Lung Cancer—Non-Small Cell Local-Regional / Small Cell

LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8500 Oral Abstract Session

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

Heather A. Wakelee, Nasser K. Altorki, Caicun Zhou, Tibor Cso}szi, Ihor O. Vynnychenko, Oleksandr Goloborodko, Alexander Luft, Andrey Akopov, Alex Martinez-Marti, Hirotsugu Kenmotsu, Yuh-Min Chen, Antonio Chella, Shunichi Sugawara, Barbara J. Gitlitz, Elizabeth Bennett, Fan Wu, Jing Yi, Yu Deng, Mark McCleland, Enriqueta Felip; Stanford University Medical Center, Stanford, CA; New York- Presbyterian Hospital, Weill Cornell Medicine, New York, NY; Tongji University Affiliated Shanghai Pul- monary Hospital, Shanghai, China; Ja�sz-Nagykun Szolnok Megyei Hete�nyi Ge�za Ko�rha�z-Rende- lointe�zet, Szolnok, Hungary; Regional Municipal Institution Sumy Regional Clinical Oncology Dispensary, Sumy, Ukraine; MI Zaporizhzhia Regional Clinical Oncological Dispensary, Zaporizhzhya, Ukraine; Leningrad Regional Clinical Hospital, Saint-Petersburg, Russian Federation; Pavlov State Medical University, Saint-Petersburg, Russian Federation; Medical Oncology Department, Vall d�Hebron University Hospital/Vall d�Hebron Institute of Oncology (VHIO), Barcelona, Spain; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan; Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital and Department of Medicine, National Yang-Ming University, Taipei, Taiwan; Unit of Pneumology, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy; Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; Genentech, Inc, South San Francisco, CA; Roche China, Shanghai, China; Genentech, Inc., South San Francisco, CA; Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain

Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB ($4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC $1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Effi- cacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received $1 dose of atezo or who had $1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC $1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclu- sions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC $1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. Research Sponsor: F. Hoffmann-La Roche.

PD-L1 TC $1% Stage II-IIIA All Randomized Stage II-IIIA ITT Atezo BSC Atezo BSC Atezo BSC (n=248) (n=228) (n=442) (n=440) (n=507) (n=498)

Median DFS, mo NR 35.3 42.3 35.3 NR 37.2 Stratified HR (95% CI) 0.66 (0.50, 0.88) 0.79 (0.64, 0.96) 0.81 (0.67, 0.99)a 2-sided P value 0.0039 0.0205 0.0395

NR, not reached. aDid not cross significance boundary.

8501 Oral Abstract Session

Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.

Hirohito Tada, Tetsuya Mitsudomi, Takeharu Yamanaka, Kenji Sugio, Masahiro Tsuboi, Isamu Okamoto, Yasuo Iwamoto, Noriaki Sakakura, Shunichi Sugawara, Shinji Atagi, Toshiaki Takahashi, Hidetoshi Hayashi, Morihito Okada, Hiroshige Yoshioka, Hidetoshi Inokawa, Kazuhisa Takahashi, Masahiko Higashiyama, Ichiro Yoshino, Kazuhiko Nakagawa, West Japan Oncology Group; Suita To- kushukai Hospital, Suita, Japan; Department of Surgery, Kindai University Faculty of Medicine, Osaka- sayama, Japan; Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan; Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Chiba, Japan; Kyushu University Hospital, Fukuoka, Japan; Department of Medical Oncology, Hiroshima City Hiroshi- ma Citizens Hospital, Hiroshima, Japan; Aichi cancer center, Nagoya, Japan; Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan; Kindai University Faculty of Medicine, Osaka, Japan; Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan; Kansai Medical University, Hirakata, Ja- pan; Yamaguchi-Ube Medical Center, Ube, Japan; Department of Respiratory Medicine, Juntendo Uni- versity School of Medicine, Tokyo, Japan; Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardivascular Diseases, Osaka, Japan; Department of General Thoracic Surgery, Chiba Uni- versity Graduate School of Medicine, Chiba, Japan; Kindai University Hospital, Osaka, Japan

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/ vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients 370 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly pro- long DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy.Clinical trial information: UMIN000006252. Research Sponsor: Astra-Zeneca.

8502 Oral Abstract Session

CTONG1103: Final overall survival analysis of the randomized phase 2 trial of erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non–small cell lung cancer.

Yi-Long Wu, Wenzhao Zhong, Ke-Neng Chen, Chun Chen, Fan Yang, Xue-Ning Yang, Chundong Gu, Weimin Mao, Qun Wang, Gui-Bin Qiao, Ying Cheng, Lin Xu, Changli Wang, Mingwei Chen, Hong-Hong Yan, Ri-qiang Liao, Xuchao Zhang, Jinji Yang, Si-yang Liu, Qing Zhou, The EMERGING Investigators; Guangdong Lung Cancer Institute, Guangdong Provincial Peoples Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong Provincial Peo- ple’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China; Peking University Cancer Hospital and Institute, Beijing, China; Fu- jian Uion Hospital, Fuzhou, China; Peking University People’s Hospital, Beijing, China; Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sci- ences, Guangzhou, China; The First Affiliated Hospital of Dalian Medical University, Dalian, China; Zhe- jiang Cancer Hospital, Hangzhou, China; Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Jilin Cancer Hospital, Changchun, China; Cancer Institute of Jiangsu Province, Nan- jing, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’an, China; Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China; Guangdong Provincial Peo- ple’s Hospital, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

Background: Median Overall survival (mOS) of stage IIIA resected NSCLC was 59.4 months (m) in CTONG 1104 adj gefitinib and 26.2m in SAKK neoadjuvant chemo trial. EMERGING-CTONG1103 showed neo-adjuvant/adjuvant erlotinib treatment significantly improved progression-free survival (PFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive resectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). Here, we present the final overall survival (OS) results from the study. Methods: This was a multicenter (17 centers in China) phase II randomized controlled trial of erlotinib（E）versus gemcitabine plus cisplatin (GC) as neoadjuvant/adjuvant therapy in pts with stage IIIA-N2 NSCLC with EGFR mutations in exon 19 or 21. From Dec 2011 to Dec. 2017, 386 pts sites were screened and 72 pts were randomly assigned to neoadjuvant/adjuvant E arm (N = 37) or GC arm(N = 35). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postoperative. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, downstaging rates of pathological lymph nodes, PFS, OS, safety, and tolerability. Data cut-off date was January, 29 2021. Results: With a median follow-up of 62.5 months, the median OS was 42.2months based on 47 (65.3%) events in ITT whole population. The mOS was 42.2m in E and 36.9m in GC (HR 0.83, 95%CI 0.47-1.47, p = 0.513). The 3-,5-year OS rate were 58.6%, 40.8% in E and 55.9%, 27.6% in GC respectively (p3-y = 0.819, p5-y = 0.252). All predefined subgroups including age, gender, EGFR mutation type had no significant difference in statistics between two arms. Subsequent treatments (ST) especially targeted therapy contributed most to OS (HR = 0.35,95% CI 0.18- 0.70). Median OS of pts receiving ST was 45.8m (n = 38), 34.6m in other treatment (n = 12), 24.6m in without ST (n = 15). For E mOS were 46.4 (n = 15; target therapy), 42.2m (n = 8; other) and 24.6m (n = 9; without, p = 0.021), for GC 42.6 (n = 23; target therapy), 30.1m (n = 4;other) and 24.6m(n = 6; without, p = 0.130). The RR was 53.3%, DCR 93.3%, mPFS 10.9m and mPPS 21.9m for patients with rechallenged EGFR TKI in E arm (n = 15). No novel unexpected SAE was observed during follow up. Conclusion: Erlotinib as neoadjuvant/adjuvant therapy for resected N2 NSCLC was feasibility and had a promising OS. The PFS survival advantage of E did not translate to OS difference in EMERGING trial (NCT01407822). Clinical trial information: NCT01407822. Research Sponsor: Chinese Thoracic Oncology Group (CTONG). LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8503 Oral Abstract Session

Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum- doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC).

Jonathan Spicer, Changli Wang, Fumihiro Tanaka, Gene Brian Saylors, Ke-Neng Chen, Moishe Liberman, Everett E. Vokes, Nicolas Girard, Shun Lu, Mariano Provencio, Tetsuya Mitsudomi, Mark M. Awad, Enriqueta Felip, Patrick M. Forde, Scott Swanson, Julie R. Brahmer, Keith Kerr, Ce�cile Dorange, Junliang Cai, Stephen Broderick; McGill University Health Center, Montre�al, QC, Canada; Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; University of Occupational and Environmental Health, Kitakyushu, Japan; Charleston Oncology, Charleston, SC; Pe- king University School of Oncology, Beijing Cancer Hospital, Beijing, China; Centre hospitalier de l’Universite� de Montre�al, Montreal, QC, Canada; University of Chicago Medicine, Chicago, IL; Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France; Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai JiaoTong University, Shanghai, China; Hospital Universitario Puerta de Hier- ro, Madrid, Spain; Kindai University Faculty of Medicine, Ohno-Higashi, Osaka-Sayama, Japan; Dana- Farber Cancer Institute, Boston, MA; Vall d’Hebron University Hospital, Vall d’Hebron Institute of On- cology, Barcelona, Spain; Johns Hopkins Kimmel Cancer Center, Baltimore, MD; Aberdeen Royal Infir- mary, Aberdeen, United Kingdom; Bristol Myers Squibb, Princeton, NJ

Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significantly improved pathological complete response (pCR) with neoadjuvant NIVO + chemo. Here we report key surgical outcomes from the study. Methods: Adults with stage IB ($ 4 cm)–IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS # 1, and no known EGFR/ALK alterations were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Definitive surgery was to be performed within 6 weeks of treatment. Primary endpoints are pCR (defined as 0% viable tumor cells in lung and lymph nodes) and event-free survival; both are evaluated by blinded independent review. Feasibility of surgery and surgery-related adverse events (AEs) are exploratory endpoints. Results: Base- line characteristics were comparable between arms; 64% of patients (pts) were stage IIIA. Definitive surgery rates were 83% with NIVO + chemo (n = 149) vs 75% with chemo (n = 135). Reasons for can- celled surgery were disease progression (12 and 17 pts, respectively), AEs (2 pts/arm), or other scenari- os (14 and 19 pts, respectively; including pt refusal, unresectability, poor lung function). Minimally invasive surgery rates were 30% and 22%, and conversion from minimally invasive to open surgery rates were 11% and 16% for NIVO + chemo and chemo, respectively. Lobectomy was performed in 77% vs 61% of pts, and pneumonectomy in 17% and 25% for NIVO + chemo vs chemo, respectively. AEs were responsible for delays of surgery in 6 pts in the NIVO + chemo arm and 9 pts in the chemo arm. An R0 resection was achieved in 83% vs 78% of pts and median residual viable tumor (RVT) cells in the primary tumor bed were 10% vs 74% for NIVO + chemo vs chemo. There was no increase in median (Q1, Q3) duration of surgery and length of hospitalization between NIVO + chemo vs chemo (184 [130, 252] vs 217 [150, 283] min; and 10.0 [7, 14] vs 10.0 [7, 14] days, respectively). Any-grade and grade 3–4 surgery-related AEs were reported in 41% vs 47% and 11% vs 15% of the NIVO + chemo vs chemo arms, respectively. Grade 5 surgery-related AEs were reported in 2 vs 0 pts in the NIVO + chemo vs chemo arms; 0 vs 3 pts died due to treatment-related AEs, respectively. Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo did not impede the feasibility and timing of surgery, nor the extent or com- pleteness of resection vs chemo alone; treatment was tolerable and did not increase surgical complications. NIVO + chemo led to increased depth of pathological response. The surgical outcome data from CheckMate 816 along with significant improvement in pCR support NIVO + chemo as a potential neoadjuvant option for patients with stage IB to IIIA resectable NSCLC. Clinical trial information: NCT02998528. Research Sponsor: Bristol Myers Squibb. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8504 Oral Abstract Session

Video-assisted thoracoscopic versus open lobectomy in patients with early-stage lung cancer: One-year results from a randomized controlled trial (VIOLET).

