer Institute, Rotterdam, Netherlands; St. Petersburg Pavlov State Medical University, St. Petersburg, Russia; Netherlands Cancer Institute, Amsterdam, Nether- lands; University Hospital of Lyon-Sud, Lyon, France; Gasthuisberg University Hospital, Leuven, Belgium; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Novartis Pharma S.A.S, Paris, France; Novartis Pharma AG, Basel, Switzerland; Massachusetts General Hos- pital Cancer Center, Boston, MA

Background: Capmatinib is a highly potent and selective MET inhibitor. Previous data of GEOMETRY mono-1 study showed a clinically meaningful overall response rate (ORR) and manageable toxicity profile in patients (pts) with METDex14–mutated NSCLC who received 1–2 prior lines of treatment (tx) (Cohort 4) and in particular a high ORR in tx-na¨ıve pts (Cohort 5b). Here we report the results in METDex14–mutated NSCLC for duration of response (DOR) and progression-free survival (PFS) as well as the updated results for ORR. Methods: GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in pts with METDex14-mutated or MET-amplified advanced NSCLC across 6 cohorts. Pts ($18 yrs) with ECOG PS 0–1, ALK and EGFR wt, and stage IIIB/IV NSCLC were eligible. Pts with METDex14 mutation (centrally confirmed) were assigned (regardless of MET amplification status/gene copy number) to Cohorts 4 and 5b and received capmatinib tablets 400 mg BID. Primary endpoint was ORR by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Key secondary endpoint was DOR by BIRC. Results: As of Nov 08, 2018, 97 pts with METDex14-mutated NSCLC (Cohort 4: 69 pts; Cohort 5b: 28 pts) were evaluable for efficacy. ORR (95% CI) by BIRC was 39.1% (27.6-51.6) in Cohort 4 and 71.4% (51.3-86.8) in Cohort 5b. While still immature at the time of this analysis, data on durability are promising: median DOR (95% CI) by BIRC was 9.72 (4.27-11.14) and 8.41 (5.55-NE) mo for Cohorts 4 and 5b, respectively; median PFS (95% CI) by BIRC was 5.42 (4.17- 6.97) and 9.13 (5.52-13.86) mo for Cohorts 4 and 5b, respectively. Safety profile remains favourable and unchanged. Most common AEs ($25% all grades) across all cohorts (n = 315), were peripheral edema (49.2%), nausea (43.2%), and vomiting (28.3%); majority of the AEs were grade 1/2. Final efficacy analysis (12-mo f-u on DOR) including biomarker data will be presented during meeting. Conclusions: These data confirm capmatinib to be a promising new treatment option for pts with METDex14-mutated advanced NSCLC regardless of the line of therapy with deep and durable responses and manageable toxicity profile. Clinical trial information: NCT02414139.

9005 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Phase II study of tepotinib in NSCLC patients with METex14 mutations.

Paul K. Paik, Remi Veillon, Alexis B. Cortot, Enriqueta Felip, Hiroshi Sakai, Julien Mazieres, Frank Griesinger, Leora Horn, Helene Senellart, Jan P. Van Meerbeeck, Javier de Castro Carpe~no, Jyoti D. Patel, Marina Chiara Garassino, Masahiro Morise, Niels Reinmuth, Santiago Viteri, Takaaki Tokito, Tomohiro Sakamoto, Jurgen ¨ Scheele, Xiuning Le; Memorial Sloan Kettering Cancer Center, New York, NY; CHU Bordeaux, Service Des Maladies Respiratoires, Bordeaux, France; Lille University Hospital, Univ. Lille, Lille, France; Vall d´Hebron University Hospital, Barcelona, Spain; Saitama Cancer Center, Saitama, Japan; CHU de Toulouse-Hopital Larrey, IUCT–Oncopole, Quai de Livraison Pharmacie, Toulouse, France; Pius-Hospital, University Department Internal Medicine- Oncology, Medical Campus University of Oldenburg, Oldenburg, Germany; Vanderbilt-Ingram Cancer Center, Nashville, TN; ICO Rene Gauducheau Center, Saint-Herblain, France; Antwerp University Hospital, Edegem, Belgium; Hospital Universitario HM Madrid Sanchinarro, Madrid, Spain; The University of Chicago Medical Center, Chicago, IL; Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy; Nagoya University Graduate School of Medicine, Nagoya, Japan; Asklepios Lung Clinic, Munich-Gauting, Germany; Dr Rosell Oncology Institute, Dexeus University Hospital, Quiron Salud Group, Barcelona, Spain; Kurume University School of Medicine, Kurume, Japan; Tottori University Hospital, Yonago, Japan; Merck KGaA, Darmstadt, Germany; MD Anderson Cancer Center, The University of Texas, Houston, TX

Background: MET exon 14 skipping (METex14) mutations - reported in 3~4% of NSCLC patients (pts) - are activating, sensitive to MET inhibition and can be conveniently detected using liquid biopsy (LBx). We report data from an ongoing single-arm phase II study of tepotinib, a highly selective MET inhibitor, in NSCLC pts with METex14 mutations identified by LBx or tumor biopsy (TBx) (NCT02864992). Methods: Pts with advanced WT EGFR/ALK NSCLC, prospectively enrolled via either LBx ($60 pts) or TBx ($60 pts, overlap anticipated) central RNA-based METex14 mutation testing, receive tepotinib 500 mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint: objective response rate (ORR) by independent review (IRC). Secondary endpoints: ORR by investigator assessment (INV) and safety. Results: To date, 85 pts have been enrolled (55 LBx pts and 52 TBx pts). At data cut-off (16 Oct 2018), in 35 evaluable LBx pts ($2 post-baseline assessments or discontinuation for any reason), ORR was 51.4% by IRC and 63.9% by INV. In 41 evaluable TBx pts, ORR was 41.5% by IRC and 58.5% by INV. Median duration of response (mDoR) and ORR by line of treatment are shown in the table. Any grade treatment- related adverse events (TRAEs) reported by $10% of 69 pts evaluable for safety were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%), asthenia (10.1%). No TRAEs were grade 4 or led to death. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). Conclusions: Tepotinib has promising activity with a long DoR across treatment lines in NSCLC pts with METex14 mutations detected by LBx or TBx. The safety profile was favorable. Recruitment is ongoing. Clinical trial information: NCT02864992.

LBx TBx Responders/Evaluable pts (%) [95% CI] IRC INV IRC INV ORR Line of therapy 1L 8/12 (66.7) 11/12 (91.7) 6/16 (37.5) 8/15 (53.3) [34.9, 90.1] [61.5, 99.8] [15.2, 64.6] [26.6, 78.7] 2L 6/11 (54.5) 7/12 (58.3) 6/12 (50.0) 9/13 (69.2) [23.4, 83.3] [27.7, 84.8] [21.1, 78.9] [38.6, 90.9] ‡3L 4/12 (33.3) 5/12 (41.7) 5/13 (38.5) 7/13 (53.8) [9.9, 65.1] [15.2, 72.3] [13.9, 68.4] [25.1, 80.8] Overall ORR 18/35 (51.4) 23/36 (63.9) 17/41 (41.5) 24/41 (58.5) [34.0, 68.6] [46.2, 79.2] [26.3, 57.9] [42.1, 73.7] mDoR, months (range) 9.8 (1.1, 17.1 (1.3, 12.4 (1.1, 14.3 (1.3, 18.0) 21.5) 18.0) 21.5)

9006 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

MET inhibitor resistance in patients with MET exon 14-altered lung cancers.

Robin Guo, Michael Offin, A. Rose Brannon, Andrew Chow, Lukas Delasos, Romel Somwar, Olivia Wilkins, Kerry Scott, Yuan Tian, Fabiola Cecchi, Todd A. Hembrough, Bob T. Li, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Natasha Rekhtman, Paul K. Paik, Marc Ladanyi, Ahmet Zehir, Alexander E. Drilon; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY; UConn Health, Farmington, CT; NantOmics, LLC, Rockville, MD; NantOmics, LLC, Santa Cruz, CA

Background: MET exon 14 alterations comprise a novel class of lung cancer drivers. MET tyrosine kinase inhibitors (TKIs) are active in patients with these cancers, but objective response rates (ORRs) are modest (~30%-40%). A subset of these cancers may harbor intrinsic resistance. Moreover, patients with initial benefit invariably develop acquired resistance. We set out to identify potential resistance mechanisms. Methods: We studied patients with stage IV MET exon 14-altered lung cancers who received a MET TKI. When feasible, tumor and/or plasma samples were collected, prioritizing paired pre- and post-TKI collection. Tumor samples underwent targeted mass spectrometry analysis (Nantomics) and DNA- (including MSK-IMPACT)/RNA-based (MSK-Fusion) next-generation sequencing (NGS). Plasma cfDNA underwent targeted NGS. ORR and progression-free survival (PFS) were assessed (RECIST v1.1). Results: 74 patients received a MET TKI (1 TKI n = 55; $2 TKIs n = 19). 91% received crizotinib as their 1st TKI. Pre-TKI MET levels in tumor tissue (range 0-2120 amol/mg) were associated with outcomes: ORR 63% (n = 7/11) and median PFS 6.9 mos with detectable MET vs ORR 0% (n = 0/5) and median PFS 4.6 mos with undetectable MET (HR for PFS 0.3). Pre-TKI RAS pathway activation was associated with response: ORR 0% (n = 0/6) with KRAS/NF1/RASA1 mutation vs ORR 29% (n = 25/87) in others. Similar outcomes were observed with pre-TKI KRAS expression (n = 16, all with detectable KRAS levels): ORR 0% (n = 0/2) in KRAS $700 amol/mg vs ORR 50% (n = 7/14) , 700 amol/mg. Acquired resistance (Jackman criteria) was seen in 29 patients, 9 with paired pre-/post-treatment samples. On-target acquired resistance was found in 2/9 patients (22%): MET D1228N (n = 1), HGF amplification (n = 1). Potential off-target acquired resistance mechanisms were found in 5/9 pts (44%): KRAS G13V (n = 1), RASA1 S742* (n = 1), MDM2 amplification (n = 2), EGFR amplification (n = 1). Conclusions: Lack of MET expression or RAS pathway activation is associated with poor MET TKI outcomes in MET exon14-altered lung cancers. On- target acquired resistance is found in , 25% of patients; HGF amplification is a novel mechanism. Off- target intrinsic/acquired resistance may be mediated by RAS/MDM2/EGFR pathway activation.

9007 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.

Pasi A. Janne, Joel W. Neal, D. Ross Camidge, Alexander I. Spira, Zofia Piotrowska, Leora Horn, Daniel Botelho Costa, Anne S. Tsao, Jyoti D. Patel, Shirish M. Gadgeel, Lyudmila Bazhenova, Viola Weijia Zhu, Howard West, Sylvie Vincent, Jian Zhu, Shuanglian Li, Gregory J. Riely; Dana- Farber Cancer Institute, Boston, MA; Stanford University and Stanford Cancer Institute, Stanford, CA; University of Colorado Cancer Center, Aurora, CO; Virginia Cancer Specialists, Fairfax, VA; Massa- chusetts General Hospital, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Beth Israel Deaconess Medical Center, Boston, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; The University of Chicago Medical Center, Chicago, IL; University of Michigan, Ann Arbor, MI; University of California San Diego Moores Cancer Center, La Jolla, CA; University of California, Irvine School of Medicine, Orange, CA; Swedish Cancer Institute, Seattle, WA; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA; Memorial Sloan Kettering Cancer Center, New York, NY

Background: TAK-788 is an oral investigational EGFR/HER2 inhibitor under evaluation in NSCLC patients (pts) with EGFR exon 20 insertions. We report results of a phase 1/2 open-label, multicenter study (NCT02716116). Methods: Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results: As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; $2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (median 3.6 mo on treatment; median 3.8 treatment cycles); 24 pts remain on treatment. Antitumor activity in pts with EGFR exon 20 insertions is shown in Table. At data cutoff, 7/14 responses were confirmed with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Rate of treatment discontinuation due to AEs was 10.7% in pts treated at 160 mg. Most common TEAEs ($20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr $3 TEAEs ($5%) were diarrhea (26%) and hypokalemia, nausea, and stomatitis (7% each). Median dose intensity for pts treated with 160 mg qd was 93%. There is no clear trend that response to TAK-788 is enriched in particular EGFR exon 20 insertion variants. Conclusions: In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. Clinical trial information: NCT02716116.

Expanded Cohort 160 mg qd n=26a Best response (unconfirmed), n (%)b CR 0 PR 14 (54) SDc 9 (35) PD 1(4) NE 2(8) Objective response, n (%) 14 (54) 95% CI 33.37–73.41 Disease control, n (%) 23 (89) 95% CI 69.85–97.55 aPts with $1 disease assessment or discontinued due to AE. bBy RECIST v1.1. cSD observed $6 weeks after first study drug administration.

9008 Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC).

Justin F. Gainor, Dae Ho Lee, Giuseppe Curigliano, Robert Charles Doebele, Dong-Wan Kim, Christina S Baik, Daniel Shao-Weng Tan, Gilberto Lopes, Shirish M. Gadgeel, Philippe Alexandre Cassier, Matthew H. Taylor, Stephen V. Liu, Benjamin Besse, Michael Thomas, Viola Weijia Zhu, Hui Zhang, Corinne Clifford, Michael Palmer, Christopher D. Turner, Vivek Subbiah; Massachusetts General Hospital, Boston, MA; University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; University of Milano, European Institute of Oncology, Division of Early Drug Development, Milan, Italy; University of Colorado, Denver, CO; Seoul National University Hospital, Seoul, South Korea; Fred Hutchinson Cancer Research Center, Seattle, WA; National Cancer Center, Singapore, Singapore; Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; University of Michigan/Rogel Cancer Center, Ann Arbor, MI; Centre Leon-B´ ´ erard, Lyon, France; Oregon Health & Science University, Portland, OR; Georgetown University Medical Center, Washington, DC; Paris-Sud University, Orsay and Gustave Roussy, Villejuif, France; Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Chao Family Com- prehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Blueprint Medicines Inc, Cambridge, MA; The University of Texas MD Anderson Cancer Center, Houston, TX

Background: RET fusions are targetable oncogenic drivers in up to 2% of NSCLC, yet no selective RET inhibitors are approved. BLU-667 is an investigational highly potent and selective RET inhibitor targeting oncogenic RET alterations, including those that confer resistance to multikinase inhibitors (MKIs). We provide an update on the registration-enabling ARROW study (NCT03037385) of BLU-667 in pts with RET-fusion+ NSCLC. Methods: The global ARROW study includes DE (30-600 mg daily [QD or BID]) and dose expansion (DX) at the recommended phase 2 dose (RP2D; 400 mg QD) in pts with advanced solid tumors. Primary objectives are overall response rate (ORR; RECIST 1.1) and safety. Results: As of 19Dec2018, 79 pts (21 DE, 58 DX) with advanced RET fusion+ NSCLC (44 KIF5B, 16 CCDC6, 19 other/pending) received BLU-667. Median number of prior therapies was 2 (range 0-8) and includes chemotherapy (76%), immunotherapy (41%), and MKI (27%). 39% had baseline brain metastases. ORR among 57 response-evaluable pts with measurable disease and at least one follow-up disease assessment was 56% (95% CI: 42, 69; 32 partial responses (PR), 9 PR pending confirmation, 20 stable disease, 5 progressive disease). 91% (29/32) of responding pts remain on treatment; 6 have achieved response duration $ 6 months. Disease control rate (DCR) was 91% (52/57). Among 30 pts at the RP2D previously treated with platinum chemotherapy, ORR was 60% (18 PRs; 7 pending confirmation). Responses occur regardless of prior treatment or RET fusion genotypes. Intracranial activity has been observed with shrinkage of brain metastases. 80% of NSCLC pts treated at RP2D remain on treatment and only 3% discontinued due to related adverse event. In NSCLC patients, treatment-related toxicity (TRT), generally low-grade and reversible (28% had $ grade 3 events), included increased AST (22%), hypertension (18%), increased ALT (17%), constipation (17%), fatigue (15%) and decreased neutrophils (15%). Conclusions: BLU-667 demonstrated potent, durable and broad antitumor activity and was well tolerated in pts with advanced RET-fusion+ NSCLC. Enrollment of the expansion is ongoing with registrational intent. Clinical trial information: NCT03037385.

9009 Clinical Science Symposium, Fri, 1:00 PM-2:30 PM

JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).

Eric B. Haura, Byoung Chul Cho, Jong Seok Lee, Ji-Youn Han, Ki Hyeong Lee, Rachel E. Sanborn, Ramaswamy Govindan, Eun Kyung Cho, Sang-We Kim, Karen L. Reckamp, Joshua K. Sabari, Meena Thayu, Kyounghwa Bae, Roland Elmar Knoblauch, Joshua Curtin, Nahor Haddish-Berhane, Laurie Jill Sherman, Matthew V. Lorenzi, Keunchil Park, Joshua Bauml; Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Seoul National University Bundang Hospital, Seoul, South Korea; National Cancer Center, Gyeonggi-Do, South Korea; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea; Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR; Washington University School of Medicine, St. Louis, MO; Gachon University Gil Medical Center, Incheon, South Korea; Asan Medical Center, Seoul, South Korea; City of Hope Comprehensive Cancer Center, Duarte, CA; NYU School of Medicine, New York, NY; Janssen Research & Development, LLC, Spring House, PA; Janssen Research and Development, Spring House, PA; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Background: JNJ-372 binds EGFR and cMet to block ligand binding, promote receptor degradation, and trigger antibody-dependent cellular cytotoxicity in models of EGFR-mutated (EGFRm) NSCLC. Here we describe the ongoing phase 1 safety, pharmacokinetics (PK), and activity of JNJ-372 in patients (pts) with NSCLC, including 3rd generation tyrosine kinase inhibitor (3GTKI)-relapsed EGFRm NSCLC and EGFR Exon20ins disease. Methods: Pts received JNJ-372 (140–1400 mg) IV weekly for the first 28-day cycle and biweekly thereafter. 1050–1400 mg doses are being explored in dose expansion. Blood samples were collected for PK analyses. Efficacy by investigator per RECIST v1.1 in pts with EGFRm NSCLC treated at $700 mg is presented. Tumors were characterized by next-generation sequencing of circulating tumor (ct)DNA and/or tumor tissue. Results: As of 17 Jan 2019, 116 enrolled pts with NSCLC were treated. Median age was 63 years, 38% were male, 77% were Asian, and 97% had EGFR mutations. Mean duration of treatment was 3.8 months, longest exposure was 20 cycles. The PK data set included pts from Korea (77%) and the US (23%). At the 1050 mg dose, 72% of pts achieved average concentrations above the EC90 based on preclinical models. Adverse events (AEs; $20%) were rash (59%), infusion related reaction (58%), paronychia (28%), and constipation (22%). Additional EGFR/ cMet-related AEs include stomatitis (17%), pruritis (15%), peripheral edema (11%), and diarrhea (7%). Grade $3 AEs were reported in 34% (8% treatment-related) with dyspnea (6%) and pneumonia (3%) most frequently observed. Among response-evaluable pts, 25/88 (28%) achieved best timepoint response of partial response (PR). 10/47 pts with prior 3GTKI therapy had best timepoint response of PR (6 confirmed), including 4 with C797S, 1 with cMet amplification, and 5 without identifiable EGFR/cMet-dependent resistance. 6/20 pts with Exon20ins had best timepoint response of PR (3 confirmed). Conclusions: JNJ-372 has a manageable safety profile consistent with EGFR and cMet inhibition. Preliminary responses were achieved in 3GTKI-relapsed disease, including C797S and cMet amplification, and Exon20ins disease; enrollment in dose expansion is ongoing. Clinical trial information: NCT02609776.

9010 Clinical Science Symposium, Fri, 1:00 PM-2:30 PM

Safety and preliminary antitumor activity of U3-1402: A HER3-targeted antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC.

Pasi A. Janne, Helena Alexandra Yu, Melissa Lynne Johnson, Conor Ernst Steuer, Michele Vigliotti, Corinne Iacobucci, Shuquan Chen, Channing Yu, Dalila B. Sellami; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Sarah Cannon Research Institute, Nashville, TN; Winship Cancer Institute of Emory University, Atlanta, GA; Daiichi Sankyo, Inc., Basking Ridge, NJ

Background: Treatment options are limited for EGFRm NSCLC resistant to EGFR TKIs. HER3 is expressed in a majority of NSCLC tumors. U3-1402 is a HER3-targeted antibody drug conjugate with a fully human HER3-targeted antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Methods: An ongoing multicenter phase 1 dose escalation and expansion study is assessing U3-1402 safety/tolerability and preliminary activity in metastatic or unresectable EGFRm NSCLC patients (pts) who are T790M negative after disease progression while on erlotinib, gefitinib or afatinib; or develop disease progression while on osimertinib regardless of T790M status. Dose escalation is based on dose-limiting toxicities (DLTs) and guided by the modified Continuous Reassessment Method. U3-1402 is administered via intravenous infusion in 21-day cycles. Pre- treatment tumor tissue is required. Results: As of 11 Nov 2018, 15 pts (6 M; 9 F) were enrolled across 3 dose levels (3.2, 4.8, 6.4 mg/kg). Median age was 63 y; 10 pts had EGFR exon 19 deletion and 5 EGFR L858R mutation. Median sum of longest diameters (SLD) at baseline was 69 (range 22–143) mm. All pts had prior EGFR TKIs; 14 had 2nd line or later osimertinib. Six had prior chemotherapy. All 11 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score 188, range 150–290). Five pts discontinued treatment: 4 due to progressive disease, 1 due to adverse event (AE). All Grade (Gr) treatment-emergent AEs (TEAEs) in $20% of pts were nausea (60%), vomiting (40%), fatigue (33%), decreased appetite (27%), and alopecia (20%). Gr$3 TEAEs were nausea (1/15; Gr3; related), hypoxia (1/15; Gr3; unrelated), and platelet count decreased (2/15; both Gr4 at 6.4 mg/kg and considered DLTs). In 13 evaluable pts, all but 1 had a decrease in SLD (median best change 229%, range +10% to 267%), 2 had confirmed partial response per RECIST v1.1 (best changes 244%, 267%). Conclusions: U3-1402 showed a manageable safety profile and preliminary antitumor activity in EGFR TKI- resistant EGFRm NSCLC. Evaluation of candidate biomarkers, including HER3 expression, which correlate with U3-1402 response is ongoing. Clinical trial information: NCT03260491.

9011 Clinical Science Symposium, Fri, 1:00 PM-2:30 PM

Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1 fusion-positive non-small cell lung cancer (TRIDENT-1 study).

Byoung Chul Cho, Alexander E. Drilon, Robert Charles Doebele, Dong-Wan Kim, Jessica Jiyeong Lin, Jeeyun Lee, Myung-Ju Ahn, Viola Weijia Zhu, Samuel Ejadi, D. Ross Camidge, Yuwei Juliet Liu, Shanna Stopatschinskaja, Jingrong Jean Cui, David Michael Hyman, Sai-Hong Ignatius Ou, Alice Tsang Shaw; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Memorial Sloan Kettering Cancer Center, New York, NY; University of Colorado, Denver, CO; Seoul National University Hospital, Seoul, South Korea; Massachusetts General Hospital, Harvard Medical School, Boston, MA; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, Orange, CA; University of Colorado Cancer Center, Aurora, CO; Turning Point Therapeutics, Inc, San Diego, CA; Turning Point Therapeutics, San Diego, CA; Turning Point Therapeutics, Inc., San Diego, CA; Chao Family Comprehensive Cancer Center, University of California, Orange, CA; Massachusetts General Hospital/Harvard Medical School, Boston, MA

Background: Repotrectinib is a next-generation ROS1/TRK/ALK TKI inhibiting ROS1 with . 90-fold greater potency than crizotinib. Preclinical studies showed robust kinase inhibitory activity of repotrectinib against all known ROS1 fusion positive resistance mutations, including the most common ROS1 solvent-front mutation (SFM) G2032R. Methods: In this ongoing phase 1 study (NCT03093116), TKI- na¨ıve and TKI-refractory ($1 TKI) patients (pts) with advanced ROS1/TRK/ALK+ solid tumors received repotrectinib treatment. Endpoints include safety, PK, and confirmed overall response (cORR). Safety analysis for all pts (n = 75) and efficacy analysis for ROS1+ NSCLC pts (n = 28) enrolled on the study was conducted. Results: As of 31-Oct-2018, 75 pts were treated with repotrectinib at dose levels from 40 mg QD to 200 mg BID. Most AEs were manageable and grade (Gr) 1-2. Common ( . 20%) treatment-related AEs were dizziness (49%), dysgeusia (48%), paresthesia (28%), and constipation (20%). Four DLTs (Gr3 dyspnea/hypoxia (n = 1); Gr2 (n = 1) and Gr3 (n = 1) dizziness at 160 mg BID, and Gr3 dizziness (n = 1) at 240 mg QD) occurred and were managed with dose modifications. The MTD has not been reached. Median number of prior TKI treatment was 1 (0-3) with all of TKI na¨ıve and 83% of TKI pre-treated pts received prior chemotherapy. Among 10 evaluable TKI-na¨ıve ROS1+ NSCLC pts, confirmed ORR by Blinded Central Review (BCR) was 90% (95% CI 56 - 100) with median duration of response (DOR) not reached ((range 5.5+ – 14.9+ months (mos)). Among 18 TKI-pretreated pts, confirmed ORR by BCR was 28%(95%CI10– 54) with DOR of 10.2 mos. Subgroup analysis showed cORR 44% (95% CI 14 - 79) in 9 prior TKI pts and treated at dose levels of 160 mg QD or above. In 7 pts with measurable target CNS lesions at baseline, the intracranial ORR was 3/3 (100%) with DOR (5.5+; 7.2+; 14.85+ mo) in TKI-na¨ıve pts and 2/4 (50%) with DOR (5.5+;14.8+, mo) in TKI-pretreated pts, respectively. Conclusions: Repotrectinib was well tolerated and demonstrated encouraging overall and intracranial clinical activity in pts with ROS1 fusion- positive NSCLC. Enrollment in phase 1 continues until the RP2D is determined. A global phase 2 study is planned. Clinical trial information: NCT03093116.

9012 Poster Discussion Session; Displayed in Poster Session (Board #335), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

IMpower150: Analysis of efficacy in patients (pts) with liver metastases (mets).

Mark A. Socinski, Robert M. Jotte, Federico Cappuzzo, Tony S. K. Mok, Howard West, Makoto Nishio, Vassiliki Papadimitrakopoulou, Francisco J Orlandi, Daniil Stroyakovskiy, Christian A. Thomas, Naoyuki Nogami, Fabrice Barlesi, Anthony Lee, Geetha Shankar, Wei Yu, Marcus Ballinger, Ilze Bara, Alan Sandler, Martin Reck; AdventHealth Cancer Institute, Orlando, FL; Rocky Mountain Cancer Centers, Denver, CO; Azienda Unita ` Sanitaria Locale della Romagna, Ravenna, Italy; Prince of Wales Hospital, Hong Kong, China; Swedish Cancer Institute, Seattle, WA; Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; The University of Texas MD Anderson Cancer Center, Houston, TX; Instituto Nacional del Torax, Santiago, Chile; Moscow City Oncology Hospital, Moscow, Russian Federation; New England Cancer Specialists, Scarborough, ME; Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan; Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, Assistance Publique Hopitauxˆ de Marseille, Marseille, France; Genentech, Inc., South San Francisco, CA; LungenClinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany

Background: Atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP]; ABCP) showed improved PFS and OS vs bev + CP (BCP) in pts with chemo-naive NSCLC (IMpower150). Benefit with ABCP vs BCP extended to key subgroups, including pts with baseline (BL) liver mets, which is a poor prognostic factor in metastatic NSCLC. Similar outcomes were not seen with atezo + chemo (IMpower150 [atezo + CP; ACP]; IMpower130; IMpower132), suggesting that the addition of bev to atezo + chemo is important for conferring clinical benefit in these pts. Here we further explore characteristics and responses of pts with BL liver mets in IMpower150. Methods: 1202 ITT pts were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were: A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min; P, 200 mg/ m2. Coprimary endpoints were OS and investigator-assessed PFS in ITT–wild-type pts. Exploratory analyses included efficacy and safety in pts with liver mets. Results: The data capture $ 20-mo follow-up in ITT pts (data cutoff: Jan 22, 2018). 162 pts had BL liver mets (ABCP, n = 52; ACP; n = 53; BCP, n = 57), with a median of 3 metastatic sites and median BL tumor SLD of 109 mm (range, 10-249). BL characteristics in these pts were generally balanced across study arms. PFS and OS were improved with ABCP vs BCP (Table). Gr 3-4 treatment-related AEs occurred in 52.1%, 36.5% and 54.5% of pts with liver mets in the ABCP, ACP and BCP arms, respectively. Conclusions: ABCP reduced the risk of death in pts with liver mets by 48% vs BCP and may represent an important new treatment option for this population. Clinical trial information: NCT02366143.

mPFS, mo HR (95% CI) Presence ABCP vs ACP vs of liver mets ABCP ACP BCP BCP BCP Yes 8.2 5.4 5.4 0.41 0.81 n = 52 n = 53 n = 57 (0.26, 0.62) (0.55, 1.21) No 8.4 6.9 7.0 0.61 0.90 n = 348 n = 349 n = 343 (0.52, 0.73) (0.77, 1.06) mOS, mo HR (95% CI) Yes 13.3 8.9 9.4 0.52 0.87 n = 52 n = 53 n = 57 (0.33, 0.82) (0.57, 1.32) No 20.4 21.0 17.0 0.82 0.84 n = 348 n = 349 n = 343 (0.66, 1.02) (0.68, 1.04) ORR, %a Difference (95% CI), % Yes 60.8 26.9 41.1 19.7 -14.2 n = 51 n = 52 n = 56 (-0.75, 40.18) (-33.65, 5.35) No 55.8 42.7 40.1 15.7 2.6 n = 346 n = 349 n = 337 (8.03, 23.4) (-5.03, 10.29) mDOR, mo HR (95% CI) Yes 10.7 5.6 4.6 0.39 0.59 n = 31 n = 15 n = 23 (0.21, 0.73) (0.29, 1.23) No 11.5 9.2 6.5 0.43 0.52 n = 193 n = 149 n = 138 (0.33, 0.55) (0.40, 0.69) a Pts with measurable disease at BL

9013 Poster Discussion Session; Displayed in Poster Session (Board #336), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC.

Shirish M. Gadgeel, Marina Chiara Garassino, Emilio Esteban, Giovanna Speranza, Enriqueta Felip, Maximilian J. Hochmair, Steven Francis Powell, Susanna Y. Cheng, Helge Bischoff, Nir Peled, Rina Hui, Martin Reck, Takayasu Kurata, Edward B. Garon, Michael J. Boyer, Jing Yang, Maria Catherine Pietanza, Delvys Rodriguez-Abreu; Karmanos Cancer Institute (currently at Uni- versity of Michigan, Ann Arbor, MI, USA), Detroit, MI; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Hospital Universitario Central de Asturias, Oviedo, Spain; Centre integrede ´ cancerologie ´ de la Monter´ ´ egie, Universite ´ de Sherbrooke, Greenfield Park, QC, Canada; Vall d’Hebron University, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Re- spiratory Epidemiology, Vienna, Austria; Sanford Health, Sioux Falls, SD; Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Thoraxklinik, Heidelberg, Germany; Davidoff Cancer Center, Tel Aviv University (currently at Soroka Medical Center, Ben-Gurion University, Beer- Sheeva, Israel), Petah Tikva, Israel; Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; Kansai Medical University Hospital, Hirakata, Japan; David Geffen School of Medicine at UCLA, Los Angeles, CA; Chris O’Brien Lifehouse, Camperdown, NSW, Australia; Merck & Co., Inc., Kenilworth, NJ; Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas De Gran Canaria, Spain

Background: Pembro + chemo significantly improved OS and PFS over chemo alone and had manageable safety as 1L therapy for metastatic nonsquamous NSCLC in the KEYNOTE-189 study (NCT02578680). The benefit was observed irrespective of PD-L1 TPS. We present updated OS based on longer follow-up and, for the first time, PFS2. Methods: Eligible pts were randomized 2:1 to pembro (n = 410) or placebo (n = 206) + pemetrexed and carboplatin or cisplatin for 4 cycles followed by pembro or placebo for up to 35 cycles + maintenance pemetrexed. Pts in the chemo arm could crossover to pembro alone upon PD. Poststudy anticancer therapy and outcomes were collected. PFS2 was defined as time from randomization to PD per investigator after start of 2L therapy or death, whichever occurred first. There was no multiplicity adjustment, and all P values are nominal. Data cutoff was 21 Sep 2018. Results: With 18.7-mo median follow-up, pembro + chemo continued to provide longer OS (HR 0.56 [95% CI 0.45-0.70], P , .00001; median 22.0 mo vs 10.7 mo) and PFS (HR 0.48 [95% CI 0.40-0.58], P , .00001). Benefit was seen in all PD-L1 TPS groups (Table). 2L+ therapy was received by 45% in the pembro + chemo arm and 59% (54% 2L+ immunotherapy) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (HR 0.49 [95% CI 0.40-0.59], P , .00001; median 17.0 mo vs 9.0 mo), with no difference by TPS (Table). Conclusions: 1L pembro + pemetrexed/platinum continued to show substantial OS benefit in metastatic nonsquamous NSCLC, regardless of PD-L1 TPS and despite 54% of pts in the placebo + chemo arm receiving subsequent immunotherapy. Median OS, PFS and PFS2 were approximately doubled with pembro + chemo. These data confirm that pembro should be given as part of 1L therapy to maximize outcomes in both PD-L1expressing and PD-L1non-expressing NSCLC. Clinical trial information: NCT02578680.

PD-L1 TPS ‡50% PD-L1 TPS 1-49% PD-L1 TPS < 1% n = 202 n = 186 n = 190 OS, HR (95% CI) 0.59 (0.39-0.88) 0.62 (0.42-0.92) 0.52 (0.36-0.74) PFS, HR (95% CI) 0.36 (0.26-0.51) 0.51 (0.36-0.73) 0.64 (0.47-0.89) PFS2, HR (95% CI) 0.47 (0.33-0.69) 0.59 (0.41-0.86) 0.46 (0.33-0.66)

9014 Poster Discussion Session; Displayed in Poster Session (Board #337), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

A phase III randomized study of nivolumab plus ipilimumab versus nivolumab for previously treated patients with stage IV squamous cell lung cancer and no matching biomarker (Lung-MAP Sub-Study S1400I, NCT02785952).

Lyudmila Bazhenova, Mary Weber Redman, Scott N. Gettinger, Fred R. Hirsch, Philip C. Mack, Lawrence Howard Schwartz, David R. Gandara, Jeffrey D. Bradley, Tom Stinchcombe, Natasha B. Leighl, Suresh S. Ramalingam, Susan S Tavernier, Katherine Minichiello, Karen Kelly, Vassiliki Papadimitrakopoulou, Roy S. Herbst; University of California, San Diego, La Jolla, CA; SWOG Statistical Center; Fred Hutchinson Cancer Research Center, Seattle, WA; Yale Cancer Center, New Haven, CT; University of Colorado Cancer Center, Denver, CO; UC Davis Comprehensive Cancer Center, Sacramento, CA; Columbia University Medical Center, New York, NY; University of California, Davis, Sacramento, CA; Washington University School of Medicine in St. Louis, St. Louis, MO; Duke Cancer Institute, Durham, NC; Princess Margaret Cancer Centre, Toronto, ON, Canada; Winship Cancer Institute, Emory University, Atlanta, GA; Idaho State University, Pocatello, ID; University of California Davis Comprehensive Cancer Center, Sacramento, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Yale University, New Haven, CT

Background: Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. Methods: S1400I is phase III randomized trial for immunotherapy-na¨ıve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity. Results: From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. Outcomes based on PD-L1 and TBM subsets are shown in table. Response rates were 18% (12-25%) and 17% (11-24%) for N+ I and N. Median follow up for patients still alive was 17.4 m. Grade $3treatment- related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% and 16% of pts on N+I and N. There were 5 grade 5 AE in N+I arm and 1 in N arm. Conclusions: S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Clinical trial information: 02785952.

N+I N Median in months Median in months HR p OS PD-L1 ‡5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86 OS PD-L1 < 5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97 OS TMB ‡10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48 OS TMB < 10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74 PFS PD-L1 ‡ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10 PFS PD-L1 < 5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06 PFS TMB ‡ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15 PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

LBA9015 Poster Discussion Session; Displayed in Poster Session (Board #338), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001.

Edward B. Garon; David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, CA

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 a.m. ET on Saturday, June 1. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

9016 Poster Discussion Session; Displayed in Poster Session (Board #339), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

Blood tumor mutational burden (bTMB) and tumor PD-L1 as predictive biomarkers of survival in MYSTIC: First-line durvalumab (D) 6 tremelimumab (T) versus chemotherapy (CT) in metastatic (m) NSCLC.

Naiyer A. Rizvi, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Michel van den Heuvel, Manuel Cobo Dols, David Vicente, Alexey Smolin, Vladimir Moiseyenko, Scott Joseph Antonia, Kazuhiko Nakagawa, Sarah B. Goldberg, Edward S. Kim, Jill Walker, Rajiv Raja, Feng Liu, Urban J. Scheuring, Solange Peters; Columbia University Medical Center, New York, NY; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Asklepios Lung Clinic, Munich-Gauting, Germany; Chungbuk National University Hospital, Chungbuk National Uni- versity College of Medicine, Cheongju, South Korea; Leningrad Regional Clinical Hospital, Oncology Department, Lunacharskogo Prospect, Russian Federation; Samsung Medical Center, Seoul, South Korea; Department of Thoracic Oncology, Netherlands Cancer Institute (NKI), Amsterdam, Nether- lands; Hospital Universitario Regional Malaga, ´ Instituto de Investigaciones Biomedicas ´ Malaga ´ (IBIMA), Malaga, ´ Spain; Hospital Universitario Virgen Macarena, Seville, Spain; Main Military Hospital, Moscow, Russian Federation; Clinical Research Center, Pesochny, St. Petersburg, Russian Federation; Moffitt Cancer Center, Tampa, FL; Kindai University Hospital, Osaka, Japan; Yale University School of Medicine, New Haven, CT; Levine Cancer Institute, Charlotte, NC; AstraZeneca, Cambridge, United Kingdom; MedImmune, Gaithersburg, MD; AstraZeneca, Gaithersburg, MD; Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland

Background: MYSTIC, an open-label, Ph3 trial of first-line D (anti-PD-L1) 6 T (anti-CTLA-4) vs platinum- based CT, showed an improvement in OS with D vs CT in pts with tumor cell PD-L1 expression $25% (PD- L1 TC $25%; HR 0.76 [97.54% CI 0.56–1.02], p = 0.036). Exploratory analyses showed bTMB was a predictive biomarker for OS with D6T vs CT. We report further exploratory analyses of OS according to PD- L1 and bTMB. Methods: Immunotherapy/CT-na¨ıve pts with mNSCLC were randomized (1:1:1) to D, D+T or CT. bTMB levels (mut/Mb) were evaluated with the GuardantOMNI platform (Guardant Health), and PD-L1 TC expression with the VENTANA PD-L1 (SP263) IHC assay. Results: DimprovedOSvsCTinptswithPD- L1 TC $25% across bTMB levels (PD-L1 TC $25%/bTMB$20 HR 0.79 [95% CI 0.45, 1.39]; PD-L1 TC $25%/bTMB , 20 HR 0.64 [95% CI 0.45, 0.90]). In contrast, D+T improved OS vs CT in pts with bTMB$20 across different PD-L1 TC expression levels (Table; PD-L1 TC $25%/bTMB$20 HR 0.44 [95% CI 0.23, 0.84]; PD-L1 TC , 1%/bTMB$20 HR 0.42 [95% CI 0.17, 0.97]). Additional cutoffs and outcomes in subgroups defined by both biomarkers will be presented. Conclusions: These exploratory analyses from MYSTIC support PD-L1 TC expression as an appropriate predictive biomarker for OS with D vs CT, while suggesting bTMB as a predictive biomarker for OS with D+T in mNSCLC. These biomarkers appear to be independent and both may be important for mNSCLC treatment decisions. Interpretation of these data may be limited by small sample sizes; further investigations are warranted. Clinical trial information: NCT02453282.

D D+T PD-L1 TC ‡25% PD-L1 TC ‡1% PD-L1 TC < 1% PD-L1 TC ‡25% PD-L1 TC ‡1% PD-L1 TC < 1%

All pts, n N = 163 N = 279 N = 95 N = 163 N = 296 N = 76 HR* (95% CI) 0.76 (0.56, 1.02)† 0.88 (0.73, 1.07) 1.18 (0.86, 1.62) 0.85 (0.61, 1.17)‡ 1.01 (0.83, 1.21) 0.73 (0.51, 1.04) bTMB ‡20, n N = 40 N = 61 N = 16 N = 32 N = 49 N = 15 HR* (95% CI) 0.79 (0.45, 1.39) 0.74 (0.48, 1.13) 0.68 (0.32, 1.42) 0.44 (0.23, 0.84) 0.52 (0.32, 0.83) 0.42 (0.17, 0.97) bTMB < 20, n N = 91 N = 152 N = 57 N = 81 N = 164 N = 40 HR* (95% CI) 0.64 (0.45, 0.90) 0.79 (0.61, 1.03) 1.38 (0.89, 2.18) 1.16 (0.83, 1.63) 1.21 (0.95, 1.55) 0.99 (0.60, 1.62)

*HRs refer to comparison of immunotherapy to CT; †97.54% CI; ‡98.77% CI

9017 Poster Discussion Session; Displayed in Poster Session (Board #340), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

Spatial and temporal heterogeneity of PD-L1 and its impact on benefit from immune checkpoint blockade in non-small cell lung cancer (NSCLC).

Lingzhi Hong, Seyedeh Dibaj, Marcelo Vailati Negrao, Alexandre Reuben, Emily Roarty, Waree Rinsurongkawong, Jeff Lewis, Don Lynn Gibbons, Boris Sepesi, Vassiliki Papadimitrakopoulou, Bonnie S. Glisson, George R. Blumenschein, Jr., Phillip Andrew Futreal, Ignacio Ivan Wistuba, Jack A. Roth, Stephen Swisher, John Heymach, George R. Simon, J. Jack Lee, Jianjun Zhang; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic / Head and Neck Medical Oncology - The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic and cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Temporal and spatial heterogeneity of PD-L1 has been reported. However, its impact on clinical benefit from immune checkpoint inhibitor (ICI) has not been clearly defined. Methods: We queried the MD Anderson Lung Cancer GEMINI database and compared PD-L1 expression (tumor proportion score by immunohistochemistry using FDA-approved antibodies) in NSCLC specimens from different organs at different time points. We assessed the predictive value of PD-L1 for benefit from ICIs in patients with metastatic NSCLC. Results: In 1398 NSCLC patients, PD-L1 level was significantly associated with biopsy sites (p = 0.007). Adrenal and liver metastases had the highest PD-L1 level and positive rate (by 1% or 50% cutoff) while PD-L1 was the lowest in bone and brain biopsies. In addition, PD-L1 was significantly higher in fresh tissues (PD-L1 staining at , 90 days after biopsy) than archival tissues (PD-L1 staining at . 90 days after biopsy), in squamous cell carcinoma than adenocarcinoma, in EGFR wild-type (WT) than EGFR mutant, in MET amplified than METWT,andinSTK11WT than mutant (p , 0.01). Among 112 patients with longitudinal specimens tested, 55 (49%) had major changes with PD- L1 at different time points falling into different clinically relevant categories ( , 1%, 1-49%, . 50%). ICIs were associated with significant decrease in PD-L1 level compared to treatment-na¨ıve counterparts (p = 0.019). Furthermore, 398 patients with EGFR/ALKWT metastatic NSCLC who received ICIs were divided into three groups based on biopsy sites including lung (n = 252); lymph node (LN, n = 85) and distant metastasis (n = 61). Higher PD-L1 level in biopsies from lung or distant metastasis was associated with significantly higher response rate, disease control rate and significantly longer progression free survival and overall survival using either 1% or 50% cutoff. However, the PD-L1 expression from LN biopsies was not associated with either response or survival in this cohort of patients. These findings remained constant in multivariate analyses. Conclusions: PD-L1 expression varies substantially across different anatomic sites and changes during clinical courses. PD-L1 in LN biopsies may not be reliable to predict clinical benefit for ICIs in NSCLC. Repeat biopsy and PD-L1 staining should be considered if only remote tissues, particularly, LN biopsies are available.

9018 Poster Discussion Session; Displayed in Poster Session (Board #341), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

Molecular correlates of PD-L1 expression in patients with non-small cell lung cancer.