Eric Kian Saik Lim, Tim J.P. Batchelor, Joel Dunning, Michael Shackcloth, Vladimir Anikin, Babu Naidu, Elizabeth Belcher, Mahmoud Loubani, Vipin Zamvar, Rosie A. Harris, Lucy Dabner, Holly E. Mckeon, Sangeetha Paramasivan, Alba Realpe, Daisy Elliot, Paulo De Sousa, Jane M. Blazeby, Chris A. Rogers; Royal Brompton and Harefield Hospitals, London, United Kingdom; Thoracic Surgery, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United King- dom; The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middles- brough, United Kingdom; Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, United Kingdom; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United King- dom; John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United King- dom; Castle Hill Hospital, Hull, United Kingdom; Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, United Kingdom; Bristol Trials Centre (CTEU), Bristol Medical School, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; National Institute for Health Research Bristol Biomedical Research Centre, Surgical Innovation Theme, Centre for Surgical Research, Bristol, United Kingdom; National Institute for Health Research Bristol Biomedical Research Centre, Surgical Innovation Theme, Centre for Surgi- cal Research, University of Bristol, Bristol, United Kingdom

Background: Video assisted thoracoscopic surgery (VATS) is a popular access for lung cancer resection. However, there is limited information from RCTs from in-hospital to one-year clinical efficacy, safety and oncologic outcomes of a minimal access approach. Methods: VIOLET is a parallel group multi-center RCT conducted in 9 centers in the United Kingdom that recruited participants with known or suspected (cT1-3, N0-1 and M0) lung cancer (ISRCTN13472721). Trial protocol: https:// bmjopen.bmj.com/content/9/10/e029507.info. Results: From July 2015 to February 2019, 503 participants were randomized to VATS (n=247) or open (n=256) lobectomy. Patients allocated to VATS had less pain with a mean difference (MD) in visual analogue score of -0.54 (95%CI -0.99 to -0.10) despite less analgesic consumption (mean ratio 0.90, 95%CI 0.80 to 1.01). After discharge pain was consistent on multiple sub-scales including overall pain (MD -7.19, -10.59 to -3.80), chest pain (MD -4.66, -7.96 to -1.36) and an 18% relative risk (RR) reduction in incision pain (RR 0.82; 0.72 to 0.94) up to one-year. Better functional recovery continued in VATS arm after discharge with better physical function (primary outcome) with MD of 4.65 (1.69 to 7.61; P=0.002) at 5 weeks and overall improvement in global health status with a MD of 4.21 (1.62 to 6.79; P=0.001). In hospital, VATS arm had fewer complications (RR 0.74, 0.66 to 0.84; P<0.001) with no difference in serious adverse events (RR 0.98, 0.59 to 1.63; P=0.948). Median hospital stay was one day shorter in the VATS arm (4 vs 5 days) corresponding to hazard ratio (HR) for discharge of 1.34, 95%CI 1.09 to 1.65; P=0.006). After discharge VATS arm had 19% less serious adverse events (RR 0.81, 0.66 to 1.00; p=0.053) and lower re- admission rates (29.0% vs. 35.9% respectively) to one-year. Of those with lymph node disease, 50.9% in the VATS and 45.9% in open arms received adjuvant treatment. There was no difference in the time to uptake of adjuvant chemotherapy (HR 1.12, 0.62 to 2.02; p=0.716). Recurrence with clinical follow up and CT at one-year was similar with 7.7% versus 8.1% in the VATS and open groups respectively. Progression-free survival (HR 0.74, 0.43 to 1.27; p=0.27) and overall survival HR 0.67, 0.32 to 1.40; p=0.282) was not significantly different. Conclusions: VATS lobectomy for lung cancer is associated with less pain, fewer in-hospital complications and shorter hospital stay, achieved without any compromise to early oncologic outcomes nor serious adverse events. Superior functional recovery continues in the post-operative period with improved physical function, lower re-admission rates and no difference in disease-free and overall survival up to one-year. Clinical trial information: ISRCTN13472721. Re- search Sponsor: UK National Institute of Healthcare Research. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8505 Oral Abstract Session

Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538.

Jeffrey A Bogart, Xiaofei F. Wang, Gregory A. Masters, Junheng Gao, Ritsuko Komaki, Charles S. Kuzma, John Heymach, William J. Petty, Laurie E. Gaspar, Saiama Naheed Waqar, Tom Stinchcombe, Jeffrey D. Bradley, Everett E. Vokes; SUNY Upstate Medical University, Syracuse, NY; Duke Cancer In- stitute, Durham, NC; Helen F Graham Cancer Center, Newark, DE; Duke University Health System, Dur- ham, NC; The University of Texas MD Anderson Cancer Center, Houston, TX; First Health of the Carolinas Cancer Ctr, Pinehurst, NC; Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Comprehensive Cancer Center of Wake Forest Baptist Health, Winston Salem, NC; University of Colorado Comprehensive Cancer Center, Auro- ra, CO; Washington University School of Medicine, St. Louis, MO; Washington University School of Medicine in St. Louis, St. Louis, MO; University of Chicago Medicine, Chicago, IL

Background: Although level 1 evidence is lacking, the majority of patients (pts) with LSCLC are treated with a high dose QD TRT regimen in clinical practice. CALGB 30610/RTOG 0538 was designed to determine if administering high dose TRT would improve overall survival (OS), compared with standard 45 Gy BID TRT, in LSCLC pts treated with chemoradiotherapy. Methods: Eligible pts had LSCLC, ECOG performance status (PS) 0-2 and regional lymph node involvement excluding contralateral hilar or supraclavicular nodes. This phase 3 trial was conducted in 2 stages. In the first stage, pts were randomized 1:1:1 to 45 Gy BID over 3 weeks, 70 Gy QD over 7 weeks, or 61.2 Gy concomitant boost (CB) over 5 weeks. For the second stage, the study planned discontinuation of one high dose arm based on interim toxicity analysis with patients then randomized 1:1 in the two remaining arms. TRT was given starting with either the 1st or 2nd (of 4 total) chemotherapy cycles. The primary endpoint was OS measured from date of randomization. Results: The trial opened 03/15/2008 and closed 12/01/2019 upon com- pleting accrual, with the CB arm discontinued 3/11/2013 after interim analysis. This analysis includes 638 pts randomized to 45 Gy BID TRT (n = 313) or 70 Gy QD TRT (n = 325). Median age was 63 years (range 37-81), the majority of pts were Caucasian (86%), female (52%), and with ECOG PS 0-1 (95%). After median follow-up of 2.84 years (IQR:1.35 -5.61) for surviving pts, QD compared to BID did not result in a significant difference in OS (HR 0.94, 95% CI: 0.76-1.2, p = 0.9). Median, 2- and 4-year OS for QD were 30.5 months (95% CI: 24.4-39.6), 56% (95% CI: 0.51-0.62), and 39% (95% CI: 0.33-0.45), and for BID 28.7 months (95% CI: 26.2-35.5), 59% (95% CI: 0.53-0.65), and 35% (95% CI: 0.29-0.42). QD also did not result in a significant difference in PFS (HR 0.96, 95% CI: 0.78- 1.18, p = 0.94). Most grade 3+ hematologic and non-hematologic adverse events (AEs) were similar between cohorts. Rates of grade 3+ febrile neutropenia, dyspnea, esophageal pain and dysphagia for QD were 12.6%,7%, 11.6% and 11.3%, and for BID 13.6%, 4%, 11.2 % and 9.5%. Grade 5 AEs were reported in 3.7% and 1.7% of the QD and BID cohorts, respectively. Results will be updated at presentation. Conclusions: High dose QD TRT to 70 Gy did not significantly improve OS compared with standard 45 Gy BID TRT. Nevertheless, favorable outcomes on the QD arm provide the most robust evidence available supporting high dose once-daily TRT as an acceptable option in LSCLC. Outcomes from this study, the largest conducted in LSCLC to date, will help guide TRT decisions for this patient population. Support: U10CA180821, U10CA180882; Clinical trial information: NCT00632853. Research Spon- sor: U.S. National Institutes of Health. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8506 Oral Abstract Session

Stereotactic ablative radiotherapy in operable stage I NSCLC patients: Long-term results of the expanded STARS clinical trial.

Joe Y. Chang, Reza J. Mehran, Lei Feng, Peter Balter, Stephen McRae, Donald A. Berry, Jack A. Roth, STARS Clinical Trials Group; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic and Cardiovascular Surgery, The University of Tex- as MD Anderson Cancer Center, Houston, TX; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Interventional Radiology, 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

Background: We published a pooled analysis of 2 randomized trials (STARS/ROSEL) that compared lobectomy with mediastinal lymph node dissection (L-MLND) vs stereotactic ablative radiotherapy (SABR) in operable stage I NSCLC. There were no significant differences in disease progression but significantly higher 3-year overall survival (OS) in the SABR arm (95% vs 79%). Owing to concerns regarding the small sample size (n = 58), short follow-up (3 years), and non-uniform use of video-assisted thoracoscopic surgery (VATS), we expanded the STARS protocol to a single-arm SABR trial with a protocol-specified comparison to a published, longitudinally-followed institutional cohort of stage IA NSCLC status post VATS L-MLND (n = 229). Methods: Inclusion criteria were stage IA NSCLC (#3 cm, N0M0 and staged by PET/CT with EBUS) with Zubrod performance status (PS) 0-2, baseline FEV1 > 40% and DLCO > 40% and deemed operable by a multidisciplinary team. SABR utilized 4-dimensional CT simulation and volumetric image guidance; 54 Gy in 3 fractions were delivered to planning target vol- umes (PTVs) located peripherally, or 50 Gy in 4 fractions to more central PTVs. All patients were followed by chest CT every three months for the first two years, every 6 months for another three years, and then annually. Non-inferiority of SABR could be claimed if the 3-year OS was not lower than the historical VATS L-MLND cohort by more than 12%. We conducted a risk-factor matched comparison study of the primary outcome between the SABR and the historical VATS L-MLND. Results: The median follow- up among the 80 SABR patients was 61 months (range, 34-79 months). The OS and progression-free survival (PFS) were 91% (95% CI: 85~98%) and 80% (95% CI: 72~89%) at 3 years, and 87% (95% CI: 79~95%) and 77% (95% CI: 68~87%) at 5 years, respectively. The 5-year cumulative incidence rate counting death as competing risk was 6.3% (95% CI: 2.3~13.2%) local, 12.5% (95% CI: 6.4~20.8%) regional, and 8.8% (95% CI: 3.8~16.2%) distant (any recurrence 17.6% (95% CI: 10.1~26.7%)). The 5 year cumulative incidence rate of second lung primary was 6.9% (95% CI: 2.5~14.6%). There were 1.3% grade 3 and no grade 4-5 toxicities. The propensity score matched (age, gender, tumor size, histology, PS) comparison of SABR vs VATS L-MLND revealed no significant differences in PFS (p = 0.063), lung cancer-specific survival (p = 0.075), or cumulative incidence rates of local (p = 0.54), regional (p = 0.97), or distant failures (p = 0.33). The SABR arm was associated with significantly higher OS (91% vs 82% at 3 years and 87% vs 72% at 5 years; p = 0.012 from log-rank test). The hazard ratio was 0.411 (95% CI: 0.193~0.875; p = 0.021). Conclusions: The long-term OS and PFS of SABR is not inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains a promising approach for this population, but multidisciplinary management is strongly recommended. Clinical trial information: NCT02357992. Research Sponsor: Varian Medical Systems. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8507 Oral Abstract Session

A randomized phase II trial of oral vinorelbine as second-line therapy for patients with malignant pleural mesothelioma.

Dean Anthony Fennell, Angela Claire Casbard, Catharine Porter, Robin Rudd, Jason Francis Lester, Marianne Nicolson, Bruno Morgan, Jeremy Peter Steele, Liz Darlison, Georgina Mary Gardner, Lisette Sheena Nixon, Terri Kitson, Ann White, Gareth Owen Griffiths, Charlotte Poile, Aarti Gaba, Sara Busacca, Catherine Jane Richards, VIM Trial Group; University of Leicester and University Hospitals of Leicester, Leicester, United Kingdom; Centre for Trials Research, Cardiff University, Cardiff, United Kingdom; Cardiff University, Cardiff, United Kingdom; Department of Oncology, St Bartholomew’s Hos- pital, London, United Kingdom; Swansea Bay University Health Board, Swansea, United Kingdom; Ab- erdeen Royal Infirmary, Aberdeen, United Kingdom; University of Leicester, Leicester, United Kingdom; St Bartholomew’s Hospital, London, United Kingdom; Southampton Clinical Trials Unit, Uni- versity of Southampton, Southampton, United Kingdom; Leicester Royal Infirmary, Leicester, United Kingdom

Background: All patients with malignant pleural mesothelioma (MPM) eventually relapse following standard chemotherapy. However, there is no standard treatment option in this setting. Vinorelbine, exhibits useful clinical activity but has not been formally evaluated in a randomised clinical trial, despite its widespread off-label use worldwide. BRCA1 regulates spindle assembly checkpoint in MPM and predicts vinorelbine sensitivity in preclinical models [1,2], suggesting that BRCA1 negative patients may be chemoresistant. Methods: VIM, a Cancer Research UK funded, investigator-initiated randomised controlled phase 2 multi-centre UK trial, enrolled patients with MPM who had progressed after first-line chemotherapy. Pts were randomised 2:1 to either vinorelbine (60mg/m2 weekly Q21d escalating to 80mg/m2 from cycle 2) + active supportive care (ASC) versus ASC until disease progression, unacceptable toxicity or withdrawal of consent. The primary outcome was progression free survival (PFS) defined as the time from randomisation to any progression (based on Modified RECIST criteria for assessment of response in malignant pleural mesothelioma) or death. The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints were overall survival (OS), tolerability and safety. Results: Between May 2016 and Oct 2018, 154 patients were recruited from 10 UK sites and randomised to vinorelbine + ASC (n=98) or ASC alone (n=56). In the Intention-to-treat analysis, after 129 events, median PFS was 4.2 months (m) for vinorelbine + ASC compared to 2.8m for ASC alone (Hazard Ratio (HR) 0.59; 95% CI: 0.41 to 0.85; one-sided p = 0.0017). 108 deaths were reported. Median OS was 9.3m for vinorelbine + ASC compared to 9.1m for ASC alone (HR=0.79; 95% CI: 0.53 to 1.17; two-sided p = 0.24). Toxicity data and subgroup analyses including the impact of BRCA1 deficiency will be presented. Conclusion: The trial met its primary endpoint. Vinorelbine demonstrates useful clinical efficacy in relapsed MPM, supporting its off-label use, as a treatment option for patients with relapsed MPM.[1] Busacca et al, J Pathol 2012, 227(2), 200. [2] Busacca et al, Mol Can- cer Res, 2021, 20(2) 379. Clinical trial information: NCT02139904. Research Sponsor: Clinical Trials Advisory and Awards Committee, Cancer Research UK Core funding. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8508 Poster Discussion Session

Real-world multiomic characterization of small cell lung cancer subtypes to reveal differential expression of clinically relevant biomarkers.

Sonam Puri, Abdul Rafeh Naqash, Andrew Elliott, Kathleen Claire Kerrigan, Shiven B. Patel, Andreas Seeber, Florian Kocher, DIPESH UPRETY, Hirva Mamdani, Amit Kulkarni, Gilberto Lopes, Balazs Halmos, Hossein Borghaei, Wallace L. Akerley, Stephen V. Liu, Wolfgang Michael Korn, Trudy G. Oliver, Taofeek K. Owonikoko; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Developmental Therapeutics Clinic/Early Clinical Trials Development Program, Division of Cancer Treat- ment and Diagnosis, National Cancer Institute, Bethesda, MD; CARIS Life Sciences, Irving, TX; Depart- ment of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Comprehensive Cancer Center Innsbruck, Innsbruck, Austria; Department of Internal Medicin V (Hema- tology and Oncology), Medical University of Innsbruck, Comprehensive Cancer Center Innsbruck, Inns- bruck, Austria; Karmanos cancer institute, Detroit, MI; Barbara Ann Karmanos Cancer Institute, Detroit, MI; University of Minnesota, Minneapolis, MN; University of Miami Miller School of Medicine, Miami, FL; Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY; Fox Chase Cancer Center, Philadelphia, PA; Georgetown University, Department of Hematology and Oncology, School of Medicine, Washington, DC; Caris Life Sciences, Phoenix, AZ; Emory University Winship Can- cer Institute, Atlanta, GA

Background: The dominant expression of four lineage-defining transcription factors (ASCL1, NEUROD1, YAP1, or POU2F3) has enabled the classification of small cell lung cancer (SCLC) into four subtypes (SCLC-A/N/Y/P, respectively). Emerging evidence suggests that YAP1 expression is associated with a T- cell inflamed phenotype, and SCLC has significant intra-tumor heterogeneity mediated by MYC-driven activation of NOTCH signaling. We performed a large-scale analysis of real-world SCLC patient samples to examine the expression of clinically relevant biomarkers across SCLC subtypes. Methods: Comprehen- sive molecular profiling of 437 small cell lung neuroendocrine tumors (including 7.3% high-grade neuroendocrine lung carcinomas) was performed using next-generation DNA sequencing (592-gene panel), RNA sequencing (whole transcriptome), and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Tumors were stratified into 5 subgroups (SCLC-A/N/Y/P and -mixed) based on the relative expression of the four transcription factors. RNA expression of key genes and previously validated immune signatures (T-cell inflamed, NK cell, and STING pathway signatures) were evaluated across subgroups. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: Median age of the study cohort was 66 years (IQR: 59-72) and 50.6% of patients were female. The majority (67.3%) of samples were derived from metastatic sites. Stratification of tumors by expression resulted in 35.7% SCLC-A, 17.6% SCLC-N, 21.1% SCLC-Y, 6.4% SCLC-P, and 19.2% SCLC-mixed samples. Compared to tumors from metastatic sites, YAP1 expression was significantly increased (p < 0.001) in primary tumors. Amongst the 14 tumors obtained from the CNS, SCLC-N (36%, n = 5) was the most common subtype identified. dMMR/MSI-high (negative MMR protein expression/ $46 altered loci per tumor) was rare overall (0.5%, n = 2); TMB (median of 9-10 mut/Mb) was similar between the SCLC subtypes. SCLC-Y was associated with the highest expression of T-cell inflamed, NK cell and STING pathway signatures (p < 0.0001 each). MYC and NOTCH gene expression (NOTCH1/2/3/4) strongly correlated with YAP1 expression. Analysis of co-mutations revealed that EGFR-sensitizing mutations (L858R and Exon 19 deletions) were recurrent (5.2%, n = 4) in SCLC-N tumors. The expression of SNF11, SSTR2, and MYC varied significantly among SCLC subtypes (p < 0.001 each), with the highest median expression of SNF11 and SSTR2 observed in SCLC-N, while MYC expression was highest in SCLC-P. Conclusions: Our analysis represents the largest real-world dataset of human SCLC tumors profiled by whole transcriptomic sequencing. The differential expression of immune genes and predictive biomarkers across SCLC subtypes may inform therapeutic vulnerabilities for rational and personalized treatment approaches in SCLC. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8509 Poster Discussion Session

Signatures of plasticity and immunosuppression in a single-cell atlas of human small cell lung cancer.