Hira Rizvi, Chaitanya Bandlamudi, Adam Jacob Schoenfeld, Jennifer L. Sauter, Kathryn Cecilia Arbour, Amanda Beras, Jacklynn V. Egger, Marc Ladanyi, Mark Donoghue, Charles M. Rudin, Barry S. Taylor, Matthew David Hellmann; Memorial Sloan Kettering Cancer Center, New York, NY; MSKCC, New York, NY; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY

Background: PD-L1 expression is the only FDA-approved predictive biomarker for patients with NSCLC treated with immune checkpoint inhibitors. The impact of tumor molecular profiling on tumor PD-L1 expression is not known. We hypothesized that somatic mutations and copy number alterations may be associated with distinct patterns of PD-L1 expression in patients with NSCLC. Methods: We examined patients with NSCLC in whom PD-L1 testing and targeted next-generation sequencing (MSK-IMPACT) were performed on the same tissue sample. PD-L1 expression was determined by IHC using the E1L3N antibody clone and categorized as PD-L1 high ($ 50%), intermediate (1-49%), or negative ( , 1%) expression. The association of PD-L1 with individual genes, pathways, tumor mutation burden, whole genome duplication (WGD), and aneuploidy (fraction of genome altered (FGA)) were evaluated. P- values , 0.05 and q-values , 0.15 were considered significant for individual genes. Results: 1023 patients with NSCLC had PD-L1 testing and MSK-IMPACT performed on the same tissue sample, 18% (n = 180) had high, 21% (n = 218) had intermediate, and 61% (n = 625) had negative PD-L1 expression. High PD-L1 expression was significantly enriched in metastatic vs primary lesions (p , 0.001). There was a minor correlation between PD-L1 and TMB (spearman rho = 0.195) and PD-L1 and FGA (spearman rho = 0.11). Similar rates of WGD were found among patients with high, intermediate, and negative PD-L1 expression (p = 0.38). Mutations in KRAS and TERT were significantly enriched in PD-L1 high compared to other groups (p = 0.001, q = 0.14; p , 0.001, q = 0.003). By contrast, mutations in EGFR and STK11 were associated with PD-L1 negativity (p , 0.001, q = 0.001; p = 0.001, q = 0.14). Pathway analysis showed DNA repair (p , 0.001), TP53 (p , 0.001), and SWI/SNF (p = 0.04) pathways significantly associated with PD-L1 high compared to PD-L1 negative expression. Conclusions: The genetic features of NSCLC are associated with distinct patterns of PD-L1 expression. This data may provide insight to how the molecular phenotype can interact with the immunologic phenotype of tumors.

9019 Poster Discussion Session; Displayed in Poster Session (Board #342), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC).

Alice Tsang Shaw, Jean-Francois Martini, Benjamin Besse, Todd Michael Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Antonello Abbattista, Francesca Toffalorio, Holger C. Thurm, Miyako Satouchi, D. Ross Camidge, Steven Chuan-Hao Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Benjamin J. Solomon; Massachusetts General Hospital, Boston, MA; Pfizer Inc, San Diego, CA; Gustave Roussy, Villejuif, France; Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville, TN; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; National University Cancer Institute, Singapore, Singapore; Memorial Sloan Kettering Cancer Center, New York, NY; Chao Family Comprehensive Cancer Center, University of California at Irvine Medical Center, Orange, CA; Pfizer Global Product Development-Oncology, Milan, Italy; Pfizer Global Product Development-Oncology, La Jolla, CA; Hyogo Cancer Center, Akashi, Japan; University of Colorado Cancer Center, Aurora, CO; Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia; Azienda Ospedaliera di Perugia, Perugia, Italy; University of Michigan/Rogel Cancer Center, Ann Arbor, MI; Vall d’Hebron Institute of Oncology, Barcelona, Spain; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Background: Lorlatinib is a selective, potent, brain-penetrant, 3rd generation (gen) ALK/ROS1 TKI approved for pts with advanced ALK+ NSCLC previously treated with a 2nd gen ALK TKI. We recently showed that ALK mutation tumor genotyping after failure of a 2nd gen ALK TKI may identify pts more likely to respond to lorlatinib.1 To identify other molecular response correlates, we evaluated if early ctDNA dynamics predict clinical outcome on lorlatinib. Methods: In pts enrolled on the ongoing ph 2 study (NCT01970865), plasma samples were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1, or 6 weeks) and end of treatment. Plasma DNA was analyzed using Guardant360. Change in variant allele fraction (dVAF)2 of ALK alterations (fusions and/or mutations) was calculated as (mean VAFC3D1) – (mean VAFBL); dVAF , 0 indicated decreased ctDNA at C3D1. BOR, PFS and OS were evaluated according to dVAF. Results: Of 121 paired BL/C3D1 samples collected from 158 ALK+ pts previously treated with one or more 2nd gen ALK TKIs, 57 (47%) harbored a detectable ALK alteration at BL. At C3D1, mean VAF of ALK fusions and/or mutations was significantly decreased compared to BL (-1.07, p = 0.0014). Mean tumor volume was reduced by 26% in pts with dVAF , 0(n= 40), but only by 12% in pts with dVAF $0 (n = 13) (p = 0.049). Mean dVAF at C3D1 was significantly decreased compared to BL for pts with CR/PR, while there was no significant difference with SD or PD/ IND; mean dVAF -1.84, -0.74, and +0.35 in pts with CR/PR, SD, or PD/IND, respectively (p = 0.0011, 0.1444 and 0.3383). Median PFS was 6.6 months (mo) in pts with dVAF , 0(n=44)and2.6moinpts with dVAF $0 (n = 13) (HR = 2.6, 95% CI: 1.2, 5.8). Median OS was 18.0 mo in pts with dVAF , 0(n= 34) and 8.6 mo in pts with dVAF $0 (n = 13) (HR 2.0, 95% CI, HR 0.9–4.6). Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in ALK+ NSCLC, with decreased ctDNA at 6 wks associated with better response and longer PFS. Further studies are needed to validate these findings and to determine whether early intervention based on dynamic ctDNA monitoring may improve outcome. References: 1. Shaw, et al. J Clin Oncol. 2019. 2. Raja, et al. Clin Cancer Res. 2018. Clinical trial information: NCT01970865.

9020 Poster Discussion Session; Displayed in Poster Session (Board #343), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial.

Caicun Zhou, Fumio Imamura, Ying Cheng, Isamu Okamoto, Byoung Chul Cho, Meng Chih Lin, Margarita Majem, Oliver Gautschi, Jhanelle Elaine Gray, Michael J. Boyer, Juliann Chmielecki, Ryan Hartmaier, Krishna Bulusu, J Carl Barrett, Rachel Hodge, Matilde Saggese, Astrid McKeown, Suresh S. Ramalingam; Shanghai Pulmonary Hospital, Tongji University, Shanghai, China; Depart- ment of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; Department of Oncology, Jilin Province Cancer Hospital, Changchun, China; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Kaohsiung, Taiwan; Department of Medical Oncol- ogy, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; University of Berne and Cantonal Hospital of Lucerne, Lucerne, Switzerland; Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL; Department of Medical Oncology, Chris O’Brien Lifehouse, Camper- down, Australia; Translational Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA; Bioscience, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom; Biometrics and Information Sciences, AstraZeneca, Cambridge, United Kingdom; Global Medical Development Oncology, AstraZeneca, Cambridge, United Kingdom; Emory University, Winship Cancer Institute, Atlanta, GA

Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third generation EGFR-TKI, showed superior efficacy to comparator EGFR-TKIs as first line treatment for EGFR mutation-positive (EGFRm) advanced NSCLC. In an exploratory analysis, we investigated clinical outcomes associated with detection of plasma EGFRm at 3 or 6 weeks (wks) after start of treatment. Methods: Treatment- na¨ıve patients (pts) with EGFRm (ex19del or L858R) locally advanced or metastatic NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily (QD) or comparator EGFR-TKIs (gefitinib 250 mg QD or erlotinib 150 mg QD). Plasma EGFR mutation analysis was conducted at baseline (BL), wks 3 and 6 by droplet digital PCR. Clearance was defined as undetectable levels of EGFRm in ctDNA at wks 3/6, where they were detectable at BL. Progression-free survival (PFS) was investigated based on early clearance of EGFRm. Results: In total 489/556 (88%) pts (osimertinib: 244/279; comparator: 245/277) had evaluable ctDNA at BL and wks 3/6. Of these, 342/489 (70%; osimertinib: 168/244; comparator: 174/245) had detectable BL EGFRm and were included in this analysis. See table. Conclusions: Clearance of plasma EGFRm after 3/6 wks of EGFR-TKI therapy was associated with a numerical improvement in PFS. The efficacy of osimertinib was superior to comparator EGFR-TKIs regardless of clearance status. Clinical trial information: NCT02296125.

Wk 3 Wk 6 Osimertinib + Comparator EGFR- TKIs D EGFRm (n = 126) ND EGFRm (n = 208) D EGFRm (n = 69) ND EGFRm (n = 258) mPFS, mo (95% CI) 9.5 (7.0, 10.9) 13.5 (11.1, 15.2) 8.3 (6.8, 10.9) 13.5 (11.1, 15.2) D EGFRm Osimertinib (n = 56) Comparator (n = 70) Osimertinib (n = 30) Comparator (n = 39) mPFS, mo (95% CI) 11.3 (9.5, 16.5) 7.0 (5.6, 8.3) 11.1 (6.8, 13.8) 8.2 (5.5, 9.9) HR (95% CI); p value 0.50 (0.3, 0.8); p = 0.001 0.70 (0.4, 1.2); p = 0.191 ND EGFRm Osimertinib (n = Comparator (n = Osimertinib (n = Comparator (n = 106) 102) 134) 124) mPFS, mo (95% CI) 19.8 (15.1, NC) 10.8 (9.7, 11.1) 19.8 (15.1, NC) 10.2 (9.5, 11.1) HR (95% CI); p value 0.41 (0.3, 0.6); p , 0.0001 0.40 (0.3, 0.6); p , 0.0001

CI, confidence interval; D, detectable; HR, hazard ratio; mo, months; mPFS, median PFS; NC, non-calculable; ND, non-detectable

9021 Poster Discussion Session; Displayed in Poster Session (Board #344), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

S1507: Phase II study of docetaxel and trametinib in patients with G12C or non-G12C KRAS mutation positive (+) recurrent non-small cell lung cancer (NSCLC).

Shirish M. Gadgeel, Jieling Miao, Jonathan W. Riess, Philip C. Mack, Gregory James Gerstner, Timothy F. Burns, Asma Taj, Wallace L. Akerley, Konstantin H. Dragnev, James Moon, David R. Gandara, Karen Kelly; Rogel Cancer Center, University of Michigan, Ann Arbor, MI; SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; UC Davis Comprehensive Cancer Center, Sacramento, CA; Illinois Cancer Care, Peoria, IL; University of Pittsburgh Cancer Institute, Pittsburgh, PA; St Marys of Michigan, Saginaw, MI; Huntsman Cancer Institute at University of Utah, Salt Lake City, UT; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Southwest Oncology Group Statistical Center, Seattle, WA; University of California, Davis, Sacramento, CA; University of California Davis Comprehensive Cancer Center, Sacramento, CA

Background: KRAS+ NSCLC remains the most common genetically defined subset of NSCLC. Despite promising pre-clinical data, MEK inhibitors have failed to provide meaningful clinical benefit both as single agents and in combination with chemotherapy in KRAS+ NSCLC patients. Pre-clinical data suggest that efficacy of MEK inhibitors in KRAS+ NSCLC differs based on specific KRAS mutations such as G12C and by status of p53 or LKB1 mutations. We conducted a phase II study to assess the efficacy of docetaxel plus trametinib in KRAS+ NSCLC patients and in specific genetic subsets. Methods: KRAS+ NSCLC patients who had progressive cancer following 1 or 2 prior regimens were eligible. Docetaxel was given at 75 mg/m2 every 3 weeks and trametinib orally at 2 mg daily. The study was 2-stage design to rule out a response rate (RR) of 17% at the 3% level with 90% power if the true rate were 37%. The study required 45 pts with a futility analysis at 30 pts; 13/45 responses would indicate a success. RR was also assessed in G12C and non-G12C cohorts and will be assessed according to presence of co-mutations in p53 and LKB1. Progression free survival (PFS) and overall survival (OS) were secondary endpoints. Multivariate analysis including age, sex, number of prior treatments, prior immunotherapy (IO) and G12C status was conducted. Results: The study enrolled 54 evaluable pts (19 G12C, 9 G12D, 9 G12A); median age 65 years; female 57%; never smokers 7%; adenocarcinoma 89%; liver metastases 31%; 2 prior regimens 70%; prior IO 57%. Outcomes are summarized in Table. Median duration of therapy was 2.2 months and most common toxicities were fatigue (78%), diarrhea (68%), nausea (57%) and vomiting (28%). One patient died of treatment related respiratory failure. There was a trend for worse PFS (HR- 1.86, p = 0.06) and survival (HR- 1.80, p = 0.14) in G12C patients. Analysis of efficacy data according to co-mutations in p53 or LKB1 is ongoing. Conclusions: Docetaxel plus trametinib met the primary endpoint ofthestudy,withaRRof33%andmediansurvivalof11.1monthsinpatientswithKRAS+ NSCLC, 70% of whom had received 2 prior regimens. Although, there was no statistical difference between KRAS+ subtypes, these data suggest that outcomes may differ between G12C and non-G12C patients. Clinical trial information: NCT02642042.

All G12C Non-G12C

Response 33% (95% CI: 21%-47%) 26% (95% CI: 9%-51%) 37% (95% CI: 21%-55%) PFS (median in months) 4.1 (95% CI- 3.1-5.1) 3.3 (95% CI: 1.5-4.3) 4.1 (95% CI: 3.4-5.6) OS (median in months) 11.1 (95% CI- 8-17) 8.8 (95% CI: 4.9-12.1) 16.3 (95% CI: 9.9-17.7)

9022 Poster Discussion Session; Displayed in Poster Session (Board #345), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM

A phase II study of talazoparib (BMN 673) in patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer (Lung-MAP Sub-Study, S1400G).

Taofeek Kunle Owonikoko, Mary Weber Redman, Lauren Averett Byers, Fred R. Hirsch, Philip C. Mack, Lawrence Howard Schwartz, Jeffrey D. Bradley, Tom Stinchcombe, Natasha B. Leighl, Tareq Al Baghdadi, Primo Lara, Jieling Miao, Karen Kelly, Suresh S. Ramalingam, Roy S. Herbst, Vassiliki Papadimitrakopoulou, David R. Gandara; Emory University, Atlanta, GA; SWOG Statistical Center; Fred Hutchinson Cancer Research Center, Seattle, WA; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Colorado Cancer Center, Denver, CO; UC Davis Compre- hensive Cancer Center, Sacramento, CA; Columbia University Medical Center, New York, NY; Wash- ington University School of Medicine in St. Louis, St. Louis, MO; Duke Cancer Institute, Durham, NC; Princess Margaret Cancer Centre, Toronto, ON, Canada; IHA Hematology Oncology Consultants, Ypsilanti, MI; University of California, Davis, Sacramento, CA; SWOG Statistical Center, Fred Hutch- inson Cancer Research Center, Seattle, WA; University of California Davis Comprehensive Cancer Center, Sacramento, CA; Winship Cancer Institute, Emory University, Atlanta, GA; Yale University, New Haven, CT

Background: This signal finding study was designed to evaluate the clinical efficacy of a PARP inhibitor, talazoparib, in advanced stage squamous cell lung cancer harboring HRRD. Methods: Eligible patients (pts) identified through the parent S1400 screening platform were required to have a deleterious mutation in any of the study-defined HRR genes [ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1) defined as the full eligible population (FEP). The primary analysis population (PAP) is defined by a subset of genes [ATM, ATR, BRCA1, BRCA2, PALB2]. Pts have platinum sensitive disease (at least stable disease on platinum doublet) and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, and not have been previously exposed to a PARP inhibitor and not be on systemic therapy within 21 days of registration. A 2- stage design with exact 93% power and 1-sided 0.07 level type I error required enrollment of 40 patients in the PAP in order to rule out an ORR of 15% or less if the true ORR is 35% or greater. At least 3 or more responses were needed in the first 20 pts in order to proceed to full enrolment of 40 pts in the PAP. The total accrual goal was 60 FEP assuming 67% of patients would be in the PAP. Results: The study enrolled 51 patients of whom 47 are eligible and analyzable for response (FEP) with 24 in the PAP. In the FEP, median age 66.7 yrs; M/F 39/8 (83/17%); 85% White and 15% Black; 77% of the pts received at least 1 prior line of treatment for stage IV. The study was closed for futility with only one response in the PAP. In the PAP (n = 24, median age 68 yrs), ORR was 4% (95%CI: 0, 21) and DCR was 54% (95%CI: 33, 74); median PFS of 2.4 months (95%CI: 1.5-2.8) and median OS was 5.2 months (95%CI: 3.8-10, 7). There were five responders in the FEP with ORR of 11%; DCR of 53% and median DoR was 1.8 months (95% CI: 1.3, 4.2); median PFS was 2.5 months (95%CI: 1.6-3.0) and median OS was 5.7 months (95% CI: 4.5-8.7). The most frequent grade $3 adverse event in the FEP were: Anemia (14.9%), thrombocytopenia (12.8%); lymphopenia (8.5%) and nausea (6.4%). Conclusions: S1400G failed to show sufficient level of efficacy for talazoparib in a biomarker defined subset of squamous lung cancer with HRRD. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Clinical trial information: NCT02154490.

9023 Poster Discussion Session; Displayed in Poster Session (Board #346), Sun, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Sun, 4:30 PM-6:00 PM c-Met expression and response to telisotuzumab vedotin (teliso-v) in patients with non-small cell lung cancer.

Rebecca Suk Heist, Monica Motwani, Fabrice Barlesi, Jonathan Wade Goldman, Karen Kelly, Yan Sun, Jun Wu, Bruce Allen Bach, D. Ross Camidge; Massachusetts General Hospital Cancer Center, Boston, MA; AbbVie Inc., North Chicago, IL; Aix Marseille University, APHM, Marseille Early Phases Cancer Trials Center CLIP, Marseille, France; Ronald Reagan UCLA Medical Center, UCLA Medical Center, Santa Monica, CA; University of California Davis Comprehensive Cancer Center, Sacramento, CA; University of Colorado Cancer Center, Aurora, CO

Background: c-Met overexpression (OE) and MET amplification (amp) are prognostic of poor outcome for non-small cell lung cancer (NSCLC). Telisotuzumab vedotin (ABBV-399; teliso-v [T]), an anti–c-Met Ab and monomethyl auristatin E drug conjugate, showed efficacy as monotherapy (mono) and combined with erlotinib (T+Er) in a phase 1/1b trial (NCT02099058) in NSCLC patients (pts) with c-Met OE. Here, c-Met OE (by immunohistochemistry [IHC]) and its association with T efficacy were explored. IHC, mRNA, and amp platforms for MET were also compared. Methods: Archival tissue from pts with NSCLC in the phase 1/1b trial was examined. c-Met was assessed centrally by IHC with SP44 Ab (Ventana Medical Systems) and pts with c-Met OE (membrane H-score [H-S] of $150) were enrolled. MET mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina). MET amp was analyzed by FISH (MET/CEP7 ratio of $2) or whole-exome sequencing (copy number $2). Efficacy in the T mono every 2 (TQ2W) or 3 (TQ3W) weeks and the T+Er EGFR mutant cohorts was assessed for IHC H-S $150 and $225. Results: As of Dec 2018, 238 pts with NSCLC were screened centrally for c-Met OE. Of these, 118 pts were enrolled. For screened pts, 76%/37% of nonsquamous (NSQ, n = 201) and 58%/16% of squamous (SQ, n = 32) pts had H-S $150/$225; 75%/41% of NSQ and 55%/16% of SQ NSCLC pts had $50% cells with 2+/3+ staining intensity. MET amp was reported for 5 pts, all with high H-S ($270); there was an association between MET amp and MET RNA levels (n = 4) (t-test p value: 0.0002). See Table for ORR and median PFS by H-S and T treatment. Conclusions: c-Met expression prevalence in NSCLC showed a similar trend as in previous reports. In T+Er-treated pts, ORR was higher for those with c-Met H-S $225 than $150– , 225, suggesting that biomarker expression may act as an effect size multiplier. Optimization of the c-Met IHC cutoff warrants further investigation. Clinical trial information: NCT02099058.

NSQ, NSQ, EGFR mutant, TQ2W TQ3W T+Er PFS, m PFS, m PFS, m H-S N ORR, % (CI) N ORR, % (CI) N ORR, % (CI) ‡150 16 37.5 5.2 17 11.8 2.7 28 35.7 5.3 (1.7, 8.8) (1.2, NA) (2.8, NA) ‡150– < 225 9 33.3 5.2 9 11 1.4 12 16.7 3.7 (0.7, NA) (1.1, NA) (1.4, NA) ‡225 7 42.9 8.0 8 12.5 NR 16 50 NR (1.2, 9.1) (1.2, NA) (2.7, NA)

NA, not available; NR, not reached.

9024 Poster Session (Board #347), Sun, 8:00 AM-11:00 AM

Time from stereotactic body radiotherapy to immunotherapy as a predictor for outcome in metastatic non small cell lung cancer.

Rodney E Wegner, Stephen Abel, Shaakir Hasan, Richard White, Gene Grant Finley, Dulabh Monga, Athanasios Colonias, Vivek Verma; Division of Radiation Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA; Allegheny Health Network, Pittsburgh, PA; Department of Radiation Oncol- ogy, Allegheny Health Network Cancer Institute, Pittsburgh, PA; Allegheny Health Networ, Pittsburgh, PA; Allegheny Health Network Cancer Institute, Pittsburgh, PA; Allegheny General Hosp, Sewickley, PA

Background: Immunotherapy has changed the face of treatment for stage IV non small cell lung cancer (NSCLC), quickly becoming the standard of care. The appropriate timing of immunotherapy in the setting of other ablative therapies, namely stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), remains to be determined. We sought to use the National Cancer Database to examine trends in immunotherapy use as well as timing as it relates to SBRT/SRS in stage IV NSCLC patients. Methods: We queried the NCDB for patients with Stage IV NSCLC diagnosed between 2004- 2015 that were treated with SRS or SBRT techniques (to any site) and had at least three months of follow up. Multivariable logistic regression was used to identify predictors of immunotherapy use. Receiver operator curve analysis was used to identify the optimal timepoint between SBRT and immunotherapy correlating with overall survival. Kaplan-meier curves were generated to determine overall survival. Multivariable cox regression was used to determine factors predictive of survival. A propensity score was generated and incorporated into Kaplan-meier and cox regressions to account for indication bias. Results: We identified 13,862 patients meeting the above eligibility criteria, 371 being treated with immunotherapy. The vast majority (75%) had chemotherapy as well. Patients with adenocarcinoma, treatment with chemotherapy, and more recent year of treatment were more likely to receive immunotherapy. Univariable Kaplan-meier analysis showed improved median survival with immunotherapy, 17 months vs. 13 months, p , 0.0001. On multivariable propensity-adjusted cox regression significant predictors for improved overall survival were younger age, lower comorbidity score, lower grade, private insurance, and female gender. Using a cutoff of 21 days after start of SBRT, patients treated thereafter were more likely to survive longer, median survival of 19 months vs 15 months, p = 0.0335. Conclusions: Immunotherapy use in Stage IV NSCLC after SBRT has increased over time, mostly in patients with adenocarcinoma and in the setting of chemotherapy. In this analysis, outcomes were improved when immunotherapy was given at least three weeks after start of SBRT.

9025 Poster Session (Board #348), Sun, 8:00 AM-11:00 AM

A comparative analysis of survival in patients with non-small cell lung cancer with brain metastases receiving intracranial radiation with and without immunotherapy.

Sunita Patruni, Ahmed Khattab, Stephen Abel, Shaakir Hasan, Saleha Rizwan, Gene Grant Finley, Dulabh K. Monga, Vivek Verma, Rodney E Wegner; Allegheny Health Network, Pittsburgh, PA; Department of Radiation Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA; AHN, Pittsburgh, PA; Allegheny Health Network Cancer Institute, Pittsburgh, PA; Medical Oncology, Allegheny Health Network, Pittsburgh, PA; Division of Radiation Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA

Background: Many patients diagnosed with advanced non-small cell lung cancer (NSCLC) will develop intracranial metastasis, contributing significantly to morbidity and mortality. Immunotherapy (IMT) has emerged as the standard of care in select cases of metastatic NSCLC, though data investigating the survival impact of IMT and radiation (XRT) in these patients is limited. To characterize the survival impact of intracranial XRT and IMT in NSCLC patients with brain metastasis, we analyzed the National Cancer Database (NCDB). Methods: We queried the NCDB for patients with metastatic NSCLC having brain metastasis receiving intracranial XRT 6 IMT. Univariable and multivariable analyses identified characteristics predictive of overall survival. Cox proportional hazard ratios with propensity matching mitigated indication bias between the two arms. Results: 13,998 NSCLC patients who received IMT (n = 545) or did not receive IMT (n = 13,545) were eligible for analysis. Univariable analysis demonstrated a median overall survival of 13.1 months (95% CI: 11.8-15.0) vs. 9.7 months (95% CI: 9.5-9.9) (p , 0.0001) and 3-year overall survival of 17% vs. 12% [p , 0.0001; HR: 0.77 (0.71-0.84)] in patients receiving and not receiving IMT respectively. Patients with N3 disease and those diagnosed between 2012 and 2014 were more likely to have received IMT. Receipt of IMT remained an independent predictor of increased survival on propensity score matched multivariable comparison (p = 0.0002). Conclusions: Receipt of IMT was an independent predictor of increased overall survival in patients with NSCLC having intracranial metastasis. Randomized, prospective studies are needed to further validate these findings.

Multivariable Cox Proportional Hazards Models for Overall Survival in NSCLC Patients Receiving Intracranial XRT with and without IMT. Characteristic Hazard of Death (95% CI) p Cox Model with Propensity Score Grade Well-differentiated Ref Moderately-differentiated 1.10 (0.95-1.27) 0.2155 Poorly-differentiated 1.28 (1.21-1.36) < 0.0001 Extracranial Disease No Ref Yes 1.17 (1.04-1.33) 0.0102 Immunotherapy No Ref Yes 0.82 (0.74-0.91) 0.0002

9026 Poster Session (Board #349), Sun, 8:00 AM-11:00 AM

Brigatinib (BRG) versus crizotinib (CRZ) in Asian versus non-Asian patients (pts) in the phase III ALTA-1L trial.

Myung-Ju Ahn, HyeRyun Kim, James Chih-Hsin Yang, Ji-Youn Han, Jong Seok Lee, Maximilian J. Hochmair, Jacky Yu-Chung Li, Gee-Chen Chang, Ki Hyeong Lee, Cesare Gridelli, Rosario Garcia Campelo, Angelo Delmonte, Dong-Wan Kim, David Kerstein, Quanhong Ni, Pingkuan Zhang, Sanjay Popat, D. Ross Camidge; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Yonsei University Severance Hospital, Seoul, South Korea; National Taiwan University, Taipei, Taiwan; Center for Lung Cancer, National Cancer Center, Gyeonggi-Do, South Korea; Seoul National University Bundang Hospital, Seoul, South Korea; Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Vienna, Austria; Hong Kong United Oncology Centre, Kowloon, China; Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea; A.O.S.G. Moscati, Avellino, Italy; Complejo Hospitalario Universitario A Coru~na, Coruna, Spain; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Seoul National University Hospital, Seoul, South Korea; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA; The Royal Marsden Hospital, London, United Kingdom; University of Colorado Cancer Center, Aurora, CO

Background: We report an analysis of BRG vs CRZ in Asian vs non-Asian pts with ALK inhibitor–naive, ALK+ NSCLC from ALTA-1L (NCT02737501). Methods: Pts were randomized 1:1 to BRG 180 mg QD (7-day lead-in at 90 mg) or CRZ 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints: BIRC-assessed ORR, intracranial (i) ORR, and iPFS. Results: 275 pts were randomized; 108 Asian (BRG/CRZ, n = 59/49), 167 non-Asian (n = 78/89); median age: Asian, 55/56 y; non-Asian, 60/60 y. 32/24% of Asians vs 22/28% of non-Asians received prior chemotherapy for advanced disease; 36/33% vs 24/28% had baseline CNS metastases. As of 19 Feb 2018, median follow-up was 10.1/10.0 mo (BRG/CRZ) in Asians vs 11.0/9.0 mo in non- Asians, with 12 vs 20 PFS events in Asians and 24 vs 43 in non-Asians. In Asians, median BIRC-assessed PFS (mo) was not reached (NR; 95% CI 11.2–NR) with BRG vs 11.1 (9.2–NR) with CRZ (HR 0.41 [95% CI 0.20–0.86]; log-rank P= 0.0261); in non-Asians, BRG PFS was NR (NR) vs 9.4 (7.3–NR) with CRZ (HR 0.54 [0.33–0.90]; log-rank P= 0.0132) (Table). AE profile of each drug was similar in Asians vs non- Asians. Most common any-grade AEs ($25%) in Asians in BRG arm: diarrhea; elevated blood CPK, ALT, and AST. Discontinuation due to AE (BRG/CRZ): 8.5/6.3% in Asian pts; 14.3/10.1% in non-Asian pts. Conclusions: BRG showed comparable improvement in PFS vs CRZ both in Asians and non-Asians in ALK inhibitor–naive ALK+ NSCLC. Clinical trial information: NCT02737501.

Asian Non-Asian BRG CRZ BRG CRZ All pts, % (95% CI) (n = 59) (n = 49) (n = 78) (n = 89) ORRa 80 (67–89) 84 (70–93) 73 (62–83) 67 (57–77) Confirmed ORR 75 (62–85) 71 (57–83) 68 (56–78) 54 (43–65) P= 0.5833b P= 0.0753b Median INV PFS, mo NR (NR) 11.1 (9.2–NR) NR (NR) 7.4 (5.7–9.4) HR 0.49 (0.23–1.02); P= 0.0519c 0.45 (0.27–0.74); P= 0.0012c With any iCNS metastases, % (95% CI) (n = 20) (n = 17) (n = 23) (n = 30) iORRa 70 (46–88) 41 (18–67) 87 (66–97) 13 (4–31) Confirmed iORR 60 (36–81) 35 (14–62) 74 (52–90) 7 (1–22) P= 0.0180b P, 0.0001b Median iPFS, mo NR (9.2–NR) 9.2 (3.7–11.1) NR (7.4–NR) 5.5 (3.7–7.5) 1-year iPFS 75 (46–90) NR (NR) 59 (31–79) 30 (13–48) HR 0.15 (0.04–0.56); P= 0.0037c 0.29 (0.12–0.70); P= 0.0030c

INV, investigator assessed. a$1 response assessment; bCochran-Mantel-Haenszel test; cLog-rank test.

9027 Poster Session (Board #350), Sun, 8:00 AM-11:00 AM

Preliminary results of single arm phase 2 trial of brigatinib in patients (pts) with progression disease (PD) after next-generation (NG) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in ALK + non-small cell lung cancer (NSCLC).

Tom Stinchcombe, Robert Charles Doebele, Xiaofei F. Wang, David E. Gerber, Leora Horn, D. Ross Camidge; Duke Cancer Institute, Durham, NC; University of Colorado, Denver, CO; Duke University Medical Center, Durham, NC; University of Texas Southwestern Medical Center, Dallas, TX; Vanderbilt University Medical Center, Nashville, TN; University of Colorado Cancer Center, Aurora, CO

Background: NG ALK TKIs are the standard first-line therapy for patients with advanced ALK + NSCLC. Brigatinib has activity against ALK resistance mutations and has CNS activity. The efficacy of brigatinib after NG ALK TKI is undetermined. Methods: Pts with stage IIIB/IV ALK + NSCLC, and PD after NG ALK TKI’s were eligible. Pts were required to have measurable disease, performance status 0-2, and adequate organ function. Pts were required to undergo tumor biopsy # 60 days of enrollment; ctDNA was collected at baseline, at time of imaging, and PD. Brigatinib treatment was 90 mg daily for 7 days and then 180 mg daily (1 cycle = 28 days). Primary objective was objective response rate (ORR), and ORR of 20% was determined to be worthy of further investigation. Response was assessed every 2 cycles. A 2-stage design was used; if . 2 responses in 20 pts in the 1st stage, study proceeded to 2nd stage; if $ 5 responses in 40 pts therapy considered active. Results: Between 3/2017 and 11/2018, 20 pts were enrolled in the 1st stage. Pt characteristics were: median age 55 years (range 32 to 71), median number of prior therapies 3 (range 1 to 6), 12 had CNS disease at the baseline (8 pts had CNS PD). ALK resistance mutation detected in 3 of 8 pts on standard of care molecular testing. ORR results were confirmed partial response (n = 8), stable disease (n = 7), PD (n = 3), unconfirmed response (n = 1), and non-evaluable due adverse events (AE’s) (n = 1). The grade 3 or 4 AE’s were: pneumonitis (n = 2); 1 of each: acute renal failure, respiratory failure, sepsis, hypertension, CPK elevation, and headache. With median follow-up of 6.7 months (11 PFS events), the median PFS was 6.4 months (95% CI: 4.6 to NE). Overall survival data is immature. 3 of 3 pts with a known ALK mutation (F1174C in 2 pts, I1171T in 1 pt) responded, 2 of 5 pts without ALK mutation responded. Additional study related tumor analysis and ctDNA analyses are ongoing. Conclusions: Brigatinib has activity after progression on next generation ALK TKI. The study is enrolling additional patients in the second stage. Detailed molecular and site of disease (CNS versus extra-CNS) activity analyses are underway Clinical trial information: NCT02706626.

9028 Poster Session (Board #351), Sun, 8:00 AM-11:00 AM

Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR-mutant lung cancers.

Adam Jacob Schoenfeld, Joseph Minhow Chan, Hira Rizvi, Natasha Rekhtman, Yahya Daneshbod, Daisuke Kubota, Jason C. Chang, Maria E. Arcila, Marc Ladanyi, Romel Somwar, Mark G. Kris, Dana Pe’er, Gregory J. Riely, Helena Alexandra Yu; MSKCC, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after developing acquired resistance to initial EGFR inhibitor. Further, studies of osi resistance to date have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements. Methods: To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had next-generation sequencing performed on tumor tissue after developing acquired resistance to osi. Results: From January 2016 to December 2018, post-osi tumor tissue was collected from 71 patients (42 with paired pre-treatment specimens). See mechanisms of resistance below. Histologic transformation was identified in 19% of initial cases and 14% of all cases. When osi is given as initial treatment, with median follow up of 17 months, early emerging MOR rarely included on-target resistance mechanisms (1/16 cases of acquired EGFR G724S). Acquired alterations representing potential resistance mechanisms included CCNE1 and MYC amplifications, and mutations in MTOR and MET H1094Y. We confirmed in preclinical studies that an amino acid substitution at MET H1094 can reduce sensitivity to osi. Conclusions: In this analysis of MOR identified on NGS from tumor tissue, we found a different spectrum of resistance mechanisms to initial and later-line osi, with histologic transformation (including squamous cell transformation) a dominant MOR, particularly in the first-line setting, that cannot be identified on plasma testing. Subsequent studies are needed to assess patients with a longer time on initial osi as there may be a temporal bias to MOR, with off-target MOR emerging earlier and on-target resistance mutations later.

First line (n = 16) Later line (n = 55) All (n = 71) Squamous transformation 235 Small cell transformation 145 On target mutation (EGFR C797X or other) 11011 Loss of T790M -1717 Fusions (ALK, RET, BRAF) 055 Amplifications (HER2, MET, EGFR) 279 Off target mutations (KRAS, BRAF, HER2) 145

9029 Poster Session (Board #352), Sun, 8:00 AM-11:00 AM

Phase Ib study: Selective histone deacetylase (HDAC) inhibitor ACY-241 + nivolumab (Nivo) in advanced non-small cell lung cancer (NSCLC).

Mark M. Awad, Yvan Le Bruchec, Brian Lu, Julieann Miller, Calin Dan Dumitru, Alexander I. Spira; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; Celgene Corporation, Summit, NJ; Virginia Cancer Specialists, Fairfax, VA

Background: Identification of new regimens for patients (pts) with relapse/refractory NSCLC is an ongoing need. HDAC inhibitor monotherapy has cytostatic activity in pts with NSCLC. The HDAC6 inhibitor ACY-241 has immunomodulatory activity and may synergize with immune checkpoint inhibitors (ICI). This phase Ib study investigated ACY-241 + nivo in metastatic NSCLC. Methods: Previously platinum-treated, ICI-na¨ıve pts with advanced NSCLC and ECOG PS # 1 were eligible. In 3 + 3 dose-escalation, pts received ACY-241 (180, 360, or 480 mg PO; d 1-28) + nivo 240 mg on d 15 of cycle 1 and d 1,15 subsequently in 28-d cycles. Primary outcomes: safety and RP2D. Secondary outcome: antitumor activity. Exploratory outcome: biomarker analyses; peripheral blood samples and tumor biopsies were collected pre- and on-treatment. Results: As of Jan 17, 2019, 18 pts were treated. Median age 66 y; 56% male, 78% PS 1, 93% stage IV, 28% PD-L1–negative, and 89% adenocarcinoma (11% squamous). No DLTs were observed at ACY-241 180 or 360 mg, and 2 DLTs were observed at 480 mg (gr 3 nausea lasting . 72 h despite medication; gr 5 cardiac arrest); 360 mg was declared RP2D. Common all-grade AEs: fatigue (22%), arthralgia (17%), and cough (17%); 1 gr 3 cerebrovascular accident (related to brain metastasis unrelated to study drug) and 1 additional gr 5 AE (myasthenia gravis, possibly related to ACY-241 and nivo) occurred. Of 13 response-evaluable pts, 8 had clinical benefit (1 CR, 3 PR [1 PD-L1–negative], 1 unconfirmed PR [tumor shrinkage followed by new lesion], 3 SD); 5 had PD. At data cutoff, treatment was ongoing in 5 pts (12 – 30 cycles). Histone and tubulin acetylation levels were transiently increased after treatment. Circulating IL-2, IL-1b, MMP- 9, and IL-10 levels increased, with undetectable TNF-a and IFN-g modulation. Treatment-related changes in tumor-infiltrating Treg, MDSC, TCM, and macrophages varied between pts but revealed a trend of increased infiltrating cytotoxic T and NK cells. Conclusions: The ACY-241 + nivo combination is feasible and can be considered for further research as a potential NSCLC treatment option. Biomarker analyses may help identify an optimal population for the combination. Clinical trial information: NCT02635061.

9030 Poster Session (Board #353), Sun, 8:00 AM-11:00 AM

Acquired resistance to MET inhibition in MET driven NSCLC.

Richard Riedel, Carina Heydt, Andreas H. Scheel, Hannah Lea Tumbrink, Johannes Bragelmann, ¨ Roberta Castiglione, Lucia Nogova, Diana S.Y. Abdulla, Sebastian Yves Friedrich Michels, Matthias Scheffler, Rieke Nila Fischer, Sophia Koleczko, Sabine Merkelbach-Bruse, Martin Sos, Reinhard Buttner, ¨ Juergen Wolf; Lung Cancer Group Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Dept. for Internal Medicine, Cologne, Germany; Lung Cancer Group Cologne, Institute of Pathology, University Hospital of Cologne, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Pathology, Cologne, Germany; University of Cologne, Cologne, Germany; Lung Cancer Group Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Dept. I of Internal Medicine, Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital of Cologne, Institute for Pathology, Cologne, Germany; University Hospital Cologne, Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, Cologne, Germany

Background: MET mutations (METΔex14), amplifications or translocations can activate oncogenic signaling in lung cancer and are sensitive to MET inhibition. Acquired resistance to therapy with MET tyrosine kinase inhibitors (TKI) occurs inevitably. Methods: Between 2015 and 2018, eighteen patients with MET-driven NSCLC were treated with capmatinib or crizotinib as single agent at our site. Rebiopsy samples from five patients were analyzed by NGS and fluoreszenz-in-situ hybridization (FISH) at time of progression. Results: Of the five patients with rebiopsy samples at time of progression, two had initially a MET amplification (one patient with low-level and one patient with high-level amplification), two patients had a METΔex14 and one patient had a KIF5B-MET fusion. Patient 1 (low-level MET amplification) showed a partial response to crizotinib. The rebiopsy revealed an acquired KRAS mutation as a potential mechanism of resistance. Patient 2 (high-level MET amplification) showed stable disease as best response to capmatinib and patient 3 (METΔex14) showed a partial response to capmatinib. Both patients developed acquired HER2 amplifications. Patient 4 (METΔex14) showed initially a partial response to crizotinib. The rebiopsy sample revealed an acquired MET kinase domain mutation (p.D1246N). As preclinical findings suggested that D1246N confers resistance to type I MET inhibitors but remains sensitive to type II inhibitors, cabozantinib was started. A CT six weeks after therapy initiation showed progressive disease. Patient 5 (KIF5B-MET) had a partial response to crizotinib. An acquired MET p.Y1248H mutation was found at time of progression. Therapy was changed to cabozantinib. A new CT scan is pending. Conclusions: Resistance to MET inhibition is heterogeneous with on- and off-target-mechanisms occurring. We found HER2 amplification as a potential new bypass mechanism. The MET mutation D1246N conferred resistance to type I and type II inhibitors. We describe the first case of an acquired mutation of the MET tyrosine kinase domain in a patient with an oncogenic MET fusion. Further investigations are needed to collect comprehensive data to understand resistance mechanisms in MET inhibition and to develop novel therapeutic strategies.

9031 Poster Session (Board #354), Sun, 8:00 AM-11:00 AM

Randomized phase III study comparing carboplatin plus pemetrexed followed by pemetrexed versus docetaxel in elderly patients with advanced non-squamous non-small-cell lung cancer (JCOG1210/WJOG7813L).

Isamu Okamoto, Hiroshi Nokihara, Kiyotaka Yoh, Shunichi Sugawara, Hidehito Horinouchi, Koichi Azuma, Yasuto Yoneshima, Haruyasu Murakami, Haruko Daga, Yukio Hosomi, Shinji Atagi, Tomohiro Ozaki, Atsushi Horiike, Yuka Fujita, Hiroaki Okamoto, Masahiko Ando, Shogo Nomura, Nobuyuki Yamamoto, Yuichiro Ohe, Kazuhiko Nakagawa; Kyushu University Hospital, Fukuoka, Japan; Tokushima University Hospital, Tokushima, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan; Kyushu University, Fukuoka, Japan; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan; Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan; Department of Thoracic Oncology, Kinki-chuo Chest Medical Center, Sakai, Japan; Kishiwada City Hospital, Osaka, Japan; Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan; Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan; Nagoya University Hospital, Nagoya, Japan; JCOG Data Center/Operation Office, National Cancer Center Hospital, Tokyo, Japan; Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan; Kindai University Hospital, Osaka, Japan

Background: The aim of this phase III randomized trial is to determine the efficacy of pemetrexed and carboplatin followed by pemetrexed for elderly patients (pts) with advanced non-squamous non-small- cell lung cancer (NSCLC). Methods: Cytotoxic chemotherapy-na¨ıve, ECOG-PS 0-1, aged 75 years or older, and advanced stage non-squamous NSCLC pts were randomized to receive either docetaxel 60 mg/m2 on day 1 every 3 weeks [DOC] or carboplatin AUC 5 mg/ml/min and pemetrexed 500 mg/m2 on day 1 every 3 weeks followed by maintenance therapy with pemetrexed 500 mg/m2 every 3 weeks after 4 cycles of carboplatin and pemetrexed [CBDCA/PEM] given until disease progression or unacceptable toxicities. The primary endpoint was OS. Non-inferiority of CBDCA/PEM arm was planned to be demonstrated if upper limit of 95% confidence interval (CI) for hazard ratio (HR) did not exceed 1.154. Results: Between August 2013 to February 2017, 433 pts with a median age of 78 years (range, 75 to 88) were randomly assigned to the DOC arm (n = 217) or the CBDCA/PEM arm (n = 216). Non- inferiority of CBDCA/PEM arm was confirmed in all enrolled patients (HR for OS, 0.850; 95% CI, 0.684 to 1.056, P , 0.01). The median OS for DOC and CBDCA/PEM arms were 15.5 months and 18.7 months, respectively. In the CBDCA/PEM arm, PFS was significantly better (HR, 0.739; 95% CI, 0.609 to 0.89) and response rate was better (28.2% vs. 36.8%; P = 0.07), and incidence of neutropenia or febrile neutropenia of grade 3 or 4 was significantly lower. Grade 3 or 4 thrombocytopenia or anemia was more common in the CBDCA/PEM arm. Four treatment-related deaths (two in each treatment arm) occurred. QOL (FACT-LCS) was favorable for CBDCA/PEM arm throughout 18 weeks after enrollment. Conclusions: Pemetrexed/carboplatin followed by pemetrexed maintenance is a valid therapeutic option for the first-line treatment of elderly pts with advanced non-squamous NSCLC. Clinical trial information: 000011460.

9034 Poster Session (Board #357), Sun, 8:00 AM-11:00 AM

A phase I study to evaluate safety, tolerability, pharmacokinetics and antineoplastic activity of BPI-7711 in patients with EGFR/T790M mutation advanced or recurrent NSCLC.

Yuankai Shi, Jian Fang, Yongqian Shu, Donglin Wang, Huiqing Yu, Yanqiu Zhao, Liangming Zhang, Bo Zhu, Xingya Li, Gongyan Chen, Jianhua Shi, Rongsheng Zheng, Jian’An Huang, Sheng Yang, Jieran Long, Wen Gao, Michael Greco, Jing Wang, Xiao Li; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Beijing Cancer Hospital, Beijing, China; Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Chongqing Cancer Hospital, Chongqing, China; Henan Provincial Cancer Hospital, Zhengzhou, China; Yantai Yuhuangding Hospital, Yantai, China; The Second Affiliated Hospital of Army Medical Uni- versity, Chongqing, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Harbin Medical University Cancer Hospital, Harbin, China; Shandong Linyi Tumor Hospital, Linyi, China; The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; The First Affiliated Hospital of Soochow University, Suzhou, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Jiangsu Province Hospital, Nanjing, China; BetaPharma, Princeton, NJ; BetaPharma, Shanghai, China

Background: BPI-7711 is a 3rd generation irreversible EGFR-TKI that is selectively against EGFR TKI–sensitizing mutations and the T790M resistance mutations. We are conducting a phase I study to determine the safety and efficacy of BPI-7711 in patients with advanced or recurrent EGFRm+/ T790M+ NSCLC. Methods: NSCLC patients who had documented disease progression after 1st/2nd generation EGFR-TKI treatment and with EGFRm+/T790M+ confirmed by central lab were enrolled in the multicenter trial (NCT03386955) into “3+3” dose escalation or expansion cohorts. BPI-7711 was orally administered at doses of 30~240 mg in capsules. Patients in dose-escalation cohorts firstly received a single dose of BPI-7711 followed by a 7-day pharmacokinetic (PK) evaluation period then received the same dose daily until disease progression or intolerable toxicity(ies) per CTCAE V4.03. Treatment efficacy per RECIST 1.1 was evaluated every 6 weeks since daily treatment commence. Once efficacy was observed in a dose, its expansion cohort was opened to enroll patients for daily treatment. Results: As of 23 December 2018, 82 patients (median age 55, 27 males, 55 females) were enrolled into 5 dose escalation cohorts (30/60/120/180/240 mg) and 4 dose expansion cohorts (30/ 60/120/180 mg). No DLT was observed and MTD was not reached. For all safety-evaluable patients, most common treatment emergent adverse events (TEAEs) ($10%) were white blood cell count decreased (21.3%), neutrophil count decreased (17.3%), upper respiratory tract infection (17.3%), vomiting (12.0%) and diarrhea (10.7%), and all were Grade 1 or 2. Grade 3~4 TEAEs were occurred in 8.0% patients and 4.0% of them were treatment-related per investigators’ judgement. SAEs were reported in 4.0% of patients, and 1.3% were treatment-related. For all efficacy-evaluable patients, the overall ORR of all doses was 54.5% (30/55) including 1.8% CR and 52.7% PR. The disease control rate (DCR) was 96.4%. For patients in 120/180 mg cohorts, the ORR was 64.1% (25/39) and DCR was 97.4%. PK analyses showed BPI-7711 exposure increased in a dose-proportional manner from 30 to 180 mg after single and multiple doses. Conclusions: BPI-7711 was well tolerated and highly effective in acquired T790M+ NSCLC patients. Phase II trials are under preparation. Clinical trial information: NCT03386955.

9035 Poster Session (Board #358), Sun, 8:00 AM-11:00 AM

Combination of metformin and gefitinib as first-line therapy for nondiabetic advanced non- small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

Yong He, Li Li, Liyan Jiang, Yubo Wang, Yizhuo Zhao, Xiaoju Zhang, Guoming Wu, Xiangdong Zhou, Jianguo Sun, Jun Bai, Biyong Ren, Kun Tian, Zhi Xu, Hualiang Xiao, Qi Zhou, Rui Han, Hengyi Chen, Haidong Wang, Zhenzhou Yang, Chan Gao; Department of Respiratory Medicine, Daping Hospital, Army Medical University, Chongqing, China; Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China; Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Pulmonary Medicine, People’s Hospital of Henan Province, Zhengzhou, China; Institute of Respiratory Disease, Xinqiao Hospital, Army Medical University, Chongqing, China; First Affiliated Hospital of Third Military University, Chongqing, China; Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China; Department of Medical Oncology, Shanxi Provincial People’s Hospital, Xi’an, China; Cancer Center, Chongqing Three Gorges Central Hospital, Chongqing, China; Depantment of Respiration, General Hospital of Chengdu Military Command, Chengdu, China; Department of Pathology, Daping Hospital, Army Medical University, Chongqing, China; Department of Oncology, Fuling Center Hospital, Chongqing, China; Cardiothoracic Surgery Department, Southwest Hospital, Army Medical University, Chongqing, China; Cancer Center, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; The Medical Department, 3D Medicines Inc., Shanghai, China

Background: Several lines of evidence suggested a role for metformin in sensitizing diabetic NSCLC patients to EGFR tyrosine kinase inhibitors (TKIs). However, data regarding its effects on non-diabetic populations remained scarce. We hereby examined metformin’s first-line use alongside gefitinib in EGFR mutation positive (EGFRm) patients without diabetes. Methods: In this trial (NCT01864681), 224 non-diabetic patients with treatment na¨ıve stage IIIB-IV EGFRm NSCLC were randomly assigned at 1:1 to receive gefitinib plus metformin or placebo. Gefitinib was administered at 250 mg once daily, while metformin/placebo was initiated at 500 mg once daily and then escalated to 1000 mg twice daily over 2 weeks. Dose reduction was permitted for metformin/placebo in case of intolerable toxicity. The primary endpoint was progression-free survival (PFS) rate at 1 year. Secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of interleukin-6 were also subjected to exploratory analysis. Results: Baseline characteristics were well balanced between treatment groups. The median duration of follow-up was 19.15 (IQR 12.99-28.44) months. The estimated 1-year PFS rate was 41.2% (95% confidence interval [CI] 30.0-52.2) in the metformin group versus 42.9% (95% CI 32.6-52.7) in the placebo group (p = 0.6268). Metformin did not increase median PFS (10.3 months vs. 11.4 months), median OS (22.0 months vs. 27.5 months), or ORR (66.0% vs. 66.7%) over placebo. No significant treatment group differences in terms of PFS were detected across subgroups either, including those with elevated levels of interleukin-6. Metformin plus gefitinib shared a similar safety profile with the control group, except for a remarkably higher incidence of diarrhea (78.38% vs. 43.24%). Conclusions: Our study did not show enhanced gefitinib efficacy upon addition of metformin and hence does not support its concurrent use with first-line EGFR-TKI therapy in non-diabetic EGFRm NSCLC patients. Clinical trial information: NCT01864681.

9036 Poster Session (Board #359), Sun, 8:00 AM-11:00 AM

SHERLOC: A phase 2 study of MM-121 plus with docetaxel versus docetaxel alone in patients with heregulin (HRG) positive advanced non-small cell lung cancer (NSCLC).

Lecia V. Sequist, Pasi A. Janne, Rudolf M. Huber, Jhanelle Elaine Gray, Enriqueta Felip, Maurice Perol, Fred R. Hirsch, Daniel Shao-Weng Tan, Geoffrey Kuesters, Alena Zalutskaya, Sergio Santillana, J. Marc Pipas, Frances A. Shepherd; Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Medizinische Klinik Innenstadt, Munich, Germany; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Vall d´Hebron University Hospital, Barcelona, Spain; Department of Thoracic Oncology, Centre Leon ´ B´erard, Lyon, France; University of Colorado Cancer Center, Denver, CO; National Cancer Center, Singapore, Singapore; Merrimack Pharmaceuticals, Cambridge, MA; Merrimack Pharmaceuticals., Inc., Cam- bridge, MA; Merrimack Pharmaceuticals. Inc., Cambridge, MA; Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada

Background: Seribantumab (MM-121) is a human monoclonal IgG2 antibody that blocks the HRG domain of HER3. Preclinical data suggest that seribantumab reverses HRG mediated drug resistance across multiple cancer models. In prior retrospective analyses, addition of seribantumab to standard of care (SOC) appeared to improve outcomes in pts with HRG+ tumors. Here we tested if seribantumab plus SOC improved progression-free survival (PFS) in pts with HRG+ lung adenocarcinoma who had received prior platinum-based therapy. Methods: SHERLOC was a randomized, open-label, multicenter, Phase 2 study in pts with advanced HRG+ adenocarcinoma of the lung. Archival or pre-treatment tumor samples were assessed for HRG+ by RNA in situ hybridization. Eligibility criteria included prior platinum-based therapy for advanced disease with # 2 total prior lines of therapy (prior IO was allowed) and no EGFR or ALK mutations. Pts were randomized 2:1 to receive seribantumab 3000 mg/docetaxel 75 mg IV q3w (experimental; exp) or docetaxel 75 mg IV q3w alone (control). Primary endpoint was PFS. Key secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse event (AEs) profile. Results: At a pre-specified interim analysis of 75% of total PFS events, 108 pts were enrolled (exp n = 71, control n = 37). Median age was 62y (range 34-83y); female 34%; one prior treatment only 39%. Median PFS was 3.0m for exp and 4.0m for control, HR = 1.66m (p = 0.084). Median OS was 7.9m for exp and 8.4m for control, HR = 1.50 (p = 0.235). ORR was 19.7% for exp and 5.6% for control (p = 0.052). Serious AEs were more frequent in the exp arm (40.8%) vs control (24.3%). Most common treatment emergent AEs (TEAEs) in the exp arm were diarrhea (47%), fatigue (37%), and neutropenia (27%). Based on a determination of futility at interim analysis, the study was terminated early. Conclusions: Seribantumab failed to improve PFS when added to docetaxel among previously treated advanced HRG+ NSCLC pts. A higher response rate and a higher incidence of TEAEs were observed in the exp arm. No further study of seribantumab is planned in NSCLC. Clinical trial information: NCT02387216.

9037 Poster Session (Board #360), Sun, 8:00 AM-11:00 AM

Lazertinib, a 3rd generation EGFR-TKI, in patients with EGFR-TKI resistant NSCLC: Updated results of phase I/II Study.

Myung-Ju Ahn, Ji-Youn Han, Sang-We Kim, Ki Hyeong Lee, Dong-Wan Kim, Yun-Gyoo Lee, Eun Kyung Cho, Gyeong-won Lee, Jong-Seok Lee, Joo-Hang Kim, Jin-Soo Kim, Young Joo Min, Sung Sook Lee, Sang Won Shin, HyeRyun Kim, Min Hee Hong, Jin Seok Ahn, Seoung Oh Lee, Sohee Kim, Byoung Chul Cho; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea; University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea; Seoul National University Hospital, Seoul, South Korea; Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea; Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea; Gyeongsang National University Hospital, Jinju, South Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea; CHA Bundang Medical Center, CHA University, Seongnam, South Korea; Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea; Division of Hematology and Oncology, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea; Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea; Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Yuhan Research Institute, Yuhan Corporation, Yongin, South Korea; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea

Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992). Methods: Patients with advanced and metastatic NSCLC who had progressed after treatment with standard EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose- escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability and efficacy. T790M mutation was required in the dose-expansion cohorts. Results: As of 26 Nov 2018, a total of 127 patients were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 89 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed. The median duration of treatment was 9.7 months and 58 patients are still ongoing. The objective response rate (ORR) was 60% in all patients, 64% in T790M+ patients, and 37% in T790M- patients by investigators assessment. In BM patients with measurable lesion (n = 14), the intracranial ORR was 50%. The median progression-free survival (PFS) was 8.1 months in all patients, 9.5 months in T790M+ patients, and 5.4 months in T790M- patients. Subgroup analysis showed that ORR was 65% and PFS was 12.2 months in T790M+ patients with $ 120 mg (n = 62). The most common treatment-emergent adverse events (TEAEs) were pruritus (27%), rash (24%), constipation (20%), decreased appetite (19%) and diarrhea (14%). TEAEs leading to dose discontinuation were observed in 3% of patients. Drug related TEAEs of grade $ 3 was observed in 3% of the patients. Conclusions: Lazertinib was safe, well-tolerated and exhibits promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. Dose extension cohorts in the 1st and 2nd line settings are underway at 240 mg dose. Clinical trial information: NCT03046992.

9038 Poster Session (Board #361), Sun, 8:00 AM-11:00 AM

The impact of sequential therapy of crizotinib followed by alectinib: Real-world data analysis of 840 ALK-inhibitor na¨ıve patients with NSCLC harboring ALK-rearrangement (WJOG9516L).

Kentaro Ito, Takeharu Yamanaka, Satomi Watanabe, Yoshihiro Hattori, Kazumi Nishino, Haruki Kobayashi, Yuko Oya, Toshihide Yokoyama, Takashi Seto, Koichi Azuma, Tomoya Fukui, Toshiyuki Kozuki, Atsushi Nakamura, Isamu Okamoto, Katsuya Hirano, Takashi Yokoi, Haruko Daga, Shinya Sakata, Kazuhiko Nakagawa, Nobuyuki Yamamoto; Matsusaka Municipal Hospital, Matsusaka City, Mie, Japan; Yokohama City University School of Medicine, Yokohama, Japan; Department of Medical oncology, Kindai University, Faculty of Medicine, Osakasayama City, Osaka, Japan; Hyogo Cancer Center, Akashi, Japan; Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan; Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan; National Kyushu Cancer Center, Fukuoka, Japan; Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan; Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan; Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan; Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; Kyushu University Hospital, Fukuoka, Japan; Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan; Department of Thoracic Oncology, Kansai Medical University Hirakata Hospital, Osaka, Japan; Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan; Kumamoto University Hospital, Kumamoto, Japan; Kindai University Hospital, Osaka, Japan; Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

Background: Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to- progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries. Methods: We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group. Results: Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P= 0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P= 0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P, 0.0001. Conclusions: The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown. Clinical trial information: UMIN000028605.

9039 Poster Session (Board #362), Sun, 8:00 AM-11:00 AM

Dendritic-cell vaccine (DCVAC) with first-line chemotherapy in patients with stage IV NSCLC: Final analysis of phase II, open label, randomized, multicenter trial.

Libor Havel, Vitezslav Kolek, Milos Pesek, Marketa ´ Cernovska, ´ Jirina Bartunkova, Radek Spisek, Ladislav Pecen, Inna Krasnopolskaya, Milada Zemanova, SLU01 Investigators; Thomayer’s Hospital, 1st Faculty of Medicine of Charles University in Prague, Prague, Czech Republic; University Hospital Olomouc, Olomouc, Czech Republic; Department of Pneumooncology, University Hospital in Pilsen, Plzen, Czech Republic; Thomayer Hospital, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic; SOTIO a.s., Prague, Czech Republic; First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

Background: Immunotherapy aiming the induction of tumor cell specific immune responses controlling the tumor growth, has emerged as a promising treatment modality in lung cancer(LuCa). Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to the standard of care chemotherapy (ct) could prolong overall survival (OS) and progression-free survival (PFS). Methods: This study evaluated the efficacy and safety of DCVAC/LuCa (active cellular immunotherapy based on dendritic cells) concomitantly added to ct (carboplatin/paclitaxel) - Arm A (A) vs DCVAC/LuCa + immune modulators (IFN-a and hydroxychloroquine) - Arm B (B)+ct vs ct - Arm C (C) in NSCLC patients (pts). Randomization 1:1:1; pts in A and B received up to 15 doses of DCVAC, ct was given 4-6 cycles in A and C. Stage IV NSCLC was confirmed histologically or cytologically, ECOG 0-1 pts were eligible. Stratification was done by histology subtype and smoking history. Primary efficacy analysis compared A vs C only as enrollment to B was closed early based on Sponsor’s assessment of further clinical development potential, there were no safety concerns or signals. Results: 112 pts at 12 sites were randomized (A/45 B/29 C/38). Patients characteristics were comparable across the study groups with the exception of gender (m/f, %: 65/35 (A) and 74/26 (C) and smoking history (75 % of smokers in A, 97 % in C). Median follow up time was 25.8 months, range 0.1-41.8. Median OS was 15.5 months in A compared to 11.8 months in C, hazard ratio (HR) 0.55, p-value 0.0232, 95% CI [0.33, 0,93], data maturity 77%. Median PFS was 6.74 in A and 5.63 months in C, HR 0.59, p-value 0.0415, 95% CI [0.36, 0.99], data maturity 86%. Overall response rate was 45% in A vs 34% in C. Most TEAEs were related to ct (anemia [35%-A, 32%-C], neutropenia [48% in A, 21%-C], thrombocytopenia [25% in A, 27% in C]). There were no grade $ 3 TEAEs solely related to DCVAC. Most common leukapheresis (lp)-related AE was vomiting in 2 pts outof67ptsundergonelp.Conclusions: Addition of DCVAC-based immunotherapy to the standard of care chemotherapy significantly improved OS in stage IV NSCLC. Clinical trial information: NCT02470468.

9041 Poster Session (Board #364), Sun, 8:00 AM-11:00 AM

Palbociclib (P) in patients (pts) with non-small cell lung cancer (NSCLC) with CDKN2A alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

Eugene R Ahn, Pam K. Mangat, Elizabeth Garrett-Mayer, Susan Halabi, Elie G. Dib, Daniel Ernest Haggstrom, Kathryn B. Alguire, Ricardo H. Alvarez, Carmen Julia Calfa, Timothy Lewis Cannon, Pamela A. Crilley, Anu G. Gaba, Alissa S. Marr, Ashish Sangal, Ramya Thota, Kaitlyn R. Antonelli, Samiha Islam, Andrew Lawrence Rygiel, Suanna S. Bruinooge, Richard L. Schilsky; Cancer Treatment Centers of America, Zion, IL; American Society of Clinical Oncology, Alexandria, VA; Medical University of South Carolina, Charleston, SC; Duke University Medical Center, Durham, NC; Sanford Health, Sioux Falls, SD; Levine Cancer Institute, Charlotte, NC; Grand Rapids Oncology Program, Grand Rapids, MI; Cancer Treatment Centers of America, Newnan, GA; Memorial Cancer Institute, Hollywood, FL; Inova Schar Cancer Institute, Fairfax, VA; Cancer Treatment Centers of America, Boca Raton, FL; Roger Maris Cancer Ctr, Fargo, ND; University of Nebraska Medical Center, Omaha, NE; Cancer Treatment Centers of America, Goodyear, AZ; Intermountain Healthcare, Murray, UT

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of NSCLC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced NSCLC, no standard treatment options, measurable disease, ECOG PS 0-2 and adequate organ function. Genomic testing was performed using commercially available tests. Pts matched to P had NSCLC with CDKN2A loss or mutation and no RB mutations. A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; a = 0.10). If $2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If $7of28ptshaveDC,the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-nine pts were enrolled from January 2017 to June 2018; 1 pt was unevaluable for response but is included in safety analyses. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off. Demographics and outcomes are summarized in Table (N = 28). One PR and 6 SD16+ were observed for a DC rate of 29% (90% CI, 15% to 37%). 10 pts had at least one grade 3 or 4 AE or SAE at least possibly related to P with the most common being cytopenias. Other grade 3-4 AEs or SAEs at least possibly related to P included fatigue, anorexia, febrile neutropenia, myocardial infarction, sepsis, vomiting, and hypophosphatemia. Conclusions: Monotherapy with P demonstrated evidence of anti-tumor activity in heavily pre-treated NSCLC pts with CDKN2A loss or mutation. Additional study is warranted to confirm the efficacy of P in pts with NSCLC with CDKN2A loss or mutation. Clinical trial information: NCT02693535.

DC rate, % (OR or SD16+) (90% CI) 29% (15%, 37%) Median PFS, wks (95% CI) 7.9 (7.0, 15.1) Median OS, wks (95% CI) 20.6 (14.0, 39.0) Drug-related AEs, grades 3-4 (% of pts) 34% Drug-related SAEs (% of pts) 17% Median age, yrs (range) 63 (41, 79) Male, % 54% ECOG Performance Status, % 0 18% 1 64% 2 18% Prior systemic regimens, % 0 4% 1-2 25% ‡3 71%

9042 Poster Session (Board #365), Sun, 8:00 AM-11:00 AM

Evaluating the role of race in outcome of advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI): Our institutional experience.

Bassel Nazha, Zhengjia Chen, Subir Goyal, Anne Engelhart, Jennifer Wilkinson Carlisle, Tyler Beardslee, Harpaul Gill, Levani Odikadze, Yuan Liu, Manoj K. Mishra, Madhusmita Behera, Suresh S. Ramalingam, Taofeek Kunle Owonikoko; Emory University Hematology Medical Oncology-Fellowship Program, Atlanta, GA; Emory University Winship Cancer Institute, Atlanta, GA; Winship Cancer Institute of Emory University, Atlanta, GA; Emory University, Atlanta, GA; Emory University Department of Medicine, Atlanta, GA; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA; Department of Biological Sciences, Alabama State University, Montgomery, AL; Department of Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, GA; Winship Cancer Institute, Emory University, Atlanta, GA

Background: Race-based differences in ICI efficacy for advanced NSCLC have not been studied due to under-representation of patients of minority background in pivotal trials. We systematically explored real-world differences in outcome in our diverse patient population. Methods: This is a retrospective review of clinical outcome of patients with advanced NSCLC treated with single-agent ICI between 2013 and July 2018 at the Winship Cancer Institute of Emory University. We performed univariate and multivariate analyses for overall survival (OS) and progression free survival (PFS) patients according to self-reported race and of OS according to gender and PD-L1 expression levels. Results: We analyzed clinical data from 90 eligible patients: Median age of 68.5 yrs, 51% male, White (W)/Black(B)/ Asians(A) made up 62.3%/30.7%/5%; 36.5% had brain metastasis at the time of ICI initiation. The majority (85.9%) had ECOG PS #2; ICI was 1st line in 15 (16.9%), 2nd line in 59 (66.3%), 3rd line in 12 (13.5%) and nivolumab was the most commonly used agent (41.1%) followed by atezolizumab (32.2%) and pembrolizumab (26.7%). The median OS for the entire population was not reached (NR) (95%CI: 15.6, NR) while 12-month and 24-month OS rates were 63.8% (52.8%, 72.8%) and 53.1% (40.2%, 64.4%). The median OS, 12-month and 24-month OS rates for W and B respectively, were 23.6 months vs. NR; HR: 1.02 (95%CI: 0.51-2.04), p = 0.9571; 61.8% (47.7%, 73.2%) vs. 59.3% (38.6%, 75.0%) and 46.0% (27.9%, 62.4%) vs. 53.9% (32.8%, 70.9%). The overall response rate was 16.7%; 23.8% vs. 11% for B and W respectively. The median duration of response was comparable at 3.36 months vs. 2.94 months for W and B. The median PFS and 12-month PFS rate for W and B respectively were 5.5 (3.2, 14.8) vs. 3.0 (1.4, 10.7) months, p = 0.1350 and 40.0% (27.1%, 52.5%) vs. 29.6% (14.1%, 47.0%). Conclusions: Real-world analysis of our institutional experience showed no significant racial disparity in advanced NSCLC patients treated with ICI. Larger multi-institutional studies to include other US minority population would make our findings generalizable.

9043 Poster Session (Board #366), Sun, 8:00 AM-11:00 AM

Real-world treatment outcome of advanced Chinese NSCLC EGFR exon 20 insertion patients.

Yan Wang, Guangjian Yang, Jun Li, Haiyan Xu, Lu Yang, Fei Xu, Yaning Yang, Bing Xia, Viola Weijia Zhu, Weini Qiu, Sai-Hong Ignatius Ou; Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China; Center of Clinical Laboratory Medicine, Chinese People’s Liberation Army General Hospital, Beijing, China; Department of Comprehensive Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China; Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College,, Beijing, China; Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing,China, China; Department of Medical Oncology, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; USC Norris Cance Center, Los Angeles, CA; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Haalthy, Beijing, China; Chao Family Comprehensive Cancer Center, University of California, Orange, CA

Background: Treatment outcome of advanced EGFR exon20 insertion (ex20ins) patients with 1st-or2nd- line chemotherapy and EGFR TKIs remains limited. Methods: Retrospective real-world analysis of clinical, molecular, and treatment outcome of a web-based patient registry and hospital chart review. Results: Between 9/13/18-10/22/18, 165 EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were registered. Data cutoff was 12/20/18. EGFR ex20ins were determined by commercial NGS (84%) or PCR (16%). 41 different molecular subtypes of EGFR ex20ins were identified. Ala767_Val769dupASV was the most common (23.0%) followed by Ser768_Asp770dupSVD (17.6%). 61% were females, 77% never-smokers, and CNS mets occurred in 22.4% of patients at time of diagnosis. Median PFS was significantly longer in patients who received 1st-line platinum-based chemotherapy (N = 105) (6.4m; 95% CI:5.7-7.1) vs. EGFR TKI (all generations, N = 23) (2.9m; 95%CI:1.5-4.3; P , 0.001) or vs. EGFR TKI (1G, N = 14) (2.6m; 95%CI:0.8-4.4; P , 0.001). Median PFS was numerically longer in patients who received 2nd-line paclitaxel-based chemotherapy (N = 34) (4.1m; 95%CI:3.3-4.9) versus patients who received 2nd-line EGFR TKIs (N = 18) (2.0m; 95%CI:0.8- 3.2; P = 0.342). Patients with CNS mets (N = 21) had shorter median PFS with 1st-line chemotherapy than those without CNS mets (N = 84) (5.5m; 95%CI:0.7-10.3 vs. 6.4m; 95%CI:5.8-7.0; P = 0.694). Patients with CNS mets had numerically shorter median PFS with 1st-line EGFR TKI (N = 7) than those without CNS mets (N = 16) (2.0m; 95%CI:0.8-3.2 vs. 2.9m; 95%CI:2.1-3.7; P = 0.077). Conclusions: Chemotherapy is superior to current approved EGFR TKIs as 1st-or2nd-line treatment of EGFR ex20ins. Patients with CNS mets had numerically poorer PFS with chemotherapy and EGFR TKI treatment. Targeted therapy against EGFR ex20ins with CNS activity is needed.

9044 Poster Session (Board #367), Sun, 8:00 AM-11:00 AM

Osimertinib induced cardio-toxicity: A retrospective review of FDA adverse events reporting system (FAERS).

Kartik Anand, Joe Ensor, Barry Trachtenberg, Eric Bernicker; Houston Methodist Cancer Center, Houston, TX; Houston Methodist Hospital, Houston, TX; Division of Cardiology, Houston Methodist Hospital, Houston, TX; Houston Methodist Hospital, Department of Medical Oncology, Houston, TX

Background: Osimertinib is an oral third generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). In the FLAURA trial (a Phase III randomized-control trial) Osimertinib arm had higher rate of cardio-toxicity compared to standard EGFR-TKIs. We queried FAERS database to find out rate of cardio-toxicity caused by Osimertinib compared to other EGFR-TKIs. Methods: We queried FAERS for “Cardiac failure”, “Electrogram QT-prolonged”, “Atrial Fibrillation(A.fib)”, “Myocardial Infarction(MI)”, “Cardiac failure congestive(CFC)” and “Pericardial Effusion(PE)” secondary to “Osimetinib”, “Erlotonib”, “Afatinib” and “Gefitinib” from 2016-2018. Disproportionality signal analysis was done by calculating Reporting Odds Ratio (ROR) with 95% confidence interval (CI). ROR was considered significant when lower limit of 95% CI was . 1. Results: Total AEs from all drugs were 5,138,230. Total AEs from all 4 TKIs were 8450, 2454 due to Osimertinib, 5836 due to other TKIs and 160 due to combination of both Osimertinib plus any of other 3 TKIs. ROR for Cardiac failure, A.fib, QT prolongation, MI, PE and CFC due to Osimertinib was 6.4(4.7-8.7), 4(2.8-5.8), 11.2(7.9-15.8), 1.6(0.9-2.6), 8.2(4.8-14) and 3.9(2.4- 6.3) respectively. ROR for Cardiac failure, A.fib, QT prolongation, MI, PE and CFC on comparing Osimertinib vs other TKIs was 2.1(1.3-3.2), 2.1(1.3-3.5), 6.6(3.4-12.8), 1.2(0.6-2.3), 1.6(0.8-3.3) and 2.3(1.2-4.6) respectively. Findings are summarized in Table. Conclusions: Rate of QT prolongation, cardiac failure, CFC and A.fib were found to be higher due to Osimertinib compared to other TKIs. EKG monitoring for QT prolongation and monitoring for signs/symptoms of heart failure should be considered while using Osimertinib.

ROR(95% CI) AE Osimertinib Osimertinib + Other TKIs Other TKIs (8450) (2454) (160) (5836) Osimertinib Osimertinib vs other TKIs Cardiac Failure(n = 86) 40 1 45 6.4(4.7-8.7) 2.1(1.3-3.2) A.fib(n = 64) 30 1 33 4(2.8-5.8) 2.1(1.3-3.5) QT prolongation(n = 49) 33 4 12 11.2(7.9- 6.6(3.4-12.8) 15.8) MI(n = 46) 16 0 30 1.6(0.9-2.6) 1.2(0.6-2.3) PE(n = 36) 14 2 20 8.2(4.8-14) 1.6(0.8-3.3) CFC(n = 34) 17 0 17 3.9(2.4-6.3) 2.3(1.2-4.6)

9045 Poster Session (Board #368), Sun, 8:00 AM-11:00 AM

Brigatinib in pretreated patients with ALK-positive advanced NSCLC.

Renaud Descourt, Maurice Perol, Gaelle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez, Alexis B. Cortot, Florian Guisier, Radj Gervais, Loick Galland, Roland Schott, Eric Dansin, Jennifer ARRONDEAU, Jean-Bernard Auliac, Christos Chouaid; CHU Morvan, Brest, France; De- partment of Thoracic Oncology, Centre Leon ´ B´erard, Lyon, France; CHI Creteil, ´ Creteil, ´ France; Medical Oncology Department, Thoracic Group, Gustave Roussy, Villejuif, France; Nouvel Hopital Civil - Service de Pneumologie, Strasbourg, France; Hopital Cochin And Tenon, Paris, France; Centre Hospital- ier Regional Universitaire Lille, Lille, France; CHU Rouen, Rouen, France; CLCC Baclesse, Caen, France; Centre Georges-François Leclerc, Dijon, France; Paul Strauss Cancer Center, Strasbourg, France; Centre Oscar Lambret, Lille, France; Hopitalˆ Cochin, Paris, France; CHI Creteil, Creteil, France; Centre Hospitalier Intercommunal (CHI) Creteil, Cr´eteil, France

Background: Brigatinib is a next-generation ALK inhibitor initially developed in pre-treated ALK+ NSCLC. Data on the efficacy of brigatinib in real world remain rare. Methods: This retrospective multicentric study analyzed ALK-+ advanced NSCLC patients pretreated with at least two tyrosine-kinase inhibitors, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors, mainly crizotinib then ceritinib in 93% patients. At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had $ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (0.06–20.7) months. Median PFS was 6.6 (95% CI, 4.8–9.9) months for the entire population. In the 91 evaluable patients, disease control rate was 78.2% (stable, 28.2%; partial response, 45.7%; complete response, 4.3%). From brigatinib start, median overall survival was 17.2 (95% CI:11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Ten (9.6%) patients had treatment discontinuation due to intolerance or patient request. Median OS from the diagnostic of NSCLC was 75,3 (95% CI, 38,2-174,6) months. Conclusions: This study confirms the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-+advanced NSCLC. These real-world results are consistent with clinical data reported in clinical trials.

9046 Poster Session (Board #369), Sun, 8:00 AM-11:00 AM

The efficacy of immune checkpoint inhibitors and PD-L1 status in patients with advanced non-small cell lung cancer harboring oncogenic driver alterations: Immuno-oncology biomarker study in LC-SCRUM-Japan.

Kiyotaka Yoh, Shingo Matsumoto, Kei Kunimasa, Masahiro Kodani, Koichi Nishi, Taku Nakagawa, Shunichi Sugawara, Tomohiro Kato, Jun Sakakibara-Konishi, Yuichiro Hayashi, Koji Tsuta, Noriko Motoi, Genichiro Ishii, Koichi Goto; National Cancer Center Hospital East, Kashiwa, Japan; Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; Faculty of Medicine, Tottori University, Tottori, Japan; Ishikawa Prefecutual Central Hospital, Kanazawa, Japan; Department of Thoracic Surgery, Omagari Kosei Medical Center, Akita, Japan; Sendai Kousei Hospital, Sendai, Japan; National Hospital Organization Himeji Medical Center, Himeji, Japan; Hokkaido Uni- versity Hospital, Sapporo, Japan; Keio University School of Medicine, Tokyo, Japan; Kansai Medical University, Osaka, Japan; National Cancer Center Hospital, Tokyo, Japan; Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan

Background: The efficacy of immune checkpoint inhibitors (ICI) and PD-L1 status in patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic alterations has not been fully investigated. We initiated this immuno-oncology biomarker study as part of nationwide genomic screening by LC-SCRUM-Japan (LC-SCRUM-IBIS). Methods: Lung cancer patients enrolled in LC- SCRUM-IBIS underwent targeted next-generation sequencing (NGS) with Oncomine Comprehensive Assay, PD-L1 immunohistochemistry (IHC) assays and further whole-exome sequencing (WES) to determine tumor mutation burden. According to subtype of oncogenic alterations, the efficacy of ICI and PD-L1 status were analyzed. Results: Between Feb 2017 and May 2018, 1017 lung cancer patients were enrolled. Of these, 832 NSCLC patients had adequate tumor samples and were included in this analysis. Targeted NGS showed that major oncogenic alterations included 157 EGFR, 83 KRAS, 33 MET, 30 HER2, 25 FGFR, 22 PIK3CA, 19 ALK, 15 ROS1, 10 RET, 5 BRAF and 13 others. High expression of PD-L1 ( . 50% of tumor cells by 22C3) were observed in RET (70%), MET (67%), ROS1 (53%), KRAS (41%) and BRAF (40%) positive tumors. One-hundred five patients were evaluable for the efficacy of ICI, including 80 non-squamous and 25 squamous histology. Among them, 104 were treated with PD-1/PD- L1 monotherapy and only 1 in combination therapy of ICI. Median treatment line was 2 (range, 1-9). The response rate was 19% (20/105) and median progression-free survival (PFS) and overall survival (OS) were 3.3 and 18.3 months. In 50 patients harboring at least one oncogenic alterations, the response rate, PFS and OS were 18% (9/50), 3.3 and 24.8 months. Among 9 responders to ICI, 3 had KRAS, 2 had MET and 1 each had ALK/EGFR/HER2/RET. Six (26%) of 23 patients with both high PD-L1 expression and at least one oncogenic alterations responded to ICI. Conclusions: PD-L1 status seemed to vary among patients with advanced NSCLC harboring oncogenic alterations. New biomarker for ICI therapy in this population should be moreover explored. Updated results on WES analysis will be presented at the meeting.

9047 Poster Session (Board #370), Sun, 8:00 AM-11:00 AM

Variation in the assessment of immune-related adverse event occurrence, grade, and timing.

David Hsieh, Mary Katherine Watters, Rong Lu, Yang Xie, David E. Gerber; Univ of Texas Southwestern Med School, Dallas, TX; UT Southwestern Medical Center, Dallas, TX; The University of Texas Southwestern Medical Center, Dallas, TX

Background: Accurate assessment of treatment toxicity is critical for patient safety, balancing clinical utility, and understanding treatment impact. Given their unpredictability and heterogeneity, immune- related adverse events (irAEs) may be particularly challenging to ascertain. Our objective was to evaluate the agreement between clinicians on the occurrence, grade, and timing of irAEs, and elucidate determinants of discordance. Methods: We performed a retrospective cohort study of 52 patients with cancer treated with immune checkpoint inhibitors at a National Cancer Institute-designated comprehensive cancer center. Two medical oncologist observers used algorithm-driven manual chart review to characterize eight well-described irAEs (adrenal insufficiency, colitis, hepatitis, hyperthyroidism, hypophysitis, hypothyroidism, pneumonitis, rash). Inter-rater agreement for incidence, severity, and timing of irAEs was determined using Cohen’s kappa coefficient (k) and weighted k with linear weights. Results: The incidence of irAEs ranged from 4-35% for observer 1 and 6-27% for observer 2, while aggregate incidence rates ranged from 8% (hypophysitis) to 40% (pneumonitis). Inter-rater agreement was generally limited for irAE incidence (k 0.37 [hypophysitis]-0.8 [hypothyroidism]). Weighted k similarly showed limited or poor agreement for most irAE grades (k 0.31-0.75). Differences in the assessment of irAE time of onset ranged from 5-188 days. Rates of discordance were greater for grade 1 (39%) and grade 2 (41%) irAEs than for grade 3-4 (20%) irAEs. Multivariable analyses showed that longer therapy duration (OR 4.8, P= 0.02) and a high Charlson Comorbidity Index (OR 4.09, P= 0.03) were significantly associated with discordant irAE assessment. Conclusions: Inter-rater reliability varied among irAEs and consistently showed poor agreement for the incidence, severity, and timing of irAEs. Agreement was greater for irAEs with distinct laboratory-based definitions (eg, hypothyroidism), higher- grade irAEs, and irAEs in patients with fewer comorbidities and shorter immunotherapy duration. These findings have implications in the clinical management of patients receiving immunotherapy and in the reporting of immunotherapy clinical trials.

9048 Poster Session (Board #371), Sun, 8:00 AM-11:00 AM

Patient-reported outcomes (PROs) with first-line durvalumab (D) 6 tremelimumab (T) versus chemotherapy (CT) in metastatic NSCLC: Results from MYSTIC.

Edward B. Garon, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Gilles Robinet, Sylvestre Le Moulec, Ronald Natale, Jeffrey Gary Schneider, Frances A. Shepherd, Marina Chiara Garassino, Sarayut Lucien Geater, Zsolt Papai-Szekely, Tran Van Ngoc, Feng Liu, Urban J. Scheuring, Anna Ryden, ´ Solange Peters, Naiyer A. Rizvi; David Geffen School of Medicine, University of California/TRIO-US Network, Los Angeles, CA; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Asklepios Lung Clinic, Munich-Gauting, Germany; Chungbuk National University Hospital, Cheongju, South Korea; Leningrad Regional Clinical Hospital, Oncology Department, Lunacharskogo Prospect, Russian Federation; Samsung Medical Center, Seoul, South Korea; CHRU de Brest-Hopitalˆ Morvan, Brest, France; Institut Bergonnie, ´ Bordeaux Cedex, France; Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA; NYU Winthrop Hospital, Mineola, NY; Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada; Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy; Prince of Songkla University, Hat Yai, Thailand; St George Hospital of Fejer County, Szekesfehervar, Hungary; Cho Ray Hospital, Ho Chi Minh, Viet Nam; AstraZeneca, Gaithersburg, MD; AstraZeneca, Cambridge, United Kingdom; AstraZeneca, Gothenburg, Sweden; Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland; Columbia University Medical Center, New York, NY

Background: MYSTIC, an open-label, Phase 3 trial of first-line D (anti-PD-L1) 6 T (anti-CTLA-4) vs platinum CT in mNSCLC, showed an improvement in overall survival (OS) with D vs CT in pts with tumor cell PD-L1 expression $25% (TC $25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02], p = 0.036; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17], p = 0.202). Here we summarize PROs from MYSTIC. Methods: Immunotherapy/CT-na¨ıve mNSCLC pts were randomized (1:1:1) to D, D+T, or CT. Symptoms, function, and global health status/quality of life (QoL) were assessed using the EORTC QLQ-C30 v3 questionnaire and its lung cancer module, QLQ-LC13. A change in score from baseline $10 points was predefined as clinically meaningful (CM). Mean changes from baseline (over 12 mos) for prespecified symptoms were analyzed using a mixed model for repeated measures (MMRM). Time from randomization to the first CM deterioration (TTD) was analyzed. Results: Among pts with PD-L1 TC $25% (n = 488), there were no differences between arms in symptoms, function, or global health status/QoL at baseline. Compliance with completing the questionnaires was $60% to wk 120 in the D6T arms, and to wk 40 (C30) and wk 44 (LC13) in the CT arm. MMRM analysis showed significant between-arm differences in changes from baseline in favor of D for fatigue (difference vs CT 29.5) and appetite loss (211.9; CM), and D+T for fatigue (211.7; CM). Significantly longer TTD (median, mos) was seen with D and D+T vs CT for appetite loss (12.8 and 5.6 vs 4.5), constipation (14.6 and 9.0 vs 5.5), nausea/vomiting (16.7 and 9.7 vs 4.5), and dyspnea (10.6 and 7.4 vs 5.6); D vs CT for diarrhea (16.3 vs 9.0), insomnia (9.3 vs 6.2), and hemoptysis (not reached vs 10.3); and D+T vs CT for fatigue (5.6 vs 2.0). Significantly longer TTD (median, mos) was also seen with D and D+T vs CT for function (cognitive [9.1 and 6.6 vs 5.2], physical [9.0 and 7.4 vs 4.2], role [D vs CT only; 7.3 vs 3.7], social [12.9 and 5.4 vs 5.2]), and global health status/QoL (5.9 and 6.8 vs 5.5). Conclusions: Pts with PD-L1 TC $25% treated with D6T had a reduced symptom burden over time and longer TTD for symptoms, function, and global health status/QoL compared to pts receiving CT. Clinical trial information: NCT02453282.

9049 Poster Session (Board #372), Sun, 8:00 AM-11:00 AM

Clonal evolution and osimertinib resistance mechanisms identified by whole exome and transcriptome sequencing in EGFR mutant NSCLC.

Nitin Roper, Anna-Leigh Brown, Sivasish Sindiri, Constance M. Cultraro, Shaojian Gao, Chul Kim, Chuong D. Hoang, Tapan K Maity, Elizabeth Akoth, Arun Rajan, Abhilash Karavattu Venugopalan, Christopher Trindade, Jun S. Wei, Anna Panchenko, Stephen M. Hewitt, Javed Khan, Udayan Guha; Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, MD; National Library of Medicine, Bethesda, MD; Genetics Branch, CCR, NCI, NIH, Bethesda, MD; Thoracic Surgery Branch, CCR, NCI, NIH, Bethesda, MD; Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD

Background: Osimertinib, a 3rd generation EGFR TKI, has been approved for treatment na¨ıve patients (pts) with metastatic EGFR mutant NSCLC. Mechanisms of resistance to osimertinib are emerging from limited studies using targeted sequencing platforms. Methods: We performed whole exome (WES) and RNA-sequencing of osimertinib resistant tumors of EGFR-mutant NSCLC pts treated in a prospective clinical trial (NCT02759835). Treatment na¨ıve EGFR mutant pts or pts with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, pts with #5 progressing sites undergo local ablative therapy (LAT; surgery, radiation, RFA) and resume osimertinib. We analyzed paired pre- treatment and post-progression tumors in 10 patients and post-progression tumors in 3 additional patients and investigated intra- and inter-metastatic tumor heterogeneity using tumors procured from LAT surgeries and autopsies. Results: Acquired, focal copy number amplifications (CNA) of oncogenes occurred in the majority of patients (54%, n = 7/13) whereas acquired osimertinib resistance mutation EGFR C797S was less common (15%, n = 2/13). Early progression on osimertinib ( , 12 months PFS) in treatment na¨ıve pts was associated with acquired, focal CNA. Despite pre-existing EGFR amplification, further amplification of the mutant allele of EGFR was the most common focal CNA (33%, n = 3/ 9). Other oncogenes amplified in resistant tumors include MET, KRAS, ERBB2 and YES1. CD274 (PD- L1) amplification occurred as the only putative mechanism of resistance in a pt without prior EGFR-TKI treatment. Using RNA-seq, we identified a pt who retained NSCLC histology, but upregulated genes associated with neuroendocrine differentiation upon osimertinib resistance. Clonal evolutionary analysis using WES of prospectively collected sensitive and resistant tumor tissue, including at autopsy is underway. Conclusions: Unbiased WES and transcriptome sequencing revealed heterogeneity, clonal evolution and novel osimertinib resistance mechanisms. Majority of pts had two or more resistance mechanisms suggesting the requirement of combination therapies to overcome resistance. Clinical trial information: NCT02759835.

9050 Poster Session (Board #373), Sun, 8:00 AM-11:00 AM

Evaluation of clonal hematopoiesis in late stage NSCLC using a next-generation sequencing panel targeting cancer genes.