Joseph Minhow Chan, Alvaro Quintanal-Villalonga, Vianne Gao, Viola Allaj, Ignas Masilionis, Ojasvi Chaudhary, Jacklynn V. Egger, Andrew Chow, Thomas Walle, Marissa Mattar, Michael Offin, W. Victoria Victoria Lai, Matthew Bott, Travis Hollman, Tal Nawy, Linas Mazutis, Triparna Sen, Dana Pe’er, Charles M. Rudin; MSKCC, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical Center, New York, NY; German Cancer Research Center, Heidelberg, Germa- ny; Washington Univ-St. Louis, St. Louis, MO

Background: Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively), which are associated with distinct therapeutic vulnerabilities. The emerging consensus on SCLC subtypes has led to new questions, such as whether subtypes are associated with different disease stages, metastatic potential, or immune microenvironments; whether there is plasticity between subtypes; and whether novel SCLC phenotypes exist. Single cell RNA sequencing (scRNA-seq) offers a unique opportunity to address these questions by dissecting intratumoral transcriptional heterogeneity and the surrounding tumor microenvironment (TME). However, efforts to apply this technology to human SCLC tumors have been limited, as these tumors are infrequently resected. Methods: We have optimized protocols to pro- cess both surgical resections and biopsies to construct the first single-cell atlas of SCLC patient tumors (N = 21), with comparative lung adenocarcinoma (LUAD) and normal lung data. We leverage computa- tional methods including diffusion maps and non-negative matrix factorization to perform a deep anno- tation of SCLC phenotypes and the surrounding immune TME. We perform validation experiments using flow cytometry, Vectra, and immunohistochemistry in independent SCLC cohorts, as well as genetic manipulation in preclinical SCLC models. Results: Our data reveals substantial transcriptional heterogeneity in SCLC both within and across tumors and confirms a pro-metastatic gene program in SCLC-N subtype characterized by epithelial-mesenchymal transformation and axonogenesis. Beyond known subtypes, we discover a PLCG2-high tumor cell population with stem-like, pro-metastatic features that recurs across subtypes and predicts significantly worse overall survival. Manipulation of PLCG2 expression in cells confirms correlation with key metastatic markers. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than SCLC-A. Moreover, the recurrent, PLCG2-high subclone is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis. Conclusions: This atlas of SCLC illustrates how canonical subtypes and a novel PLCG2-high recurrent tumor subclone enlist di- verse gene programs to create tumor heterogeneity and facilitate metastasis in a profoundly immuno- suppressed TME. Our dataset provides further insight into tumor and immune biology in SCLC at single- cell resolution, with potential implications for design of novel targeted therapies and immunotherapeu- tic approaches. Research Sponsor: U.S. National Institutes of Health, Other Foundation. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8510 Poster Discussion Session

Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC).

Taofeek K. Owonikoko, Ste�phane Champiat, Melissa Lynne Johnson, Ramaswamy Govindan, Hiroki Izumi, W. Victoria Victoria Lai, Hossein Borghaei, Michael J. Boyer, Rene J. Boosman, Horst-Dieter Hummel, Fiona Helen Blackhall, Noemi Reguart, Afshin Dowlati, Yiran Zhang, Sujoy Mukherjee, Mukul Minocha, Yanchen Zhou, Aditya Shetty, Nooshin Hashemi Sadraei, Luis G. Paz-Ares; Department of He- matology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Drug Development Department (DITEP), Gustave Roussy, Paris-Saclay University, Villejuif, France; Lung Cancer Research, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; Divisions of Hematology and On- cology, Washington University Medical School, St. Louis, MO; Department of Thoracic Oncology, Na- tional Cancer Center Hospital East, Kashiwa, Chiba, Japan; Thoracic Oncology Service, Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA; Chris O’Brien Lifehouse, Camperdown, NSW, Australia; The Netherlands Cancer Institute, Amsterdam, Netherlands; Translational Oncology/Early Clinical Trial Unit (ECTU), Comprehensive Cancer Center Mainfranken, University Hospital Wu€rzburg, Wu€rzburg, Germany; Department of Medical Oncology, The Christie NHS Foundation Trust, Division of Cancer Sciences, Manchester, United Kingdom; Department of Medical Oncology, Hospital Barcelona, Barcelona, Spain; Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleve- land, OH; Amgen Inc., Thousand Oaks, CA; Amgen Inc San Francisco, South San Francisco, CA; Hospi- tal Universitario 12 de Octubre, CNIO-H12o Lung Cancer Clinical Research Unit, Universidad Complutense & CiberOnc, Madrid, Spain

Background: DLL3, an inhibitory Notch ligand, is a promising target as it is highly expressed in SCLC compared to normal tissue. AMG 757, a half-life extended BiTE immuno-oncology therapy, binds DLL3 on tumor cells and CD3 on T cells, leading to T cell-dependent killing of tumors. Results from the first nine dosing cohorts showing preliminary efficacy of AMG 757 (confirmed partial response [PR], 14% of pts) were previously presented. Here, updated safety, efficacy, and pharmacokinetic data from 10 cohorts from the ongoing phase 1 study of AMG 757 in SCLC are reported (NCT03319940). Methods: AMG 757 (0.003100 mg) was administered IV every 2 weeks ± step dosing. Eligible patients (pts) had SCLC that progressed after $1 platinum-based regimen. Antitumor activity was assessed by modified RECIST 1.1. Results: As of 11 Jan 2021, 64 pts enrolled at 10 dose levels (DLs; 0.003100 mg) had received $1 AMG 757 dose and were available for analyses. Median age was 64 (range, 3280) y; 63 pts (98%) had ECOG PS 01 and median number of prior lines of therapy was 2 (range, 16), with 28 pts (44%) receiving prior PD-1/PD-L1 therapy. Median treatment duration was 6 (range, 0.171) wk. Treat- ment-related AEs occurred in 53 pts (83%): 16 (25%) $ grade (G) 3, 4 (6%) $G4, 1 (2%) G5 (pneumonitis; DL5 [0.3 mg]). AEs led to discontinuation in 1 pt (G3 encephalopathy, DL10 [100 mg]). Cytokine release syndrome (CRS; graded per Lee 2014 criteria) was reported in 27 pts (42%): G2 in 7 (11%), $G3 in 1 (2%). CRS presented mainly as fever (31%), tachycardia (17%), nausea (13%), fatigue (9%), and hypotension (9%). CRS was usually reversible and was managed with supportive care, corticosteroids, and/or anti-IL-6R. CRS did not lead to any treatment discontinuations. Sixty pts treated across 10 DLs, with a median follow-up of 4.2 (range, 0.218.6) mo, were evaluated for efficacy. Con- firmed PR across all DLs was reported in 8/60 pts (13%), with 5/8 pts (63%) pts achieving unconfirmed PR at 100 mg (DL10). The median time to response was 1.7 (range, 1.23.7) mo. The estimated duration of response was >6 months in 71% pts (95% CI: 26, 92) with any PR. Disease control rate was 43%, with any tumor shrinkage in 23/60 pts (38%). AMG 757 serum exposures increased approximately dose proportionally within the evaluated dose range. Conclusions: AMG 757 has an acceptable safety profile at doses up to 100 mg. Responses were rapid and durable. Encouraging anti-tumor activity was seen across dose ranges, with ongoing unconfirmed PR in 5/8 pts (63%) at the highest DL. The study is ongoing; updated data, including response rates and duration of response, will be presented. Clinical trial information: NCT03319940. Research Sponsor: Amgen Inc. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8511 Poster Discussion Session

Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial.

David R. Spigel, Corinne Faivre-Finn, Jhanelle Elaine Gray, David Vicente, David Planchard, Luis G. Paz-Ares, Johan F. Vansteenkiste, Marina Chiara Garassino, Rina Hui, Xavier Quantin, Andreas Rimner, Yi-Long Wu, Mustafa Ozguroglu, Ki Hyeong Lee, Terufumi Kato, Maike de Wit, Euan Macpherson, Michael Newton, Piruntha Thiyagarajah, Scott Joseph Antonia; Sarah Cannon Research Institute/Ten- nessee Oncology, Nashville, TN; The Christie NHS Foundation Trust & The University of Manchester, Manchester, United Kingdom; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Hospi- tal Universitario Virgen Macarena, Seville, Spain; Department of Medical Oncology, Thoracic Unit, Gus- tave Roussy, Villejuif, France; CiberOnc, Universidad Complutense and CNIO, Hospital Universitario 12 de Octubre, Madrid, Spain; University Hospital KU Leuven, Leuven, Belgium; Department of Medi- cal Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; Montpellier Cancer Institute (ICM)and Montpellier Cancer Research Institute (IRCM), INSERM U1194, Montpellier, France; Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Chi- na; Istanbul University-Cerrahpas¸a, Cerrahpas¸a School of Medicine, Istanbul, Turkey; Chungbuk Na- tional University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea; Kanagawa Cancer Center, Yokohama, Japan; Vivantes Klinikum Neukoelln, Berlin, Germany; AstraZe- neca, Macclesfield, MD, United Kingdom; AstraZeneca, Gaithersburg, MD; AstraZeneca, Cambridge, United Kingdom

Background: In the placebo-controlled Phase III PACIFIC trial of patients with unresectable Stage III NSCLC whose disease had not progressed after platinum-based concurrent chemoradiotherapy (cCRT), durvalumab improved overall survival (OS) (stratified hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.53–0.87; p=0.0025; data cutoff [DCO] Mar 22, 2018) and progression-free survival (PFS) (stratified HR 0.52, 95% CI 0.42–0.65; p<0.0001; DCO Feb 13, 2017) based on the DCOs used for the primary analyses, and the degree of benefit remained consistent in subsequent updates. Durvalumab was associated with a manageable safety profile, and did not detrimentally affect patient-reported outcomes, compared with placebo. These findings established consolidation durvalumab after CRT (the ‘PACIFIC regimen’) as the standard of care in this setting. We report updated, exploratory analyses of OS and PFS, assessed approximately 5 years after the last patient was randomized. Methods: Patients with WHO PS 0/1 (and any tumor PD-L1 status) whose disease did not progress after cCRT ($2 overlap- ping cycles) were randomized (2:1) 1–42 days following cCRT (total prescription radiotherapy dose typically 60–66 Gy in 30–33 fractions) to receive 12 months’ durvalumab (10 mg/kg IV every 2 weeks) or placebo, stratified by age (<65 vs $65 years), sex, and smoking history (current/former smoker vs never smoked). The primary endpoints were OS and PFS (blinded independent central review; RECIST v1.1) in the intent-to-treat (ITT) population. HRs and 95% CIs were estimated using stratified log-rank tests in the ITT population. Medians and OS/PFS rates at 60 months were estimated with the Kaplan–Meier method. Results: Overall, 709/713 randomized patients received treatment in either the durvalumab (n/ N=473/476) or placebo (n/N=236/237) arms. The last patient had completed study treatment in May 2017. As of Jan 11, 2021 (median follow-up duration of 34.2 months in all patients; range, 0.2–74.7 months), updated OS (stratified HR 0.72, 95% CI 0.59–0.89; median 47.5 vs 29.1 months) and PFS (stratified HR 0.55, 95% CI 0.45–0.68; median 16.9 vs 5.6 months) remained consistent with the results from the primary analyses. The 60-month OS rates were 42.9% and 33.4% with durvalumab and placebo, respectively, and 60-month PFS rates were 33.1% and 19.0%, respectively. Updated treatment effect estimates for patient subgroups will be presented. Conclusions: These updated survival analyses, based on 5-year data from PACIFIC, demonstrate robust and sustained OS plus durable PFS benefit with the PACIFIC regimen. An estimated 42.9% of patients randomized to durvalumab remain alive at 5 years and approximately a third remain both alive and free of disease progression. Clinical trial information: NCT02125461. Research Sponsor: AstraZeneca. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8512 Poster Discussion Session

KEYNOTE-799: Phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC.