Stephanie J. Yaung, Frederike Fuhlbruck, ¨ Johnny Wu, Fergal Casey, Maureen Peterson, Wei Zou, John F. Palma, Namrata S. Patil, Yuqiu Jiang; Roche Sequencing Solutions, Inc., Pleasanton, CA; Roche Sequencing Solutions, Inc., Potsdam, Germany; Genentech, Inc., South San Francisco, CA

Background: Somatic mutations derived from the expansion of clonal populations of blood cells (clonal hematopoiesis of indeterminate potential, or CHIP) may be detected in sequencing of cell-free DNA (cfDNA) samples. We evaluated the potential implications of CHIP in targeted sequencing of lung cancer plasma samples using matched peripheral blood mononuclear cells (PBMC) to identify CHIP. Methods: Samples were evaluated from OAK, a phase 3 trial of atezolizumab in locally advanced or metastatic NSCLC following failure with platinum-based therapy. 94 samples from Cycle 1 Day 1 (C1D1) plasma and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a 198-kb next- generation sequencing panel targeting cancer genes. Plasma samples from subsequent cycles of therapy (C2D1, C3D1, and C4D1) were also sequenced with the same panel. Using median input amounts of 22.8 ng cfDNA and 50 ng PBMC DNA, we obtained median deduplicated depths of 5413 and 5070, respectively. Results: In C1D1 cfDNA, a median of 120 single nucleotide variants were detected per sample, with 5.13% of variants not identified in matched PBMC (i.e., putative tumor- derived somatic variants) versus 94.87% of variants identified in matched PBMC (i.e., germline or CHIP variants). While the majority of PBMC-matched variants were SNPs with allele frequency (AF) around 50% or 100% as expected, there was a median of 1 (range 0-8) PBMC-matched cfDNA variants per sample with AF below 10%. Consistent with CHIP, the number of PBMC-matched cfDNA variants per subject below AF 10% were positively associated with age (p-value = 0.0145), and TP53 was the most frequently mutated gene. We found similar results in plasma samples from subsequent cycles. Conclusions: Plasma and PBMC sequencing analysis identified potential mutations derived from CHIP. However, 39% of cfDNA samples had zero potential CHIP mutations identified in the study, possibly due to the specific regions targeted by the AVENIO assay. While this study suggests that only a small percentage of variants detected by the AVENIO Surveillance panel in lung cancer are derived from CHIP, further studies are warranted to assess the impact and removal of these variants.

9051 Poster Session (Board #374), Sun, 8:00 AM-11:00 AM

First-in-human phase 1 study of DS-1062a in patients with advanced solid tumors.

Jacob M. Sands, Toshio Shimizu, Edward B. Garon, Jonathan Greenberg, Ferdinand M. Guevara, Rebecca Suk Heist, Fumiaki Kobayashi, Yutaka Noguchi, Daisuke Okajima, Naoyuki Tajima, Alexander I. Spira, Noboru Yamamoto, Aaron Elliott Lisberg; Dana-Farber Cancer Institute, Boston, MA; National Cancer Center Hospital (NCCH), Tokyo, Japan; David Geffen School of Medicine, University of California/TRIO-US Network, Los Angeles, CA; Daiichi Sankyo, Basking Ridge, NJ; Massachusetts General Hospital Cancer Center, Boston, MA; Daiichi Sankyo, Co., Ltd., Tokyo, Japan; Virginia Cancer Specialists, Fairfax, VA; National Cancer Center Hospital, Tokyo, Japan; University of California, Los Angeles, Los Angeles, CA

Background: DS-1062a is a trophoblast cell-surface antigen 2 (TROP2)-targeting antibody drug conjugate. TROP2 is highly expressed in epithelial cancers, including non-small cell lung cancer (NSCLC). Overexpression of TROP2 may be associated with poor survival in some solid tumors. Preclinical studies showed promising antitumor activity of DS-1062a in mouse models with TROP2-positive tumors. Preliminary results are reported in the dose escalation part of this phase 1 study. Methods: This is an ongoing phase 1 study of DS-1062a in patients (pts) with advanced solid tumors in the US and Japan (NCT03401385). Adult (age $20 years in Japan or $18 years in US) pts with measurable disease per RECIST v1.1 and sufficient tumor tissue sample for TROP2 measurement were eligible. Pts were excluded if they had multiple primary malignancies or untreated brain metastases. Endpoints included safety, pharmacokinetics, and efficacy. Results: As of November 16, 2018, 22 pts with advanced NSCLC were treated with DS-1062a at doses of 0.27-mg/kg (n = 4), 0.5-mg/kg (n = 5), 1.0-mg/kg (n = 7), and 2.0-mg/kg (n = 6). Overall, mean (standard deviation) treatment duration and cumulative dose were 7.8 (4.1) weeks and 181.8 (141.4) mg, respectively, with a median of 2 (range 1–6) cycles initiated. The majority (n = 18; 81.8%) of pts had $1 treatment- emergent adverse event (TEAE). The most common TEAE, fatigue (n = 9), was the only grade $3 treatment-related TEAE (n = 1; 2.0-mg/kg). Serious TEAEs, reported in 5 pts in the 0.27-mg/kg (n = 2), 0.5-mg/kg (n = 2), and 2.0-mg/kg (n = 1) cohorts, were not treatment-related. TEAEs leading to discontinuation occurred in 1 pt in the 0.27-mg/kg cohort (pleural effusion; not treatment-related). One pt died due to progressive disease. Peak concentration (Cmax) and area under the curve from time 0 to last measurable concentration (AUClast) increases were generally dose proportional. Of 18 tumor evaluable pts, 1 had a partial response (PR; 1.0-mg/kg), and 8 had stable disease (SD). Conclusions: DS-1062a was well tolerated at doses up to 2.0-mg/kg. An observable PR and multiple pts with SD warrant further evaluation of DS-1062a. The maximum tolerated dose has not been reached, and this study is ongoing. Clinical trial information: NCT03401385.

9052 Poster Session (Board #375), Sun, 8:00 AM-11:00 AM ml-RECIST: Machine learning to estimate RECIST in patients with NSCLC treated with PD-(L)1 blockade.

Kathryn Cecilia Arbour, Luu Anh Tuan, Hira Rizvi, Adam Yala, Matthew David Hellmann, Regina Barzilay; Memorial Sloan Kettering Cancer Center, New York, NY; Massachusetts Institute of Technology, Cambridge, MA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY

Background: Real-world evidence (RWE) is increasingly important for discovery and may be an opportunity for regulatory approval. Effective use of RWE relies on determining treatment-specific outcomes, such as overall response rate (ORR) and progression-free survival (PFS), which are challenging to accurately evaluate retrospectively and at scale. We hypothesized the use of machine learning of text radiology reports from patients with NSCLC treated with PD-1 blockade could be used to train a model that estimates RECIST-defined outcomes. Methods: 2753 imaging reports from 453 patients with advanced NSCLC treated with PD-1 blockade were collected and separated into independent training (80%, n = 362) and validation (20%, n = 92) cohorts. Reports were limited to interval of PD-1 blockade. RECIST reads performed by thoracic radiologists on all patients served as “gold standard” to determine ORR, occurrence of, and date of progression. Baseline reports were compared to all follow up reports to determine machine-learning RECIST (ml-RECIST). A four layers neural-network model for classification was proposed to solve the three above tasks. Results: In the training cohort, ml-RECIST best estimated ORR by RECIST (accuracy CR/PR 84%, SD 82%, POD 91%). ml-RECIST estimated PFS by RECIST accurately predicting progression occurred at any time (86%) and exact progression date (65%). Date of progression was closely correlated (Pearson’sr coefficient = 0.91, 95% CI:0.89-0.94, p , 0.001) in patients determined to have progressed by both methods. Similar accuracy of ml-RECIST was observed in the validation cohort (accuracy CR/PR 84%, SD 80%, POD 90%; progression occurred 86%, progression date 72%). Accuracy was consistent when RECIST reads were performed prospectively as part of clinical trials vs retrospectively for standard of care treatment (e.g. CR/PR 82% vs 88%, respectively). ml-RECIST-defined response similarly determined improvement in overall survival compared to RECIST (HR = 0.19, p , 0.001 vs HR = 0.26, p , 0.001 respectively). Conclusions: Machine learning-RECIST ("ml-RECIST") accurately estimates outcomes using imaging text reports. ml-RECIST may be tool to determine outcomes expeditiously and at scale for use in RWE studies, enabling more useful and reliable applications of large clinical databases.

9053 Poster Session (Board #376), Sun, 8:00 AM-11:00 AM

Circulating free DNA as a prognostic biomarker in patients with advanced ALK+ NSCLC treated with alectinib from the global phase III ALEX trial.

Rafal Dziadziuszko, Solange Peters, Tony S. K. Mok, D. Ross Camidge, Johannes Noe, ´ Malgorzata Nowicka, Walter Bordogna, Peter N. Morcos, Vlatka Smoljanovic, Alice Tsang Shaw; Medical University of Gdansk, ´ Department of Oncology and Radiotherapy, Gdansk, ´ Poland; Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland; Prince of Wales Hospital, Hong Kong, China; University of Colorado Cancer Center, Aurora, CO; F. Hoffmann-La Roche Ltd., Basel, Switzerland; Roche Innovation Center, New York, NY; Massachusetts General Hospital/Harvard Medical School, Boston, MA

Background: Circulating free DNA (cfDNA) released predominantly by tumors into the blood correlates with tumor load, but correlation with outcomes after ALK inhibitor treatment is poorly understood. Here, we examine the prognostic potential of cfDNA in the phase III ALEX trial of alectinib versus crizotinib in previously untreated patients with advanced ALK+ NSCLC. Methods: Data cutoff was December 1, 2017. Median cfDNA was determined from 276 baseline samples; patients were stratified into ‘#median’ and ‘ . median’ biomarker-evaluable populations (BEP). Results: Median cfDNA was 11.5ng/mL. Baseline characteristics were mostly balanced between the crizotinib (#median, n = 72; . median, n = 67) and alectinib (#median, n = 66; . median n = 71) BEPs. However, the alectinib . median BEP had more active smokers (7.0% vs crizotinib 1.5%), more measurable/non- measurable CNS lesions (47.9% vs 41.8%) and more patients with TP53 short-variant (SV) (44.8% vs 32.8%); the alectinib #median BEP had more active smokers (7.6% vs crizotinib 2.8%). Alectinib exposure was not substantially different between relevant BEPs. Higher cfDNA amount was associated with measurable/non-measurable CNS lesions and TP53 SV. Tumor burden positively correlated with normalized cfDNA amount (Pearson correlation 0.204; p , 0.001). Median PFS by investigator in the #median BEP was 34.9 months alectinib vs 14.8 crizotinib (HR 0.37, 95% CI 0.22–0.61, p , 0.0001); in the . median BEP it was 14.8 months alectinib vs 8.6 crizotinib (HR 0.43, 95% CI 0.28–0.64, p , 0.0001). Response rates in the #median BEP were 82.3% alectinib vs 70.4% crizotinib; in the . median BEP, 70.2% alectinib vs 55.4% crizotinib. Median duration of response in the #median BEP was not reached for alectinib vs 21.0 months for crizotinib; in the . median BEP, 33.1 months alectinib vs 7.3 crizotinib. Conclusions: Tumor burden positively correlated with cfDNA amount; patients with #median cfDNA at baseline had better prognosis than those with . median cfDNA. Alectinib consistently improved PFS, DOR and ORR versus crizotinib across BEPs, reducing the risk of tumor progression by . 50% compared with crizotinib. Clinical trial information: NCT02075840.

9054 Poster Session (Board #377), Sun, 8:00 AM-11:00 AM

First subsequent treatment after discontinuation of durvalumab in unresectable, stage III NSCLC patients from PACIFIC.

David Planchard, Byoung Chul Cho, Jhanelle Elaine Gray, Luis G. Paz-Ares, Mustafa Ozguroglu, Augusto E. Villegas, Davey B. Daniel, David Vicente, Shuji Murakami, Rina Hui, Takayasu Kurata, Alberto Chiappori, Ki Hyeong Lee, Maike De Wit, Yu Gu, Catherine Wadsworth, Phillip A. Dennis, Scott Joseph Antonia; Gustave Roussy, Villejuif, France; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain; Istanbul University-Cerrahpas¸a, Cerrahpas¸a School of Medicine, Istanbul, Turkey; Cancer Specialists of North Florida, Jacksonville, FL; Tennessee Oncology, Chattanooga, TN; Hospital Universitario Virgen Macarena, Seville, Spain; Kanagawa Cancer Center, Yokohama, Japan; Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Japan; Chungbuk National University Hospital, Chung- buk National University College of Medicine, Cheongju, South Korea; Vivantes Klinikum Neukoelln, Berlin, Germany; MedImmune, Gaithersburg, MD; AstraZeneca, Alderley Park, United Kingdom; AstraZeneca, Gaithersburg, MD

Background: In the phase 3 PACIFIC trial of unresectable, stage III NSCLC patients (pts) without progression after concurrent chemoradiotherapy (cCRT), durvalumab (durva) significantly improved PFS and OS with similar safety compared to placebo (pbo). We performed exploratory analyses to characterize first subsequent treatment (Tx) after discontinuation of durva. Methods: Pts with WHO PS 0/1 and any tumor PD-L1 status were randomized (2:1) 1–42 days after $2 cycles of platinum-based cCRT to durva 10 mg/kg IV or pbo Q2W up to 12 months, stratified by age, sex and smoking history. Pts were classified by the use or not of first subsequent Tx and category of first systemic Tx (platinum doublet CT [PDCT], single-agent CT [SCT], immunotherapy [IT] or targeted therapy [TT]). Results: As of Mar 22, 2018, 216/476 (45.4%) and 153/237 (64.6%) in the durva and pbo arms, respectively, had a RECIST-based PFS event per BICR (5.7% and 8.4% due to death). 195 (41.0%) and 128 (54.0%) received first subsequent Tx, most of which were systemic Tx (158 [33.2%] and 109 [46.0%]): PDCT (16.4% and 19.0%), SCT (8.6% and 8.4%), IT (4.2% and 13.5%) or TT (3.8% and 5.1%); 7.8% and 8.0% received RT only. Time to first subsequent therapy or death (TFST) was longer with durva vs pbo (HR 0.58; 95% CI 0.47–0.72; median 21.0 vs 10.4 months). Baseline characteristics of pts with or without first subsequent Tx were similar, and similar across durva or pbo arms. Among pts with systemic Tx, baseline characteristics (including pre-cCRT PD-L1 status) were generally similar, except pts on TT, more of whom were EGFR+ (70.0% vs 0–6.6% of other systemic Tx groups) with commonly associated phenotypes (more females, Asians, non-smokers and non-squamous pts). Best overall response to first systemic Tx will be presented. Conclusions: Due to longer PFS and fewer progression events with durva vs pbo, fewer pts on durva required subsequent Tx and, per TFST, much later. With the exception of IT, use of each subsequent Tx was similar between the durva and pbo arms with PDCT the most common. Baseline characteristics were similar for pts with or without first subsequent Tx and pts who received first systemic Tx, except for pts who received TT, as expected due to their molecular profile.

9055 Poster Session (Board #378), Sun, 8:00 AM-11:00 AM

Tracking plasma KRAS mutations (mu) in lung adenocarcinoma (LUAC) patients (p) and branching evolution.

Jillian Bracht, Niki Karachaliou, Richard B. Lanman, Daniel Dix, Iris Faull, Rebecca Nagy, Noemı´ L´opez, Ramon Palmero, Santiago Viteri Ramirez, Margarita Majem, Alvaro Taus, Enric Carcereny Costa, Javier Garde, Francois Riva, Andrea Malfettone, Miguel Sampayo, Ana Drozdowskyj, Enriqueta Felip, Rafael Rosell; Pangaea Oncology, IOR, Quiron-Dexeus ´ University Institute, Laboratory of Cellular and Molecular Biology, Barcelona, Spain; University Hospital Sagrat Cor, Barcelona, Spain; Guardant Health, Inc., Redwood City, CA; Guardant Health, Redwood City, CA; Medsir-Medica Scientia Innovation Research, Barcelona, Spain; Department of Medical Oncology, Catalan Institute of Oncology, Hospitalet (Barcelona), Spain; Dexeus University Hospital, Quiron Salud Group, Barcelona, Spain; Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Hospital del Mar, Barcelona, Spain; Institut Catal`ad’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; MedSIR- Medica Scientia Innovation Research, Barcelona, Spain; MedSIR - Medica Scientia Innovation Research, Barcelona, Spain; Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), Badalona, Barcelona, Spain; Lung Cancer Unit, Hospital Universitari Vall d’Hebron and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain and Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain and Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, Badalona, Barcelona, Spain

Background: KRAS m in LUAC p are recalcitrant to therapy. In mice models and p, STK11 m confer poor prognosis. Patients with KRAS, or KRAS with TP53 m, benefit from immunotherapy (IO). We used a cell free DNA (cfDNA) sequencing platform to sub-group 53 LUAC p with KRAS m from the Spanish Lung Liquid versus Invasive biopsy Program (SLLIP, NCT03248089), according to the coexistence of TP53 and STK11 m. We evaluated the treatment outcome in the KRAS subgroups and we explored the mutational evolution at 2 weeks (w), and at the end of the study (EOS). Methods: SLLIP was a multicenter observational study in patients with treatment-na¨ıve metastatic LUAC. Genotyping, with a clinically validated cfDNA assay (Guardant360) was performed at 3 time points: before start of treatment, at 2 w, and upon progression or at 12 months (mo). Oncoprints were constructed based on mutation status and variant allele frequency (VAF). Results: 53 p with KRAS alterations were included. 36 male; median age 59; 46 current/ex-smokers; 64% received 1st line platinum-based chemotherapy (CT), 4% platinum-based CT+IO, 8% platinum-based CT plus bevacizumab, and 24% other or no therapy. 13 p had only KRAS m (K-only group), 25 p had KRAS + TP53 m (KP group), and 15 p had KRAS + STK11 with or without TP53 m (KS group). Median progression-free survival was 3.5 mo for all 53 p, 4.8 mo for the K-only group, 4.4 mo for the KP group, and only 2.6 mo for the KS group (p = 0.05 for KS versus K-only). The average VAF for K-only, KP, and KS groups at EOS were 6.4%, 9.7%, and 46%, respectively. When looking at p with cfDNA analysis at the three time points, the following were observed: In the K-only group, 25% lost KRAS m at 2 w and 50% at EOS. 50% and 75% gained TP53 m, at 2 w and EOS, respectively. None gained STK11 at the 2 time points. In the KP group, 40% lost KRAS m at 2 w but all had KRAS m at EOS. 20% and 10% lost TP53 m, at 2 w and EOS, respectively. 10% gained STK11 m at the 2 time points. In the KS group, 33% lost KRAS m at the 2 time points. All and 33% lost STK11 m at 2 w and EOS, respectively. 66% gained TP53 at the 2 time points. Conclusions: Subgroups of KRAS m traced in cfDNA confirm dismal prognosis to 1st line therapies. These findings prompt us to tailor IO for K-only or KP subgroups. For p with STK11 m, restoration of the STK11 function is warranted. Clinical trial information: NCT03248089.

9056 Poster Session (Board #379), Sun, 8:00 AM-11:00 AM

Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.

Hiroe Kayatani, Keisuke Aoe, Kadoaki Ohashi, Hiroshige Yoshioka, Akihiro Bessho, Nobuhisa Ishikawa, Masahiro Yamasaki, Toshiyuki Kozuki, Nobukazu Fujimoto, Yutaka Ueda, Syuuji Bandoh, Isao Murakami, Hirohisa Ichikawa, Tetsuya Kubota, Keisuke Sugimoto, Nagio Takigawa, Takashi Sumikawa, Katsuyuki Kiura; Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan; National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Japan; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan; Depart- ment of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Japan; Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan; Department of Respiratory Medicine, Hiroshima Prefectural Hospital, Hiroshima, Japan; Hiroshima Red Cross and Atomic-Bomb Survivors Hospital, Hiroshima, Japan; Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan; Department of Medical Oncology, Okayama Rosai Hospital, Okayama, Japan; Department of Respiratory Med- icine, Kagawa Prefectural Central Hospital, Takamatsu, Japan; Faculty of Medicine, Kagawa University, Kitagun, Japan; National Hospital Organization Higashihiroshima Medical Center, Higashi-Hiroshima, Japan; Department of Respiratory Medicine, KKR Takamatsu Hospital, Takamatsu, Japan; Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan; Department of Respiratory Medicine, Kobe Red Cross Hospital, Kobe, Japan; Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan; Tottori Prefectural Central Hospital, Tottori, Japan; Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR- mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR- TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population.

Group N Group P IHC 0 IHC 1+ IHC 2+ IHC 3+ (n = 71) (n = 148) (n = 51) (n = 7) Complete Response 4610 Partial Response 45 83 33 4 Stable Disease 836102 Progressive Disease 3951 Not Evaluated 41420 Overall response rate 69% 60% 67% 57% Disease control rate 80% 84% 86% 86% Time to treatment failure (months) 19.1 13.1

9057 Poster Session (Board #380), Sun, 8:00 AM-11:00 AM

Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study.

Jonathan W. Riess, Susan G. Groshen, Karen L. Reckamp, Heather A. Wakelee, Geoffrey R. Oxnard, Sukhmani Kaur Padda, Marianna Koczywas, Zofia Piotrowska, Lynette M. Sholl, Cloud P. Paweletz, Christie J. Lau, Jill Kolesar, Philip C. Mack, Jeffrey Moscow, Pasi A. Janne, Primo Lara, Edward M. Newman, David R. Gandara; UC Davis Comprehensive Cancer Center, Sacramento, CA; USC/Norris Comp Cancer Ctr, Los Angeles, CA; City of Hope Comprehensive Cancer Center, Duarte, CA; Stanford Cancer Institute, Stanford, CA; Dana-Farber Cancer Institute, Boston, MA; Massachusetts General Hospital Cancer Center, Boston, MA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA; University of Kentucky Markey Cancer Center, Lexington, KY; National Cancer Institute, Rockville, MD

Background: Osi (3rd gen EGFR TKI) has robust activity in 1st line EGFR mutant NSCLC and TKI resistant T790Mpos NSCLC but progressive disease (PD) occurs and outcomes with Osi alone are poor in T790Mneg, C797Xpos and EGFR exon 20 insertion (ins20) disease. This study examined the EGFR monoclonal antibody Neci with Osi in select settings of EGFR TKI resistance. Methods: Using a 3+3 design, Neci was examined in advanced EGFR mutant NSCLC at dose levels (DL) of 600 mg (DL1) & 800 mg (DL2) D1, D8 IV q21 days + Osi 80 mg qd. Four expansion cohorts (ExC; 18 each) included: A) T790Mneg PD on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 3rd gen TKI, C) T790Mpos PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy. Central T790M testing by ddPCR in ExC A-C. Additional studies performed include: NGS panel of . 400 genes, EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR as exploratory analyses. Adverse events (AEs) graded (Gr) by CTCAEv5 with ORR and PFS by RECIST 1.1. Results: Dose escalation and ExC B completed accrual. In total 55 pts were evaluable (Table). 1 pt had DLT at DL2, Gr 3 sinus bradycardia. Drug related Gr 3 AEs were seen in 27% (15) of pts, mainly rash (7;13%). ctDNA showed decreased mutant allele frequency with therapy in all pts studied with detected EGFR at baseline, with complete plasma clearance in a pt with detectable C797S. Conclusions: The RP2D (Osi 80 mg qd and Neci 800 mg D1, D8 IV on q21d cycle) is feasible and tolerable. In ExC A,T790Mneg pts with 1st/2nd gen EGFR TKI as last treatment, using curtailed sampling, the pre-specified efficacy signal was reached for Osi + Neci comparing favorably to Osi alone in analogous pts from the AURA trial. Clinical activity was also seen in EGFR-dependent resistance (T790Mpos C797Spos) after PD on 3rd gen TKI and in EGFR ins 20. Clinical trial information: NCT02496663.

ORR (N, %) Median PFS (95% CI) months PD on 1st or 2nd gen TKI 6/21 (29%) 4.1 (2.5, 8.5) T790Mneg**1st or 2nd gen TKI as last therapy 4/18 (22%) 3.9 (1.3, 8.3) T790Mpos 0/1 (0%) T790Munk 2/2 (100%) PD on 3rd gen TKI 4/30 (13%) 2.5 (1.3, 5.3) T790Mneg 0/19 (0%) 1.5 (1.1, 2.6) T790Mpos 4/10 (40%) 5.3 (2.3, 7.5) T790Munk 0/1 (0%) T790Mpos/C797Spos 2/4 (50%) 6.4 EGFR ins 20 2/4 (50%) 5.3

9058 Poster Session (Board #381), Sun, 8:00 AM-11:00 AM

Impact of time to treatment initiation (TTI) on survival of patients with newly diagnosed non-small cell lung cancer (NSCLC).

Abdel-Ghani Azzouqa, Ruqin Chen, Yanyan Lou, Sikander Ailawadhi, Rami Manochakian; Mayo Clinic, Jacksonville, FL; Mayo Clinic Florida, Jacksonville, FL; Department of Hematology and Oncology, Jacksonville, FL

Background: Lung Cancer is the leading cause of cancer related deaths in the USA. NSCLC comprises about 85% of lung cancer cases. Although timeliness of care in patients with NSCLC is considered an important aspect of quality care, there are conflicting data about its impact on clinical outcomes. The primary objective of this study is to determine if there is an association between TTI and survival in patients with NSCLC. Methods: In this retrospective study, we reviewed data from our multi-site Mayo Clinic Cancer Center registry and identified patients with newly diagnosed NSCLC from 2000 to 2016. TTI was calculated from time of diagnosis to time of first treatment (surgery, radiation therapy or systemic therapy). Analyses were performed by SAS software 9.4. Log-Rank test was used to compare survival. Cox regression multivariate model was used to evaluate the prognostic value of variables to survival. Results: 10010 patients (53% males and 47%) were reviewed. Median age at diagnosis was 70. Median TTI was 12 days for stage I, and 20 days for stage II, III and IV. We compared outcomes of patients with TTI . 20 days to TTI #20 days. Outcomes were stratified based on age, gender, grade, and stage. Median Overall Survival (OS) was significantly better for patients with TTI #20 days compared to TTI . 20 days (39.1 vs 28.6 months P-value , 0.0001). Further stratification, based on stage, showed significantly better OS for stage I and II patients with TTI #20 days compared to TTI . 20 days (103.4 vs. 63.9 months P-value , 0.0001 and 72.3 vs. 46.8 months P-value 0.0014 respectively). OS for stage III patients with TTI #20 days was not significantly different from patients with TTI . 20 days (30.6 vs. 28.5 months P-value 0.118). Interestingly, stage IV patients had worse OS if TTI #20 days compared to TTI . 20 days (8.3 vs. 12.8 months P-value , 0.0001). Conclusions: Our study showed an association between TTI and survival of patients with NSCLC. Shorter TTI was associated with better survival in stage I and II patients and worse survival in stage IV patients. Our study further highlights the controversy surrounding the topic of impact of timeliness of care on survival in patients with cancer, specifically NSCLC across different stages.

9059 Poster Session (Board #382), Sun, 8:00 AM-11:00 AM

Real-world practice patterns and impact of PD-L1 expression testing in patients with advanced non-small cell lung cancer.

Michael Leapman, Carolyn J Presley, Weiwei Zhu, Pamela R. Soulos, Kerin B. Adelson, Daniel J. Boffa, Cary Philip Gross; Yale School of Medicine, New Haven, CT; The Ohio State University, Columbus, OH; Yale University, New Haven, CT; Section of Thoracic Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT

Background: Several tests measuring programmed cell death ligand 1 (PD-L1) expression are available to select patients with advanced non-small cell lung cancer (aNSCLC) for PD-1 axis therapy including FDA approved companion diagnostics (CoDx), as well as complementary (CyDx) and laboratory developed tests (LDTs). However, it is unknown how rapidly PD-L1 expression testing has become adopted, which type of tests are used, or whether testing affects first-line therapy. Methods: We retrospectively reviewed the Flatiron Health electronic health record-derived database, reflecting real- world care at community oncology practices in the U.S. We evaluated trends in the use of PD-L1 expression testing within 12 months of diagnosis. Among patients diagnosed after FDA approval of PD-L1 testing prior to first-line therapy (Oct 2016), and without other identifiable driver mutations, we used multivariable logistic regression to examine the association between PD-L1 testing and receipt of first-line PD-1 axis therapy. We further examined the association between PD-L1 expression result (using overall reported status or % staining) and choice of first-line therapy. Results: We identified 49,546 patients with aNSCLC from 2011 through the third quarter of 2018. The use of PD-L1 expression testing increased from 7.0% in 2015 to 70.6% in 2017 (p , 0.01). Among those receiving testing, the proportion of patients receiving CoDx increased from 29.9% in 2015 to 73.0% in 2017 with corresponding reductions in CyDx and LDTs. PD-L1 expression testing was associated with use of PD1-axis therapy in the first-line (OR = 2.92, 95% CI 2.59-3.30). Among 4,942 treated patients diagnosed after Oct 2016, those with $50% staining more frequently received first line PD-1 axis therapy (82.9%) than those with intermediate (35.5%) or low (25.8%) positive staining; conversely, patients with $50% were less likely to receive chemotherapy alone or combination with PD-1 axis therapy. Conclusions: PD-L1 expression testing was rapidly adopted following FDA approval of companion diagnostic testing for aNSCLC. Although the results of PD-L1 expression testing inform the choice of first-line therapy, a substantial proportion of patients are not tested prior to first line treatment.

9060 Poster Session (Board #383), Sun, 8:00 AM-11:00 AM

Therapeutic and prognostic impacts of specific gene alterations for squamous cell lung cancer: A result of nationwide genome screening in Japan (LC-SCRUM-Japan).

Terufumi Kato, Shingo Matsumoto, Shigeki Umemura, Kiyotaka Yoh, Kazumi Nishino, Haruko Daga, Yukari Tsubata, Noriyuki Ebi, Shingo Miyamoto, Masato Shingyoji, Shigeki Hashimoto, Taku Nakagawa, Satoshi Hara, Koichi Goto; Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan; Shimane University Hospital, Izumo, Japan; Department of Respiratory Med- icine, Iizuka Hospital, Iizuka, Japan; Japanese Red Cross Medical Center, Tokyo, Japan; Division of Respirology, Chiba Cancer Center, Chiba, Japan; Department of Respiratory Medicine, Ikeda Municipal Hospital, Osaka, Japan; Department of Thoracic Surgery, Omagari Kosei Medical Center, Daisen, Japan; Respiratory Division, Department of Internal Medicine, Itami City Hospital, Itami, Japan

Background: Various gene alterations occur during the development of squamous cell lung cancer (SqLC), but specific gene alterations for SqLC and their clinical significance remain unknown. Methods: In a nationwide genome screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer patients for genetic alterations using a next-generation sequencing (NGS) system, Oncomine Comprehensive Assay, and have established a large-scale clinico-genomic database. Results: Since February 2013 to December 2018, a total of 6692 lung cancer patients (686 SqLCs, 5360 non- squamous non-small cell lung cancers [Non-sq] and 646 small cell lung cancers [SCLCs]) had been enrolled in the LC-SCRUM-Japan. The success rate of the NGS assay was 91%. Of 639 SqLCs analyzed, 274 (48%) had potentially targetable gene alterations, including 77 NFE2L2 (encoding NRF2) mut, 50 PIK3CA mut, 46 FGFR1 amp, 40 EGFRmut/amp, 36 PTEN mut, 23 KRAS mut, 6 AKT1 mut, 6 MET ex14skip, 5 ALK fusions, 2 FGFR3 fusions. Among the alterations detected, NFE2L2 mut and FGFR1 amp were significantly frequent in SqLC than Non-sq or SCLC (NFE2L2, 12.1% vs. 1.0% vs. 1.3%; p , 0.001, and FGFR1, 7.2% vs. 1.1% vs. 3.4%; p , 0.001). In advanced SqLC patients who received platinum-containing chemotherapies, the median progression-free survival (mPFS) was significantly shorter in NFE2L2-mutated patients (NRF2-type) than NFE2L2/FGFR1-negative patients (nonNF-type) (3.8 [95%CI, 2.9-5.1] vs. 4.5 [95%CI, 3.8-5.4] months, p = 0.03), and similarly, the mPFS of FGFR1-amplified patients (FGFR1-type) (3.5 months [95%CI, 1.5-4.9]) tended to be shorter than that of nonNF-type (p = 0.07), although the response rates were equivalent among the three types. NRF2-type also showed shorter overall survival (OS) than nonNF-type (median OS, 10.4 [95%CI, 6.9- 22.3] vs. 16.6 [95%CI, 13.6-21.7] months, p = 0.10). Therapeutic efficacy of nivolumab or pembrolizumab was not different among these types in the current follow-up data. Conclusions: Our large scale genome screening identified specific gene alterations for SqLC and the alterations were associated with a less efficacy of chemotherapy and worse prognosis, suggesting the need for the development of genotype-directed therapeutic strategy for SqLC patients.

9061 Poster Session (Board #384), Sun, 8:00 AM-11:00 AM

Anti-PD-1/PD-L1 plus chemotherapy versus chemotherapy alone in first-line treatment for patients with metastatic NSCLC that were PD-L1 negative or less than 1%.

Thierry Landre, Gaetan Des Guetz, Kader Chouahnia, Cherifa Taleb, Alain Vergnenegre, Christos Chouaid; Hopitalˆ René Muret, HUPSSD, UCOG 93 (APHP), Sevran, France; Service d’Oncologie Medicale, ´ CHU Limoges, Limoges, France; CHU Avicenne, Bobigny, France; Hopitalˆ René Muret, HUPSSD, Geriatric Oncology Unit (APHP), Sevran, France; Unite d’Oncologie Thoracique, Limoges, France; Centre Hospital- ier Intercommunal (CHI) Creteil, Créteil, France

Background: Clinical efficacy of single agent anti-PD-1/PD-L1 in patients with Non-Small-Cell-Lung- Cancer (NSCLC) that were PD-L1 negative or , 1% is controversial. Recent studies have evaluated the combination of anti-PD-1/PD-L1 to chemotherapy (CT) for this population in the first line setting. Methods: We performed a meta-analysis (MA) of randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with undetectable PD-L1 expression or , 1%. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. Results: Four studies evaluated atezolizumab + CT (IMpower 130,131,132 and 150), three studies pembrolizumab + CT (Keynote 021, 189 and 407) and one study evaluated nivolumab + CT (CheckMate 227). The eight eligible studies included 2037 patients (1246 with PD-L1 negative and 791 with PD-L1 expression , 1%). Most of the patients were men and smokers, with a median age of 64 years. There were 1423 Non-squamous (69.8 %) and 614 Squamous tumors (30%). The combination (PD-1/PD- L1 inhibitor + CT) was significantly associated with improvement of OS (hazards ratio [HR], 0.75; 95% CI 0.63–0.89; p , 0.0001), PFS (HR, 0.72; 95% CI 0.65–0.80; p , 0.0001) and ORR (relative ratio [RR], 2.59; 95% CI 1.46–4.60; p , 0.0001). Moreover, median duration of response (DOR) was statistically longer with combination (8.1 months versus 4.9; p , 0.0008). Conclusions: For patients with untreated NSCLC with low ( , 1%) or undetectable PD-L1 expression, the anti-PD-1/PD-L1 combination with chemotherapy, compared with chemotherapy alone, is associated with significantly improved OS, PFS, and ORR.

9062 Poster Session (Board #385), Sun, 8:00 AM-11:00 AM

Real-world utilization of EGFR TKI therapies and treatment outcomes in patients with advanced EGFR-sensitizing mutation-positive NSCLC.

Gregory J. Riely, Christine Marie Lovly, Carlo GM Messina, Stefanie Bienert, Kimberly Alexander, William Pao, Shrujal Baxi, Robert Charles Doebele; Memorial Sloan Kettering Cancer Center, New York, NY; Vanderbilt-Ingram Cancer Center, Nashville, TN; F. Hoffmann-La Roche AG, Basel, Switzerland; F. Hoffmann-La Roche AG, Pleasanton, CA; Flatiron Health, New York, NY; University of Colorado Cancer Center, Aurora, CO

Background: In patients with advanced non-small cell lung cancer (aNSCLC) with non-squamous histology, treatment guidelines recommend molecular testing for EGFR mutations and first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) in those with sensitizing EGFR mutations. We investigated real- world treatment regimens and outcomes in aNSCLC patients with EGFR-sensitizing mutations from US community oncology clinics. Methods: The Flatiron Health electronic health record-derived database contains deidentified data from . 55,000 aNSCLC patients. Our retrospective cohort included patients diagnosed from Jan-2014 to Mar-2018 who had a positive EGFR test prior to initiation of 1L therapy. Patients with EGFR T790M mutations were excluded. Demographics, clinical characteristics, treatment and survival outcomes were compared between patients receiving 1L EGFR TKIs vs other 1L anti-cancer therapies. Minimum follow-up after initiation of 1L therapy was 4 months. Results: 23,321 patients had non-squamous or NOS histology. Of those, 1107 had sensitizing EGFR mutations detected prior to 1L treatment (median age 70 years, 67% women, 58% Caucasian). 910 (82%) received EGFR TKIs and 197 (18%) received other 1L therapies (including chemotherapy, immunotherapy and anti-VEGF therapy). 2L treatment data were available for 519 patients: 317 (61%) received EGFR TKIs and 202 (39%) received other therapies. In the 1L setting, median treatment duration was longer for patients receiving EGFR TKIs than for those receiving other therapies (8 vs. 4 months, unadjusted HR 1.70; 95% CI 1.45–1.99; p , 0.0001). Median overall survival (OS) was not affected by the type of 1L treatment (21 months vs 20 months, p = 0.55). Conclusions: Real-world examination of treatment patterns and outcomes in US community oncology clinics showed that nearly 20% of aNSCLC patients with non- squamous or NOS histology and EGFR sensitizing mutations prior to initiation of 1L therapy did not receive 1L EGFR TKIs. In those who did, guideline-concordant use of EGFR TKIs was associated with longer 1L treatment duration but no improvement in OS, supporting the generalizability of results from randomized clinical trials.

9063 Poster Session (Board #386), Sun, 8:00 AM-11:00 AM

Characterization of 648 non-small cell lung cancer (NSCLC) cases with 28 unique HER2 exon 20 insertions.

Sai-Hong Ignatius Ou, Russell Madison, Jacqulyne Ponville Robichaux, Jeffrey S. Ross, Vincent A. Miller, Siraj Mahamed Ali, Alexa Betzig Schrock, John Heymach; Chao Family Comprehensive Cancer Center, University of California, Orange, CA; Foundation Medicine, Inc., Cambridge, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; SUNY Upstate Medical University, Syracuse, NY

Background: EGFR and HER2 (ERBB2) exon 20 insertion (ex20ins) mutations represent a subset of driver alterations in NSCLC, which historically have largely not responded to available targeted therapies. Recently, inhibitors specifically targeting ex20ins have shown efficacy in the clinic. Previous studies have described the landscape of EGFR ex20ins in NSCLC (PMID: 29981927), but similar descriptions of HER2 ex20ins are lacking. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on 39,644 tissue and 4,062 blood-based circulating tumor DNA (ctDNA) samples from 43,706 unique patients with advanced NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA for tissue samples and reported as mutations/Mb. Results: HER2 ex20ins were detected in 1.5% (648/43,706) of NSCLC cases (614 tissue and 34 ctDNA). HER2 ex20ins represented 35% (648/1,845) of HER2-altered NSCLCs overall, while 46% (843/1,845) of cases had HER2 amplification ($5 copies), 17% (320/1,845) had a non-ex20ins HER2 short variant (SV; most commonly S310F in 84 cases and V659E in 29 cases), and 1.8% (34/1,845) had HER2 amplification + SV. There were 28 unique ex20ins including most commonly A775_G776insYVMA (69%, 450/648), G776 . VC (12%, 76/648) and P780_Y781insGSP (8.6%, 56/648). Cases with HER2 ex20ins were significantly enriched for adenocarcinoma histology (89% vs 66%), female gender (64% vs 51%) and low TMB (95% vs 65% TMB , 10 mut/Mb) compared to HER2 wild-type cases (all p , 0.0001). HER2 amplification (7 median copies, range 5-39) co-occurred in 16% (103/648) of HER2 ex20ins cases. Co-occurrence of other known NSCLC drivers in HER2 ex20ins cases was rare (0.8%, 5/648). In contrast, non-HER2ex20ins cases with HER2 amplification or other HER2 SVs each had co-occurring known driver alterations in ~30% of cases. There was no significant difference in histology, gender, age, HER2 co-amplification or TMB in cases with YVMA vs non-YVMA ex20ins. Conclusions: HER2 ex20ins are found in 1.5% of NSCLCs and are generally mutually exclusive of other known drivers. Detection of these alterations may be critical to identify matched targeted therapy options for this subset of patients.

9065 Poster Session (Board #388), Sun, 8:00 AM-11:00 AM

Prognostic significance of radiologic features of pneumonitis induced by anti-PD-1 therapy.

Satoshi Watanabe, Takeshi Ota, Masachika Hayashi, Hiroyuki Ishikawa, Takao Miyabayashi, Masaki Terada, Kazuhiro Sato, Takashi Ishida, Hiroshi Tanaka, Akira Iwashima, Satoshi Shoji, Koichiro Nozaki, Kosuke Ichikawa, Rie Kondo, Hirohisa Yoshizawa, Toshiaki Kikuchi; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Shibata Hospital, Shibata-City, Japan; Niigata University Graduate School of Medical and Dental Sciences, Niigata-City, Japan; Niigata University Medical and Dental Hospital, Niigata-City, Japan; Department of Respiratory Medicine, Niigata City General Hospital, Niigata, Japan; Saiseikai Niigata Daini Hospital, Niigata, Japan; Nagaoka Red Cross Hospital, Nagaoka, Japan; Niigata Prefectural Central Hospital, Joetsu, Japan; Department of Respiratory Medicine, Niigata Cancer Center Hospital, Niigata, Japan; Nagaoka Chuo General Hospital, Nagaoka, Japan; Niigata Medical Center, Niigata-City, Japan

Background: Anti-PD-1 therapy is now a standard treatment for patients with NSCLCs. Pneumonitis induced by immune-check point inhibitors is potentially fatal; however, some studies have shown that antitumor effects were enhanced in patients with pneumonitis. Although several radiologic patterns of pneumonitis induced by anti-PD-1 therapy have been reported, the association between radiologic features and clinical outcomes, especially enhancement of antitumor effects remains unclear. Methods: We retrospectively evaluated data of NSCLC patients treated in 1st to 3rd line with anti- PD-1 antibodies (nivolumab or pembrolizumab) at Niigata Lung Cancer Treatment Group. Pneumonitis was diagnosed by the treating investigators. The chest CT scans of patients with pneumonitis were independently reviewed by one radiologist and two pulmonologists to classify pneumonitis into 5 subtypes: cryptogenic organizing pneumonia-like (COP), ground glass opacities (GGO), interstitial, hypersensitivity and pneumonitis not otherwise specified (NOS). Results: Of 231 patients who received anti-PD-1 antibodies, pneumonitis developed in 33 patients (14.3%) at 7 institutions between January 2016 to October 2017. Of 33 patients with pneumonitis, the median age was 66 (range 45 to 82 years), 7 were female, 25 received nivolumab, and 8 received pembrolizumab. Sixteen patients were classified as GGO, 16 patients had COP-like appearance and one patient had NOS. The median survival time was significantly longer among patients with COP than among those with GGO (not reached vs. 7.8 months; HR 0.29, 95% CI 0.09-0.81; p = 0.0071). Pneumonitis improved in 94% (31 of 33) of cases, and one patient died from pneumonitis. The overall response ratio (CR+PR) was 44% in patients with COP and 31% in patients with GGO (p = 0.47). There was no statistical difference in OS between patients with systemic corticosteroid therapy for pneumonitis and those without (not reached vs. 14.8 months; HR 1.4, 95% CI 0.52-4.1; p = 0.51). Conclusions: Patients with pneumonitis classified as COP had significantly longer survival time than those with pneumonitis classified as GGO. Radiologic features of pneumonitis may reflect clinical outcomes after anti-PD-1 therapy.

9066 Poster Session (Board #389), Sun, 8:00 AM-11:00 AM

Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase II clinical trial–Updated report on progression-free and overall survival.

Sebastian Yves Friedrich Michels, Jeremy Franklin, Bartomeu Massuti, Martin Sebastian, Hans-Ulrich Schildhaus, Enriqueta Felip, Christian Grohe, Delvys Rodriguez-Abreu, Helge Bischoff, Enric Carcereny, Jesus ´ Corral, Anne-Marie C. Dingemans, Amelia Insa, Martin Reck, Sacha Rothschild, Egbert F. Smit, Mariano Provencio, Reinhard Buttner, ¨ Rafael Rosell, Juergen Wolf; Lung Cancer Group Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Dept. for Internal Medicine, Cologne, Germany; Institute of Medical Statistics and Computational Biology, University Hospital Cologne, Cologne, Germany; Alicante University Hospital ISABIAL, Alicante, Spain; University Hospital of Frankfurt, Frankfurt, Germany; Institute of Pathology, University Hospital Essen, Essen, Germany; Vall d´ Hebron University Hospital, Barcelona, Spain; Department for Pneumology, Berlin Evangelical Lung Clinic, Berlin, Germany; Hospital Universitario Insular de Gran Canaria, Las Palmas De Gran Canaria, Spain; Thoraxonkologie, Thoraxklinik, Heidelberg, Germany; Medical Oncology Department. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, B.ARGO GROUP Badalona Applied Research Group in Oncology, Badalona, Spain; Department of Oncology. Clı´nica Universidad de Navarra, Pamplona, Spain; Maastricht University Medical Center, Maastricht, Netherlands; Hospital Clinico Universitario de Valencia, Valencia, Spain; LungenClinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; Medical Oncology, Department of Internal Medicine, University Hospital Basel, Basel, Switzerland; Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands; Hospital Universitario Puerta de Hierro, Majadahonda, Spain; University of Cologne, Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, Cologne, Germany; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain and Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain and Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, Badalona, Barcelona, Spain

Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: $18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator- assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. . = 2), brain metastases (yes vs. no) or CD74-rearrangement (CD74-ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.

9067 Poster Session (Board #390), Sun, 8:00 AM-11:00 AM

Efficacy of platinum-pemetrexed combination chemotherapy in ALK+ non-small cell lung cancer refractory to second-generation ALK TKIs.

Jessica Jiyeong Lin, Adam Jacob Schoenfeld, Viola Weijia Zhu, Beow Y. Yeap, Emily Chin, Marguerite Rooney, Andrew J. Plodkowski, Subba Digumarthy, Ibiayi Dagogo-Jack, Justin F. Gainor, Sai-Hong Ignatius Ou, Gregory J. Riely, Alice Tsang Shaw; Massachusetts General Hospital, Harvard Medical School, Boston, MA; MSKCC, New York, NY; Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Massachusetts General Hospital, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Chao Family Comprehensive Cancer Center, University of California, Orange, CA; Massachusetts General Hospital/Harvard Medical School, Boston, MA

Background: Second-generation (gen) ALK tyrosine kinase inhibitors (TKIs) are standard first- and second-line therapies in patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). After progression on second-gen TKI(s), standard options include platinum (PT)-based chemotherapy (chemo) or the third-gen ALK TKI lorlatinib. The efficacy of PT-based chemo is established in treatment-naive pts but is undefined in pts who have failed prior ALK TKIs. Here we evaluate the efficacy of PT/pemetrexed (pem)-based chemo in pts with ALK+ NSCLC refractory to second-gen TKIs. Methods: A retrospective study was performed at three institutions. Pts were eligible if they had advanced ALK+ NSCLC refractory to $1 second-gen TKI, and received PT-pem-based chemo. Medical records and imaging were reviewed to determine outcomes. Results: Among 55 eligible pts, chemo regimens included: PT/pem (31/55, 56%), PT/pem/bevacizumab (bev) (6/55, 11%), PT/pem/PD-1 inhibitor (3/55, 5%), PT/pem with ALK TKI (8/55, 15%), PT/pem/bev with TKI (6/55, 11%), and PT/ pem/PD-1 inhibitor with TKI (1/55, 2%). Pts had received one (6/55, 11%), two (38/55, 69%), or more (11/55, 20%) prior TKIs. Six pts (11%) previously received adjuvant or neoadjuvant chemo. Radio- graphic data for response evaluation was available for 39 pts. Among 36 pts with measurable baseline disease, confirmed ORR was 31% (11/36; 95% CI, 16-48%); 13 (36%) had stable disease. The median duration of response was 5.4 months (95% CI, 1.5-7.1 months). The median progression-free survival (PFS) for the entire cohort was 4.0 months (95% CI, 2.8-4.6 months). Chemo (PT/pem +/- bev or PD-1 inhibitor) plus ALK TKI (n = 15) was associated with a significant increase in PFS compared to chemo without TKI (n = 40) (median PFS 6.8 vs 3.2 months; HR 0.306; p = 0.002). Similarly, PT/pem plus ALK TKI (n = 8) was associated with increased PFS compared to PT/pem without TKI (n = 31) (median PFS 6.8 vs 2.9 months; HR 0.358; p = 0.036). Conclusions: The efficacy of PT-pem-based chemo is limited after failure of second-gen ALK TKIs but may be higher in pts who receive chemo plus ALK TKI, suggesting a potential role for ongoing ALK inhibition. The modest benefit of PT-pem-based chemo highlights the need for other therapeutic strategies for pts refractory to second-gen TKIs.

9068 Poster Session (Board #391), Sun, 8:00 AM-11:00 AM

Longitudinal analysis of plasma ALK mutations during treatment with next-generation ALK inhibitors.

Ibiayi Dagogo-Jack, Marguerite Rooney, Rebecca Nagy, Subba Digumarthy, Emily Chin, Jennifer Ackil, Justin F. Gainor, Jessica Jiyeong Lin, Richard B. Lanman, Alice Tsang Shaw; Massachusetts General Hospital, Boston, MA; Guardant Health, Inc., Redwood City, CA; Massachusetts General Hospital, Harvard Medical School, Boston, MA

Background: Next-generation ALK tyrosine kinase inhibitors (TKIs) are the cornerstone of management of ALK-positive (ALK+) lung cancer. Each ALK TKI has a unique spectrum of activity against distinct ALK kinase domain mutations (muts). Plasma genotyping is a promising strategy for identifying ALK muts at relapse on ALK TKIs. Methods: To detect ALK muts, we performed next-generation sequencing (Guardant360) of circulating tumor DNA from patients (pts) with ALK+ lung cancer relapsing on a second-generation (2nd-gen) ALK TKI (n = 65) or the third-generation (3rd-gen) TKI lorlatinib (n = 26). Results: Among 65 pts progressing on a 2nd-gen TKI, 49 (75%) had only received one 2nd-gen ALK TKI prior to analysis: n = 42 alectinib, n = 3 each brigatinib/ceritinib, and n = 1 ensartinib. We detected an ALK mut in 42/65 (65%) specimens at relapse, among which ALK G1202R (32%) and I1171X (23%) were the most common. Sixteen (25%) pts had $2 ALK muts at progression on a 2nd-gen TKI. Among 26 pts progressing on lorlatinib (all of whom had previously relapsed on a 2nd-gen ALK TKI), we identified ALK muts in 20 (76%), including 14 (54%) with $2 ALK muts. Detection of $2 ALK muts was more common at relapse on lorlatinib compared to a 2nd-gen TKI (p = 0.013). To assess the evolution of ALK muts during treatment with different TKIs, we analyzed serial plasma specimens from 20 pts treated with sequential 2nd-gen/2nd-gen or 2nd-gen/3rd-gen TKIs. Among six pts who received alectinib followed by brigatinib, repeat plasma analysis at brigatinib progression revealed persistence of pre-brigatinib ALK muts in two pts (one L1196M and one G1202R), expansion of G1202R in one pt, and acquisition of new ALK muts in three pts. Among 14 pts who received a 2nd-gen TKI followed by lorlatinib, 11 had persistence of pre-lorlatinib ALK muts and 8 acquired $1 additional ALK muts at lorlatinib progression. The most frequently acquired ALK mut was D1203N in four of eight cases. Conclusions: ALK resistance muts are prevalent at relapse on next-generation ALK TKIs and increase with each successive generation of ALK TKIs. These findings suggest that sequential therapy with increasingly potent ALK TKIs may select for compound ALK muts and/or fuel tumor heterogeneity.

9069 Poster Session (Board #392), Sun, 8:00 AM-11:00 AM

Clinical outcomes of EGFR+ NSCLC pts treated with immune checkpoint inhibitors (ICI).

Zofia Piotrowska, Rosemary G. Cobb, Mandeep Banwait, Nicolas Marcoux, Meghan Mooradian, Ibiayi Dagogo-Jack, Jessica Jiyeong Lin, Rebecca Suk Heist, Alice Tsang Shaw, Justin F. Gainor, Lecia V. Sequist; Massachusetts General Hospital Cancer Center, Boston, MA; Massachusetts General Hospital, Boston, MA; Hotel- Dieu De Quebec, Quebec, QC, Canada; MGH Cancer Center, Boston, MA; Massachusetts General Hospital, Harvard Medical School, Boston, MA; Massachusetts General Hospital/Harvard Medical School, Boston, MA; Massachusetts General Hospital Cancer Center/ Harvard Medical School, Boston, MA

Background: ICIs have limited efficacy in EGFR+ NSCLC with ORR ~10% if PDL1 . 25% in ATLANTIC, yet ICIs are often used in later lines of therapy as pts and providers feel there may be little risk. The impacts of ICI in this setting are poorly understood. We describe our institutional experience of ICI use in EGFR+ NSCLC. Methods: MGH pts with advanced EGFR+ NSCLC treated with ICI (any line) were retrospectively reviewed for demographics, PDL1, treatment duration and patient outcomes. Disease flare was defined as hospital/hospice admission due to progression or death (Chaft CCR 2011) within 30d of ICI. Results: 40 pts with EGFR+ NSCLC (22 del19, 11 L858R, 5 ins20, 2 other) received ICI between 7/2012-12/2018. 13 were on a clinical trial. 4 had SCLC transformation. Median # of prior therapies = 3 (range, 0-8). Of 16 with PDL1 quantified, 8 had PDL1 . 25%. ICI regimens were: nivolumab (nivo; n = 16), pembrolizumab (pembro; 9), atezolizumab (atezo; 3), ipilimumab/nivo (7), carboplatin/pemetrexed (pem)/pembro (3), pem/pembro (1), paclitaxel/atezo (1). 18 pts stopped TKI #21d prior to ICI start. Median duration of treatment (DOT) was 25 days (range, 1-1482). DOT was . 1 yr for 2 pts (5%), treated with 1st-line nivo/erlotinib (erlo) and 3rd-line nivo. All 8 pts with PDL1 . 25% had DOT , 2 mos. Disease flare within 30d of ICI occurred in 16/40 (40%) overall, 8/18 (44%) who stopped TKI #21d of ICI start, and 14/26 (54%) who received ICI in 4thline or later. 8 pts had concurrent TKIs (4 erlo/nivo, 2 erlo/pembro, 1 erlo/atezo, 1 osimertinib (osi)/nivo); 3/8 discontinued ICI for toxicity (all 3 treated first-line). 5 pts received osi immediately post-ICI. There was no pneumonitis on osi post-ICI; 1 pt developed gr3 LFTs and gr4 hypoNa. Conclusions: In this real world cohort of EGFR+ NSCLC, clinical benefit from ICI (assessed by DOT) was rare, including pts with high PDL1. 5% had durable benefit (both pts received ICI in earlier lines of therapy). A previously underappreciated negative outcome of ICI is that admission to hospital, hospice or death within 30d of ICI occur in up to 54% pts. This may be related to disease flare or hyperprogression and suggests that use of ICI in heavily pretreated EGFR+ NSCLC may negatively impact outcomes at end-of-life and should be used with caution.

9070 Poster Session (Board #393), Sun, 8:00 AM-11:00 AM

Time-to-treatment discontinuation (TTD) and real-world progression-free survival (rwPFS) as endpoints for comparative efficacy analysis between entrectinib trial and crizotinib real-world ROS1 fusion-positive (ROS1+) NSCLC patients.

Robert Charles Doebele, Laura Perez, Huong Trinh, Michael Martinec, Reynaldo Martina, Todd Riehl, Matthew Krebs, Neal J. Meropol, William Bruce Wong, Gracy Crane; University of Colorado, Denver, CO; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Genentech, South San Francisco, CA; University of Liverpool, Liverpool, United Kingdom; Division of Cancer Sciences, The University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom; Flatiron Health, New York, NY; F. Hoffmann-La Roche Ltd, Welwyn Garden City, United Kingdom

Background: Entrectinib is an oral tyrosine kinase inhibitor for ROS1+ NSCLC. Three phase 1/2 single-arm studies showed entrectinib efficacy in this population (Doebele WCLC 2018). Due to the rarity of ROS1+ pts generating direct comparative evidence in prospective randomized trials is difficult. We identified a retrospective real-world cohort of ROS1+ NSCLC pts from electronic health records (EHR), to compare crizotinib, the current standard of care, to entrectinib as reported in clinical trials. Methods: Crizotinib- treated pts with advanced ROS1+ NSCLC diagnosed 1 Jan 2011 to 30 Jun 2018, were identified with technology-enabled abstraction in the Flatiron Health EHR-derived database ( . 2.1 million cancer pts from US oncology practice). Entrectinib trial inclusion/exclusion criteria were applied to match the crizotinib cohort as closely as possible. Primary endpoint: TTD, adapted from Gong (ASCO 2018); rwPFS (physician/scan report) and OS were secondary outcomes. Time-to-event analyses used Kaplan-Meier survival curves and Cox proportional hazard models on propensity score weighted populations; age, gender, race/ethnicity, smoking status, brain metastasis and previous lines of therapy were prognostic factors. Results: We analyzed 53 entrectinib and 69 crizotinib ROS1+ NSCLC pts. Median weighted TTD: entrectinib, 14.6 mo (95% CI: 8.3–23.8); crizotinib, 8.8 mo (95% CI: 8.2–9.9). When rwPFS from crizotinib was compared to trial PFS, entrectinib had longer PFS vs crizotinib (weighted HR: 0.44; 95% CI: 0.27–0.74). Median OS with entrectinib was not reached (median follow-up: 15.5 mo); weighted median OS with crizotinib was 18.5 mo (95% CI: 15.1–19.9). Findings were consistent across multiple sensitivity analyses. Conclusions: Entrectinib was associated with longer TTD and PFS in ROS1+NSCLC pts vs a matched real-world crizotinib population. Control populations derived from real-world cohorts can supplement evidence from clinical trials in settings where new standards of care are needed, but where only limited data are available and randomization is not feasible.

9071 Poster Session (Board #394), Sun, 8:00 AM-11:00 AM

Whole exome sequencing (WES) of non-small cell lung cancer (NSCLC) for tumor mutational burden (TMB) analysis and long-term benefit to immune checkpoint inhibitors (ICIs).

Enriqueta Felip, Alejandro Navarro, Ana Callejo, Alex Martinez Marti, Susana Cedres, Nuria Pardo, Javier Ros, Juan David Assaf, Anna Pedrola, Cristina Viaplana, Irene Sansano, Jose Jimenez, Paolo Nuciforo, Miriam Sanso, ´ Rodrigo Dienstmann, Ramon Amat, Francesco M Mancuso, Ana Vivancos; Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barce- lona, Spain; Vall d’Hebron University Hospital/Vall d´Hebron Institute Oncolgy (VHIO), Barcelona, Spain; Vall d´Hebron University Hospital /Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall d’Hebron University Hospital /Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain; Vall D´ Hebron University Hospital, Barcelona, Spain; Vall d´Hebron University Hopsital, Barcelona, Spain; Oncology Data Science Group, Vall D’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Oncology Data Science (ODysSey) Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain; Vall d’Hebron University Hospital, Barcelona, Spain; Molecular Pathology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Cancer Genomics Group, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain; Oncology Data Science Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Thoracic Cancer Group, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain; Cancer Genomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Cancer Genomics Lab and Molecular Pathology Lab, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

Background: ICIs have significantly changed the therapeutic landscape of advanced NSCLC. As such, characterizing predictive markers of long-term clinical benefit is a critical objective. TMB quantification using targeted gene panels associates with long-term response to ICIs in NSCLC patients (Rizvi H ASCO 18). Although TMB quantified by targeted NGS correlates with that of WES, caution may be needed when using smaller panels. Methods: Here we analyzed WES of tumors and matched normal tissue from 67 NSCLC patients including 42 treated with ICIs. We correlated TMB with clinico-pathological features and outcomes. TMB was categorized as high vs. low according to the upper quartile of cohort distribution. Results: The median TMB was 2.68 non-synonymous variants (nSNVs)/Mb, ranging from 0 to 15.6 nSNVs/Mb, with upper quartile at 5.42 nSNVs/Mb. TMB was higher for smoker/current smoker (median 3.51) compared to never smokers (median 0.94, p = 0.0048) but no differences were seen in elderly ( . 70 years) vs. young patients or across histologies (squamous, adeno and other) and stages at diagnosis. In patients treated with ICIs, median TMB was 5.44 for those achieving complete response, 3.87 for patients with partial response and 2.42 for patients with progressive disease (PD) (p = 0.04). Moreover, improved clinical outcomes were associated with higher TMB (Table). In patients treated with ICIs, TMB as continuous variable had an impact on progression free survival (PFS) (p = 0.03). Median PFS was 22.3 months (mo) (14-not reached) for those with high TMB and 6.4 mo (3-16) for those with low TMB (HR 0.34, 0.13-0.9, p = 0.03). Median overall survival was not reached for those patients with high TMB and 32 mo (22-43) for those with low TMB (HR 0.29, 0.1-0.86, p = 0.02). Conclusions: High TMB correlates with long-term ICI benefit in NSCLC patients. Mutations in individual genes potentially linked to long-term benefit or resistance to ICIs will be presented.

TMB in the 4 subgroups based on benefit to ICIs. < 6mo 6-18 mo > 18 mo and PD > 2 years ongoing ICI benefit N=17 N=9 N=8 N = 8 p value Median TMB 1.92 1.61 4.58 6.08 0.04 High TMB 5.8% 11.1% 25% 37.5% 0.01

9072 Poster Session (Board #395), Sun, 8:00 AM-11:00 AM

First-in-human phase 1 study of the antibody-drug conjugate (ADC) SAR408701 in advanced solid tumors: Dose-expansion cohort of patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC).

Anas Gazzah, Sophie Cousin, Valentina Boni, Charles Ricordel, Tae Min Kim, Jin-Soo Kim, Carole Helissey, Itziar Gardeazabal, Mustapha Chadjaa, Aurore Allard, Semra Yoruk, Fabrice Barlesi; Department of Drug Development (DITEP), Gustave Roussy, Villejuif Cedex, France; Institut Bergoni´e, Bordeaux, France; START Madrid-Centro, Madrid, Spain; Service de Pneumologie, CHU Rennes, Rennes, France; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea; Clinical Research Unit, Department of medical oncology, HIA Begin, ´ Saint-Mande, ´ Paris, France; Vall D’Hebron Institute of Oncology, Barcelona, Spain; Sanofi R&D, Oncology, Vitry-Sur-Seine, France; Sanofi, Chilly-Mazarin, France; Sanofi, Istanbul, Turkey; Aix Marseille University, INSERM, CNRS, CRCM, APHM, CEPCM CLIP2, Marseille, France

Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a cell-surface glycoprotein highly expressed in several tumor types. This Phase 1, open-label, dose-escalation, dose- expansion study (NCT02187848) investigated SAR408701, a DM4 conjugated ADC targeting CEACAM5, in pts with advanced solid tumors. During dose escalation, maximum tolerated dose (MTD) of SAR408701 was 100 mg/m2 IV once every 2 weeks in 14-day cycles. Interim analysis of an ongoing expansion cohort in pts with NSQ NSCLC with CEACAM5 expression in $ 50% of the tumor cell population is reported. Methods: SAR408701 was administered at MTD. Primary endpoint: overall response rate (ORR; expansion phase). Secondary endpoints include safety and pharmacokinetics (PK). Tumor assessments were performed every 4 cycles (8 weeks). Results: As of Aug 2, 2018, 22 pts with NSQ NSCLC (21 adenocarcinoma; 1 not yet reported) received SAR408701 at MTD. Median age: 60 years; male: 72.7%; ECOG PS (n = 21): 0 = 38.1%, 1 = 61.9%. Median number of prior anticancer therapies for advanced disease was 3; 66.7% (14/21) received $ 3 lines; 59.1% had prior anti-tubulin- based treatments. Pts received a median of 6.5 cycles. 15 pts discontinued due to progressive disease and 1 due to an adverse event (AE; peripheral neuropathy); 6 pts remain on study. ORR was estimated at 22.7% (5/22 pts; 90% CI 11.5–39.9); 40.9% had stable disease. Most frequently occurring all-grade treatment-emergent AEs (TEAEs) were corneal events (40.9%; including keratitis 22.7% [1 Grade 3] and keratopathy 18.2%), dyspnea (31.8%; 5 Grade $ 3), asthenic conditions (31.8%) and diarrhea (27.3%). 6 pts had $ 1 dose modification due to a TEAE. PK analysis was performed in 14 pts at Cycle 1; mean Cmax, AUC, clearance and t1/2z were 53.1 mg/mL, 297 mg.day/mL, 0.685 L/day and 6.19 days, respectively. Conclusions: In pts with advanced NSQ NSCLC and CEACAM5 expression in $ 50% of tumor cells, SAR408701 had a favorable safety profile. Interim analysis of 22 pts achieved the predefined boundary for efficacy ($ 4 of 30 pts). These data support further development in NSQ NSCLC. Funding: Sanofi Clinical trial information: NCT02187848.

9073 Poster Session (Board #396), Sun, 8:00 AM-11:00 AM

Phase I/Ib study of pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Updated results.

Andreas Nicholas Saltos, Tawee Tanvetyanon, Eric B. Haura, Ben C. Creelan, Scott Joseph Antonia, Michael Rahman Shafique, Hong Zheng, Wenjie Dai, Zhihua Chen, James Joseph Saller, Nishan Tchekmedyian, Kristen Goas, Ram Thapa, Theresa A. Boyle, Dung-Tsa Chen, Amer A Beg, Jhanelle Elaine Gray; Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL; Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL; Department of Biostatistics/Bioinformatics, Moffitt Cancer Center and Research Institute, Tampa, FL; Department of Pathology, Moffitt Cancer Center and Research Institute, Tampa, FL; Pacific Shores Medical Group, Huntington Beach, CA

Background: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may augment response to immune checkpoint inhibitors (ICI). We report updated results from a phase I/Ib trial testing the combination of oral HDACi vorinostat (V) with PD-1 inhibitor pembrolizumab (P) in mNSCLC. Methods: In phase I, pts with ICI-na¨ıve or ICI-pretreated mNSCLC were treated with P (200mg IV q3 wk) + V (200 or 400 mg PO daily). In phase Ib expansion, pts were required to have progressed on prior ICI treatment. Primary endpoints were safety/tolerability; secondary endpoints included RR, PFS, DOR, and OS. Tissue and blood specimens from pre- and on- treatment were collected for correlative analyses to determine tumor gene expression changes, T cell density and levels of myeloid-derived suppressor cells. Results: Between 3/2016 - 12/2018, Phase I: 13 pts were treated (4 at 200mg, and 9 at 400mg V dose); and Phase Ib: 20 pts were treated. Median age: 68 (range 38-82); Females: 11 (33%); ECOG 1: 31 (94%); and never/former/current smokers: 3/22/8 (9%/67%/24%). PD-L1 expression was , 1% in 8/33 (18%), $1-49% in 7/33 (21%), $ 50% in 9/33 (27%) and unknown in 11/30 (33%). No DLTs or treatment related deaths were observed. The RP2D was P 200mg and V 400mg. Most common any grade AEs was fatigue (11%) and nausea/vomiting (8%). 2 (6%) patients had treatment discontinued due to toxicity. 30 pts are evaluable for response, 6 ICI-na¨ıve and 24 ICI-pretreated. 4 (13%) had PR (2 confirmed), 16 (53%) had SD, and 10 (33%) had PD for a disease control rate of 67%. In the ICI-pretreated Ib cohort, 3 pts (1 confirmed; 2 unconfirmed) had a PR and 10 had SD (8 confirmed). For ICI-pretreated pts, mPFS was 3.2 and mOS was 7.3 months, and 1-year PFS was 17% (4 pts). For ICI-na¨ıve, mPFS was 7.6 months and mOS was 16 months. CD8 T cell presence in tumor stromal regions was associated with benefit to P + V treatment. Conclusions: P + V were well tolerated. The combination demonstrates preliminary antitumor activity despite progression on prior ICI treatment and stromal CD8 T cells may be associated with benefit from P + V treatment. A randomized phase II portion of this study, examining P combined with V vs. placebo in immunotherapy na¨ıve pts, is ongoing. Clinical trial information: NCT02638090.

9074 Poster Session (Board #397), Sun, 8:00 AM-11:00 AM

Nintedanib plus docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): Preliminary efficacy and safety results of the non-interventional study VARGADO.

Christian Grohe, ´ Wolfgang Blau, Wolfgang Gleiber, Siegfried Haas, Harald Mueller-Huesmann, Mathias Schulze, Judith Atz, Rolf Kaiser; ELK, Berlin, Berlin, Germany; University Hospital Giessen, Giessen, Germany; University Hospital Frankfurt, Frankfurt, Germany; Friedrich-Ebert Hospital Neumuenster, Neumuenster, Germany; Bruederkrankenhaus St. Josef, Paderborn, Germany; Praxis Dr. Schulze, Zittau, Germany; Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Background: The treatment landscape of non-targetable advanced NSCLC pts has changed consider- ably following the introduction of ICIs. Data are scarce regarding optimal treatment choice and treatment sequence for pts who progressed on ICI. Methods: VARGADO (NCT02392455) is a prospective non-interventional study investigating the efficacy and tolerability of the oral triple angiokinase inhibitor nintedanibplus docetaxel in pts with advanced lung adenocarcinoma after first-line chemotherapy. The present analysis focused on its clinical activity in pts who received nintedanib plus docetaxel in 3rd line following progression on ICIs in 2nd line. Results: 25 pts whose disease has progressed on previous ICI therapy received subsequently nintedanib plus docetaxel. Median age was 59 years (range: 45 – 76); 17/25 pts (68.0%) were men, 17/25 pts (68.0%) were ECOG PS0/1, and 24/ 25 pts (96.0%) were current or former smokers. 1st line chemotherapy included pemetrexed (18/25 pts, 72.0%), cisplatin (15/25 pts, 60.0%), carboplatin (12/25 pts, 48.0%), bevacizumab (8/25 pts, 32.0%), vinorelbine (4/25 pts, 16.0%), paclitaxel (2/25 pts, 8.0%), and docetaxel (1/25 pts, 4.0%). 2nd line treatment included nivolumab (18/25 pts, 72.0%) and pembrolizumab (6/25 pts, 24.0%). Under nintedanib and docetaxel, 9/20 pts (45.0%) showed a partial response, and 7/20 pts (35.0%) showed stable disease, resulting in a DCR of 80.0% (16/20 pts). Median PFS was 5.5 months (95%CI 2.5 – 8.2). Treatment emergent adverse events (TEAEs) grade $3, serious TEAEs, and TEAEs leading to discontinuation occurred in 15/25 pts (60.0%), 13/25 pts (52.0%), and 9/25 pts (36.0%), respectively. Conclusions: Nintedanib, in combination with docetaxel, showed clinically meaningful efficacy and an acceptable safety profile in advanced lung adenocarcinoma pts following chemotherapy and ICIs. These findings support the use of nintedanib plus docetaxel as a therapeutic option in lung adenocarcinoma pts progressing under ICI therapy. Clinical trial information: NCT02392455.

9075 Poster Session (Board #398), Sun, 8:00 AM-11:00 AM

Phase II study of ABBV-399 (Process II) in patients with C-MET positive stage IV/recurrent lung squamous cell cancer (SCC): LUNG-MAP sub-study S1400K (NCT03574753).

Saiama Naheed Waqar, Mary Weber Redman, Susanne M. Arnold, Fred R. Hirsch, Philip C. Mack, Lawrence Howard Schwartz, David R. Gandara, Tom Stinchcombe, Natasha B. Leighl, Suresh S. Ramalingam, Saloni H. Tanna, Ryan S. Raddin, Katherine Minichiello, Karen Kelly, Jeffrey D. Bradley, Roy S. Herbst, Vassiliki Papadimitrakopoulou; Washington University School of Medicine, St. Louis, MO; SWOG Statistical Center; Fred Hutchinson Cancer Research Center, Seattle, WA; Markey Cancer Center, University of Kentucky, Lexington, KY; University of Colorado Cancer Center, Denver, CO; UC Davis Comprehensive Cancer Center, Sacramento, CA; Columbia University Medical College, New York, NY; University of California, Davis, Sacramento, CA; Duke Cancer Institute, Durham, NC; Princess Margaret Hospital, Toronto, ON, Canada; Winship Cancer Institute, Emory University, Atlanta, GA; Georgia NCORP/Oncology Specialists of Northeast Georgia, Gainsville, GA; Southeast COR NCORP/Bon Secours St. Francis Medical Center Cancer Institute, Midlothian, VA; University of California Davis Comprehensive Cancer Center, Sacramento, CA; Washington University School of Medicine in St. Louis, St. Louis, MO; Yale University School of Medicine, New Haven, CT; University of Texas MD Anderson Cancer Center, Houston, TX

Background: Lung-MAP is a platform trial to assess targeted therapies in SCC. S1400K was designed to evaluate the response to ABBV-399, an antibody-drug conjugate targeting C-MET, in patients with C- Met positive SCC. Methods: Patients with previously treated SCC with c-MET positive tumors (H score $150, Ventana SP44 assay), PS#1, adequate organ function, peripheral neuropathy # grade (G) 2, edema # G2, albumin $3 g/dL, hepatic involvement by tumor , 50%. Patients were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor (ICI) na¨ıve) and cohort 2 (ICI refractory). ABBV-399 2.7 mg/kg was administered intravenously over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), response within cohort, duration of response (DoR), and toxicities associated with ABBV-399. Interim analysis was planned after 20 evaluable patients, with $ 3 responses needed to continue enrollment. Results: Between 2/15/18 and 10/16/2018, 50 patients (17% of patients screened) were assigned to S1400K, 28 patients enrolled (15 in cohort 1 and 13 in cohort 2), 25 were determined eligible, of whom 23 received ABBV-399 and were assessed for adverse events. There were 3 G5 events (2 pneumonitis, both in cohort 2 and 1 bronchopulmonary hemorrhage) and 4 G3 events. S1400K was temporarily closed on 10/16/2018 for interim analysis and safety concerns, and formally closed on 12/ 21/2018. Two responses were reported, both in cohort 1 (1 complete and 1 unconfirmed partial response, CR and UPR) for a response rate of 9% (95% CI: 0-20%). The CR remains on treatment at 4 months and DoR for the UPR was 2.3 months. Ten patients had stable disease and disease control rate was 52% (3-73%). The median OS and PFS were 4.7 and 2.4 months. Conclusions: ABBV-399 failed to meet the pre-specified response needed to justify continuing enrollment. Pneumonitis was an unanticipated toxicity observed in patients with SCC with previous immunotherapy exposure. Clinical trial information: NCT03574753.

9076 Poster Session (Board #399), Sun, 8:00 AM-11:00 AM

Identification and use of treatment (tx) options in patients (pts) with advanced non-small cell lung cancer (aNSCLC) after comprehensive genomic profiling (CGP): A real-world study.

Celine Mascaux, Lukas Bubendorf, Fabrice Barlesi, James W. Clendening, Qing Zhang, Kieran Mace, Adam Gondos, Stefan Foser, Lisa I. Wang, Luis G. Paz-Ares; Aix-Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France; University Hospital Basel, Basel, Switzerland; F. Hoffmann-La Roche Ltd, Mississauga, ON, Canada; Genentech, Inc., South San Francisco, CA; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Hospital Universitario Doce de Octubre, Medical Oncology Department, Madrid, Spain

Background: The number of targeted txs for NSCLC is increasing. By analyzing numerous molecular alterations, CGP may open more targeted tx options than single biomarker testing. Methods: We analyzed a database linking Flatiron Health electronic health record-based clinical and Foundation Medicine, Inc. (FMI) CGP genomic alteration (GA) data in US pts diagnosed from 1/2011 with aNSCLC, primarily from community practices, and with follow-up through 6/2018. We examined the prevalence and distribution of genomic findings, and agreement between tx received and CGP-directed tx options (approved for aNSCLC/other tumors) on the FMI report as a measure of clinical utility. The latter was evaluated in a subset of pts with sufficient tx and follow-up data after FMI testing. Results: Among 5112 FMI-tested pts (first test observed 8/2012), 49% had their FMI test before starting any line of tx, 97% had $ 1 GA with known/likely function (median = 5), and 85% had $ 1 potential tx option (52% had $ 1 option for aNSCLC and 33% had $ 1 for another tumor type only). In 1366 pts evaluable for tx agreement after FMI testing, 572 (42%) received a tx listed on the FMI report and 111 (8%) were enrolled in clinical trials. Pts with a tx option approved for aNSCLC were more likely to have a tx agreeing with an option on the FMI report (67% of 754) v pts with a tx option approved in another tumor type only (8% of 612). Among the 1366 pts, 14% had EGFR/ALK/ROS1/BRAF (EARB) tx options only. The remaining 1170 had a non-EARB tx option, either as their only option (1014; 87%), or in addition to an EARB tx option (156; 13%). The non-EARB tx options included 377 pts (32%) with a tumor mutational burden-associated tx option. In these 1170 pts, 341 (29%) had an agreeing tx besides EARB, and 100 (9%) were enrolled on trials. Conclusions: FMI CGP identified potential NSCLC-specific tx options/ 1 a clinical trial opportunity for 52% of pts with aNSCLC. Of the pts evaluated for tx agreement, almost /2 received a tx agreeing with an option on the FMI report and/or were enrolled in a clinical trial. FMI CGP adds value beyond single biomarker testing by identifying txs and trial options in a meaningful proportion of pts.

9077 Poster Session (Board #400), Sun, 8:00 AM-11:00 AM

DNA damage response gene alterations are associated with high tumor mutational burden and clinical benefit from programmed death 1 axis inhibition in non-small cell lung cancer.

Biagio Ricciuti, Michael L. Cheng, Gonzalo Recondo, Mizuki Nishino, Renato Umeton, Lynette M. Sholl, Mark M. Awad; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, Boston, MA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Radiology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Department of Pathology, Brigham and Women’sHospital,Boston,MA

Background: DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. Methods: Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD- (L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. DDR positive (DDRpos) cases were defined as those with pathogenic DDR alterations (per COSMIC and ClinVar databases). DDR negative (DDRneg) cases were defined as either DDR wild-type or those with non-pathogenic DDR alterations. Results: Of 468 pts with successful NGS who received ICIs, 242 (51.7%) were identified as having any DDR alteration. Of them, 74 (15.8% in the entire cohort) were defined as DDRpos with pathogenic alterations in the following genes: ATM (41.9%), MLH1/MSH2/MSH6 (18.9%), BRCA1/2 (16.2%), CHEK1/2 (9.4%), FANC genes (9.4%), BAP1 (5.4%), RAD genes (5.4%), ERCC4/6 (4.0%), POLE (2.7%), ATR (2.7%). DDRpos and DDRneg groups were balanced in terms of age, performance status, gender, histology, oncogenic driver mutation, smoking status, ICI line, baseline brain metastases. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.1 vs 9.8 mutations/megabase, P = 0.007). No difference in median PD-L1 tumor proportion score was observed between groups (30% vs 25%, P = 0.33). Compared to DDRneg pts (N = 394), DDRpos pts had a significantly higher objective response rate (31.1% vs 19.1%, P = 0.03), and longer median progression-free survival (4.3 vs 2.6 months, HR: 0.71 [95%CI: 0.53-0.95], P = 0.02) and overall survival (16.3 vs 9.8 months, HR: 0.63 [95%CI: 0.45-0.89], P = 0.009) with PD-(L)1 therapy. Conclusions: Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC pts treated with PD-1 axis inhibition.

9078 Poster Session (Board #401), Sun, 8:00 AM-11:00 AM

Efficacy of ramucirumab and docetaxel given either before or after immune checkpoint inhibitors in patients with lung cancers.

Michael Offin, Chongrui Xu, Harsh Jain, Alex Makhnin, Sara A. Hayes, Andrew J. Plodkowski, Darragh Halpenny, Charles M. Rudin, Mark G. Kris, Alexander E. Drilon, Bob T. Li, Paul K. Paik; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) and Guangdong Academy of Medical Sciences, Guangzhou, China; Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Ramucirumab and docetaxel (RamDoce) is a treatment for lung cancer patients after platinum-based therapy regardless of histology, the presence of oncogenic drivers, or prior immune checkpoint inhibition (ICI). Past data has shown a possible differential response to chemotherapy based on ICI exposure. We determined the activity of RamDoce given to patients before or after ICI. Methods: We evaluated patients with stage IV lung cancers who received RamDoce at MSK from 1/2015 - 6/2018. We grouped them based on timing of RamDoce: Before (including never receiving ICI) or After ICI. Ram was given at 8-10mg/kg with Doce 60-75mg/m2 every 2-3 weeks. Demographics, oncogene status and histologic comparisons were done with Mann-Whitney and Fisher’s exact tests. Time to treatment discontinuation (TTD) and overall survival (OS), were compared by long-rank test. Results: 194 patients received RamDoce: 78 Before and 116 After ICI. Median line of therapy for RamDoce in both cohorts was 3. Demographics in the Before and After ICI respectively included: 45 vs 53 female (p = 0.56), 50 vs 96 ever-smokers (p = 0.004), 59 vs 64 years old (p = 0.003), 73 vs 103 adenocarcinoma (p = 0.30). 83% (64/77) of patients with available tissue were PD-L1 negative. TMB was similar between cohorts (7.8 vs 6.1 mut/Mb, p = 0.68). Before ICI had a greater proportion of oncogenes present (64% vs 47%, p = 0.02). Combining Cohorts, TTD for EGFR-mutant (n = 41) and KRAS-mutant (n = 45) lung cancers was 4.0 and 3.9 months respectively vs 2.3 months for EGFR/KRAS-WT (p = 0.051). There was no difference in TTD for adenocarcinoma (n = 176) vs squamous cancers (n = 15, 2.6 vs. 3.1 months respectively; HR 0.8, 95% CI 0.4-1.7, p = 0.51). We saw no difference in TTD between Before (1.5 months) and After ICI (3.0 months, HR 0.88, 95% CI 0.7-1.2, p = 0.39). There was no difference in OS: Before ICI (1.6 years) and After ICI (2.0 years; HR 1.1, 95% CI 0.8-1.5, p = 0.49). Conclusions: There was no difference in TTD or OS for RamDoce when given before or after ICI. There was a trend toward prolonged benefit from RamDoce in EGFR/KRAS-mutant lung cancers. Data on the efficacy of RamDoce in oncogene-driven groups can help guide care and serve as a benchmark for new drug evaluations.

9079 Poster Session (Board #402), Sun, 8:00 AM-11:00 AM

Phase II randomized trial of afatinib with or without cetuximab as first-line treatment for EGFR mutated non-small cell lung cancer (NSCLC) patients (IFCT-1503 ACE-Lung).

Alexis B. Cortot, Anne Madroszyk, Etienne Giroux Leprieur, Olivier Molinier, Elisabeth A. Quoix, Henri Berard, Josianne Otto, Isabelle Rault, Judith Raimbourg, Jose Hureaux, Lionel Moreau, Didier Debieuvre, Hugues Morel, Marc G. Denis, Elodie Amour, Franck Morin, Denis Moro-Sibilot, Jacques Cadranel, French Cooperative Thoracic Intergroup (IFCT); Centre Hospitalier Regional Uni- versitaire Lille, Lille, France; Institut Paoli-Calmettes, Marseille, France; APHP Hopital Ambroise Pare and Universite Paris-Saclay, Boulogne-Billancourt, France; Le Mans Regional Hospital, Le Mans, France; University Hospital of Strasbourg, Strasbourg, France; Hopital D’instruction Des Armes Sainte- Anne, Toulon, France; CLCC Lacassagne, Nice, France; Centre Hospitalier, Saint-Quentin, France; Centre Rene Gauducheau, Saint Herblain, France; Academic Hospital, Angers, France; Centre Hospitalier Pneumologie Colmar, Colmar, France; GHRMSA, Mulhouse, France; CHR, Orleans, ´ France; Nantes University Hospital, Nantes, France; IFCT, Paris, France; Intergroupe Francophone de Can- c´erologie Thoracique, Paris, France; Grenoble University Hospital, Grenoble, France; Hopitalˆ Tenon, AP-HP and FacultedeM´ ´ edecine Pierre et Marie Curie, Universite ´ Paris VI, Paris, France

Background: First-line treatment of metastatic EGFR-mutated NSCLC relies on EGFR-TKIs. However, all patients (pts) eventually develop progression. Dual inhibition of EGFR with afatinib (A), an irreversible pan-erbB TKI, and cetuximab (C), an EGFR monoclonal antibody, has shown activity in EGFR-mutated pts with acquired resistance to TKIs, regardless of the T790M status. Methods: We conducted a phase II randomized trial in advanced NSCLC pts harboring an activating EGFR mutation, who had not received prior therapy. Pts were treated with A (40 mg/d) until progression alone or with C 500 mg/m² every 2 weeks during 6 months (mos) (beginning at D15 at 250 mg/m²). Primary endpoint was time-to-treatment failure (TTF) at 9 mos for pts with del19 and L858R mutations. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS). Prospective monitoring of the T790M mutation was performed on circulating tumoral DNA (ctDNA) by digital PCR. Results: Trial was stopped early due to futility analysis after 118 pts were enrolled (59 in each arm). Baseline characteristics were balanced between the 2 arms, and especially for the types of EGFR mutation (del19, 55.9 vs 50.8%; L858R, 39 vs 40.7%; others, 5.1 vs 8.5% in AC and A arms, respectively). Treatment-related AEs of any grades were similar, although there was an excess of grade 3 AEs in the AC arm (50 vs 37.3%), but no of grade 5. The excess in grade 3-5 AEs was essentially due to cutaneous (96.6 vs 81.4%), eyes (32.8 vs 27.1%), hematological (22.4 vs 15.3%) but not to digestive toxicities (89.7 vs 98.3%). Among the 117 pts included in the efficacy analysis, 9-months TTF was 63.3% (47.5-75.6) in arm A and 65.8% (50.1-77.66) in arm AC. Median TTF was 11.1 mos (8.3-not reached [NR]) and 10.8 mos (9.2-13.7) in arms A and AC, respectively. Median PFS was 11.1 mos (8.3-NR) and 12.8 mos (9.2-13.7), respectively. Median OS was 20.8 mos (17.5-NR) and NR (17-NR), respectively. Conclusions: Efficacy of AC was similar to that of A alone. These results don’t support further evaluation of this combination in this setting. Results of ctDNA monitoring will be reported during the meeting. Clinical trial information: NCT02716311.

9080 Poster Session (Board #403), Sun, 8:00 AM-11:00 AM

Quantification of circulating free and circulating tumor DNA in pretreated EGFR mutant NSCLC to inform patient outcomes.

Alexandra Pender, Curtis Hughesman, Elaine Law, Amadea Kristanti, Kelly McNeil, Tracy Tucker, Ian Bosdet, Sean Young, Janessa J. Laskin, Aly Karsan, Stephen Yip, Cheryl Ho; British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology, BC Cancer Agency and University of British Columbia, Vancouver, BC, Canada; BC Cancer, Vancouver, BC, Canada; BC Cancer Agency, Vancouver, BC, Canada

Background: EGFR T790M testing is standard of care for EGFR mutant (EGFRm) NSCLC progressing on 1st/2nd generation TKIs to select patients for osimertinib. Circulating free DNA (cfDNA) levels are measured prior to circulating tumour DNA (ctDNA) testing using droplet digital PCR (ddPCR) to measure activating/resistant EGFR mutations. We reviewed cfDNA levels and ctDNA mutational status to determine the influence on patient outcome. Methods: Following extraction of cfDNA from plasma using the QIAamp Circulating Nucleic Acid Kit, cfDNA levels are measured with a Qubit 2.0 Fluorometer. Custom ddPCR assays were used to test for the appropriate EGFR activating mutation and the EGFR T790M resistance mutation using the Bio-Rad QX200 system. The custom designed ddPCR assays have a limit of detection of , 0.1% variant allele fraction. All patients undergoing ctDNA testing from February-December 2018 were identified. Baseline characteristics and follow up data were collected retrospectively. OS was calculated from date of metastatic diagnosis to death/last follow- up. Results: 142 patients with EGFR mutant adenocarcinoma had EGFR ctDNA testing: results 52% indeterminant, 32% T790M, 16% activating EGFRm only. At the time of testing: median age 66, 64% female, 57% never smokers 53% Asian; systemic treatment (tx) 62% first line only, 25% two lines and 13% $ three lines. First TKI therapy: 32% afatanib, 66% gefitinib, 2% erlotinib. Median cfDNA concentration was 5.65 ng/ml (range 0.50-217.72). The 5 yr OS was 72% below cfDNA median and 25% above the median. Tx after ctDNA testing for below and above cfDNA median: 52 vs 33% original TKI, 34 vs 55% osimertinib, 14 vs 12% other systemic tx. Multivariate analysis shows that even accounting for age, sex and ctDNA mutation result, cfDNA concentration remains an independent predictor of outcome (HR 2.36, 95% CI 1.08-5.18, p = 0.032). Conclusions: cfDNA concentration can predict patient outcome in patients with EGFR mutant NSCLC progressing on TKI regardless of ctDNA testing results. Clinicians may consider switching to chemotherapy for patients with high cfDNA and without detectable EGFR T790M ctDNA to avoid missing the window for therapy instead of awaiting repeat EGFR T790M testing

9081 Poster Session (Board #404), Sun, 8:00 AM-11:00 AM

NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry.