Salma K. Jabbour, Ki Hyeong Lee, Nicolaj Frost, Valeriy Vladimirovich Breder, Dariusz M. Kowalski, Issam Abdelkarim Alawin, Evgeny Levchenko, Noemi Reguart, Alex Martinez-Marti, Baerin Houghton, Jean-Baptiste Paoli, Sufia Safina, Keunchil Park, Takefumi Komiya, Amy Sanford, Vishal Boolell, Hong Liu, Ayman Samkari, Steven M. Keller, Martin Reck; Department of Radiation Oncology, Rutgers Can- cer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea; Department of Infectious Diseases and Respiratory Medicine, Char- ite�–Universita€tsmedizin Berlin, corporate member of Freie Universita€t Berlin, Humboldt-Universita€t zu Berlin, and Berlin Institute of Health, Berlin, Germany; N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Southwestern Regional Medical Center, Inc., Cancer Treatment Centers of America, Tulsa, OK; Petrov Research Institution of Oncology, Saint-Petersburg, Russian Federation; Thoracic On- cology Unit, Hospital Cl�ınic de Barcelona, Barcelona, Spain; Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Barcelona, Spain; Mid North Coast Cancer Institute, Port Macquarie Base Hospital, Port Macquarie, NSW, Australia; Radiotherapie, Clinique Clairval, Marseille, France; Medical Oncology, Republican Dispensary of Tatarstan MoH, Kazan, Russian Federation; Divi- sion of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Hematology/Medical Oncology, Parkview Cancer Institute, Fort Wayne, IN; Sanford Health, Sioux Falls, SD; Ballarat Health Services, Ballarat, VIC, Australia; Merck & Co., Inc., Kenil- worth, NJ; LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshans- dorf, Germany

Background: KEYNOTE-799 (NCT03631784) is an ongoing study of the anti–PD-1 antibody pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in patients (pts) with unresectable, locally advanced stage III NSCLC. Pri- or results from this study in a subset of pts (primary efficacy population) showed an ORR of 69.6% in cohort A (squamous and nonsquamous, n = 112) and 70.5% in cohort B (nonsquamous, n = 61), and grade $3 pneumonitis in 8.0% and 7.9% of pts, respectively. Here, we present results for all pts enrolled in KEYNOTE-799. Methods: This nonrandomized, multisite, open-label phase 2 trial enrolled pts aged $18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA–C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received 1 cycle of carboplatin AUC 6 and paclitaxel 200 mg/m2 and pembro 200 mg. After 3 wks, pts received carboplatin AUC 2 and paclitaxel 45 mg/m2 QW for 6 wks and 2 cycles of pembro 200 mg Q3W plus standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous only) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2,and pembro 200 mg Q3W, and TRT in cycles 2 and 3. All pts received an additional 14 cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review (BICR) and the incidence of grade $3 pneumonitis (per NCI CTCAE v4.0). Efficacy and safety were assessed in all pts as-treated. Results: Of 216 pts enrolled in KEYNOTE-799 (cohort A, n = 112; cohort B, n = 104), 112 in cohort A and 102 in cohort B received treatment. As of Oc- tober 28, 2020, the median (range) time from first dose to database cutoff was 18.5 (13.6–23.8) mo in cohort A and 13.7 (2.9–23.5) mo in cohort B. ORR (95% CI) was 70.5% (61.2%–78.8%) in cohort A and 70.6% (60.7%–79.2%) in cohort B. Median DOR was not reached in either cohort (Table). ORR was similar regardless of PD-L1 status ([TPS <1% and TPS $1%]; Cohort A, 66.7% and 75.8%; Cohort B, 71.4% and 72.5%) and tumor histology (Cohort A, squamous, 71.2% and nonsquamous, 69.2%). Grade $3 pneumonitis occurred in 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Grade 3–5 treatment-related AEs occurred in 72 pts (64.3%) in cohort A and 51 (50.0%) in cohort B. Conclusions: Pembro plus cCRT continues to demonstrate promising antitumor activity, regardless of PD-L1 TPS and tumor histology, and manageable safety in pts with previously untreated, locally advanced, stage III NSCLC with longer follow-up. Clinical trial information: NCT03631784. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Ken- ilworth, NJ, USA.

Cohort A Cohort B n = 112 n = 102

ORR, % (95% CI) 70.5 (61.2–78.8) 70.6 (60.7–79.2) Median DOR, mo (range) NR (1.7+ to 19.7+) NR (1.8+ to 21.4+) DOR $12 mo, % 79.7 75.6 Median PFS, mo (95% CI) NR (16.6–NR) NR (NR–NR) 12-mo PFS rate, % 67.1 71.6 Median OS, mo (95% CI) NR (NR–NR) NR (21.9–NR) 12-month OS rate, % 81.3 87.0

NR, not reached. “+” indicates no PD since the time of last disease assessment. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8513 Poster Discussion Session

AFT-16: Phase II trial of neoadjuvant and adjuvant atezolizumab and chemoradiation (CRT) for stage III non-small cell lung cancer (NSCLC).

Helen J. Ross, David E. Kozono, James John Urbanic, Terence Marques Williams, Carter DuFrane, Ilze Bara, Katja Schulze, Jane Michelle Brockman, Xiaofei F. Wang, Junheng Gao, Everett E. Vokes, Tom Stinchcombe; Thoracic Oncology, Phoenix, AZ; Dana-Farber Cancer Institute, Boston, MA; University of California, San Diego, Department of Radiation Medicine and Applied Sciences, San Diego, CA; City of Hope, Duarte, CA; Alliance Foundation Trials, Boston, MA; Genentech, Inc., South San Francisco, CA; Genentech, Inc, South San Francisco, CA; Duke Cancer Institute, Durham, NC; Duke University Health System, Durham, NC; University of Chicago Medicine, Chicago, IL

Background: A minority of the approximately 40,000 US patients diagnosed annually with stage III NSCLC can be cured by concurrent CRT. Standard adjuvant immune checkpoint inhibitors (ICI) improve outcome for those patients who complete CRT with good performance status (PS) and without disease progression, but most patients diagnosed with unresectable stage III NSCLC will not meet the criteria for adjuvant ICI. AFT-16 investigated safety and efficacy of neoadjuvant and adjuvant atezolizumab as a strategy that may allow more patients to benefit from ICI. Methods: Eligible patients received 4 cycles (cy) of atezolizumab 1200 mg IV q 21 days followed by CRT with 60 Gy + weekly carboplatin and paclitaxel (CP), CP consolidation and adjuvant atezolizumab to complete 1 year of therapy (17 cy). The primary endpoint of disease control rate at 12 weeks (wks) has been reported. Secondary endpoints reported here include overall response rate, safety, and progression-free and overall survival (PFS, OS) measured from the start of induction therapy. Correlative science data and quality of life endpoints will be reported elsewhere. Results: 64 patients with unresectable stage III NSCLC, PS 0-1 and no active autoimmune disease or significant organ dysfunction were enrolled at 13 Alliance for Clinical Trials in On- cology sites from 11/2017 to 7/2019. 62 patients who received at least one dose of atezolizumab are included in this analysis. Median age was 63.9 years (range 38.1-86.5). Patients were 51.6% female, 77.4% white, 88.7% current & former smokers and 56.5% PS 0. All patients are off study treatment. Mean cycles of treatment received was 9 (1-17). 46 patients were alive at median follow up 24.1 mo (range 3 – 34.1 mo). PFS at 12 and 18 mo from start of induction atezolizumab was 66% (95%CI 55- 79) and 57% (95%CI 45-71) respectively. Median PFS was 23.7 mo (95%CI 13.2-NE). OS at 18 mo was 84% (95%CI 75-94). Median OS is not yet estimable. Atezolizumab was well tolerated. One grade (gr) 4 Guillain-Barre syndrome and 1 each gr 3 pneumonia, pneumonitis and colitis were attributable to neoadjuvant atezolizumab. The remaining 9 severe adverse events were unrelated to ICI. Conclusions: Atezolizumab prior to and following CRT for stage III unresectable NSCLC was well tolerated with encouraging PFS and OS without unexpected safety signals. Analysis of correlative endpoints and quality of life are ongoing. Further study of induction atezolizumab is warranted in patients with unresectable stage III NSCLC. Support: https://acknowledgments.alliancefound.org; Clinical trial information: NCT03102242. Research Sponsor: Alliance for Clinical Trials in Oncology Foundation. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8514 Poster Discussion Session

Racial differences in incidence, outcomes, and genomic alterations in small cell lung cancer.

Leyla Bayat, Pingfu Fu, Shufen Cao, Afshin Dowlati; University Hospital Case Western Medical Center, Cleveland, OH; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH; Department of Biostats and Epidemiology, Case Western Reserve University, Cleveland, OH; Case Western Reserve University and University Hospitals Case Medical Center, Cleve- land, OH

Background: While the incidence of small cell lung cancer (SCLC) has been decreasing in recent years, an increasing proportion of our patients are younger African American (AA) women. There have been no studies describing these changes as well its impact on outcome and potential genomic differences amongst white and AA populations. Methods: We maintain a clinical/genomic/pathological database of all patients with SCLC treated at our comprehensive cancer center starting from 1998. We compared the baseline characteristics and outcomes (Overall survival [OS] and progression-free survival [PFS]) between AA and white patients, and between females and males. In addition, we looked at genomic alterations in >350 cancer-related genes and compared the frequency and types of mutations in our study population. Results: A total of 917 patients with SCLC were included (median age 66 years, 486 female, 179 African American). Amongst the African American patients, 67.6% were female, a striking difference compared to the white population, where only 49.1% were women (P<0.001). In multivariable analysis, there was no association between gender or race with OS or PFS (P> 0.05). There was an increase in mutational frequency in AA women compared to both AA men and white patients. PIK3CA and KIT mutations were more frequent in females while APC mutations were more frequent in males (P=0.041 for all comparisons). There was a trend toward increased mutational frequencies in TP53, PTEN, and NOTCH1 in AA patients. The relative frequency of gene alterations is shown in the table. In univariable analysis, NOTCH1 mutation was associated with improved OS (HR 0.24 [0.06-0.96], P=0.04). Conclusions: In this large cohort of patients with SCLC followed over 2 decades, there was a striking 2-fold higher incidence of SCLC in AA females than in AA males, although there were no differences in OS or PFS by sex or race. Several genomic alterations occur in higher frequencies in AA patients and AA women, in particular, have higher mutational frequencies. Research Sponsor: None.

Male Female (n = 51) (n = 51) p-value

STK11 (wild/mutant) 46/5 50/1 0.092 AKT2 (wild/mutant) 50/1 47/4 0.169 FBXW7 (wild/mutant) 50/1 47/4 0.169 PIK3CA (wild/mutant) 51/0 47/4 0.041 APC (wild/mutant) 47/4 51/0 0.041 KIT (wild/mutant) 51/0 47/4 0.041 ATRX (wild/mutant) 51/0 48/3 0.079 AXL (wild/mutant) 51/0 48/3 0.079 EP300 (wild/mutant) 51/0 48/3 0.079 MYST3 (wild/mutant) 48/3 51/0 0.079 NFE2L2 (wild/mutant) 48/3 51/0 0.079 PDGFRA (wild/mutant) 51/0 48/3 0.079

Relative frequency of each alteration in female and male patients. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8515 Poster Discussion Session

Impact of socioeconomic disparities on diagnosis and overall survival in small cell lung cancer: A National Cancer Database analysis.

Logan Roof, Wei Wei, Katherine Tullio, Nathan A. Pennell, James Stevenson; Cleveland Clinic, Cleve- land, OH; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Cleveland Clinic Foundation, Cleveland, OH

Background: Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagno- ses in the United States. The demographics of this disease have evolved over time; in the 1970s 28% of patients with SCLC were female, while in the early 2000s, 50% were female. Remarkable differences in incidence, mortality rates, and trends by race and geographic location have also been noted. There has been a paucity of data regarding changes in epidemiology and patient demographics in SCLC since the early 2000s. Given recent treatment advances, the impact these factors have on patient outcomes for SCLC requires further evaluation. Methods: We identified all patients with SCLC in the NCDB from 2004 to 2016. Differences in demographic, disease, and treatment characteristics were assessed by year of diagnosis using Chi-square test. The effect of age, race, insurance status, income, distance to treatment center, and education level on overall survival (OS) was assessed by log-rank test. Results: There were 137,253 cases of SCLC diagnosed in the NCDB between 2004-2010 and 124,796 cases between 2011-2016. Patients diagnosed after 2010 were significantly older, had more comorbidities, had more stage IV disease, were more frequently treated at academic centers, more commonly had gov- ernment primary payer insurance, and lived significantly further away from their treatment center. There were significant differences in gender, race/ethnicity groups, education level, and residence area, with more females, more African Americans, more patients without a high school diploma, and more rural patients diagnosed after 2010. OS in general improved between the two time periods, with median OS of 8.41 months (95% CI: 8.34-8.48%) and 5-year OS rate of 6.8% (95% CI: 6.6-6.9%) in patients diagnosed between 2004-2010 and median OS of 8.61 months (95% CI: 8.54-8.67%) and 5-year OS rate of 8.7% (95% CI: 8.5-8.9%) in patients diagnosed after 2010, despite an increase in stage IV disease in the latter group. Some of the differences in demographics were associated with changes in OS. Older patients, male patients, Caucasian patients, patients with stage IV disease, patients with govern- ment primary payer insurance, and rural patients all had significantly worse OS. Patients without comorbidities and patients treated at an academic center had significantly better OS. OS was found to significantly increase as both income and education level increase. Conclusions: SCLC continues to be a frequent cancer diagnosis. Despite improvement in overall survival during the time frame studied, there were significant disparities noted in key demographics that negatively affect access to healthcare re- sources, including rural communities, distance to an academic center, income, insurer, and education level. Collective efforts to impact these disparities will likely lead to improved outcomes for patients with SCLC. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8516 Poster Discussion Session

Racial disparities in lung adenocarcinoma: The contribution of African ancestry.

Michelle Jeung-Eun Lee, Eric Chang, Manan Shah, Sanjay R. Jain; Morehouse School of Medicine, At- lanta, GA; Morehouse School of Medicine, Stone Mountain, GA

Background: Racial disparities in lung cancer are well-known with African Americans disproportionally affected by lung cancer in terms of incidence and survival. Previous comparative analyses of molecular features of lung cancer revealed racial differences in genomic profiles, which supports somatic differences arising from genetic ancestry. Using The Cancer Genome Atlas (TCGA), we investigated the genetic alterations in lung adenocarcinomas (LUAD) on individuals of African (AFR) ancestry. Methods: The genomic and clinical data of TCGA PanCancer Atlas LUAD were downloaded through the GDC Data Portal. Given that substantial proportion of the US population consist of genetically admixed populations, we utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral compositions. This dataset contains 518 samples, including 393 self- reported whites and 52 African Americans. For each case the proportion of European, AFR, East Asian, native American ancestry was estimated. The dominant ancestry was defined as $50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global ancestry analysis identified 50 AFR ancestry cases with mean ancestry of 78.3%. The dominant AFR ancestry group matched the self-reported race with 96% accuracy. We identified 9 subjects with $90% AFR ancestry, 22 subjects with 80-90% AFR ancestry, 12 subjects with 70-80% AFR ancestry, and 7 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene, and $90% AFR ancestry had the highest rate of mutations (77.8%) compared with 80- 90% AFR ancestry (68.2%), and 70-80% AFR ancestry (66.8%). We evaluated classic driver gene mutations (EGFR, KRAS, NRAS, PIK3CA, ALK) and found only 33% of $90% AFR ancestry subjects carry a known driver mutation, compared to 58-77% in lower proportion of AFR ancestry subjects. Higher AFR ancestry was associated with worse overall survival (OS) and progression free survival (PFS). Medi- an OS was 14.5 months for $90% AFR ancestry compared to 71.47 months in 70-80% AFR ancestry (P = 0.048). $90% AFR ancestry had median PFS of 12.8 months compared to 33.5 months in 80- 90% AFR ancestry, and 47.1 months in 70-80% AFR ancestry (P = 0.002). Conclusions: This study demonstrates the power of genomic study to investigate the etiology of health disparities by analyzing the effect of ancestry on genetic alterations in LUAD. Our results reveal different mutation loads even among AFR ancestry patients. We observed that AFR ancestry is associated with worse OS, suggesting possible influence of germline ancestry in subsequent somatic alterations. Further work is needed to explore how genetic ancestry impacts tumorigenesis and cancer progression to eliminate lung cancer disparities. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8517 Poster Discussion Session

Residual ctDNA after treatment predicts early relapse in patients with early-stage NSCLC.

Davina Gale, Katrin Heider, Malcolm Perry, Giovanni Marsico, Andrea Ruiz-Valdepen~as, Viona Rundell, Jerome Wulff, Garima Sharma, Karen Howarth, David Gilligan, Susan Harden, Doris M. Rassl, Robert Rintoul, Nitzan Rosenfeld; Cancer Research UK Cambridge Institute, Cambridge, United Kingdom; Ini- vata Ltd, Cambridge, United Kingdom; Cambridge Clinical Trials Unit-Cancer Theme, Cambridge, Unit- ed Kingdom; Addenbrooke’s Hospital, Cambridge, United Kingdom; Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom; Department of Oncology, University of Cambridge, Cambridge, United Kingdom

Background: Liquid biopsies based on circulating tumor DNA (ctDNA) analysis are being investigated for detection of residual disease and recurrence. Conclusive evidence for utility of ctDNA in early-stage non-small cell lung cancer (NSCLC) is awaited. Due to low ctDNA levels in early-stage disease or post- treatment, effective methods require high analytical sensitivity to detect mutant allele fractions (MAF) below 0.01%. Methods: We analysed 363 plasma samples from 88 patients with NSCLC recruited to the LUng cancer CIrculating tumour DNA (LUCID) study, with disease stage I (49%), II (28%) and III (23%). 62% were adenocarcinomas. Plasma was collected before and after treatment, and at 3, 6 and 9 months after surgery (N = 69) or chemoradiotherapy (N = 19). Additional plasma was collected at disease relapse for 17 patients. Median follow-up was 3 years, and 40 patients progressed or died of any cause. We employed the RaDaR™ assay, a highly sensitive personalized assay using deep sequencing of up to 48 tumor-specific variants. Variants identified by tumor exome analysis were tested by deep sequencing of tumor tissue and buffy coat DNA to verify somatic mutations and exclude clonal hematopoi- esis. The RaDaR assay demonstrated 90% sensitivity at 0.001% MAF in analytical validation studies. Results: ctDNA was detected in 26% of samples, at median MAF of 0.047% (range: 0.0007% to > 2%), and prior to treatment in 87%, 77% and 24% for disease stage III, II and I respectively. For 62 patients, plasma was collected at a landmark timepoint, between 2 weeks and 4 months after initial treatment. ctDNA detection at the landmark timepoint was strongly predictive of clinical disease relapse, with Hazard Ratio of 20.7 (CI: 7.7-55.5, p-value < 0.0001). All 11 cases with ctDNA detected at landmark had disease progression, a median of 121 days after detection, and these included all 8 patients that relapsed within 300 days of treatment. Across 27 patients whose disease progressed during the study, ctDNA was detected at any timepoint post-treatment in 17 cases, with a median lead time of 203 days, and up to 741 days prior to clinical progression. ctDNA was detected post-treatment, in 13 of the 15 patients that progressed and had ctDNA detected prior to treatment. Conclusions: Our results support an emerging paradigm shift, by demonstrating that liquid biopsies can reliably detect recurrence of NSCLC at a preclinical stage, many months before clinical progression, thereby offering the opportunity for earlier therapeutic intervention. Clinical trial information: NCT04153526. Research Sponsor: Cancer Research UK. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8518 Poster Discussion Session

Leveraging phased variants for personalized minimal residual disease detection in localized non-small cell lung cancer.