Michael ¨ Duruisseaux, Stephen V. Liu, Ji-Youn Han, Valerie Gounant, Jin-Yuan Shih, Alison M. Schram, Alexa Betzig Schrock, Siraj Mahamed Ali, Fanny Magne, Isabelle Monnet, Denis Moro-Sibilot, Torsten-Gerriet Blum, Tejas Patil, Robert Charles Doebele, D. Ross Camidge, Lucia Anna Muscarella, Jacques Cadranel, Alexander E. Drilon; Hospices Civils de Lyon Cancer Institute, Chest Department, Hopitalˆ Louis Pradel, Bron, France; Georgetown University Medical Center, Washington, DC; Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea; Service d’Oncologie thoracique Hopitalˆ Bichat, APHP, Paris, France; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Memorial Sloan Kettering Cancer Center, New York, NY; Foundation Medicine, Inc., Cambridge, MA; Hopitalˆ de Villefranche-Sur-Saone,ˆ Villefrahce-Sur-Saone,ˆ France; Service de pneumologie, Centre Hospitalier Intercommunal de Creteil, Creteil, France; Service Hospitalier Universitaire Pneumologie Physiologie Poleˆ Thorax et Vaisseaux Centre Hospitalier Universi- taire Grenoble Alpes, Grenoble, France; HELIOS Kliniken Emil von Behring Center of Lung Disease, Berlin, Germany; University of Colorado Cancer Center, Aurora, CO; University of Colorado, Denver, CO; Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Hopitalˆ Tenon, AP-HP and FacultedeM´ ´ edecine Pierre et Marie Curie, Universite ´ Paris VI, Paris, France

Background: NRG1 fusions are potentially actionable driver events enriched in NSCLCs, particularly invasive mucinous adenocarcinomas (IMAs). These fusions activate HER3/HER2, supporting the therapeutic use of HER3 and/or HER2 inhibitors, but optimal treatment strategies remain unclear. Methods: A global, multicenter network of thoracic oncologists (6 countries, 13 institutions) identified patients with pathologically confirmed NRG1 fusion-positive NSCLCs. Anonymized clinical/pathologic features and clinical outcomes were collected retrospectively. Best response to systemic therapy was determined (RECIST v1.1). PFS was calculated (Kaplan-Meier). Results: 80 NRG1 fusion-positive NSCLCs were identified. RNA-based sequencing identified 66% (n = 53/80), DNA-based sequencing 18% (n = 14/80), and FISH 16% (n = 13/80) of cases. The most common upstream partners were CD74 (45%), SLC3A2 (31%), and SDC (9%). Most patients were female (64%) and never smokers (58%). Histology was adenocarcinoma in 95% (IMA, 91%), squamous 4%, large cell neuroendocrine 1%. At diagnosis, most patients had non-metastatic disease (stage: I 33%, II 27%, III 18%, IV 22%). The lifetime frequency of brain metastases was 15%. 12 patients received the HER2 inhibitor afatinib for stage IV disease. PD was the best response in 55% (n = 6/11) of evaluable patients with 18% PR (n = 2/ 11) and SD 18% (n = 2/11); median PFS was 3.5 months (range 0.6-16.5 months). 19 patients received platinum-based chemotherapy; most patients had SD as their best response (47%, n = 8); PD 41% (n = 7), PR 12% (n = 2). PD-L1 was negative in the majority of tumors (79%, n = 26/33) and none had high PD-L1 expression (range 0-20%). No responses to single-agent anti-PD-1/L1 therapy were observed (PD n = 5/6, SD n = 1/6: nivolumab/atezolizumab). No responses to chemoimmunotherapy (carboplatin, pemetrexed, pembrolizumab) were observed (SD n = 4/5, PD n = 1/5). Conclusions: RNA-based testing is an important component of NRG1 fusion detection. Novel targeted therapeutic approaches are needed as overall outcomes with afatinib are poor. NRG1 fusion-positive NSCLCs do not highly express PD-L1 and outcomes with immunotherapy 6 chemotherapy are poor.

9082 Poster Session (Board #405), Sun, 8:00 AM-11:00 AM

Impact of KRAS allele subtypes and concurrent genomic alterations on clinical outcomes to programmed death 1 axis blockade in non-small cell lung cancer.

Biagio Ricciuti, Gonzalo Recondo, Renato Umeton, Mizuki Nishino, Lynette M. Sholl, Mark M. Awad; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Bio- statistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; Department of Radiology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA; Brigham and Women’s Hospital, Boston, MA

Background: Immune checkpoint inhibitors (ICI) treatment can result in durable responses for KRAS- mutant (mut) non-small cell lung cancer (NSCLC). The impact of KRAS allele subtypes and concurrent genomic alterations on ICIs efficacy is unknown. Methods: We collected clinicopathologic and genomic data from patients (pts) with advanced NSCLC treated with programmed death (PD)-1 axis inhibition at the Dana-Farber Cancer Institute. We evaluated outcomes to ICIs according to KRAS mut alleles and concurrent STK11 and KEAP1 mut. Results: Of 617 ICI-treated NSCLCs, 181 (29.3%) had KRAS mut. Median TMB (mTMB) and median PD-L1 tumor proportion score (TPS) were similar between KRAS mut and KRAS wild type (wt) tumors. Among tumors with KRAS codon 12 mut, mTMB was higher in G12V (n = 37, 12.2 mut/Mb) compared to G12C (n = 84, 11.4 mut/Mb), G12D (n = 20, 9.4 mut/Mb) and G12A (n = 13, 10.1 mut/Mb), P = 0.05. Tumors with KRAS transversions (Tv) (n = 156) had higher mTMB compared to those with KRAS transitions (Ti) (n = 25) (10.9 vs 7.6 mut/Mb, P = 0.03). Median PD-L1 TPS was similar across KRAS mut alleles. Pts with KRAS G12V had longer median progression-free survival (mPFS) (5.5 vs 2.7 months, HR:0.62 [95%CI:0.40-0.96], P = 0.03) and overall survival (mOS) (17.5 vs 9.7 months, HR:0.62 [95%CI:0.36-0.99], P = 0.05), compared to non-G12V. Pts with KRAS Tv had longer mPFS and mOS compared to pts with Ti (mPFS: 3.4 vs 2.0 months, HR: 0.58 [95%CI:0.37-0.92], P = 0.02; mOS: 10.9 vs 5.4 months, HR:0.59 [95%CI:0.35-0.99], P = 0.048). Clinicopathologic features and STK11/KEAP1 mut were balanced across all KRAS mut alleles. Among KRAS mut pts, those with KEAP1 (n:52) and STK11 (n:50) concurrent mut had shorter mPFS (KEAP1 mut 1.8 vs. KEAP1 wt 4.1 months, HR: 0.55 [95%CI:0.38-0.80], P = 0.002; STK11 mut 1.8 vs STK11 wt 4.6 months, HR:0.46 [95%CI:0.32-0.67], P , 0.0001) and mOS (KEAP1 mut 4.8 vs KEAP1 wt 15.1 months, HR: 0.51 [95%CI:0.34-0.76], P = 0.001; STK11 mut 4.8 vs STK11 wt 13.6 months, HR:0.51 [95%CI:0.34-0.76], P = 0.001). KEAP1 and STK11 mut did not impact outcome in KRAS wt pts. Conclusions: KRAS allele subtypes and concurrent genomic alterations impact ICI efficacy in NSCLC.

9083 Poster Session (Board #406), Sun, 8:00 AM-11:00 AM

Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis.

Joel W. Neal, Daniel Hausrath, Heather A. Wakelee, Kristen Cunanan, Stephen V. Liu, Mandeep Banwait, Lecia V. Sequist, Kevin Stirling, Zofia Piotrowska; Stanford University and Stanford Cancer Institute, Stanford, CA; Department of Medicine, Stanford University, Stanford, CA; Stanford Cancer Institute, Stanford, CA; Department of Statistics, Stanford University, Stanford, CA; Georgetown University Medical Center, Washington, DC; Massachusetts General Hospital, Boston, MA; Massachusetts General Hospital Cancer Center/Harvard Medical School, Boston, MA; Massachusetts General Hospital Cancer Center, Boston, MA

Background: First generation EGFR TKIs are well tolerated with chemotherapy (chemo), and have evidence of improved efficacy in EGFR-mutant NSCLC. Osimertinib (osi) is a 3rd-generation EGFR TKI with improved T790M and CNS activity. Safety and outcome data combining osi and concurrent chemo are limited. Methods: EGFR-mutant pts who received osi with chemo between 12/2015 and 8/2018 were retrospectively identified at two institutions. Pt demographics, toxicities and outcomes were collected by chart review. Results: 35 pts received osi + chemo, 29/35 pts had CNS mets. 16/35 had . = one prior chemo and/or immunotherapy, 34/35 previously received a 1st/2nd gen EGFR TKI (25/35 T790M+ at progression), and all 35 had prior progression on osi. 47 osi + chemo regimens were abstracted: carboplatin/pemetrexed+/-bevacizumab (n = 17), cisplatin/pem (1), carbo/taxane (2), pem+/- bev (7), taxane (7), gemcitabine (8), irinotecan (3), vinorelbine (2); 32/35 pts had platinum. Osi was dosed at 80 mg QD (32), 160 mg QD (2), or 80mg QOD (1). Toxicities (table) occasionally led to treatment delay (n = 5), osi dose-reduction (2) and discontinuation (3). Median overall survival (mOS) from metastatic diagnosis was 48.4 mo (95% CI 30.7-NR); mOS from first osi was 19.6 mo (95% CI 16.1- 32.6). Median duration of treatment (mDOT) for first regimen of chemo + osi was 5.3 mo (95% CI 4.1- 9.5); stratifying by chemo, mDOT for platinum doublet + osi was 6.1 mo (95% CI 4.7-NR) and mDOT for osi + single agent was 3.2 mo (95% CI 2.4-5.3). In the 29 pts with brain mets receiving their first regimen of osi + chemo, 6 had CNS progression but only 2 required radiation at progression. Conclusions: Osimertinib is tolerable in combination with many standard chemo regimens for EGFR-mutant NSCLC. mDOT for platinum doublet and single agent are similar to historical controls, but CNS disease control appears better than expected for chemotherapy alone. Adding chemotherapy at the time of progression on osimertinib may be considered for selected pts, particularly those with known CNS mets.

Adverse Event Any Grade Gr 3 Gr 4 AST/ALT Elevation 12 (34%) 1 (3%) 0 Anemia 25 (71%) 2 (6%) 0 Neutropenia 14 (40%) 5 (14%) 1 (3%) Thrombocytopenia 23 (66%) 1 (3%) 0 Pneumonitis 000

9084 Poster Session (Board #407), Sun, 8:00 AM-11:00 AM

Health-related quality of life (HRQoL) results from ALTA-1L: Phase 3 study of brigatinib vs crizotinib as first-line (1L) ALK therapy in advanced ALK+ non-small cell lung cancer (NSCLC).

Rosario Garcia Campelo, Huamao Mark Lin, Maurice Perol, Mohammad Jahanzeb, Sanjay Popat, Yanyan Zhu, Pingkuan Zhang, D. Ross Camidge; Medical Oncology Service, University Hospital A Coru~na (XXIAC-SERGAS), A Coru~na, Spain; Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA; Department of Thoracic Oncology, Centre Leon ´ B´erard, Lyon, France; University of Miami Sylvester Comprehensive Cancer Center, Deerfield Beach, FL; The Royal Marsden Hospital, London, United Kingdom; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA; University of Colorado Cancer Center, Aurora, CO

Background: Results from ALTA-1L (NCT02737501), an international, multicenter trial, showed that brigatinib vs crizotinib as 1L ALK therapy significantly prolongs progression-free survival (PFS; HR: 0.49, 95% CI, 0.33, 0.74) in advanced ALK+ NSCLC. HRQoL was evaluated as a secondary objective. Methods: ALK+ NSCLC patients were randomized 1:1 to brigatinib 90 mg daily for 7 days, then 180 mg daily or crizotinib 250 mg twice daily as 1L ALK therapy; treatment cycles were 28 days. HRQoL was assessed with the EORTC QLQ-C30 and LC13. Change from baseline, duration of improvement and time to worsening were analyzed in the ITT-PRO population (n = 131 for both groups). Results: HRQoL compliance was . 90% for brigatinib and crizotinib. Global health status (GHS)/QoL improved starting at cycle 2, with clinically meaningful improvement ($10-point increase) noted with brigatinib at cycles 528, 10213, 17 and 19 and crizotinib at cycle 6. Brigatinib substantially improved overall HRQoL vs crizotinib, as demonstrated by the estimated mean difference on change from baseline (4.1, P, 0.05) and duration of improvement for GHS/QoL (HR = 0.16, P, 0.001). Improved GHS/QoL with brigatinib vs crizotinib was also supported by improvement in several functional domains (Table) and for these symptoms (P, 0.05): fatigue, nausea/vomiting and appetite loss. No domains significantly favored crizotinib. Brigatinib showed a trend to prolong time to worsening of dyspnea vs crizotinib (HR 0.65, 95% CI 0.38, 1.12). Table: HRQoL results brigatinib vs crizotinib Clinical trial information: NCT02737501. Conclusions: Consistent with the prolongation of PFS seen in 1L treatment of advanced ALK+ NSCLC, brigatinib improved HRQoL and prolonged the duration of improvement in GHS/QoL, and the majority of functional and symptom domains vs crizotinib.

Duration of improvement Change from baseline Median, mo Est mean difference (95% CI) HR GHS/QoL 4.1 (0.1, 8.1)c NE vs 12.0 0.16a Functional Domain Physical 3.6 (0.1, 7.2)c NE vs NE 0.23b Role 3.6 (-1.1, 8.4) NE vs 12.0 0.48c 0.48c Emotional 5.1 (1.8, 8.3)b NE vs NE 0.45 Cognitive 3.8 (0.6, 6.9)c 11.1 vs 9.2 0.54 Social 2.9 (-1.3, 7.1) NE vs NE 0.30b

NE, not evaluable aP, 0.001; bP, 0.01; cP, 0.05

9085 Poster Session (Board #408), Sun, 8:00 AM-11:00 AM

Targeting NFE2L2/KEAP1 mutations in advanced NSCLC with the TORC1/2 inhibitor TAK-228.

Paul K. Paik, Linda Su Hyun Ahn, Michelle S. Ginsberg, Andrew J. Plodkowski, Rachel Kim, L. Austin Doyle, Charles M. Rudin; Memorial Sloan Kettering Cancer Center, New York, NY; Mt Sinai Medcl Ctr, Palisades Park, NJ; Greenbaum Cancer Center, Baltimore, MD

Background: Despite efforts over the past decade, no targeted therapy options exist for SQCLC pts. We have identified a heretofore untargeted oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of patients with SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through RagD (Shibata Cancer Res 2010). We report translational studies and results from an ongoing phase 2 trial of the oral TORC1/2 inhibitor TAK-228. Methods: Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells (NFE2L2 E79K mut) treated with TAK-228, everolimus, rapamycin, or deforolimus. Pts with stage IV SQCLC harboring NFE2L2 or KEAP1 mutations and NSCLC harboring KRAS + NFE2L2 or KEAP1 co-mutations are treated on an NCI CTEP phase 2 study of TAK228 3mg po qd (continuous 28 day cycles; NCT02417701). Primary endpoint: ORR. Secondary endpoints: PFS. The study utilizes a Simon 2-stage design for each cohort with H0 = 5% (N$1/5 responses), HA = 40% (N$2/10 responses). Results: TAK-228 exhibited increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK-228 alone was cytotoxic at sub-[mM] (IC50 68nM); all other rapalogs exhibited IC50s . 10mM. This was associated with marked decrease in pS6, pAKT, and pERK. Tumor response (-55%) was seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog. N = 15 evaluable pts have been treated on study (7 NFE2L2,3KEAP1,5KRAS + NFE2L2 or KEAP1). 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; there were no unexpected AEs. Within SQCLC NFE2L2 pts ORR = 29% (2/7 PR) and DCR = 100%. Prolonged duration of response is present, with PFS = 10.5mo, 11.4mo (18.2mo tx beyond PD), 6mo (8mo tx beyond PD), 5.5mo+, 4.5mo, and 1.5mo+. Within SQCLC KEAP1 pts DCR = 66% (2SD, 1PD) with PFS = 7.4mo+, 3mo+, 1mo. Data for the KRAS + NFE2L2/KEAP1 arm will be presented. Conclusions: TAK228 is tolerable with evidence of pre-clinical activity, radiographic responses, and prolonged DOR in biomarker-selected NSCLC pts. Accrual is ongoing. Clinical trial information: NCT02417701.

9086 Poster Session (Board #409), Sun, 8:00 AM-11:00 AM

A phase 1/2 study of osimertinib and bevacizumab as initial treatment for patients with metastatic EGFR-mutant lung cancers.

Helena Alexandra Yu, Rachel Kim, Alex Makhnin, Linda Su Hyun Ahn, Ai Ni, Sara A. Hayes, Robert J. Young, Gregory J. Riely, Mark G. Kris; Memorial Sloan Kettering Cancer Center, New York, NY; Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Osimertinib (osi) demonstrated improved progression-free survival (PFS) over erlotinib as initial treatment (trmt) for EGFR-mutant (EGFR+) lung cancers. The addition of bevacizumab (bev) to erlotinib as initial trmt resulted in improved PFS compared to erlotinib alone (16 vs 10 months, HR 0.41). The phase 1 study of osi and bev confirmed the ability to combine osi and bev at full doses. Methods: The phase 2 study is assessing safety and efficacy of the combination. The primary endpoint is PFS at 12 months; secondary endpoints include overall response (ORR), overall survival (OS), and CNS PFS. All pts had interval CNS as well as systemic imaging. Pre-treatment and post-progression (PD) tumor tissue and interval plasma samples are being collected to identify mechanisms of resistance (MOR) and for biomarker assessment. Results: From Nov 2016 to May 2018, 49 pts were enrolled, including 6 pts from the phase 1. Median age: 60; Women 69%; Never-smokers 65%. 13 pts had CNS metastases (9 untreated, 5 measurable) prior to study initiation. 49 pts are eligible for response; 34/49 pts had a confirmed partial response (PR)(ORR 69%). PFS at 12 months is 0.70 (95% CI: 0.57-0.84), with 8/49 pts on study without PD for less than 12 months. All pts with measurable CNS disease had a PR in the CNS; PD in the CNS was uncommon (17%). 24 pts remain on study without PD; 2 are being treated beyond PD. Reasons for study discontinuation include PD (n = 16), resection of all sites of disease (n = 3), withdrawal of consent (n = 3), unrelated death (n = 2), toxicity (n = 1). The most frequent trtmt-related adverse events (any grade) were thrombocytopenia (61%), diarrhea (57%), hypertension (55%), and rash (47%). 24% required a dose reduction of osi, 18% discontinued bev and median doses of bev was 17. 9 pts have paired pre-trtmt and post-progression tissue biopsies; MOR identified include squamous cell (n = 2) and small cell (n = 1) transformation, PTEN loss, and CCNE amplification. Conclusions: Combination osi and bev was well-tolerated and efficacy to date supports further evaluation. Results of secondary endpoints including PFS, mechanisms of resistance, cfDNA data are forthcoming. A randomized study of osi compared to osi and bev is planned (EA5182). Supported by AstraZeneca Clinical trial information: NCT02803203.

9087 Poster Session (Board #410), Sun, 8:00 AM-11:00 AM

Pembrolizumab alone or with chemotherapy for PD-L1 positive NSCLC: A network meta-analysis of randomized trials.

Mark Doherty, Seanthel Delos Santos, Amanda Putri Rahmadian, Louis Everest, Kelvin K. Chan; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Odette Cancer Centre, University of Toronto, Toronto, ON, Canada

Background: Pembrolizumab (P) has replaced chemotherapy (C) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression . / = 50%. Among PD-L1 unselected patients, P+C is superior to C alone. This network meta-analysis compared P alone with P+C in patients with . / = 50% PD-L1 positive NSCLC. Methods: An indirect network was constructed to compare P and P+C through the control arms of the Keynote 024, 189 and 407 (PD-L1 . / = 50% subgroup) trials. Baseline characteristics and chemotherapy outcomes were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicities including immune- related adverse events (irAE) were extracted from trial results. Toxicity results were unavailable for the PD-L1 . / = 50% subgroups of KN 189 & 407, so overall study results were used. Survival outcomes are expressed as hazard ratios (HRs) or restricted mean survival time (RMST) ratios, and toxicity and ORR as risk difference (RD). Results: 507 patients were included: 154 on P, 430 on C and 483 on P+C. Patient characteristics across trials were similar in age, sex, performance status and smoking history. All trials had similar chemotherapy outcomes (PFS 6, 4.9, 4.8 mos) suggesting similar populations. Network meta- analysis showed no difference between P+C and C alone in OS (HR 0.85, 95%CI 0.45-1.59, p = 0.60) or PFS (HR 0.73, 95%CI 0.48-1.1, p = 0.13), but P+C was associated with higher ORR (+16.9%, 95%CI 0.7-33%, p = 0.04). RMST analysis suggested fewer early PFS events with P+C (0-6 mo RMST ratio 1.25, RMST difference 1.02 mo, p = 0.002), with the difference disappearing at 1 year (0-12 mo RMST ratio 1.16, p = 0.07). No difference in RMST for OS was found. Overall toxicities, hematologic and grade 3-5 toxicities were higher with P+C compared with P alone (table). Conclusions: Among patients with . /= 50% PD-L1 positive NSCLC, P+C did not improve OS or PFS compared with P alone, but was associated with higher ORR. RMST analysis suggested fewer early progression events using P+C.

All Grade Toxicities (P+C vs P) Grade 3-5 Toxicities (P+C vs P) RD (%) 95% CI p RD (%) 95% CI p Any 17.3 8.7, 25.8 , 0.01 23.3 4.7, 41.9 0.014 Led to Discontinuation 12 1.9, 22 0.02 7.4 0.5, 14.3 0.035 Neutropenia 25.9 17.2, 34.5 , 0.01 14.7 5.3, 24.1 0.002 Vomiting 20.5 12.2, 28.7 , 0.01 -0.8 -4.7, 3.1 0.69 Thrombocytopenia 16.5 9.6, 23.4 , 0.01 6 1.3, 107 0.012 Any irAE -9.1 -25.8, 7.6 0.29 -3.1 -9.1, 2.8 0.30 Hypothyroidism -2.7 -8.1, 2.8 0.34 NA Severe skin reaction -3.2 -7.1, 0.7 0.11 -3.4 -6.7, -0.1 0.045

9088 Poster Session (Board #411), Sun, 8:00 AM-11:00 AM

Randomized multicenter phase II trial evaluating the sequencing of PD-1 inhibition with pembrolizumab (P) and standard platinum-based chemotherapy (C) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) (AFT-09).

Thomas A. Hensing, Xiaofei F. Wang, Junheng Gao, Tom Stinchcombe, Michael V. Knopp, Arkadiusz Z. Dudek, Stephen L. Graziano, Jyoti D. Patel, Bryan Faller, Konstantin H. Dragnev, David E. Kozono, Everett E. Vokes; NorthShore University Health System/University of Chicago, Evanston, IL; Duke University Medical Center, Durham, NC; Duke University Health System, Durham, NC; Duke Cancer Institute, Durham, NC; Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH; Health Partners Cancer Care Center, St. Paul, MN; Regional Oncology Center, Syracuse, NY; The University of Chicago Medical Center, Chicago, IL; Missouri Baptist Medical Center, St Louis, MO; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Dana-Farber Cancer Institute, Boston, MA; Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medicine,Chicago,IL

Background: KEYNOTE-024 established single-agent P as a 1st-line option for pts with metastatic NSCLC without targetable alterations and PD-L1 tumor proportion score (TPS) $ 50%. KEYNOTE-189 and 407 established concurrent C + P as a treatment option irrespective of PD-L1 expression. In this randomized phase II selection trial, we explored sequencing of C and P in this pt. population. Methods: Eligible pts were randomized 1:1 to (arm A) C (carboplatin (AUC 6) + pemetrexed 500 mg/m2 (non- squamous) or paclitaxel 200 mg/m2 (squamous)) x 4 cycles followed by P 200 mg x 4 cycles, or the reverse sequence (arm B) of P x 4 cycles followed by C x 4 cycles. After 8 cycles, pts on both arms were eligible to receive maintenance P for up to 24 months. Primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review. Secondary endpoints included progression free survival (PFS) per RECIST 1.1 and overall survival (OS). Efficacy endpoints were also evaluated by PD-L1 expression. Results: 89 pts (47 arm B & 42 arm A) were enrolled and are included in the analysis (PD-L1 TPS 0/1-49%/$50% = 24 pts (34%)/25 pts (36%)/21 pts (30%)). There was no significant difference in ORR (36% vs 38%, p = 0.829), median PFS (2.7 vs 5.5 months (mo), HR 1.25, 95% CI 0.77-2.02, p = 0.363) or OS (13.1 vs 19.8 mo, HR 1.25, 95% CI 0.69-2.25, p = 0.4573), arm B (Px4→C) vs arm A (Cx4→P). Multivariable Cox regression analysis demonstrated significant interaction between treatment and PD-L1 TPS ( , 50% vs $ 50%) for PFS (HR 6.76, 95% CI 2.14-21.35, p = 0.0011) and a trend for OS (HR 5.02, 95% CI 0.92-27.55, p = 0.0632), arm B vs arm A. Incidence of grade $3 adverse events was 71% for arm A and 65% for arm B. No new safety signals were observed. Conclusions: In pts with stage IV NSCLC and PD-L1 TPS $ 50% there was an observed improvement in PFS and OS in favor of C followed by P vs P x 4 followed by C. Given small # of pts and trial design, this observation should be considered hypothesis-generating, but supports further exploration of sequential C + P in this setting. Support:Merck Sharp & Dohme Corp.; https://acknowledgments.alliancefound.org Clinical trial information: NCT02591615.

9089 Poster Session (Board #412), Sun, 8:00 AM-11:00 AM

Single-arm, phase II study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation.

Guanghui Gao, Xingya Li, Qiming Wang, Yiping Zhang, Jianhua Chen, Yongqian Shu, Yanping Hu, Yun Fan, Jian Fang, Gongyan Chen, Jun Zhao, Jianxing He, Fengying Wu, Jianjun Zou, Xiaoyu Zhu, Caicun Zhou; Shanghai Pulmonary Hospital, Shanghai, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Cancer Hospital, Zhengzhou, China; Zhejiang Cancer Hospital, Hangzhou, China; Hunan Cancer Hospital, Changsha, China; Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Hubei Cancer Hospital, Wuhan, China; Beijing Cancer Hospital, Beijing, China; Harbin Medical University Cancer Hospital, Harbin, China; The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Jiangsu Hengrui Medicine Co. Ltd, Shanghai, China

Background: HER2 exon 20 mutation is a well-known oncogenic driver in non-small cell lung cancer (NSCLC) and its testing is recommended by NCCN guidelines for NSCLC patients. However, up to now, there has been no approved targeted therapy for this patient population. Pyrotinib is an oral, irreversible pan-Her tyrosine kinase inhibitor (TKI) against HER1, HER2 and HER4, which, combined with chemotherapy, has recently been approved in China for HER2 positive advanced breast cancer. Methods: Stage IIIB or IV NSCLC patients with HER2 exon 20 mutation (confirmed in a central lab) and previously treated with at least one platinum-based chemotherapy were enrolled in this open-label, multi-center, single-arm phase II study. Patients with active brain metastases or prior use of HER2 TKI agents were excluded. Eligible patients received pyrotinib 400 mg once daily until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included safety, progression-free survival (PFS), time to disease progression (TTP), duration of response (DOR) and overall survival (OS). This trial is registered on ClinicalTrials.gov (NCT02834936). Results: Between October 20, 2016 and December 10, 2018, 60 patients (33 female, 27 male) were enrolled. The median age was 57 years (range: 40, 72). A majority were stage IV patients (95%). Over 58% of patients have been treated with two or more prior chemotherapy regimens. As of Jan 21, 2019, the ORR as evaluated by investigators was 31.7% (95% CI 20.3%, 45.0%). Median DOR was 7.0 months (95% CI 5.5, 11.0) and median PFS was 6.8 months (95% CI 4.1, 8.3). 26.7% patients reported treatment-related grade 3 AEs. Diarrhea (20.0%) was the only treatment-related grade 3 AE that occurred in $ 2 patients. Treatment-related grade 4 AE was reported in 1 subject (elevated gamma-glutamyl transferase). The anti-tumor activities of pyrotinib was shown in various mutation types. Conclusions: Pyrotinib as a single agent demonstrated promising anti-tumor activity and acceptable safety profile in heavily pretreated HER2 mutant NSCLC patients. Clinical trial information: NCT02834936.

9090 Poster Session (Board #413), Sun, 8:00 AM-11:00 AM

Clinicopathologic profile and treatment outcomes of non-sensitizing EGFR and HER2 (ERBB2) activating mutations in NSCLC: Results from a single-center retrospective study.

Tejas Patil, Rao Rashid Mushtaq, Sydney Marsh, Christine Azelby, Miheer Pujara, Dara Aisner, William T. Purcell, Erin Lynn Schenk, Paul A. Bunn, Jose Maria Pacheco, D. Ross Camidge, Robert Charles Doebele; University of Colorado Cancer Center, Aurora, CO; Hurley Medical Center, Flint, MI; University of Colorado School of Medicine, Aurora, CO; University of Colorado Hospital, Aurora, CO; University of Colorado Comprehensive Cancer Center, Aurora, CO; Mayo Clinic, Rochester, MN; University of Colorado Denver, Aurora, CO; Baylor Coll of Medcn, Houston, TX; University of Colorado, Denver, CO

Background: The clinicopathologic characteristics and optimal treatment strategies for non-sensitizing EGFR (ns-EGFR)andHER2 activating mutations in NSCLC remain unclear. Methods: Single-center retrospective study of patients seen at University of Colorado from 2008 – 2018 with stage IV NSCLC was performed. Clinicopathologic features and treatment outcomes of patients with ns-EGFR (Exon 18, Exon 20, L861Q) and HER2 mutations were collected. Best response to TKI was determined (RECIST v1.1). PFS was calculated using Kaplan-Meier method. Results: Among 359 patients, we identified 49 ns-EGFR (36 Exon 20,10Exon 18,3L861Q)and28HER2 mutations (27 Exon 20, 1 gene amplification) detected via NGS (65/77), real-time PCR (9/77), FISH (1/77) and undocumented (2/77). PDL1 . 50% was seen in 44% ns-EGFR and 57% HER2. Adenocarcinoma was the most common histology (97%). Most patients were female (62%), never smokers (63%), and presented with metastatic disease (stage: I 5%, II 4%, III 6%, IV 85%). HER2+ NSCLC demonstrated a tropism for lung metastases (64%) that was significant when compared to EGFR Exon 19, EGFR L858R, ALK, ROS1, and KRAS cohorts (p , 0.001). No differences were found when other metastatic sites were compared. Among evaluable patients, response rates to TKI therapy is shown. Aggregate median PFS on TKI for ns-EGFR and HER2+ NSCLC was 6 months compared to EGFR Exon 19 (15 months; p , 0.01; HR 0.4; CI 0.24 – 0.67) and EGFR L858R (22 months; p , 0.01; HR 0.27 and 0.8; CI 0.14 – 0.54). Aggregate median OS for ns-EGFR and HER2+ NSCLC was 28 months with no differences when compared to EGFR Exon 19 and L858R subgroups. Conclusions: HER2+ NSCLC appears to have a predisposition for lung metastases. Higher DCR was observed with newer generation TKIs, but novel targeted therapeutic approaches are needed as overall outcomes remain poor.

Erlotinib Osimertinib All TKI Gefitinib Afatinib Clinical trials NS-E HER2 Total NS-E HER2 Total NS-E HER2 Total NS-E HER2 Total CR 000000000000 PR 303000202101 SD 12 2 14 4 0 4 1 0 1 7 2 9 PD 12 2 14 7 1 8 1 1 2 4 0 4 Total 27 4 31 11 1 12 4 1 5 12 2 14 ORR (%) 100407 DCR (%) 55 33 60 71

9091 Poster Session (Board #414), Sun, 8:00 AM-11:00 AM

Safety and efficacy of abivertinib (AC0010), a third-generation EGFR tyrosine kinase inhibitor, in Chinese patients with EGFR-T790M positive non-small cell lung cancer (NCSLC).

Qing Zhou, Lin Wu, Luo Feng, Tongtong An, Ying Cheng, Jianying Zhou, Junling Li, Ji Feng Feng, Li Zhang, Baohui Han, Walson Xu, Lvyu Zhu, Li Xu, Xiao Xu, Feng Roger Luo, Yi-Long Wu; Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; Department of Thoracic Medicine, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University (Hunan Cancer Hospital), Changsha, China; Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, China; Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China; Department of Oncology, Jilin Province Cancer Hospital, Changchun, China; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Jiangsu, China; Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China; ACEA Pharmaceutical Research, Hangzhou, China; ACEA Therapeutics Inc., San Diego, CA

Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were $ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment- related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE ($2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR- TKI. Clinical trial information: NCTNCT02330367.

9092 Poster Session (Board #415), Sun, 8:00 AM-11:00 AM

Final PFS analysis and safety data from the phase III J-ALEX study of alectinib (ALC) vs. crizotinib (CRZ) in ALK-inhibitor na¨ıve ALK-positive non-small cell lung cancer (ALK+ NSCLC).

Takashi Seto, Makoto Nishio, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Young Hak Kim, Koichi Azuma, Yuichi Takiguchi, Hiroshige Yoshioka, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takashi Asakawa, Tomohide Tamura; National Kyushu Cancer Center, Fukuoka, Japan; Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; Tokushima University Hospital, Tokush- ima, Japan; Nagoya University Graduate School of Medicine, Nagoya, Japan; Kyoto University Hospital, Kyoto, Japan; Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan; Department of Medical Oncology, Graduate School of Medicine Chiba University, Chiba, Japan; Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Japan; Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; Center for Innovative Clinical Medicine, Okayama Unversity Hospital, Okayama, Japan; Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Hyogo Cancer Center, Akashi, Japan; Department of Thoracic Oncology, National Hospital Organization Shi- koku Cancer Center, Matsuyama, Japan; Kindai University Hospital, Osaka, Japan; Department of Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan; Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan; St Luke’s International Hospital, Tokyo, Japan

Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor na¨ıve ALK+ NSCLC demonstrated superior progression-free survival (PFS) of ALC compared with CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p , 0$0001) by the Independent Review Facility (IRF) (data cutoff, December 3 2015, Hida et al., Lancet 2017) . Here, we report the final PFS and OS 2nd interim data (data cutoff, June 30 2018). Methods: ALK+ NSCLC (by IHC and FISH or RT-PCR) patients were randomized 1:1 either to receive ALC (300 mg BID, n = 103) or CRZ (250 mg BID, n = 104). Stratification factors included ECOG PS, treatment line, and clinical stage. Primary endpoint was PFS according to the blinded IRF. Secondary endpoints included OS, objective response rate, and safety. Results: After a median follow-up of 42.2 months in the ALC arm and 42.4 months in the CRZ arm, an event of disease progression or death occurred in 54% and 86% in the ALC arm and the CRZ arm, respectively. The final PFS HR was 0.37 (95%CI 0.26-0.52): median IRF-PFS was 34.1 months (95% CI 22.1– not estimated) in the ALC arm and 10.2 months (95%CI 8.3–12.0) in the CRZ arm. HRs for the time to CNS progression or death was 0.33 (95%CI 0.11–0.93) and 0.20 (95%CI 0.08–0.49) with or without CNS metastases at baseline, respectively. The 2nd interim analysis of OS was still immature (events 30.1% in the ALC arm, 31.7% in the CRZ arm; stratified HR 0.80, 95%CI 0.35–1.82). Most of patients (77.9%) in the CRZ arm received ALC as a subsequent therapy whereas only 10.7% of patients in the ALC arm received CRZ. Proportion of patients with grade 3–4 AEs (37% vs 61%), AEs leading to interruption (40% vs 82%) or discontinuation (12% vs 23%) were lower in the ALC arm than the CRZ arm. There were no treatment-related deaths in either arm. Conclusions: In the final PFS analysis, ALC continued to demonstrate the superiority in IRF-PFS in ALK-inhibitor na¨ıve ALK+ NSCLC regardless of baseline CNS metastases with a favorable safety profile. The updated result of OS will be presented in the future congress. Clinical trial information: JapicCTI-132316.

9093 Poster Session (Board #416), Sun, 8:00 AM-11:00 AM

Preliminary immunogenicity, safety, and efficacy of JNJ-64041757 (JNJ-757) in non-small cell lung cancer (NSCLC): Results from two phase 1 studies.

Julie R. Brahmer, Melissa Lynne Johnson, Manuel Cobo Dols, Santiago Viteri Ramirez, Juan Coves, Ammar Sukari, Mark M. Awad, Ravi Salgia, Vassiliki Papadimitrakopoulou, Arun Rajan, Alicia Jones Allred, Mark Wade, Gary Mason, Enrique Zudaire, Roland Elmar Knoblauch, Nicole L. Stone, Matthew V. Lorenzi, Raffit Hassan; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Sarah Cannon Research Institute, Nashville, TN; Hospital Regional Universitario de Malaga, Malaga, ´ Spain; Dr Rosell Oncology Institute, Dexeus University Hospital, Quiron Salud Group, Barcelona, Spain; Hospital de Son Llatzer, ` Palma De Mallorca, Spain; Department of Oncology, Karmanos Cancer Institute/ Wayne State University, Detriot, MI; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Janssen Research & Developemnt, Spring House, PA; Janssen Research & Development, Spring House, PA; Janssen Research & Developemnt, Raritan, NJ; Janssen Research and Development, Spring House, PA; Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD

Background: The immunogenicity, safety, and efficacy of JNJ-757, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy expressing human mesothelin (MSLN), were evaluated in patients (pts) with advanced NSCLC (adenocarcinoma) as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2). Methods: Adult pts with Stage IIIB/IV NSCLC who had received prior systemic therapy (including 1 platinum-based chemotherapy, prior PD-1/PD-L1 therapy allowed) were included. Dose-limiting toxicities, adverse events (AEs), tumor response, T cell response, and JNJ- 757 bacterial shedding profile were evaluated in pts treated with JNJ-757 (108 or 109 colony forming units [CFU]) alone or JNJ-757 (109 CFU)+nivolumab 240 mg combination therapy until progression. Results: In the monotherapy trial, 18 pts (median age 63.5 years; women 61%) were treated with JNJ- 757 108 or 109 CFU with a median duration of 1.4 months (range 0-29). Most common AEs were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours, suggesting transient activation of an innate immune response to JNJ-757. Treatment-related grade $3 AEs were infrequent (4 [22%]). Induction of peripheral proinflammatory cytokines and lymphocyte activation was observed post-treatment with transient MSLN-specific T cell responses in 10/13 evaluable pts, consistent with the mechanism of action of JNJ-757. With monotherapy, 4/18 response-evaluable pts had stable disease (SD) $16 weeks, including 1 pt with a 53% reduction in target lesions. In the combination therapy study, 12 pts were enrolled (median age 63.5 years; women 33%). The most common AEs were pyrexia (67%) and chills (58%); 6 pts had grade $3 AEs including 2 cases of treatment-related fatal pneumonitis. Best overall response for the combination was SD in 4/9 evaluable pts. JNJ-757 in combination with nivolumab suggested increased risk of pneumonitis. Conclusions: As monotherapy, JNJ-757 was tolerable with mild infusion-related fever and chills supporting the initiation of the combination therapy study. However, the risk-benefit profile of JNJ-757+nivolumab, did not support proceeding to phase 2. Clinical trial information: NCT02592967, NCT03371381.

9094 Poster Session (Board #417), Sun, 8:00 AM-11:00 AM

Deep learning-based predictive biomarker for immune checkpoint inhibitor response in metastatic non-small cell lung cancer.

Sehhoon Park, Chang Ho Ahn, Geunyoung Jung, Sarah Lee, Kyunghyun Paeng, Jiwon Shin, Inwan Yoo, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Yoon La Choi, Sang-Yong Song, Se-Hoon Lee; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Lunit Inc., Seoul, South Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Pathology, Samsung Medical Centre, Sungkyunkwan University, Seoul, South Korea; Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunk- wan University School of Medicine, Seoul, South Korea

Background: In the era of immunotherapy, immune checkpoint inhibitor (ICI) has changed the treatment paradigm in metastatic non-small cell lung cancer (NSCLC). Along with clinical trials, there is an ongoing investigation to discover the predictive biomarker of ICI which so far has unsatisfactory reliability. As an effort to enhance the predictive value of ICI treatment, we applied deep learning and developed artificial intelligent (AI) score (range from 0 to 1) to analyze the specific context of immune- tumor microenvironment (TME) extracted by scanned images from H&E slides. Methods: As a ground work, deep learning-based H&E image analyzer, Lunit SCOPE, has been trained with H&E images (n = 1824) from ICI naive NSCLC samples. For the calculation of AI score, training was conducted using responder/non-responder labeled ICI treated samples from the exploratory cohort. The ICI responder was defined as the patient with a best overall response of partial or complete response and stable disease for more than 6 months. The positivity of PD-L1 immunohistochemistry (IHC) was assessed manually by pathologists. Results: The exploratory cohort is composed of NSCLC patients treated with ICI (n = 189) in Samsung Medical Center, and response to ICI was observed in 72 (38.1%) patients. Median follow-up duration was 6.8 months (6.6~8.2). Samples with PD-L1 IHC positive, defined by $ 1%, was observed in 138 (73.0%) patients. AI score was significant higher in the responder group (median: 0.391 vs 0.205, P = 6.14e-5), and the patients with AI score above the cut-off (0.337) showed a better response to ICI (odds ratio [OR] 3.47 P = 7.34e-5) which is higher than patients with PD-L1 $ 1% (OR 1.92, P = 0.069). High AI score group (n = 83) showed significantly favorable PFS compared to low AI score group (n = 106, median PFS: 5.1m vs 1.9m, hazard ratio [HR] 0.51, P = 9.6e-5) and this outcome was independent with PD-L1 status (P = 6.0e-5). In subgroup analysis, PFS of PD-L1 high / AI score high group (n = 63) had longer median PFS (6.7m) compared to both PD-L1 high / AI score low group (n = 70, 4.0m, P = 0.001) and PD-L1 low/AI score low group (n = 35, 1.9m, P = 4.0e-6). Tumor infiltrating lymphocyte (TIL) density of cancer epithelium was significantly correlated with AI score (Pearson’s r = 0.310, P = 1.43e-5), which suggests that AI score may partly reflect TME represented by TIL. Conclusions: The AI score by machine- learned information, extracted from H&E images without additional IHC stain, could predict responsiveness and PFS of ICI treatment independent of PD-L1 IHC positivity.

9095 Poster Session (Board #418), Sun, 8:00 AM-11:00 AM

Efficacy and safety of IBI305 compared with bevacizumab in advanced non-squamous NSCLC patients as first-line treatment in a randomized, double-blind, phase III study.

Li Zhang, Bin Wu, Linian Huang, Meiqi Shi, Yunpeng Liu, Yanqiu Zhao, Lijun Wang, Shun Lu, Gongyan Chen, Baolan Li, Conghua Xie, Jian Fang, Nong Yang, Yiping Zhang, Jiuwei Cui, Yong Song, Cuiying Zhang, Xiaodong Mei, Bangwei Cao, Lan Yang; Sun Yat-sen University Cancer Center, Guangzhou, China; Affiliated Hospital of Guangdong Medical University, Zhanjiang, China; The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; Jiangsu Cancer Institute and Hospital, Nanjing, China; The First Hospital of China Medical University, Shenyang, China; Henan Provincial Cancer Hospital, Zhengzhou, China; The Second Affiliated Hospital of Xingtai Medical College, Xingtai, China; Department of Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai JiaoTong University, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China; Beijing Chest Hospital, Capital Medical University, Beijing, China; Zhongnan Hospital of Wuhan University, Wuhan, China; Beijing Cancer Hospital, Beijing, China; Hunan Provincial Cancer Hospital, Changsha, China; Zhejiang Cancer Hospital, Hangzhou, China; The First Hospital of Jilin University, Changchun, China; Nanjing General Hospital of Nanjing Military Command (NGH)- Jinling Hospital, Nanjing, China; Innver Mongolia People’s Hospital, Hohhot, China; Anhui Provincial Hospital, Hefei, China; Beijing Friendship Hospital, Beijing, China; The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

Background: IBI305 is a recombinant humanized anti-VEGF monoclonal antibody, a biosimilar candidate to bevacizumab in analytical and functional comparisons. Pharmacokinetic similarity has been demonstrated in healthy males. Here we present primary efficacy and safety results from a phase 3 comparative study in non-small cell lung cancer (NSCLC). Methods: In this double- blind, active-controlled study, subjects with advanced non-squamous NSCLC on first-line treatment with carboplatin and paclitaxel were randomized (1:1) to IBI305 or bevacizumab (15 mg/kg IV Q3W). After six cycles, patients were on maintenance treatment with IBI305 or bevacizumab (7.5 mg/kg IV Q3W) till progression. Clinical equivalence of the primary endpoint, confirmed objective response rate (ORR) was evaluated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) between study arms with the prespecified margin (0.75, 1.33). Results: A total of 450 subjects were randomized (IBI305: n = 224; bevacizumab: n = 226). Baseline characteristics were well balanced between treatment arms. ORR evaluated by Independent Radiological Review Committee (IRRC) in full analysis set (FAS) was 44.3% (98/221) for IBI305 and 46.4% (102/220) for bevacizumab; the RR for ORR was 0.95 (90% CI: 0.803, 1.135). Sensitive analysis result on RRs of ORR in Intention to Treat (ITT) population (IBI305: n = 224; bevacizumab: n = 226) and other analysis set were consistent and all within the prespecified equivalence margin. The medium PFS were 8.4 months for IBI305 and 8.3 months for bevacizumab and duration of response (DOR) was also similar in both arms. Treatment- emergent adverse events (TEAEs) were well balanced between treatment arms and consistent with the known adverse event profile of bevacizumab. Patients developing binding antibodies were 0.5% in the IBI305 arm vs 0% in the bevacizumab arm; no subject tested positive for neutralizing antibodies. Conclusions: This is the first released phase 3 clinical study with maintenance treatment for bevacizumab biosimilar in NSCLC patients till now. The comparative study met its predefined primary endpoint that the RR for confirmed ORR was within the prespecified equivalence margin. There was no significant difference between the two arms in safety profile and immunogenicity. Clinical trial information: NCT02954172.

9096 Poster Session (Board #419), Sun, 8:00 AM-11:00 AM

A plasma miRNA signature classifier identifies PD-L1 ‡ 50% NSCLC nonresponders to immune checkpoint inhibitors.

Claudia Proto, Arsela Prelaj, Carla Verri, Diego Signorelli, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Benedetta Trevisan, Mensah Mavis, Filippo G. De Braud, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri; Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy; Unit of Tumor Genomics, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Background: A sizable proportion of PD-L1$50% NSCLC patients (pts) do not respond to single agent immune checkpoint inhibitors (ICI) and no biomarker is able to identify non responders. A three levels plasma microRNA signature classifier (MSC), reflecting an immunosuppressive profile of immune cell subsets, has already shown its ability to identify pts treated with ICI with a worse prognosis independently from PD-L1 expression. Aim of this trial is to prospectively test the ability of MSC to identify at diagnosis PD-L1$50% non responders to ICI. Methods: we prospectively collected baseline plasma samples from 41 consecutive advanced EGFR/ALK/ROS1 wild-type NSCLC pts with PD-L1 TPS $50% treated with ICI as first (n = 28) or further line treatment to run the MSC molecular test. Pts were stratified in high (H) vs intermediate/low (I/L) risk levels. Overall response rate (ORR) and the relative risk of response (RR) were evaluated by 2x2 contingency table using Fisher exact test. Cox proportional hazard models were used to define crude and adjusted hazard ratio (HR). Results: According to RECIST 1.1 criteria, 14 (34%) pts respond to ICIs. With a global median follow-up of 9.8 months, median progression free survival (PFS) and overall survival (OS) were 7.9 months and not reached, respectively. Ten (24%) NSCLC pts were MSC H risk level. ORR was 0% in MSC H vs 45% in MSC I/L risk pts (RR = 0.10; 95%CI = 0.00-0.90; p = 0.0080). Median PFS was 11.4 months for MSC I/L pts vs 2.3 months for MSC H risk (HR = 0.26 95%CI = 0.11-0.62; p = 0.0021). Median OS was not reached for MSC I/L vs 2.7 months for MSC H risk pts (HR = 0.17 95%CI = 0.06-0.48; p = 0.0008). Data remained significant adjusting for age, sex, pack-years and ECOG performance status at the baseline: PFS HR = 0.24 (95%CI = 0.09-0.66; p = 0.0054) and OS HR = 0.15 (95%CI = 0.05-0.51; p = 0.0023). Conclusions: plasma MSC shows promising results for treatment selection with ICI. So far, MSC is the only molecular test able to identify a group of NSCLC pts with PD-L1$50% who do not respond to single agent immunotherapy. Ongoing trials are validating these results and testing the possible predictive effect of MSC in chemotherapy plus immunotherapy combinations.

9097 Poster Session (Board #420), Sun, 8:00 AM-11:00 AM

Phase 1 dose-expansion study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1 (ASS1)–deficient non-squamous non- small cell lung cancer.

Akhila Ganeshi Wimalasingham, Melissa Mary Phillips, Louise Lim, Sukaina Rashid, Peter Edward Hall, Ramsay Khadeir, Jeremy P. C. Steele, John Conibear, Xiaoxing Feng, Stephen Ellis, Pui Ying Chan, Jim Thomson, Amanda L. Johnston, John S. Bomalaski, Simon Pacey, Michael Sheaff, Peter Wojciech Szlosarek; Barts Health NHS Trust, London, United Kingdom; Barts Cancer Institute, London, United Kingdom; Queen Mary University London, London, United Kingdom; St. Bartholomews’ Hospital, London, United Kingdom; St Bartholomew’s Hospital, London, United Kingdom; Washington State Univ, Pullman, WA; Barts Health Trust, London, United Kingdom; Polaris Pharmaceuticals Inc., San Diego, CA; Agouron/Pfizer, San Diego, CA; University of Cambridge, Cambridge, United Kingdom

Background: Pegylated arginine deiminase (ADI-PEG20) targets ASS1-ve tumors, including non–small- cell lung cancer (NSCLC), by potentiating pemetrexed cytotoxicity via arginine depletion. In Beddowes et al (JCO 2017) we showed a 100% disease control rate in thoracic cancers treated with ADI-PEG20, cisplatin and pemetrexed (ADIPemCis). Thus, we tested ADIPemCis in a phase I dose-expansion cohort study of patients (pts) with non-squamous NSCLC. Methods: Good performance (ECOG 0-1) advanced non-squamous NSCLC pts were enrolled at the maximum tolerated dose (MTD) of ADIPemCis, using tumoral ASS1 loss as a selection biomarker. Pem (500mg/m2) and Cis (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for up to 4 cycles with maintenance ADI-PEG20 or Pem in responding pts. Primary endpoint was tumor response rate (RR by RECIST 1.1), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We also measured plasma [arginine] and [citrulline], anti-ADI-PEG20 antibodies, and PD-L1 expression. Results: 21 of 70 screened pts (median age 60.1) were enrolled between April 15 and August 17. A confirmed partial response (PR) was observed in 55.6 % (n = 10/18 evaluable pts). Median PFS and OS were 4 months (95% CI 2.9-4.8) and 7.2 months (95% CI 5.1-18.4), respectively. 9% (n = 2/21) remain alive on subsequent therapies. 43% (n = 9/21) experienced grade 3/4 treatment-related toxicities, commonly non-febrile neutropenia. Plasma [arginine] declined rapidly and [citrulline] increased; both changes persisted at 16 weeks. 55% of pts’ tumors (n = 6/11 ) were PD-L1 , 1% by immunohistochemistry. Conclusions: The ADIPemCis regimen is active and safe in ASS1-ve NSCLC pts almost doubling the expected RR. However, the short survival compared with ASS1-agnostic historical controls indicates that ASS1 (and frequent PD-L1) loss selects for a biologically more aggressive and immunorefractory NSCLC phenotype. The iTRAP study opening Q2 of 2019 will assess the safety and tolerability of ADIPemPlatinum(Carbo) with atezolizumab in pts with ASS1-deficient non-squamous NSCLC. Clinical trial information: NCT02029690.

9098 Poster Session (Board #421), Sun, 8:00 AM-11:00 AM

A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy.

Enriqueta Felip, Paal Brunsvig, Nuria Vinolas, Santiago Ponce Aix, Enric Carcereny Costa, Manuel Domine ´ Gomez, Jose Manuel Trigo Perez, Edurne Arriola, Rosario Garcia Campelo, James F. Spicer, Jonathan Robert Thompson, Ana Laura Ortega Granados, Robert J Holt, Katherine Lorens, James B. Lorens, Muhammad Shoaib, Abdul Siddiqui, Emmett V. Schmidt, Michael Jon Chisamore, Matthew Krebs; Hospital Universitari Vall d’Hebron, Barcelona, Spain; Oslo University Hospital, Oslo, Norway; Hospital Clinic, Barcelona, Spain; Hospital 12 de Octubre, Madrid, Spain; Institut Catalad ` ’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; Hospital Uni- versitario Fundacion ´ Jimenez ´ Dı´az, Madrid, Spain; Hospital Virgen de la Victoria, Malaga, ´ Spain; Hospital del Mar, Barcelona, Spain; Medical Oncology Service, University Hospital A Coru~na (XXIAC- SERGAS), A Coru~na, Spain; King’s College London, London, United Kingdom; Medical College of Wisconsin Affiliated Hospitals, Menomonee Falls, WI; Medical Oncology, Complejo Hospitalario de Jaen,Ja´ ´ en, Spain; BerGenBio ASA, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway; BergenBio ASA, Bergen, Norway; Merck & Co., Inc., Kenilworth, NJ; Merck & Co., Inc., Rahway, NJ; The Christie NHS Foundation Trust and The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom

Background: AXL is an RTK implicated in epithelial-to-mesenchymal transition and as a resistance mechanism to multiple therapies including anti-PD1. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods: This is a Phase II single-arm, two-Stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously treated, IO na¨ıve pts (n = 48 in total) with Stage IV lung adenocarcinoma. The primary endpoint was ORR according to RECIST 1.1 with predefined minimum requirement for 18% RR in the first Stage (n = 24) to proceed to Stage 2. Secondary endpoints included DCR, PFS, OS and safety. Tumour biopsies were analysed for PD-L1 (22C3 pharmDx), AXL, and infiltrating immune cells. Results: Stage 1 completed enrolment in Apr ‘18. As of Feb ‘19, 38 pts (24 and 14 in Stage 1 and 2, respectively) have been dosed with the combination; median age 66 (range 39-79) yr, 59% male, all previously received one prior line of platinum-based chemotherapy or a licensed EGFR/ALK-directed therapy. The most common TRAEs (occurring in . 15% of pts) were transaminase increases (37%), diarrhoea (29%), and asthenia (17%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments. At time of writing, Stage 1 had met the efficacy threshold to proceed to Stage 2 with continued enrolment. Among 29 pts evaluable for response 7 PRs were reported (24%). For AXL positive pts (10/21 with available biopsies), ORR was 40%. PD-L1 status was known for 5 responders: 4 pts (80%) were PD-L1 negative or weakly positive. In Stage 1, mPFS was 4.0 months (95% CI 1.9 – NR) and 5.9 months in AXL positive pts (n = 10; 3.0 - NR). mOS was not mature. Conclusions: Overall, bemcentinib in combination with pembrolizumab was well tolerated and promising clinical activity was seen, particularly in pts with AXL positive disease. Updated results will be reported at the meeting, incl 12-month OS for Stage 1 and preliminary efficacy of Stage 2. Clinical trial information: NCT03184571.

9099 Poster Session (Board #422), Sun, 8:00 AM-11:00 AM

Cancer cachexia, sarcopenia and hand-GRIP strength (HGS) in the prediction of outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): A prospective, observational study.

Sofia Agelaki, Konstantinos Rounis, Chara Papadaki, Alexia A Monastirioti, Lampros Vamvakas, Ioannis Gioulbasanis, Dimitrios Mavroudis, Dimitris A Makrakis; Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece; Department Of Medical Oncology, University General Hospital of Heraklion, Heraklion, Greece; Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece; University Hospital of Larissa, Larissa, Greece; University of Crete Medical School, Heraklion, Greece

Background: Cancer cachexia syndrome, affecting up to 80% of patients (pts) with NSCLC, is characterized by systemic inflammation, negative protein and energy balance and poor patient outcome. HGS has been independently correlated with outcome in pts with advanced cancer. We investigated the potential association between cachexia, sarcopenia and HGS with outcome in pts with advanced NSCLC treated with ICIs. Methods: Fifty-five pts with NSCLC treated with ICIs were included in the analysis. Patient and disease characteristics and data on outcome measures were prospectively collected. Cancer cachexia was defined as weight loss . 5% in the last 6 months, BMI , 20% (or baseline skeletal muscle index at the level of the 3rd lumbar vertebra consistent with sarcopenia) and any degree of weight loss . 2%. Baseline HGS was measured using the JAMAR analogue dynamom- eter. Results: Median age was 69 years, 50% of pts had non-squamous histology, 69% had PS 0-1, 61% had cancer cachexia and mean HGS was 27 kgs. Partial response, stable disease and progressive disease was recorded in 16%, 33% and 51% of pts, respectively. Median PFS was 4 months and median OS was 7.8 months. There was no association of cachexia or HGS with tumor burden, number of metastatic sites, LDH or neutrophil/lymphocyte ratio. Cachexia had a negative impact on HGS (p = 0,001). Pts with cachexia had lower response rates (4% vs 37%, p = 0.002), disease stabilization rates (32% vs 81%, p = 0.003) and shorter PFS (3.7 vs 8.2 months, p = 0.008) compared to non-cachectic pts. In multivariate analysis, cachexia independently predicted for shorter PFS (HR = 2.7, CI: 1.15 – 6.46, p = 0.023). Data on sarcopenia are being analyzed and will be presented at the meeting. Conclusions: Cancer cachexia is associated with lower response rates and disease stabilization rates and independently predicts for shorter PFS in pts with NSCLC treated with ICIs. To our knowledge this is the first report demonstrating a between the host’s immune and metabolic responses. The study of cancer cachexia may offer a new platform for the development of novel biomarkers of resistance to ICIs.

9100 Poster Session (Board #423), Sun, 8:00 AM-11:00 AM

DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).

Hirva Mamdani, Jerry Chen, Seongho Kim, Yahya Ibrahim, Mohammad Fahad Bin Asad, Jorge J. Nieva, Rebecca Feldman, Abdul Rafeh Naqash, Stephen V. Liu, Patrick C. Ma, David Craig Portnoy, Hossein Borghaei, Nagla Fawzy Abdel Karim, Yanis Boumber, Ari M. Vanderwalde, Alexander I. Spira, Shadia Ibrahim Jalal; Karmanos Cancer Institute, Detroit, MI; Wayne State University School of Medicine, Detroit, MI; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI; Wayne State University, Detroit, MI; University of Southern California, Los Angeles, CA; Caris Life Sciences, Phoenix, AZ; East Carolina University/Vidant Cancer Center, Greenville, NC; Georgetown University Medical Center, Washington, DC; WVU Cancer Institute, West Virginia University, Morgantown, WV; The West Clinic, Memphis, TN; Fox Chase Cancer Center, Philadelphia, PA; Augusta University, Augusta, GA; Division of Hematology/Oncology, The University of Tennessee Health Science Center, West Cancer Center, German- town, TN; Virginia Cancer Specialists, Fairfax, VA; Indiana University School of Medicine, Indianapolis, IN

Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes (ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as $10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high ($50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( , 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with $3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of $3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.

9101 Poster Session (Board #424), Sun, 8:00 AM-11:00 AM

Crizotinib versus pemetrexed-based chemotherapy in patients with advanced ROS1- rearranged non-small cell lung cancer.

Lan Shen, Shun Lu; Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; Shanghai Chest Hospital, Jiao Tong University, Shanghai, China

Background: ROS1 rearrangement is an important therapeutic target that occurs in approximately 1-2% of patients with non-small cell lung cancer (NSCLC). It has been shown that ROS1-rearranged patients could benefit from crizotinib treatment. However, the efficacy of crizotinib as compared with pemetrexed-based chemotherapy in such patients is unknown. Methods: Advanced ROS1- rearranged NSCLC patients receiving crizotinib or pemetrexed-based chemotherapy as first-line treatment in Shanghai Chest Hospital between August 2010 and December 2017 were retrospectively reviewed. Clinical characteristics, treatments and survival outcomes data were abstracted. Results: Of 77 patients included, 30 patients (39.0%) received crizotinib and 47 patients (61.0%) received pemetrexed-based chemotherapy as their first-line treatment. The median follow-up was 26.8 months. The objective response rate was significantly better with crizotinib than with pemetrexed-based therapy (86.7% vs 44.7%, P , 0.001). The disease control rate wasc 96.7% with crizotinib, as compared with 85.1% with pemetrexed-based therapy (P = 0.140). The median progression-free survival was significantly longer with crizotinib versus pemetrexed-based therapy (18.4 months [95% confidence interval [CI]: 6.8-30.0] vs 8.6 months [95% CI:7.1-10.2], P , 0.001). No significant difference in overall survival (OS) was observed between the two groups (Not reach vs 28.1 months [95% CI:18.7- 38.5], P = 0.173). Six patients (20%) in the crizotinib group switched to pemetrexed-based therapy in subsequent lines, while twenty-nine patients (61.7%) in the chemotherapy group crossed over to receive crizotinib after progression. There was no significant difference in median OS between patients who received crizotinib first and those who received pemetrexed-based treatment prior to crizotinib (38.6 months [95% CI: 0-81.0] vs 32.7 months [95% CI:14.3-51.1], P = 0.890). Conclusions: Crizotinib is superior to pemetrexed-based chemotherapy as an initial treatment for advanced ROS1- rearranged NSCLC patients. The sequence of crizotinib treatment and pemetrexed-based chemotherapy does not influence OS.

9102 Poster Session (Board #425), Sun, 8:00 AM-11:00 AM

Determinants of early discontinuation of first-line chemotherapy, and associated outcomes among elderly with advanced non-small cell lung cancer.

Pramit Nadpara; Virginia Commonwealth University Massey Cancer Center, Richmond, VA

Background: Chemotherapy is the primary treatment modality in elderly with Advanced-NSCLC (Adv- NSCLC), with ASCO/NCCN guideline recommending First-Line Chemotherapy (FL-Chemo) for at least 4 months. The objective of this study was to identify the determinants, and outcomes of early discontinuation of FL-Chemo, in a nationwide sample of elderly patients. Methods: We used NCI’s Surveillance, Epidemiology, and End Results registry linked Medicare (SEER-Medicare) 2007-2014 files. We included patients with NSCLC diagnosis in 2007-2013, age $65, AJCC Stage IIIB/IV, receiving only FL-Chemo (Identified using HCPCS/CPT codes), and surviving at least 9 months post- diagnosis. We excluded those with non-continuous Medicare enrollment, or HMO enrollment. Patients receiving 1-3 months (vs. 4-7 months) of FL-Chemo were characterized as those experiencing early discontinuation. Patient’s performance status and comorbidity burden were assessed using previously validated algorithms. Survival was calculated from the diagnosis date to the date of death/study end date. Chi-square test, logistic regression, survivor function, proportional hazards regression, and propensity score–adjusted modeling were conducted. Results: We identified 1,029 patients (meeting inclusion and exclusion criteria) with incident Adv-NSCLC during the study years. Of those, 43.2% patients experienced early discontinuation. Adjusted analysis revealed Age as the only significant factor associated with early FL-Chemo discontinuation, with odds increasing with increase in age (p , 0.035). Other patient factors (non-clinical and clinical factors including performance score, comorbidity) were not associated with early discontinuation in any model. Survival outcomes and mortality risk were poor among those experiencing early discontinuation, however the difference was not statistically significant (p , 0.165). Conclusions: A large proportion of elderly with Adv-NSCLC experience early discontinuation of FL-Chemo. Even after controlling for variability in patient performance score and comorbidity burden, Age remained a key factor associated with early discontinuation, raising a cause for concern. Future studies need to explore the impact of Age along with patient reported Quality of Life on early treatment discontinuation.

9103 Poster Session (Board #426), Sun, 8:00 AM-11:00 AM

Early mortality in metastatic lung cancer: A SEER population data analysis.

Opher Globus, Jair Bar, Amir Onn, Inbal Uri, Sivan Lieberman, Jonathan Weidenfeld, Rakefet Manu-Sitton, Yael Eshet, Yaacov Richard Lawrence, Damien Urban; Sheba Medical Center, Ramat Gan, Israel; Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel; Sheba Medical Center, Tel Hashomer, Israel

Background: Millions of dollars invested in improving outcomes for metastatic lung cancer patients are essentially aimed at extending long term survival, with significant benefits being achieved over the last decade. However, little is known about lung cancer patients who die rapidly after diagnosis, potentially being deprived of these advances. We analyzed population-based data to describe real-world outcomes in metastatic lung cancer patients focusing on patients with early mortality. Methods: Using the Survival, Epidemiology and End Results (SEER) Database we analyzed adult metastatic lung cancers diagnosed between 1994-2014. This period was divided into 3 equal time periods: 1994-2000 (TP1), 2001-2007 (TP2) and 2008-2014 (TP3). Early mortality was defined as death within 2 months of diagnosis. Correlations between categorical variables were analyzed with chi squared tests and survival was analyzed using the Kaplan-Meier method. Results: Of 276,527 patients diagnosed with metastatic lung cancer, median age was 67 (range 20-105) and 154,465 (56%) were males. Thirty eight percent (103,830) of all patients died within 2 months of diagnosis. Of these early deaths, 96,344 (92.8%) were due to lung cancer. While the 2-year survival almost doubled from TP1 compared to TP3 (6% vs 11%, p , 0.001), the percentage of patients who died within 2 months only marginally improved (39.7% vs. 36.2% in TP1 vs TP3, respectively). For patients surviving at least 2 months, 2-year survival increased from 10% to 18% in TP1 vs TP3 (p , 0.001). Factors associated with early mortality include age . 65 (45% vs 31%), unmarried status (42% vs 34%), male sex (39% vs 36%), liver metastases (47% vs 32%) and large cell carcinoma vs adenocarcinoma (44% vs 36%) (all p , 0.001). Conclusions: While there has been a steady improvement in the long-term overall survival of patients with metastatic lung cancer, over one third of patients still die within 2 months of diagnosis. This has only marginally improved in the last 20 years. Research is urgently needed to identify causative and treatable factors.

9104 Poster Session (Board #427), Sun, 8:00 AM-11:00 AM

Randomized phase I/II trial of pembrolizumab with and without radiotherapy for metastatic non-small cell lung cancer.

James William Welsh, Hari Menon, Chad Tang, Vivek Verma, Mehmet Altan, Kenneth R. Hess, Patricia de Groot, Quynh Nguyen, George R. Simon, Ferdinandos Skoulidis, Joe Y. Chang, Vassiliki Papadimitrakopoulou, John Heymach; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Texas MD Anderson Cancer Center, Houston, TX; Allegheny General Hospital, Pittsburgh, PA; Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: We present findings of a randomized phase I/II trial studying PD-1 blockade with and without radiotherapy to lung lesions in patients with metastatic NSCLC. Methods: Patients with metastatic NSCLC were randomized to receive pembrolizumab with or without lung-directed radiotherapy (RT). RT referred to stereotactic body radiation therapy (SBRT, 50 Gy in 4 fractions or 70 Gy in 10 fractions) or traditional fractionation (45 Gy in 15 fractions). Pembrolizumab (200mg IV) was started on day 1 and given every 3 weeks for up to sixteen cycles. The primary endpoint was out-of-field response rate (RR), which refers to complete (CR) or partial response (PR) per irRC criteria. Results: Of 124 enrolled patients, 103 received treatment, 5 withdrew consent, 15 screen failures, and 1 was not financially cleared. Twenty-one patients completed 16 cycles of pembrolizumab; 16 patients received SBRT and 20 received traditional RT. Seven patients received salvage RT after progression on pembrolizumab alone and 15 patients received RT six months before starting the trial. In the combined-modality arm, there were 2 grade 4 toxicities and 9 grade 3 toxicities related to treatment. In the pembrolizumab arm, there were zero grade 4 toxicities and five grade 3 toxicities. At the present time, 72 patients were evaluable for response, 36 in both arms; median follow-up was 15.4 months (range: 1.4-125.2 months). RR for out-of-field lesions was 22% and 25% for the pembrolizumab + RT vs pembrolizumab respectively (p = 1.00); median PFS was 10.9 months (95% CI, 8.1-15.3 months) and 8.4 months (95% CI, 3.9-17.1 months) respectively (p = 0.83). When comparing the SBRT vs traditional fractionation sub-cohorts, non-irradiated RR was 38% and 10% respectively (p = 0.10); median PFS was 21.1 and 6.8 months respectively (p = 0.03). Within the pembrolizumab arm, comparing patients who received prior RT vs those that did not, RR was 33% and 19% respectively (p = 0.26). Conclusions: RT, while safe, did not increase the out-of-field response rate in NSCLC patients treated with pembrolizumab. Exploratory analysis suggests responses may be enhanced by SBRT, but not traditional fractionation, which warrants further investigation. Clinical trial information: NCT02444741.

9105 Poster Session (Board #428), Sun, 8:00 AM-11:00 AM

Project Switch: Docetaxel as a potential synthetic control in metastatic non-small cell lung cancer (mNSCLC) trials.

Michael E. Menefee, Yutao Gong, Pallavi Shruti Mishra-Kalyani, Rajeshwari Sridhara, Bindu Kanapuru, Gideon Michael Blumenthal, Richard Pazdur; FDA, Silver Spring, MD; U.S. Food and Drug Admin- istration, Silver Spring, MD

Background: Docetaxel is a common comparator arm to test novel therapies in post-platinum mNSCLC trials. The advent of Real World Evidence (RWE) has renewed interest in the use of synthetic control arms (control arms from previously conducted randomized trials) to improve accrual to trials and increase patient access of promising experimental agents. We reviewed legacy second-line (2L) mNSCLC trials to assess the impact of switching docetaxel control arms from one trial to another and compare to an experimental regimen. Methods: We identified 5 contemporary 2L trials that enrolled 2013 patients receiving an experimental therapy vs. docetaxel: 5 immunoncology head-to-head trials (one with 2 arms) and one anti-VEGF add-on trial. Kaplan-Meier curves of overall survival (OS) and progression-free survival (PFS) were produced for docetaxel controls. We calculated OS and PFS hazard ratios and 95% confidence intervals for each synthetic trial. A pooled doc arm was also compared with each experimental agent. Results: See Table. Conclusions: Both individual and pooled docetaxel switching of control arms approximated the original OS HR and 95% CI. Methods such as bootstrapped sampling and propensity score matching will be performed in an effort to more closely approximate the original trial characteristics.

Original OS HR Range of Switch doc OS HR Pooled doc OS HR N (95% CI) (Range of 95% CI) (95% CI) Trial 1 292 0.75 (0.62, 0.91) 0.71 – 0.86 (0.58 – 1.02) 0.79 (0.67, 0.92) Trial 2 144 0.68 (0.51, 0.89) 0.64 – 0.75 (0.50 – 0.94) 0.69 (0.55, 0.85) Trial 3 613 0.79 (0.68, 0.90) 0.65 – 0.71 (0.54 – 0.88) 0.69 (0.61, 0.78) Trial 4 344 0.73 (0.59, 0.89) 0.78 – 0.87 (0.64 – 1.05) 0.80 (0.69, 0.94) Trial 5 346 0.63 (0.51, 0.78) 0.67 – 0.75 (0.55 – 0.91) 0.69 (0.59, 0.82) Trial 6 618 0.86 (0.75, 0.98) 0.79 – 0.96 (0.66 – 1.10) 0.89 (0.79, 1.00)

9106 Poster Session (Board #429), Sun, 8:00 AM-11:00 AM

Immune-checkpoints inhibitors in metastatic non small cell lung cancer with rare histology.

Diego Signorelli, Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Martina Imbimbo, Giulia Galli, Alessandro De Toma, Filippo Pagani, Giovanni Randon, Giovanni Fuca, ` Benedetta Trevisan, Monica Ganzinelli, Nicoletta Zilembo, Alessandra Fabbri, Filippo G. De Braud, Marina Chiara Garassino, Arsela Prelaj; Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Adult Mesenchymal and Rare Tumor Unit, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Instituto Nazionale Per Lo Studio E, Milan, Italy

Background: Immune-checkpoints inhibitors (ICIs) have clearly improved prognosis of metastatic lung squamous carcinoma and adenocarcinoma, while their benefit remains uncertain in patients (pts) with rare NSCLC histotypes (RH). The study aim was to evaluate ICIs efficacy in RH. Methods: We retrospectively collected data from consecutive metastatic NSCLC pts treated with ICIs at our Institution from 4/2013 to 12/2018. Objective response rate (ORR) and disease control rate (DCR) were assessed. Fisher’s exact test was used to compare ORR and DCR in RH versus not-RH (NRH). Univariate and multivariate survival analyses were estimated by Kaplan-Meier and Cox progression hazard models. Results: Of 268 pts, 31 (11.6%) had RH: 16 sarcomatoid, 7 pulmonary enteric adenocarcinoma, 4 large cell neuroendocrine carcinoma and 4 adenosquamous carcinoma. In RH group, median age was 67 years old (range 41-81), most were males (71%) and smokers (90.3%); ECOG PS was: 0 (16.1%), 1 (67.8%) and 2 (16.1%). PD-L1 , 1%, 1-49%, $50% and unknown expression were reported in 22.6%, 19.3%, 35.5% and 22.6% pts, respectively. Twelve pts received ICIs as first and 19 as second or further-line. ORR was 22.6% in RH, 20.3% in NRH (p = 0.81); DCR was 35.5% in RH, 53.1% in NRH (p = 0.08). After a median follow-up of 20 months (m) (95% CI 4.0 – 36.7 m), median progression-free survival (PFS) was 2.6 m (95% CI 1.9-3.3 m) in RH vs 2.6 m in NRH (95% CI 2.1 – 3.0 m); median overall survival (OS) was 4.6 m (95% CI 0.03-12.0 m) in RH vs 9.2 m (95% CI 7.4 – 10.9 m) in NRH. No statistically significant differences were seen between the two groups (p = 0.729 for PFS, p = 0.601 for OS). At multivariate analyses adjusted for age, sex, smoke, PS, PD-L1 status, line of therapy and histotype (RH vs NRH), only low PS and first line treatment showed better PFS and OS (p , 0.001 and p = 0.003, respectively) in overall population. Conclusions: Our analysis, limited by the small and heterogeneous RH sample size, reported no significant differences between RH and NRH in terms of ORR, DCR and survival. However, looking at OS and DCR data, RH seem to have worse outcome. Correlation between histotype and pts characteristics and survival analyses in a larger cohort of ICIs treated NSCLC pts is ongoing. Specific prospective trials are needed to evaluate ICIs role in RH.

9107 Poster Session (Board #430), Sun, 8:00 AM-11:00 AM

Fast-progression (FP), hyper-progression (HPD) and early deaths (ED) in advanced non-small cell lung cancer (NSCLC) patients (pts) upon PD-(L)-1 blockade (IO).

Roberto Ferrara, Laura Mezquita, Matthieu Texier, Jihene Lahmar, Clarisse Audigier-Valette, Laurent Tessonnier, Julien Mazieres, Solenn Brosseau, Laura Leroy, Boris Duchemann, Corentin Lefebvre, Remi Veillon, Virginie Westeel, Stephane Champiat, David Planchard, Jordi Remon, Anas Gazzah, Jean-Charles Soria, Caroline Caramella, Benjamin Besse; Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy; Medical Oncology Department, Gustave Roussy, Villejuif, France; Gustave Roussy, Villejuif Cedex, France; Hopitalˆ Sainte Musse, Toulon, France; Nuclear Medicine Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France; Hopitalˆ Larrey, Centre Hospitalier Universitaire Toulouse, Toulouse, France; Hopitalˆ Bichat, Assistance Publique-Hopitauxˆ de Paris (Paris public hospitals), Paris, France; Gustave Roussy, Villejuif, France; Laboratory of Immunomonitoring in Oncology, Gustave Roussy, Villejuif, France; Medical Oncology Toulouse, Toulouse, France; CHU Bordeaux, Service Des Maladies Respiratoires, Bordeaux, France; University of Franche-Comte, ´ Besancon, France; Institut Gustave Roussy, Nantes, France; Medical Oncology Department, Thoracic Group, Gustave Roussy, Villejuif, France; Centro Integral Oncologı´a Clara Campal Barcelona, HM-Delfos, Barcelona, Spain; Department of Drug Development (DITEP), Gustave Roussy, Villejuif Cedex, France; Radiology Department, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay and Gustave Roussy, Villejuif, France

Background: HPD was described in 13.8% of NSCLC pts upon single-agent IO and correlated with high metastatic burden and poor prognosis. Other progression (PD) patterns as FP and ED within 12 weeks have been reported respectively in 4.7% and 5.6% of atezolizumab treated NSCLC pts. Whether FP/ED and HPD are different or overlapping patterns is currently unknown. Methods: We analyzed FP, ED and HPD in a multicentric (8 centers) retrospective cohort of IO treated NSCLC pts (11/2012-04/2017). Eligibility criteria required 2 CT scans before and one after IO start. HPD was defined as RECIST v 1.1 PD at first CT scan and a variation per month of tumor growth rate (TGR upon IO – TGR before IO) . 50%. ED was defined as deaths due to disease PD within 12 wks of IO start. FP was defined as $ 50% increase in the sum of long diameters within 6 weeks (wks) from baseline. The associations between PD patterns and pts’ characteristics were performed using Fisher or t-student tests. Median overall survival (mOS) was estimated by Kaplan-Meier method and compared by log-rank test. Results: Out of 406 NSCLC pts, 46% were $65 years, 72% had non-squamous NSCLC, . 90% received single agent IO in $2 line. 56 (13.8%) were HPD by TGR analysis. Among 72 pts (18%) who performed a CT scan within 6 wks after IO start, 6 (8.3%) were FP. These 6 FP pts were also classified as HPD by TGR analysis, while the other 50 (89%) of 56 HPD pts were not FP. The rate of PD in $ 3 sites (54% vs 0%, p = 0.002), the rate of liver PD (62% vs 5%, p = 0.002), the baseline tumor burden (BTB) (mean 1766 26 mm vs 55 6 6 mm, p , 0.0001) and the TGR upon IO (mean 4396 119% vs 216 6 41%, p = 0.03) were significantly higher in FP pts compared to HPD pts who were not FP. At 4.4 months of median follow-up, FP pts had significantly worse mOS compared to HPD pts not FP [0.7 months (95% CI 0.6,0.8) vs 1.6 months (95% CI 1.1, 2.1); p = 0.02]. Of 406 IO treated pts, 46 (11%) were ED within 12 wks, and 21 (46%) of ED pts had also HPD by TGR analysis. Conclusions: FP and ED are not a surrogate of HPD. FP occurs in a small subgroup (11%) of HPD and correlates with more aggressive features (PD in $3 sites, liver-PD, high BTB, high TGR upon IO) and worse OS. ED within 12 wks overlapped with HPD for only 46% of pts.

9108 Poster Session (Board #431), Sun, 8:00 AM-11:00 AM

Non-small cell lung cancer (NSCLC) case study examining whether results in a randomized control arm are replicated by a synthetic control arm (SCA).

Ruthie Davi, Mark Chandler, Barbara Elashoff, Andrea Stern Ferris, Andrew Howland, David Lee, Antara Majumdar, Mark Stewart, Larry Strianese, Elizabeth Stuart, Xiang Yin, Antoine Yver; Medidata Solutions, New York, NY; Medidata Solutions, Inc., New York, NY; LUNGevity Foundation, Potomac, MD; Friends of Cancer Research, Washington, DC; Johns Hopkins University, Baltimore, MD; Daiichi Sankyo, Inc., Basking Ridge, NJ

Background: The FDA’s accelerated approval (AA) pathway provides conditional approval for an investigational product (IP) after positive effect on a surrogate endpoint has been provided, allowing patients earlier access to the therapy. Confirmation of a positive effect on the clinical endpoint after conditional approval is required and usually includes a randomized trial. However, such a trial is challenged by availability of the IP outside the trial. Recruitment becomes more difficult, and patients assigned to control are more likely to drop-out and use the non-assigned IP, which may bias the observed treatment effect. In AA settings we propose a SCA composed of patient level data from previous clinical trials to augment or replace the randomized control. Validity of this approach in one case study is assessed by examining if a SCA can replicate the outcomes of a target randomized control (TRC) from a recent NSCLC trial. Methods: The patients for the NSCLC SCA were required to have satisfied the key eligibility criteria of the target trial and were further selected using a propensity score- based approach to balance the baseline characteristics in the SCA and TRC. All patient selections were made without knowledge of patient outcomes. Results: The results show comparable balance in observed baseline characteristics of the SCA and TRC was achieved. Overall survival (OS) in TRC was replicated by SCA. The Kaplan Meier curves for OS in the SCA and TRC visually overlap. In addition, the log rank test (p = 0.65) and hazard ratio of 1.04 (95% CI: (0.88, 1.23)) were not statistically significant. Conclusions: If the SCA had been in place of the randomized control in this study, conclusions about the treatment effect would have been the same. While this may not hold when it is not possible to balance the groups on all confounders, this suggests that in some settings, SCA could augment or replace the randomized control in future trials easing recruitment, retention, and crossover challenges without compromising the understanding of the treatment effect. Future work should examine in what settings SCA is appropriate and consider the implications of potential unobserved confounders.

9109 Poster Session (Board #432), Sun, 8:00 AM-11:00 AM

Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC) after checkpoint inhibitor treatment failure.

Daniel Morgensztern, Rachel E. Sanborn, Lyudmila Bazhenova, Saiama Naheed Waqar, Lori McDermott, Jeff Hutchins, David L. Rimm, Luis E. Raez, Corey J. Langer, Roger B. Cohen; Washington University School of Medicine, St. Louis, MO; Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR; University of California, San Diego, La Jolla, CA; Heat Biologics, Durham, NC; Heat Biologics, Inc., Durham, NC; Yale School of Medicine, New Haven, CT; Memorial Cancer Institute, Florida International University, Miami, FL; University of Pennsylvania Perelman School of Medicine, Phila- delphia, PA

Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with the gp96-Ig fusion protein that functions as an antigen chaperone for cross presentation and dendritic cell activation. DURGA is a multi-cohort study evaluating the combination of HS-110 and anti-PD-1 monoclonal antibodies in patients with advanced NSCLC. We report on Cohort B, consisting of patients with progressive disease (PD) after receiving a minimum of 4 months of treatment (tx) with a checkpoint inhibitor (CPI) at any time prior to study entry. Methods: Patients (pts) with previously treated NSCLC received weekly HS0110 (1 X 107 cells) intradermally for 18 consecutive weeks and nivolumab IV 240 mg every 2 weeks until intolerable toxicity or PD. Tissue was tested at baseline for PD-L1 expression ($ 1% or , 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined as . 10% CD8+ lymphocytes in the tumor stroma. The primary endpoint was objective response rate by RECIST 1.1. Results: As of the September 2018 data cut-off, 20 pts were enrolled. 18 pts (90%) had PD after both chemotherapy and CPI, and 14 (70%) had CPI as their most recent line of tx. The median number prior tx lines was 2 [range 1 to 6]. 3 pts (15%) achieved partial response and 8 pts (40%) had stable disease. Disease control rate was 55%. Progression-free survival (PFS) was 2.7 months (95% CI, 1.8 – 4.0 months) with a median follow up of 6 months. Pts experiencing injection site reactions (ISR) had improved PFS (median NR vs 2.2 months; HR 0.23, p = 0.063) compared to those without ISR. Of 3 patients with confirmed response, 2 were TIL low/PD-L1 positive, and one was TIL high/PD-L1 negative. All pts experienced at least one adverse event (AE), 80% of which were grade 1 or 2. The most common AEs were fatigue (42%), cough and dyspnea (22.6% each) and anemia (16.1%). There were no grade 5 AEs. Conclusions: The combination of HS-110 and nivolumab is well tolerated. Pts continue to be enrolled in this cohort and early data suggest that the addition of HS-110 to nivolumab may restore responsiveness after tumor progression on prior CPI therapy. Clinical trial information: NCT02439450.

9110 Poster Session (Board #433), Sun, 8:00 AM-11:00 AM

Real-world characteristics and outcomes of patients with advanced non-small cell lung cancer (aNSCLC) receiving immune checkpoint inhibitor.

Sean Khozin,JizuZhi,MonikaJun,LiChen,WendyS.Rubinstein,MarkS.Walker,GeorgeAnthonyKomatsoulis, Jeremy Roberts, Ryan Fukushima, Denise Lau, Brigham Hyde, Edward Stepanski, Robert S. Miller; U.S. Food and Drug Administration, Silver Spring, MD; Concerto HealthAI, Boston, MA; American Society of Clinical Oncology’s (ASCO) CancerLinQ, Alexandria, VA; ACORN Research LLC, Memphis, TN; Tempus, Chicago, IL

Background: Immune Checkpoint Inhibitors (ICIs) were first approved for the treatment of aNSCLC in 2014, and since this time have seen rapid adoption in the marketplace. We sought to describe the characteristics of patients with aNSCLC receiving ICIs in the real-world, as well as to examine treatment patterns and outcomes in the time since initial ICI approval. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database. Adult patients with a curated diagnosis of Stage III or IV NSCLC who received $1doseofanICIandhad$2 clinical visits were eligible for inclusion. Stage III patients were excluded if they received any local therapy , 1 year prior to receiving ICI. Patients were also excluded if they received ICI prior to the first FDA approval date. Demographic and clinical characteristics of aNSCLC patients receiving ICI are reported. Outcomes including time to treatment discontinuation (TTD), time to next treatment (TTNT), real-world progression free survival (rwPFS) and overall survival (OS) were examined via the Kaplan Meier method. Results: Among 2,425 aNSCLC ICI patients included in this analysis, median age was 68.0 years (IQR 60.7, 75.2], 54% were male and 73% of patients were white. Non-squamous histology accounted for 64% of aNSCLC ICI users, and 81% had Stage IV disease. Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 in 77% and 2+ in 23% of patients, and 70% were current or former smokers. The majority (75%) of patients received ICI as second-line or later therapy. Treatment outcomes and survival are reported in the Table. Conclusions: This analysis demonstrates that aNSCLC patients receiving ICI therapy in the real-world are older than what was reported in some clinical trials, though survival outcomes were similar. Further research to examine impact of covariates on outcomes is warranted.

aNSCLC Patients Endpoints Median (95% Confidence Interval) TTD 4.17 (3.88 - 4.54) TTNT 12.2 (11.1 - 13.8) rwPFS 4.17 (3.85 - 4.54) OS 12.4 (11.3 - 13.5)

9111 Poster Session (Board #434), Sun, 8:00 AM-11:00 AM

Outcomes to first-line pembrolizumab in patients with non-small cell lung cancer and a PD-L1 tumor proportion score ‡90%.

Elizabeth Jimenez Aguilar, Biagio Ricciuti, Justin F. Gainor, Mizuki Nishino, Anika E. Adeni, Safiya Subegdjo, Sara Khosrowjerdi, Rachel Peterson, Subba Digumarthy, Corinne Liu, Jennifer L. Sauter, Hira Rizvi, Kathryn Cecilia Arbour, Brett W. Carter, John Heymach, Mehmet Altan, Matthew David Hellmann, Mark M. Awad; Dana-Farber Cancer Institute, Boston, MA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; Massachusetts General Hospital, Boston, MA; Department of Radiology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; Massachusetts General Hospital, Cambridge, MA

Background: In non-small cell lung cancers with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of $50%, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared to platinum-doublet chemotherapy. Whether higher PD-L1 expression levels within the TPS range of 50-100% predict for even greater benefit to pembrolizumab is currently unknown. Methods: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment for advanced NSCLC with a PD-L1 TPS of $50%. Results: Among 196 patients with NSCLC treated with first-line pembrolizumab, the ORR was 43.8% (95%CI: 36.8-51.1). At a median follow-up of 12.6 months (95%CI: 11.6-13.7), the mPFS was 6.2 months (95% CI: 4.2-8.2) and the mOS was not reached. The median PD-L1 TPS among patients who experienced a response to pembrolizumab was significantly higher than in patients with stable or progressive disease (TPS 90% vs 70%, P , 0.001), so a TPS cut point of 90% was chosen for further analysis. Baseline clinicopathological characteristics were well-balanced between patients with a PD-L1 TPS of 50-89% vs 90-100%. Compared to patients with a PD-L1 TPS of 50-89% (N = 114, 58.2% of the cohort), patients with a TPS of 90-100% (N = 82, 41.8% of the cohort) had a significantly higher ORR (61.0% versus 31.6%, P , 0.001), a significantly longer mPFS (13.2 versus 3.7 months, HR: 0.48 [95% CI: 0.33-0.71], P , 0.001), and a significantly longer mOS (NR versus 16.0 months, HR: 0.38 [95% CI: 0.21-0.70], P = 0.002). After adjusting for ECOG performance status and smoking history, PD-L1 TPS of 90-100% was significantly associated with improved mPFS (HR: 0.51 [95% CI: 0.34-0.75], P , 0.001) and mOS (HR: 0.38 [95% CI: 0.21- 0.70], P = 0.001). Conclusions: Among patients with NSCLC and a PD-L1 TPS $50%, clinical outcomes are improved in the subgroup of patients with a PD-L1 TPS of $90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.