David Matthew Kurtz, Jacob J. Chabon, Brian Sworder, Lyron Co Ting Keh, Joanne Soo, Stefan Alig, Andre Schultz, Andrea Garofalo, Emily G. Hamilton, Binbin Chen, Mari Olsen, Everett James Moding, Chih Long Liu, Ash A. Alizadeh, Maximilian Diehn; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Foresight Diagnostics, Aurora, CO; Stanford University, Stanford, CA; Stanford University Medical Center, Stanford, CA; Stanford School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA; Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA

Background: Detection of circulating tumor DNA (ctDNA) has prognostic value in lung cancer and could facilitate minimal residual disease (MRD) driven approaches. However, the sensitivity of ctDNA detection is suboptimal due to the background error rates of existing assays. We developed a novel method leveraging multiple mutations on a single cell-free DNA molecule (“phased variants” or PVs) resulting in an ultra-low error profile. Here we develop and apply this approach to improve MRD in localized NSCLC. Methods: To identify the prevalence of PVs, we reanalyzed whole genome sequencing (WGS) from 2,538 tumors and 24 cancer types from the pan-cancer analysis of whole genomes (PCAWG). We applied Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) to track personalized PVs in localized NSCLC. We compared PhasED-Seq to a single nucleotide variant (SNV)-based ctDNA method. Results: In the PCAWG dataset, we found that PVs were common in both lung squamous cell carcinomas (LUSC, median 1,268/tumor; rank 2nd) and adenocarcinomas (LUAD, median 655.5/tumor; rank 3rd). However, PVs did not occur in stereotyped genomic regions. Thus, to leverage PhasED-Seq, we performed tumor/normal WGS to identify PVs, followed by design of personalized panels targeting PVs to allow deep cfDNA sequencing. We performed personalized PhasED-Seq for 5 patients with localized NSCLC. PVs were identified from WGS of tumor FFPE and validated by targeted resequencing in all cases (median 248/case). The background rate of PVs was lower than that of SNVs, even when consider- ing duplex molecules (background: SNVs, 3.8e-5; duplex SNVs, 1.0e-5; PVs, 1.2e-6; P < 0.0001). We next assessed PhasED-Seq for MRD detection in 14 patient plasma samples. Both SNVs and PhasED- Seq had high specificity in healthy control cfDNA (95% and 97% respectively). Using SNVs, ctDNA was detected in 5/14 samples; PhasED-Seq detected all of these with nearly identical tumor fractions (Spearman rho = 0.97). However, PhasED-Seq also detected MRD in an additional 5 samples contain- ing tumor fractions as low as 0.000094% (median 0.0004%). We analyzed serial samples from a patient with stage III LUAD treated with chemoradiotherapy (CRT) and durvalumab. SNV-based ctDNA and PhasED-Seq detected similar MRD levels (0.8%) prior to therapy. However, 3 samples collected during CRT, as well as before and during immunotherapy, were undetectable by SNVs. SNV-based ctDNA then re-emerged at disease recurrence. PhasED-Seq detected MRD in all 3 samples not detected by SNVs with tumor fractions as low as 0.00016%, including prior to immunotherapy (8 months prior to progression). Similar improvements were seen in samples not detected by SNVs from 2 additional patients. Conclusions: Personalized ctDNA monitoring via PVs is feasible and improves MRD detection in localized NSCLC. PhasED-Seq allows clinical studies testing personalized treatment based on MRD. Research Sponsor: U.S. National Institutes of Health, Conquer Cancer Foundation of the American Society of Clinical Oncology, Other Foundation. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8519 Poster Discussion Session

Early detection of lung cancer using cfDNA fragmentation.

Dimitrios Mathios, Jakob Sidenius Johansen, Stephen Cristiano, Jamie Medina, Jillian Phallen, Klaus Richter Larsen, Daniel Bruhm, Noushin Niknafs, Hans J. Nielsen, Gerrit A. Meijer, Claus Lindbjerg Andersen, Stig Egil Bojesen, Robert Scharpf, Victor E. Velculescu; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, Herlev and Gentofte Hospital, Copenhagen, Denmark, Herlev, Denmark; Johns Hopkins Medical Institu- tions, Baltimore, MD; Johns Hopkins University School of Medicine, Baltimore, MD; Johns Hopkins University, Baltimore, MD; Bispebjerg University Hospital, København NV, Denmark; Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark; Netherlands Cancer Institute, De- partment of Pathology, Amsterdam, Netherlands; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Univer- sity of Copenhagen, Herlev, Denmark

Background: Lung cancer incidence and mortality are increasing worldwide despite more effective treatments. This is primarily due to the late stage of diagnosis when treatments are less effective. Although large randomized trials have demonstrated a significant decrease in lung cancer mortality through screening of high-risk individuals with chest low dose computed tomography (LDCT), LDCT has made little impact in the community, mainly due to lack of accessibility. There is therefore an unmet clinical need for development of cost-effective and easily implemented tests for early lung cancer detection. Methods: We have previously shown that altered genome-wide fragmentation of cell free DNA (cfDNA) is a common characteristic of many cancers. In this study, we leverage this knowledge to increase the sensitivity of lung cancer detection by interrogating characteristics of the size distribution of cfDNA fragments across the genome using machine learning methods. The approach we present, called DELFI (DNA evaluation of fragments for early interception) generates a score that reflects the presence of tumor-derived DNA in plasma based on a multi-feature genomic analysis that assesses millions of cfDNA fragments for tumor-derived genomic and epigenomic changes in a small amount of blood (2-4 mls) via inexpensive low coverage (1-2x) whole genome sequencing. We applied this methodology in a prospectively collected cohort of 365 individuals under investigation for lung cancer and we prospectively validated it in a separate case-control cohort of patients with newly diagnosed early stage lung cancer as well as individuals without cancer (n=427). Results: These analyses revealed high performance for detection of early and late stage disease (Table). When DELFI was used as a prescreen for LDCT it increased specificity from 58% with CT imaging alone to 80% using the combined approach. The DELFI score was significantly associated with T and N stage in lung cancer cases (p<0.0001) as well as with overall survival (p=0.003). In a multivariable analysis including age, histology and stage, DELFI score was an independent prognostic factor of overall survival (HR=2.53; p=0.0003). Finally, we determined that genome-wide fragmentation profiles can be used to distinguish small cell lung cancer from non- small cell lung cancer with high accuracy (AUC 0.98). Conclusions: These findings provide key insights into cfDNA fragmentation in patients with cancer and a new and easily accessible avenue for non-invasive diagnosis and molecular profiling of lung cancer. Research Sponsor: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, SU2C in-Time Lung Cancer Interception Dream Team Grant, Other Foundation, Pharmaceutical/Biotech Company, U.S. National Institutes of Health.

Sensitivity of DELFI followed by LDCT for lung cancer detection*. Sensitivity DELFI DELFI, LDCT Stage Stage I (n=8) 88% 100% Stage II (n=7) 86% 86% Stage III (n=30) 93% 93% Stage IV (n=49) 92% 98% Histology Adenocarcinoma (n=46) 87% 94% Squamous (n=25) 96% 100% Small cell (n=8) 100% 100% Other (n=15) 93% 93%

*Sensitivities refer to the fraction of cases detected at single or combined test specificities of 80%. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8520 Poster Session

Updated overall survival (OS) and exploratory analysis from the randomized, phase II EVAN study of erlotinib (E) versus vinorelbine plus cisplatin (NP) as adjuvant therapy in Chinese patients with stage IIIA EGFR+ NSCLC.

Dongsheng Yue, Shi-Dong Xu, Qun Wang, Xiaofei Li, Yi Shen, Heng Zhao, Chun Chen, Weimin Mao, Wei Liu, Junfeng Liu, Lan-Jun Zhang, Haitao Ma, Qiang Li, Yue Yang, Yongyu Liu, Haiquan Chen, Zhenfa Zhang, Bin Zhang, Fuyu Gong, Changli Wang; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Harbin Medical University Cancer Hospital, Harbin, China; Department of Tho- racic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Thoracic Sur- gery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China; The First Hospital of Qing Dao University, Qingdao, China; Department of Thoracic Surgery, Shanghai Chest Hospital,Shanghai Jiao Tong University, Shanghai, China; Fujian Uion Hospital, Fuzhou, China; Zhejiang Cancer Hospital, Hangzhou, China; First Hospital of Jilin University, Changchun, China; Hebei Provincial Tumor Hospi- tal, Sijiazhuang, China; Cancer Center, Lung Cancer Research Center, Sun Yat-sen University, Guang- zhou, China; The First Affiliated Hospital of Suzhou University, Suzhou, China; Thoracic Surgery Department, Sichuan Cancer Hospital Institute/Sichuan Cancer Center/School of Medicine,University of Electronic Science and Technology of China, Chengdu, China; Thoracic Surgery II, Peking University Cancer Hospital, Beijing, China; Liaoning Cancer Hospital, Shenyang, China; Department of Thoracic Surgery, Fudan University, Shanghai Cancer Center, Shanghai, China; The Medical Department, 3D Medicines Inc. Shanghai, P.R. China, Shanghai, China; Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

Background: The EVAN study of E vs NP in stage III EGFR+ NSCLC has met its primary endpoint and been previously published: 2-year disease-free survival was 81.4% (95% CI, 69.6–93.1) in E group vs 44.6% (95% CI, 26.9-62.4) in NP group (HR, 1.823; 95% CI, 1.194–2.784; P=0.0054). We report 5-year OS and exploratory results from EVAN with a further 43 month follow up (cutoff date: Jan 6, 2021). Methods: Patients with stage IIIA EGFR+ NSCLC were randomized assigned (1:1) into either E arm (n=51, 150mg/day) or NP arm (n=51, vinorelbine 25mg/m2 on day 1, 8 and cisplatin 75mg/m2 on day 1 of a 21-day cycle). In order to explore the relationship between patient benefits and co-occurring variants, 47 patients received whole exome sequencing (WES) analysis (E, n=24; NP, n=23). Results: Median follow-up time was 54.8 months for E and 63.9 months for NP. E improved OS and 5-year survival rate compared with NP in ITT population. The median OS was 84.2m (95% CI, 78.1,-) with E vs 61.1m (95% CI, 39.6-82.1) with NP (HR, 0.318; 95% CI, 0.151-0.670). The 5-year survival rates were 84.8% (95%CI, 72.0-97.6) and 51.1% (95% CI, 34.7-67.5), respectively. In the WES analysis, we found that the most frequent genes with co-occurring variants at baseline were TP53, MUC16, FAM104B, KMT5A and DNAH9, and additional EGFR variants, each with similar prevalence regardless of EGFR-activating mutation subgroup. Moreover, in the erlotinib-treated patients, the SNP mutation of UBXN11 was associated with significantly worse DFS (P=0.0111). Conclusions: This is the first randomized study of EGFR-TKI to demonstrate a clinically meaningful improvement in OS vs chemotherapy in stage III EGFR+ NSCLC (5-year survival rate 84.8% in E vs 51.1% in NP). The co-occurring variants at baseline may be associated with reduced DFS. Further studies are required to confirm our results (EVAN, NCT01683175). Clinical trial information: NCT01683175. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8521 Poster Session

Different exposure duration of adjuvant icotinib in stage II-IIIA non-small cell lung cancer patients with positive EGFR mutation (ICOMPARE study): A randomized, open-label phase 2 study.