9112 Poster Session (Board #435), Sun, 8:00 AM-11:00 AM

Efficacy of PD-1 monoclonal antibody SHR-1210 plus apatinib in patients with advanced nonsquamous NSCLC with wild-type EGFR and ALK.

Caicun Zhou, Guanghui Gao, Yi Na Wang, Jun Zhao, Gongyan Chen, Zhihua Liu, Kangsheng Gu, Meijuan Huang, Jianxing He, Jianhua Chen, Zhiyong Ma, Ji Feng Feng, Jianhua Shi, Quanren Wang, Ying Yang, Xinmin Yu, Ying Cheng, Yu Yao, Shengxiang Ren; Pulmonary Hospital of Tongji University, Shanghai, China; Shanghai Pulmonary Hospital, Shanghai, China; Thoracic Oncology Department, The First Affiliated Hospital Zhejiang University, Hangzhou, China; Beijing Cancer Hospital, Beijing, China; Harbin Medical University Cancer Hospital, Harbin, China; Jiangxi Cancer Hospital, Nanchang, China; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, He Fei, China; Department of Thoracic Cancer, Cancer Center, West China Hospital, Sichuan Univeristy, Chengdu, China; The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Hunan Cancer Hospital, Changsha, China; The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China; Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Jiangsu, China; Shandong Linyi Tumor Hospital, Linyi, China; Jiangsu HengRui Medicine Co., Ltd., Shanghai, China; BGI Genomics, Tianjin, China; Zhejiang Cancer Hospital, Hangzhou, China; Department of Oncology, Jilin Province Cancer Hospital, Changchun, China; Department of medical Oncology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi‘’an, China; Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

Background: Our preclinical study suggested combination of PD-1 monoclonal antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. This was an open-label, multicenter, phase 1/2 study of intravenous SHR-1210 plus oral apatinib in patients with advanced NSCLC. Here, we reported preliminary efficacy and safety outcomes of SHR-1210 plus apatinib in patients with wild-type EGFR and ALK. Methods: In dose-escalation phase, advanced non-squamous NSCLC patients (pts) previously treated with at least 2nd line chemotherapy were enrolled to explore 2 dose levels of apatinib (250, 375mg/d) + SHR-1210 (200mg, q2w). 250mg/d of apatinib was selected to be combined with SHR-1210 in phase II trial. Pts previously treated with 1st line platinum-based chemotherapy were enrolled. Primary endpoint was ORR per RECIST 1.1. Archived or fresh tumor tissues and blood samples were taken before the treatment, PD-L1 expression and tumor mutation burden (TMB) were tested and correlated with efficacy. TMB was detected by Oseq-pan cancer panel (including 636 genes and 1.95Mb), and then calculated by in-house algorithm developed by BGI Genomics Co., Ltd. Results: 96 pts with advanced non-squamous NSCLC harboring wild-type EGFR and ALK were recruited. 23 had $2 prior lines of systemic treatment, and 73 had 1 prior line of treatment. Median age was 57, male 79.8%, adenocarcinoma 93.9%, ex-smokers 56.7%. ORR and DCR in 91evaluable pts were 29.7% and 81.3%, respectively. Blood TMB (bTMB) test was available in 80/91 evaluable patients and the cut-point was 1.54 muts/Mb as determined by receiver operating characteristic curve. ORR in pts with high bTMB was 50% (19/38). At data cutoff of 20 Jan 2019, 20/27 responders were still on treatment (table). Across all 96pts, 54(56.2%) grade $3TRAEs.AEsof grade $3 occurring in 2 or more pts included hypertension, hand-foot syndrome, gamma-glutamyl transferase increase, proteinuria, abnormal hepatic function and alkaline phosphatase increase. Conclusions: SHR-1210 plus apatinib demonstrated promising anti-tumor activity with acceptable safety in patients with non-squamous NSCLC, especially in those with high bTMB. Prospective study is needed to validate the clinical outcome and bTMB as a predictor of efficacy. Clinical trial information: NCT03083041.

ORR DCR mDOR (mos) mPFS (mos) ‡2 prior lines 33.3% 85.7% 5.9 6.4 3/7 ongoing 1 prior lines 28.6% 80.0% NR NR 17/20 ongoing bTMB-H 50.0% 81.6% NR 8.3 14/19 ongoing bTMB-L 16.7% 76.2% NR 5.6 5/7 ongoing

9113 Poster Session (Board #436), Sun, 8:00 AM-11:00 AM

Validation of broad panel clinical sequencing-based genomic risk stratification in patients with advanced lung adenocarcinomas.

Sam Whipple, Axel Martin, Michael Martinec, Kathryn Cecilia Arbour, Venkatraman E. Seshan, Gregory J. Riely, Gracy Crane, Ronglai Shen; Genentech, Inc., South San Francisco, CA; Memorial Sloan Kettering Cancer Center, New York, NY; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY; Roche Products Ltd., Welwyn, United Kingdom

Background: We recently established the ability of broad-panel clinical sequencing data to stratify overall survival of patients with advanced lung adenocarcinomas in a single institutional experience (Shen, Riely et al., JCO Precision Oncology 2019). Here we sought to assess its generalizability to a broader range of patients (including patients from multiple community and academic sites) using a different sequencing panel, with an integrated electronic health record and genomic database. Methods: We identified 2,779 next-generation sequencing-tested patients with advanced lung adenocarcinomas from the Flatiron-Foundation Medicine Clinico-Genomic database. A genomic risk model developed from the initial discovery cohort (n=1,054) was used to calculate a risk score for each patient in the validation cohort, scaled between 0 and 10, indicating the risk of cancer specific mortality. Results: Patients in the validation cohort were classified into four risk categories with median survival ranging from 37.6 months (95% CI: 32.9-43.8) in the low risk group (n=534) to 10.9 months (95% CI: 8.0-16.5) in the highest risk group (n=75), representing a hazard ratio of 3.0 (95% CI: 2.2- 4.1) and closely matching the discovery cohort observations. A smaller proportion of patients were deemed high risk in the validation cohort (2.7% vs 10% in the discovery cohort). There were some differences in the frequencies of the most common genomic alterations between the validation and discovery cohorts, including TP53 (57.3% vs 55.1%), KRAS (32.8% vs 30%), EGFR (18.6% vs 29.4%) as well as overlapping STK11 and KEAP1 co-mutations (2.4% vs 10%). Conclusions: We demonstrate that a clinical tumor sequencing-based genomic risk stratification strategy can be applied broadly across cohorts and different sequencing panels and platforms, to improve the understanding of heterogeneity in clinical outcome for patients with metastatic lung adenocarcinomas and the mutation and co-mutational patterns that underlie such heterogeneity.

TPS9114 Poster Session (Board #437a), Sun, 8:00 AM-11:00 AM

Randomized open-label study of M7824 versus pembrolizumab as first-line (1L) treatment in patients with PD-L1 expressing advanced non-small cell lung cancer (NSCLC).

Myung-Ju Ahn, Fabrice Barlesi, Enriqueta Felip, Edward B. Garon, Claudio Marcelo Martin, Tony S. K. Mok, Everett E. Vokes, Laureen S. Ojalvo, Andre Koenig, Isabelle Dussault, Luis G. Paz- Ares; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Aix-Marseille University, Marseille, France; Hospital Universitari Vall d’Hebron, Barcelona, Spain; Ronald Reagan UCLA Medical Center, Los Angeles, CA; Alexander Fleming Institute, Buenos Aires, Argentina; The Chinese University of Hong Kong, Shatin, China; University of Chicago Medicine and Biological Sciences, Chicago, IL; EMD Serono, Billerica, MA; Merck KGaA, Darmstadt, Germany; University Hospital 12 de Octubre, Madrid, Spain

Background: Transforming growth factor b (TGF- b) promotes tumor progression via immune- and non–immune-related processes. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-bRII (a TGF-b “trap”) fused to a human IgG1 monoclonal antibody against PD-L1. Targeting these independent and complementary pathways may restore and enhance antitumor responses. An expansion cohort of the NCT02517398 study of patients with advanced NSCLC (n = 80) treated with M7824 in the second-line setting presented at ESMO 2018 showed an objective response rate of 86% in the subgroup with high PD-L1 tumor expression at the recommended phase 2 dose (1200 mg intravenously [IV] every 2 weeks [Q2W]). Observed data support the hypothesis that M7824 may be superior to other PD-(L)1 inhibitors, including pembrolizumab, for the treatment of NSCLC. Based on the promising antitumor activity and manageable safety profile, this study will evaluate M7824 treatment in patients with advanced NSCLC in the 1L setting. Methods: Here we present a global, randomized trial comparing M7824 vs pembrolizumab in the 1L treatment of patients with metastatic NSCLC with high PD-L1 expression levels. Patients in this study must have a histologically confirmed diagnosis of advanced NSCLC with high PD-L1 expression on tumor cells (defined as either $80% by the Dako 73-10 pharmDx kit or $50% by the Dako 22C3 pharmDx kit since both assays are expected to select a similar patient population at their respective cut-offs). ECOG performance status must be 0 or 1. Patients must not have received prior systemic treatment for advanced NSCLC. Patients with tumors with actionable mutations (for which targeted therapy is locally approved) are not eligible. Patients will receive 1200 mg Q2W or pembrolizumab 200 mg Q3W as an IV infusion until confirmed disease progression, unacceptable toxicity, or trial withdrawal. Dual primary endpoints are progression- free survival and best overall response; key secondary endpoints include overall survival, duration of response, and safety. Estimated enrollment is 300 patients. Clinical trial information: NCT03631706.

TPS9115 Poster Session (Board #437b), Sun, 8:00 AM-11:00 AM

Phase 2 study of brigatinib in patients (pts) with anaplastic lymphoma kinase (ALK)2 positive, advanced non–small cell lung cancer (NSCLC) that progressed on alectinib or ceritinib.

Edward S. Kim, Sai-Hong Ignatius Ou, Fabrice Barlesi, Tony S. K. Mok, Myung-Ju Ahn, Veronica Bunn, Pingkuan Zhang; Levine Cancer Institute, Atrium Health, Charlotte, NC; Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA; Aix Marseille University, INSERM, CNRS, CRCM, APHM, CEPCM CLIP2, Marseille, France; Prince Wales Hospital, Shatin, China; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA

Background: Second-generation ALK tyrosine kinase inhibitors (TKIs) alectinib and ceritinib have demonstrated efficacy and acceptable safety in ALK TKI-pretreated and TKI-naive NSCLC. However, as with crizotinib, resistance to alectinib and ceritinib eventually develops, with secondary resistance mutations detected in approximately 50% of pts. Brigatinib is a next-generation ALK TKI designed to have potent and broad activity against ALK mutants. Post-crizotinib, brigatinib demonstrated high systemic and CNS objective response rates (ORR) and the longest reported median progression-free survival (PFS) of any ALK inhibitor in this setting (16.3–16.7 mo) (Huber. JClinOncol2018;36; Bazhenova. Ann Oncol 2017;28); efficacy was demonstrated regardless of mutations. Based on non- clinical and clinical data, brigatinib may show efficacy in ALK+ NSCLC that has developed resistance or failed to respond to alectinib/ceritinib. This trial was designed to assess efficacy and safety of brigatinib in pts with ALK+ NSCLC that has progressed on alectinib or ceritinib. Methods: This is a phase 2, open-label, single-arm, multicenter, international trial (NCT03535740) in pts ($18 y) with locally advanced/ metastatic NSCLC and disease progression on alectinib or ceritinib (6 prior crizotinib; #3 different systemic regimens for locally advanced/metastatic disease). Pts receive oral brigatinib 180 mg QD with 7- day lead-in at 90 mg QD. Treatment beyond progression or escalation to brigatinib 240 mg QD is permitted. Primary endpoint: independent review committee (IRC)2assessed confirmed ORR (cORR) per RECIST v1.1. Secondary endpoints: investigator (INV)-assessed cORR, duration of response (INV- and IRC-assessed), PFS, disease control rate, and time to response; in pts with baseline brain metastases: IRC-assessed intracranial cORR, duration of intracranial response, and intracranial PFS; OS; safety/ tolerability; and HRQoL. Exploratory endpoints include biomarker analyses. The study was initiated in Dec 2018 at 78 sites (North America, Europe, Asia), with a planned sample size of 103 pts. Accrual is ongoing. Clinical trial information: NCT03535740.

TPS9116 Poster Session (Board #438a), Sun, 8:00 AM-11:00 AM

TACTICAL: A phase I/II trial to assess the safety and efficacy of MSCTRAIL in the treatment of metastatic lung adenocarcinoma.

Alice Davies, Beth Sage, Krishna Kolluri, Doraid Alrifai, Rebecca Graham, Ben Weil, Rita Rego, Owen Bain, P. Stephen Patrick, Kim Champion, Alex Day, Bilyana Popova, Graham Wheeler, Dan Fullen, Tammy Kalbur, Martin Forster, Mark Lowdell, Sam Janes; Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom; Raigmore Hospital, NHS Highlands, Inverness, United Kingdom; Centre for Cell Gene and Tissue Therapy, London, United Kingdom; Centre for Cell, Gene & Tissue Therapeutics, Royal Free London NHS Foundation Trust, London, United Kingdom; Centre for Cell, Gene and Tissue Therapeutics, London, United Kingdom; Centre for Advanced Biomedical Imaging, University College London, London, United Kingdom; Cancer Research UK & UCL Cancer Trials Centre, London, United Kingdom; Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom; UCL Translational Research Office, London, United Kingdom; UCL Cancer Institute, UCLH, London, United Kingdom

Background: Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has its limited therapeutic efficacy. We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression. Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1]. Methods: TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment na¨ıve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study, patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL. 46 patients will then be randomised into a multi-centre phase II double blind, placebo-controlled trial to receive SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12 weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC therapy in cancer. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42. Clinical trial information: NCT03298763.

TPS9117 Poster Session (Board #438b), Sun, 8:00 AM-11:00 AM

Biomarker-directed precision oncology of pembrolizumab-based combination therapy for non-small cell lung cancer: Phase II KEYNOTE-495/KeyImPaCT study.

Martin Gutierrez, Matthew David Hellmann, Matthew A. Gubens, Charu Aggarwal, Daniel Shao Weng Tan, Enriqueta Felip, Joanne Wing Yan Chiu, Jong Seok Lee, James Chih-Hsin Yang, Edward B. Garon, Andrea Basso, Hua Ma, Lawrence Fong, Alex Snyder, Jianda Yuan, Roy S. Herbst; Hackensack University Medical Center, Hackensack, NJ; Memorial Sloan Kettering Cancer Center, New York, NY; UCSF Medical Center, San Francisco, CA; University of Pennsylvania, Philadelphia, PA; SingHealth Duke NUS Academic Medical Centre, Singapore, Singapore; Vall d´Hebron University Hospital, Barcelona, Spain; University of Hong Kong, Hong Kong, China; Seoul National University Bundang Hospital, Seoul, South Korea; National Taiwan University, Taipei, Taiwan; University of California, Los Angeles, Los Angeles, CA; Merck & Co., Inc., Kenilworth, NJ; University of California San Francisco, San Francisco, CA; Yale University, New Haven, CT

Background: Pembrolizumab-based combination immunotherapy aims to improve clinical outcomes over pembrolizumab monotherapy. A biomarker-based therapeutic approach may be associated with improved response to different combination therapies of immune checkpoint inhibitors and may improve overall outcomes in NSCLC. The randomized, multicenter, open-label, phase 2 KEYNOTE-495 trial (NCT03516981) will evaluate the clinical usefulness of biomarker-informed, pembrolizumab-based combination therapy in patients with treatment-naive, advanced NSCLC. Methods: This is a group- sequential, adaptive randomization trial. Patients will have histologically or cytologically confirmed treatment-naive, advanced NSCLC, documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements, measurable disease per RECIST v1.1, and ECOG PS 0-1. Tumor tissue from patients will be initially screened for 2 validated, independent, next-generation biomarkers: T cellinflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on results of biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow,TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh.Withineachgroup,patientswillberandomlyassignedtoreceive pembrolizumab 200 mg Q3W intravenously (IV) combined with either MK-4280 200 mg Q3W (antiLAG- 3) IV or lenvatinib 20 mg orally once daily, with the randomization assignment adaptively modified based on interim efficacy analyses. Response will be assessed by imaging every 9 weeks for the first year and every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. Treatment arms may be terminated during the interim analysis due to safety, prespecified futility criteria, or both. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries. Clinical trial information: NCT03516981.

TPS9118 Poster Session (Board #439a), Sun, 8:00 AM-11:00 AM

Randomized, double-blind, phase 3 trial of first-line pembrolizumab + platinum doublet chemotherapy (chemo) 6 lenvatinib in patients (pts) with metastatic nonsquamous non–small-cell lung cancer (NSCLC): LEAP-006.

Rina Hui, Makoto Nishio, Martin Reck, Delvys Rodriguez-Abreu, Tamer M. Fouad, Doreen Flaim, Lina Yin, Thao Dang, Roy S. Herbst; Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Lung Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; Hospital Universitario Insular de Gran Canaria, Las Palmas De Gran Canaria, Spain; Eisai Inc., Woodcliff Lake, NJ; Merck & Co., Inc., Kenilworth, NJ; Department of Medical Oncology, Yale University School of Medicine, Yale Comprehensive Cancer Center, New Haven, CT

Background: Lenvatinib (multiple-receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptors a, c-kit, and RET) has antitumor activity in combination with pembrolizumab (anti–PD-1 inhibitor) or with chemo in advanced NSCLC. LEAP-006 (NCT03829319) evaluates first-line lenvatinib with pembrolizumab + chemo for metastatic nonsquamous NSCLC. Methods: This randomized, double-blind, 2- part, phase 3 study enrolls pts $18 years with histologically/cytologically confirmed metastatic, nonsquamous, treatment-naive NSCLC without sensitizing genetic aberrations. Pts receive lenvatinib 8 mg daily or matching placebo + pembrolizumab 200 mg + pemetrexed 500 mg/m2 + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 Q3W (4 cycles) followed by maintenance pembrolizumab (35 cycles) + lenvatinib/placebo + pemetrexed (no limit). In part 1 (open-label safety run-in), ~12 pts receive lenvatinib + pembrolizumab + chemo (n $6 in each chemo arm). If , 3 dose-limiting toxicities (DLTs; select prespecified AEs) occur in 6 pts in each arm in cycle 1, part 2 will begin enrolling. If $3 DLTs occur in 6 pts in each arm, enrollment in part 1 may continue with advisement by the study oversight committee. In part 2, pts are randomized 1:1 to lenvatinib or placebo + pembrolizumab + chemo, stratified by PD-L1 tumor proportion score ( , 50%/$50%), geographic site (East Asian/other), and ECOG PS (0/1). Tumor imaging occurs at baseline and Q6W until wk 18; then Q9W until wk 54; then Q12W until verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. The primary endpoint in part 1 is safety. The primary endpoints in part 2 are PFS (RECIST v1.1 by BICR) and OS, analyzed by Kaplan-Meier method and stratified log-rank test. Secondary endpoints in part 2 are ORR and DOR (RECIST v1.1 by BICR), safety, and quality of life. Enrollment into part 1 will begin in March 2019. For part 2, approximately 714 pts will enroll in 160 sites in 17 countries. Clinical trial information: NCT03829319.

TPS9119 Poster Session (Board #439b), Sun, 8:00 AM-11:00 AM

SAVANNAH: A Phase II trial of osimertinib plus savolitinib for patients (pts) with EGFR- mutant, MET-driven (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC), following disease progression on osimertinib.

Geoffrey R. Oxnard, Mireille Cantarini, Paul Frewer, George Hawkins, Jane Peters, Paul Howarth, Ghada F. Ahmed, Tarjinder Sahota, Ryan Hartmaier, Xiaocheng Li-Sucholeiki, Myung-Ju Ahn; Dana- Farber Cancer Institute, Boston, MA; AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom; AstraZeneca, Waltham, MA; Samsung Medical Center, Seoul, South Korea

Background: The toxicity profile of the third-generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET- amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of pts) and AURA3 (19% of pts) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations. Methods: Eligible pts will have histologically/cytologically confirmed EGFR-mutant NSCLC, and MET+ disease by central FISH, central IHC, or local NGS (retrospectively confirmed by central FISH/IHC). Pts must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Pts will receive osimertinib 80 mg plus weight-based dosing with savolitinib 300 or 600 mg PO QD, in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in pts who are MET+ by central FISH. Secondary endpoints include: ORR (MET+ by central IHC and all pts); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance (MET+ by central FISH, central IHC, and all pts); safety, and pharmacokinetics (all pts). Based on the TATTON study, we anticipate enrolling ~172 MET+ pts to include $117 pts with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed. Clinical trial information: NCT03778229.

TPS9120 Poster Session (Board #440a), Sun, 8:00 AM-11:00 AM

A multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non- squamous non-small cell lung cancer: TORG1833.

Yoshiro Nakahara, Terufumi Kato, Reiko Isomura, Nobuhiko Seki, Naoki Furuya, Katsuhiko Naoki, Takeharu Yamanaka, Hiroaki Okamoto; Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan; Clinical Trial Management Office, Kanagawa Cancer Center, Yokohama, Japan; Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan; Department of Internal Medicine, Division of Respiratory Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; Department of Respiratory Medicine, Kitsasto University School of Medicine, Sagamihara, Japan; Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan; Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan

Background: Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways are shown to be interrelated in several preclinical studies. Furthermore, recent clinical studies have shown the adding effect of an anti VEGF monoclonal antibody with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Thus, osimertinib plus ramucirumab would be the promising candidate for the new standard treatment in EGFR mutation positive NSCLC. Methods: This study is an investigator initiated trial. Previously untreated EGFR mutation positive advanced non squamous NSCLC patients aged 20 years or older with a performance status of 0 or 1 are randomized at a 1:1 ratio to receive osimertinib (80mg) every day either without or with ramucirumab (10mg/kg) every 2 weeks until evidence of disease progression or development of unacceptable toxicity. The primary endpoint of the study is progression free survival (PFS) assessed by the central image reviewer. Secondly endpoints include PFS (assessed by an attending physician), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), safety and toxicity profile. Stratification factors are gender and the type of EGFR mutation (exon 19 deletion, Leu858Arg point mutation in exon 21). We determined that, with a sample size of 120 patients (60 in each arm), the trial will have 80% power to show a hazard ratio for disease progression or death of 0.667 at a one-sided alpha level of 0.2 (as calculated on the basis of 80 such events) for comparison between the two arms with 1.5-year accrual and 2-year follow-up periods. Study enrollment began in November 2018 and is continued for 3.5 years among 20 sites of Thoracic Oncology Research Group (TORG). Seven patients were enrolled at time of submission. Clinical trial information: 184146.

TPS9121 Poster Session (Board #440b), Sun, 8:00 AM-11:00 AM

ATALANTE-1 randomized phase III trial, OSE 2101 versus standard treatment as second- or third-line in HLA-A2 positive advanced non-small cell lung cancer (NSCLC) patients.

Enriqueta Felip, Giuseppe Giaccone, Rafal Dziadziuszko, Fabrice Denis, Teresa Moran, Didier Debieuvre, Manuel Cobo, Domenico Galetta, François Roger Vanel, Giampiero Romano, Anne Madroszyk, Christos Chouaid, Francois-Regis Ferrand, Werner Hilgers, Federico Cappuzzo, Philippe Masson, Nir Peled, Berangere Vasseur, Jordi Remon, Benjamin Besse; Vall d´Hebron University Hospital, Barcelona, Spain; Georgetown University, Washington, DC; Medical University of Gdansk, ´ Department of Oncology and Radiotherapy, Gdansk, ´ Poland; Institut Inter-Regional de Cancerologie ´ Jean Bernard, Le Mans, France; Institut Catalàd’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; Emile Muller Hospital, Mulhouse, France; Hospital Regional Universitario de Malaga, Málaga, Spain; Medical Oncology Department, Clinical Cancer Center Giovanni Paolo II, Bari, Italy; UnitedeCancerologie ´ Thoracique, Nouvel Hopital Civil, Strasbourg, France; Oncologia Medica, Lecce, Italy; Institut Paoli- Calmettes, Marseille, France; Centre Hospitalier Intercommunal (CHI) Creteil, Creteil, ´ France; Hopitalˆ Inter-Armées de Bégin, Saint-Mandé, France; Institut Sainte Catherine, Avignon, France; U.O. Ospedale Santa Maria delle Croc, Ravenna, Italy; Centre Hospitalier De Cholet, Cholet, France; Clalit Health Services, Soroka Medical Center, Beer-Sheeva, Israel; OSE Immunotherapeutics, Paris, France; Centro Integral Oncologıá Clara Campal Barcelona, HM-Delfos, Barcelona, Spain; Paris-Sud University, Orsay and Gustave Roussy, Villejuif, France

Background: New treatment strategies are needed for advanced NSCLC patients who progress on treatment with immune checkpoint inhibitors (ICI). Tedopi (OSE2101) is a neoepitope vaccine restricted to HLA-A2 positive patients (45%) targeting five tumor-associated antigens frequently expressed in lung cancer cells, ACE, HER2, MAGE2, MAGE3 and P53. Previously, in a phase II trial (Barve et al.JCO 2008), Tedopi showed a median overall survival (OS) of 17.3 months with a manageable safety profile in advanced NSCLC patients. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard of care (SoC) treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy. Methods: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements; progressive disease to platinum-based chemotherapy (ChT) with sequential or concurrent ICI; HLA-A2 positivity (blood test); ECOG PS 0-1; with treated and asymptomatic brain metastases,, are randomized 2:1 to receive 5mg Tedopi subcutaneously Q3W for 6 cycles, then Q8W for the reminder of the year and finally Q12W, or SoC treatment with: docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W (in non-squamous and pemetrexed-na¨ıve patients). Treatment continues until progression, intolerable toxicity or consent withdrawal, in both arms. Patients are stratified by histology, best response to first line, and line rank of ICI. Tumor assessment is performed every 6 weeks (RECIST 1.1). Primary endpoint is OS. Secondary end points are PFS, ORR, DCR, and duration of response, quality of life and safety. This is a superiority study with a hazard ratio of 0.7, two-sided alpha 5% and power 80%, after 278 events are observed. An independent analysis (1year OS rate) is planned in the first 84 patients treated with Tedopi. Last trial review by the DMC in June 18 suggested that the trial continues as planned. Translational research will be performed evaluating pharmacodynamic markers of efficacy such as immunogenicity response against Tedopi vaccine neo- antigens, as well as parameters in liquid and tissue biopsies. End January 19, 87 patients (51 Tedopi, 36 Soc) have been enrolled. Clinical trial information: NCT02654587.

TPS9122 Poster Session (Board #441a), Sun, 8:00 AM-11:00 AM

Prospective study of germline and somatic alterations for early onset lung cancer patients (EOLUNG MASTER protocol).

Maria Jove, Mireia Gausachs, Joaquim Bosch-Barrera, Enric Carcereny Costa, Alex Teule, Angel Izquierdo, Matilde Navarro, Ramon Palmero, Noelia Vilari~no, Jose Carlos Ruffinelli, Elia Sais, Teresa Moran, Anna Estival, Claudia Fina, Joan Brunet, Gabriel Capella, Conxi Lazaro, Ernest Nadal; Institut Catala ` d’Oncologia, L’Hospitalet, Barcelona, Spain; Institut Catala d’Oncologia, Universitary Hospital Dr. Josep Trueta, Girona, Spain; Institut Catalad ` ’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; Institut Catalad ` ’Oncologia L’Hospitalet, Barcelona, Spain; Programa de Cancer ` Hereditari – Institut Catala ` d’Oncologia, Girona, Spain; Programa de Cancer ` Hereditari – Institut Catalad ` ’Oncologia, Barcelona, Spain

Background: Lung cancer (LC) is a rare disease among young adults. Polymorphisms in genes involved in carcinogenic metabolism of tobacco and/or xenobiotic metabolism have been identified in those patients. The growing use of next generation sequencing (NGS) unravelled germline mutations in genes associated with hereditary cancer in patients with LC. However, germline DNA mutations have not been systematically studied in young adults with LC. Early onset LC patients are likely to harbor actionable somatic mutations. Broad hybrid NGS can identify actionable genomic alterations in LC patients deemed driver negative by routine molecular analysis. Trial Design: This is a multicentre, prospective, single-cohort study to determine whether young patients with LC harbor germline mutations and to evaluate the impact of NGS using Foundation One platform on the therapeutic options and overall survival for this specific patient population. Major inclusion criteria: 1) patients already or newly diagnosed of non-small cell lung cancer at any stage at age , 51; 2) to have sufficient tumor sample to perform standard molecular diagnosis (EGFR/ALK/ROS1/BRAF); 3) to provide written informed consent for the study. Methods: After signing the informed consent form, family history of cancer and smoking history will be collected and a peripheral blood sample will be obtained. Germline targeted sequencing will be carried out in our centre using a customized hereditary cancer panel (I2HCP) of 136 genes designed to cover the coding exons and intron-exon boundaries of genes associated with moderate or high risk of hereditary cancer. Patients with clinical criteria for hereditary cancer or harboring pathogenic or probably pathogenic germline alteration will be referred to the genetic counselling unit. Patients will follow the usual clinical pathway for biomarker analysis and in case of remaining tumour material it will be used for conducting comprehensive genomic profiling through Foundation One platform. When tumour material available will not be sufficient to perform NGS, a tumour re-biopsy will be considered. Enrolment begun on June 2018 and, to date, a total of 41 patients have been included in the study.

TPS9123 Poster Session (Board #441b), Sun, 8:00 AM-11:00 AM

MS201944-0170: A phase IIa study to investigate the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in patients with advanced squamous NSCLC.

Fortunato Ciardiello, Manuel Cobo Dols, Oscar Juan Vidal, Luis G. Paz-Ares, Javier de Castro Carpe~no, Enriqueta Felip, Rosario Garcia Campelo, Gyorgy Losonczy, Zsuzsanna Szalai, David Vicente, Andreas Schroder, ¨ Frank Beier, Prasad Bhandge, Gabriella Galffy; Universita ` Degli Studi della Campania Luigi, Naples, Italy; Hospital Regional Universitario de Malaga, Malaga, ´ Spain; Hospital Universitari i Politecnic ´ La Fe, Valencia, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital Universitario HM Madrid Sanchinarro, Madrid, Spain; Hospital Universitari Vall d’Hebron, Barcelona, Spain; Complejo Hospitalario Universitario A Coru~na, Coruna, Spain; Semmelweis Egye- tem, Budapest, Hungary; Petz Aladar Megyei Oktato Korhaz, Gyor, Hungary; Hospital Universitario Virgen Macarena, Seville, Spain; Merck KGaA, Darmstadt, Germany; Pulmonology Hospital Torokba- lint, Torokbalint, Hungary

Background: Preclinical studies have demonstrated that cetuximab plus chemotherapy results in immunogenic cell death and an increase in CD8+ T cells in the tumor microenvironment. Avelumab (an anti–PD-L1 antibody) has previously shown antitumor activity in NSCLC. We hypothesize that the combination of cetuximab with platinum-based chemotherapy and avelumab may have synergistic antitumor activity. Methods: This phase IIa, single-arm, multicenter study is investigating the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in patients with advanced squamous NSCLC who are treatment naive in the advanced setting (NCT03717155). Eligibility criteria include histologically confirmed stage IV, metastatic or recurrent NSCLC with squamous histology, with no prior systemic therapy for metastatic NSCLC, no prior therapy with any antibody/drug targeting T-cell coregulatory proteins, and ECOG PS of 0 to 1. Patients with a tumor harboring an activating EGFR mutation or ALK rearrangement are excluded. Patients will receive doublet chemotherapy (cisplatin 75 mg/m2 on day 1, gemcitabine 1250 mg/m2 on days 1 and 8), cetuximab on days 1 (250 mg/m2)and8(500mg/m2), and avelumab 800 mg on days 1 and 8 for a total of four 3-week cycles. Thereafter, avelumab (800 mg) and cetuximab (500 mg/m2) will be administered as maintenance treatment Q2W until disease progression, unacceptable toxicity, or withdrawal. Enrollment in a safety run-in, which will evaluate the safety and tolerability of avelumab in combination with cetuximab plus gemcitabine and cisplatin, is planned for the first 6 patients. Enrollment began on October 30, 2018. Study enrollment will continue until approximately 40 evaluable patients have been recruited. The primary endpoint is confirmed best overall response per RECIST 1.1 by investigator assessment. Secondary endpoints include safety (NCI CTCAE v5.0) and tolerability of the combination, duration of response, survival, and tumor biomarkers. The study is ongoing at sites in Hungary and Spain. Clinical trial information: NCT03717155.

TPS9124 Poster Session (Board #442a), Sun, 8:00 AM-11:00 AM

The CANOPY program: Canakinumab in patients (pts) with non-small cell lung cancer (NSCLC).

Luis G. Paz-Ares, Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Gilberto Castro, Pedro De Marchi, Enriqueta Felip, Yasushi Goto, Alastair Greystoke, Shun Lu, Darren Wan Teck Lim, Vassiliki Papadimitrakopoulou, Martin Reck, Benjamin J. Solomon, David R. Spigel, Daniel Shao-Weng Tan, Michael Thomas, James Chih-Hsin Yang, Bruce E. Johnson; University Hospital 12 de Octubre, Madrid, Spain; David Geffen School of Medicine, University of California/TRIO-US Network, Los Angeles, CA; St. Orsola-Malpighi University Polyclinic, Bologna, Italy; Aix-Marseille University, Marseille, France; Yonsei University College of Medicine, Seoul, South Korea; Instituto do CancerdoEstadodeSˆ ~ao Paulo, S~ao Paulo, Brazil; Hospital de Cancerˆ de Barretos, S~ao Paulo, Brazil; Vall d’Hebron Institute of Oncology, Barcelona, Spain; National Cancer Center Hospital, Department of Thoracic Oncology, Tokyo, Japan; Newcastle upon Tyne Hospitals, Newcastle, United Kingdom; Shanghai Chest Hospital, Jiao Tong University, Shanghai, China; National Cancer Center Singapore, Singapore, Singapore; University of Texas MD Anderson Cancer Center, Houston, TX; LungenClinic, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; National Cancer Centre Singapore, Singa- pore, Singapore; Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universit¨atsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Dana-Farber Cancer Institute, Boston, MA

Background: Inflammatory pathways can be pro-tumorigenic or anti-tumorigenic. The cytokine interleukin-1b (IL-1b) can promote the infiltration of immunosuppressive cells into the tumor microenvironment leading to a pro-tumorigenic microenvironment that promotes carcinogenesis, tumor invasiveness, and immunosuppression. Canakinumab is a human monoclonal antibody that binds and neutralizes IL-1b. Previous clinical data (CANTOS study) has shown that canakinumab could significantly reduce lung cancer incidence and mortality. This data along with the preclinical results that IL-1b does support tumorigenic inflammation provide the rationale to investigate the therapeutic role of canakinumab in lung cancer. Methods: Three Phase 3 trials have been designed in parallel to evaluate canakinumab in NSCLC (Table). Clinical trial information: NCT03447769, NCT03631199, NCT03626545.

CANOPY-A CANOPY-1 CANOPY-2 (NCT03447769) (NCT03631199) (NCT03626545) Study design Prospective, multicenter, randomized, double-blind, placebo controlled Two parts: Part 1 (open-label, safety run-in) and Part 2 (randomized, placebo controlled) Population* Stages IIA-IIIA and IIIB (T . Previously untreated stage IIIB/IIIC-IV squa- Previously treated with PD-(L) 5cm N2) completely mous and non-squamous 1 inhibitors and CTx, stage resected IIIB-IV Treatment arms 1:1 to canakinumab or Part 2 - 1:1 to canakinumab or placebo + Part 2 - 1:1 to canakinumab and placebo platinum-chemotherapy (CTx) + pembrolizumab or placebo + docetaxel randomization Estimated 1500 pts Part 1: »27 pts (3 cohorts of »9 pts each, based Part 1: »9 pts enrollment on different CTx) Part 2: 226 pts Part 2: 600 pts Stratification Stage, histology and geo- PD-L1 status, geographic region and histology Number of prior lines of graphic region therapy and histology Treatment Canakinumab 200 mg Q3W, s.c. scheme 18 cycles of treatment 4 cycles of induction (canakinumab or placebo treated until PD + CTx + pembrolizumab), followed by maintenance (canakinumab or placebo + pembrolizumab 6 pemetrexed) until progressive disease (PD) Primary Disease free survival Part 1: incidence of dose limiting toxicity (DLT) Part 1: incidence of DLT in endpoints in first 42 days of treatment first 42 days of treatment Part 2: PFS and OS Part 2 : OS

*stages as per AJCC/UICC v.8

TPS9125 Poster Session (Board #442b), Sun, 8:00 AM-11:00 AM

A multicenter, open label, randomized phase III study of atezolizumab with platinum- pemetrexed and with or without bevacizumab for patients with advanced nonsquamous non-small cell lung cancer (WJOG11218L APPLE Study).

Yoshimasa Shiraishi, Haruko Daga, Satoshi Ikeda, Akito Hata, Hideaki Mizutani, Tomohiro Sakamoto, Haruhiro Saito, Osamu Hataji, Hiroshi Tanaka, Atsushi Horiike, Hideo Saka, Tsuneo Shimokawa, Masahide Mori, Katsuya Hirano, Koichi Azuma, Tetsuya Mitsudomi, Takashi Seto, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Isamu Okamoto; Kyushu University Hospital, Fukuoka, Japan; Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan; Kurashiki Central Hospital, Kurashiki City, Japan; Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan; Saitama Cancer Center, Saitama, Japan; Tottori University Hospital, Yonago, Japan; Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan; Respiratory Center, Matsusaka Mu- nicipal Hospital, Matsusaka, Japan; Department of Respiratory Medicine, Niigata Cancer Center Hospital, Niigata, Japan; Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Respiratory Medicine, Nagoya Medical Center, Nagoya, Japan; Yokohama Municipal Citizen’s Hospital, Yokohama-Shi, Japan; De- partment of Internal Medicine, Toneyama National Hospital, Toyonaka, Japan; Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan; Division of Respir- ology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan; Department of Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan; National Kyushu Cancer Center, Fukuoka, Japan; Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan; Kindai University Hospital, Osaka, Japan

Background: First-line treatment of non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune-checkpoint inhibitor. Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of immune-checkpoint inhibitors through blockade of vascular endothelial growth factor–mediated immunosuppression. The aim of this trial is to demonstrate an additional effect of bevacizumab administered together with platinum combination therapy and the immune-checkpoint inhibitor atezolizumab in patients with advanced nonsquamous NSCLC. Methods: Cytotoxic chemotherapy–na¨ıve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed-carboplatin (APP) or atezolizumab, pemetrexed-carboplatin, and bevacizumab (APPB). Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable side effects during treatment with at least one approved tyrosine kinase inhibitor. After four cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab plus pemetrexed plus bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival (according to central image review). Secondary end points are progression-free survival (determined by the attending physician), overall survival, response rate, response duration, and adverse events. Stratification factors are PD-L1 tumor proportion score ($50% vs. , 50%), stage, and driver gene alterations. We determined that, with a sample size of 350 patients (175 in each arm), the trial will have 80% power to show a hazard ratio for disease progression or death of 0.727 at a one-sided alpha level of 0.025 (as calculated on the basis of 311 such events) for comparison between the APPB and APP groups. Clinical trial information: 194565.

TPS9126 Poster Session (Board #443a), Sun, 8:00 AM-11:00 AM

ORION: A Phase 2, randomized, multicenter, double-blind study to assess efficacy and safety of durvalumab+olaparib vs durvalumab alone as maintenance therapy in Stage IV non-small cell lung cancer (NSCLC).

Myung-Ju Ahn, Yufan Liu, Teresa Improta, Michelle Marcovitz, Kate DiPiazza, Mark C. Lanasa; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Astra- Zeneca, Gaithersburg, MD; AstraZeneca, Cambridge, United Kingdom; AstraZeneca Pharmaceuticals, Gaithersburg, MD

Background: Systemic chemotherapy for first-line (1L) metastatic NSCLC shows mixed outcomes. Results from studies using immunotherapy alone or combined with chemotherapy as 1L treatment in patients (pts) with metastatic NSCLC represent a substantial advance, but further improvement is needed. Increased DNA damage triggered by polyadenosine 5’diphosphoribose polymerase inhibition may confer antitumor activity, modify tumor immunogenicity, and further sensitize tumors to immune checkpoint inhibition, thus promoting a more durable antitumor response. This Phase 2, randomized, multicenter, double-blind study (NCT03775486) is designed to assess the efficacy and safety of durvalumab + olaparib vs durvalumab alone as maintenance therapy in pts whose Stage IV NSCLC has not progressed following 1L platinum-based chemotherapy + durvalumab. Methods: Adult pts with Stage IV NSCLC with tumors lacking activating EGFR mutations and ALK fusions are eligible. In the initial therapy phase, all pts will receive durvalumab (1500 mg IV) concurrent with platinum-based doublet therapy. Durvalumab + chemotherapy will be administered for 4 cycles for both squamous NSCLC (nanoparticle albumin-bound [nab]-paclitaxel + carboplatin or gemcitabine + carboplatin/cisplatin) and nonsquamous NSCLC (nab-paclitaxel + carboplatin or pemetrexed + carboplatin/cisplatin). Pts whose disease does not progress (complete or partial response [CR/PR] or stable disease [SD]; investigator-assessed RECIST 1.1) will be randomized (1:1) to durvalumab (1500 mg IV, every 4 weeks) + either olaparib (300 mg, oral, BID) or its matching placebo until disease progression. Randomization will be stratified based on objective response to durvalumab + chemotherapy (CR/PR or SD) during the initial therapy phase and histology (squamous or nonsquamous). The primary endpoint is PFS (investigator-assessed, RECIST 1.1). Secondary endpoints are OS, PFS in pts with homologous recombination repair related gene mutation, ORR, duration of response, HRQoL, pharmacokinetics and immunogenicity of durvalumab, and safety. Pt enrollment is ongoing. Clinical trial information: NCT03775486.

TPS9127 Poster Session (Board #443b), Sun, 8:00 AM-11:00 AM

Chemotherapy in KRAS-mutated chemotherapy naive non-small cell lung cancer patients: A phase III comparing cisplatin-pemetrexed with carboplatin-paclitaxel-bevacizumab: NVALT 22 (NCT02743923).

Anne-Marie C. Dingemans, Egbert F. Smit, Joop De Langen, Harm van Tinteren, NVALT ONCOLOGY; Maastricht University Medical Center, Maastricht, Netherlands; Vrije Universiteit VU Medical Centre, Amsterdam, Netherlands; VU University Medical Center, Amsterdan, Netherlands; Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands

Background: In a retrospective analysis of KRAS mutated non-small cell lung cancer (NSCLC) patients response and progression free survival (PFS) to first line chemotherapy was better for carboplatin- paclitaxel-bevacizumab then other first line combinations (Mellema Lung Cancer, 2015:90:249-54). Methods: Trial Design: Multi-center open label randomized phase III study. After stratification for KRAS mutation (G12V versus G12C versus other), performance status (0-1 vs. 2) and brain metastasis (yes of no) patients will be 1:1 randomized to carboplatin-paclitaxel-bevacizumab or cisplatin-pemetrexed q3wks for up to six cycles. Continuation maintenance with bevacizumab and pemetrexed is allowed until progression. Study population: histologically or cytologically confirmed stage IIIB or stage IV KRAS mutated NSCLC patients who are eligible for platinum-based chemotherapy and are chemotherapy na¨ıve. Previous anti-PD(L1) therapy for advanced disease is allowed (amendment 25.1.2018). Response will be assessed according to RECIST 1.1, CT scans will be made every 6 weeks until progression. Blood and archival tissue will be optionally collected for translational research. This may help to identify subgroups of patients who are likely better treated with a specific treatment regimen. Statistical analysis: The trial was designed to demonstrate superiority of the carboplatin-paclitaxel- bevacizumab treatment over cisplatin-pemetrexed with an assumed hazard ratio of 0.67. In total 201 events are required for the final analysis, corresponding to a total sample size of 240 patients to be accrued. There is a single interim analysis planned after 101 events have been observed. Primary endpoint: PFS defined by the response criteria in solid tumors (RECIST) and assessed by independent review. Secondary endpoints: Overall response rate, Overall Survival, outcome according to type of KRAS mutation, response assessed by CRABB criteria. Study progress: Currently 25 sites are open across the Netherlands and 170 of the 240 required patients are randomized (February 12, 2019). Clinical trial information: NCT02743923.