Chao Lyu, Rui Wang, Shaolei Li, Shi Yan, Yuzhao Wang, Jinfeng Chen, Liang Wang, Yinan Liu, Zhanlin Guo, Jia Wang, Yuquan Pei, Lei Yu, Nan Wu, Jun Chen, Yanheng Liu, Shanqing Li, Bing Han, Lieming Ding, Li Mao, Yue Yang; Thoracic Surgery II, Peking University Cancer Hospital, Beijing, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; Beijing Cancer Hospital, Beijing, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Depart- ment of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, China; THE Affi- lated Hospital of Inner Mongolia Medical University, Hohhot, China; Department of Thoracic Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing City, China; Tianjing Medical University General Hospital, Tianjin, China; Inner Mongolia People’s Hospital, Hohhot, China; Peking Union Medi- cal College Hospital, Beijing, China; PLA Pocket Force Characteristic Medical Center, Beijing, China; Betta Pharmaceuticals Co., Ltd., Hangzhou, China; Betta Pharmaceuticals, Hangzhou, China

Background: EGFR-TKI has been widely used in the treatment for advanced non-small cell lung cancer (NSCLC). Previous studies, such as the EVIDENCE study and the ADAURA study, have confirmed that patients with EGFR-mutated NSCLC could benefit from adjuvant EGFR-TKI treatment. However, the optimal duration time of adjuvant EGFR-TKIs has not been clearly defined. Methods: In this multicenter, randomized, phase 2 trial, eligible patients with II-IIIA stage EGFR mutation-positive NSCLC after R0 resection were randomized in 1:1 to receive adjuvant icotinib for 1 year (group A) or 2 years (group B). The primary endpoint was disease-free survival (DFS). Results: Between September 2013, and Septem- ber 2018, 109 patients from 8 centers were enrolled in this study, among whom 55 were randomized to group A and 54 to B. As of August 24, 2020 (data cutoff), the median follow-up was 44.1 months (95%CI 37.1-49.9), 31 (56%) of 55 patients in the 1-year group and 25 (46%) of 54 patients in the 2-year group had DFS events. The median DFS was 48.92 months (95%CI 33.15, 70.11) in 2-year group and 32.89 month (95%CI 26.61, 44.78) in 1-year group, respectively. 2-year icotinib significantly prolonged DFS (HR 0.521, 95%CI 0.278, 0.976; p = 0.039). OS events were observed in 20 patients, the OS was not mature yet. Icotinib was re-given for 32 patients with disease recurrence or metastasis as first-line treatment, objective response occurred in 66.7% of 30 patients with measurable disease. Treatment-related adverse events were recorded in 41 of 55 (75%) patients in 1-year group and 36 of 54 (67%) patients in 2-year group, and grade 3 or 4 treatment-related adverse events occurred in 4 (7%) of 55 patients in the 1-year group versus 3 (6%) of 54 in the 2-year group, respectively. No treatment-related deaths or interstitial lung disease were reported. Conclusions: 2-year adjuvant treatment with icotinib resulted in a significantly lower risk of recurrence than 1-year adjuvant icotinib in patients with stage II-IIIA NSCLC positive EGFR mutations and was not associated with increased toxic effects. Clinical trial information: NCT01929200. Research Sponsor: Betta pharmaceuticals. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8522 Poster Session

Two-year follow-up of single PD-1 blockade in neoadjuvant resectable NSCLC.

Shugeng Gao, Ning Li, Shunyu Gao, Qi Xue, Shuhang Wang, Fang Lv, Liang Zhao, Fan Zhang, Ziran Zhao, Kai Su, Fengwei Tan, Yun Ling, Zhijie Wang, Wei Tang, Jianming Ying, Ning Wu, Jie Wang, Jie He; Thoracic Surgery Department, National Cancer Center/National Clinical Research Center for Can- cer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Pathology Department, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Medical Oncology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei- jing, China; Radiology Department, National Cancer Center/National Clinical Research Center for Can- cer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Nuclear Medicine Department, National Cancer Center/National Clinical Research Cen- ter for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Col- lege, Beijing, China

Background: Early stage non-small-cell lung cancer (NSCLC) could benefit from anti-programmed cell death-1 (PD-1) monotherapy; however, the survival profiles remain to be disclosed. Here, we presented the two-year follow-up outcomes from a phase 1b study of sintilimab, an anti-PD-1 inhibitor in the neoadjuvant setting of NSCLC. Methods: Treatment-naive pts with resectable NSCLC (stage IA–IIIB) received two cycles of sintilimab followed by surgical resection. Postoperative treatment of sintilimab was at the discretion of investigator. The primary endpoint was AE, and key secondary endpoints included major pathological response (MPR), disease free survival (DFS) rate of 1 year and 2 years, and overall survival (OS) rate of 2 years. Results: Among 40 enrolled pts, 36 (90%) underwent R0 resection and were included in the R0 resection population. By data cutoff (January 20, 2021), the median follow-up for DFS and OS for all the enrolled pts was 23.9 (IQR 20.5–24.4) months and 26.4 (IQR 24.2–29.0) months. A total of 12 (33.3%) pts experienced relapse, and 6 pts died. The 1-yr and 2-yr DFS rate was 91.7%/73.3%. The 2-yr OS rate for overall population and R0 population was 87.5%/91.7%, respectively. In the R0 resection population, the median DFS and OS were both not reached. Superior 2-year DFS rates were observed in pts who achieved MPR (MPR vs. Non-MPR: 86.7% vs. 63.8%). DFS of pts with non-squamous cell carcinoma tended to be shorter than that of pts with squamous cell carcinoma (HR 2.71 [95%CI 0.67–11.0], p=0.1479). Pts with tumor mutation burden (TMB) $10 mutations/Mb and PD-L1 tumor proportion score (TPS)$50% tended to have a better 2-yr DFS rate compared to those with TMB<10 and TPS<50. [table] For the post-hoc event free survival (EFS) analysis, the same trend was observed with DFS among different subgroups, and patients with TMB $10 mutations/Mb had a significant improved EFS (HR 0.125[95% CI 0.02,1.03], P=0.0222). Conclusions: Anti-PD-1 monotherapy emerged to be a promising neoadjuvant therapeutic strategy for resectable NSCLC with improved clinical outcomes. MPR could serve as a surrogate efficacy biomarker in this setting. Clinical trial information: ChiCTR-OIC-17013726. Research Sponsor: None.

DFS for R0 resection population. Median, mo, 1-yr rate, 2-yr rate, Groups N (Event) (95%CI) HR (95%CI) P % %

Total 36 (9) NR (NE–NE) NA NA 91.7 73.3 non-squamous 6 (3) 30 NR (16.9–NE) 2.71 (0.67–11.0) 0.1479 100 90.0 50.0 squamous (6) NR 78.7 (NE–NE) non-MPR MPR 21 (7) 15 NR (19.2–NE) 2.58 0.2202 95.2 63.8 (2) NR (0.535–12.45) 86.7 86.7 (NE–NE) PD-L1 TPS$50 10 (1) 20 NR (10.4–NE) 0.253 0.1653 90.0 90.0 TPS (7) NR (0.03–2.06) 95.0 61.0 <50 (18.3–NE) TMB$10 10 (1) 11 NR (23.4–NE) 0.156 0.0534 100 90.9 83.3 TMB<10 (5) NR (0.018–1.348) 52.0 (15.9–NE) non-responder 28 (8) NR (NE–NE) NR 2.31 0.4179 92.9 69.7 responder* 8 (1) (10.4–NE) (0.29–18.48) 87.5 87.5 Stage I/II Stage 14 (2) 16 NR (NE–NE) NR — — 95.0 79.3 III (5) (18.3–NE) 87.5 67.5

*, assessed by investigator per RECIST v1.1. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8523 Poster Session

Statewide rates of adjuvant checkpoint inhibitor use after definitive chemoradiation for stage III non-small cell lung cancer.

Alex K. Bryant, Huiying Yin, Matthew J. Schipper, Peter Alexander Paximadis, Thomas Pence Boike, Derek P. Bergsma, Benjamin Movsas, Munther Isa Ajlouni, Robert Timothy Dess, Melissa A. Mietzel, Randi Kendrick, Merita Seferi, Michael M. Dominello, Martha Matuszak, Reshma Jagsi, James Hayman, Lori J. Pierce, Shruti Jolly; Department of Radiation Oncology, Rogel Cancer Center, Universi- ty of Michigan, Ann Arbor, MI; University of Michigan, Ann Arbor, MI; Barbara Ann Karmanos Cancer In- stitute, Wayne State University, Detroit, MI; Detroit Med Ctr, Petoskey, MI; Henry Ford Hospital, Detroit, MI; Henry Ford Health System, Detroit, MI; Henry Ford Health Syst, Detroit, MI; Department of Radiation Oncology, Rogel Comprehensive Cancer Center at the University of Michigan, Ann Arbor, MI; Wayne State University, Karmanos Cancer Institute, Detroit, MI

Background: In the landmark PACIFIC trial, adjuvant durvalumab after definitive chemoradiation for unresectable stage III non-small-cell lung cancer (NSCLC) produced a 11% absolute overall survival benefit at two years compared to placebo, and the US Food and Drug Administration approved durvalumab for this indication in February 2018. We investigated the real-world use of adjuvant durvalumab and other immune checkpoint inhibitors (ICI) in a contemporary cohort of patients. Methods: We identified patients with unresectable stage III (AJCC 8th edition) NSCLC treated with definitive chemoradiation from February 2018 to March 2020 from a statewide radiation oncology quality consortium, representing a mix of community (n=22 centers, 336 patients) and academic practice settings (n=5 centers, 64 patients) across the state of Michigan. Use of adjuvant durvalumab or other ICI (atezolizumab, nivolumab, or pembrolizumab) was ascertained at the time of routine three- or six-month follow-up after completion of chemoradiation. Baseline characteristics of patients treated with or without adjuvant ICI were compared with the Chi-squared test for categorical variables and a two-sided t-test for continuous variables. Results: Of 400 patients with unresectable stage III NSCLC treated with definitive chemoradiation, 268 (67%) received adjuvant ICI. Of these, the majority received durvalumab (86%) followed by pembrolizumab (7.5%) and nivolumab (6.0%). The proportion of patients receiving ICI remained stable throughout the study period with no discernable time trends. Eight-five percent of white patients received ICI compared with 77% of black patients (p=0.04), but there were no differences in gender (54.5% male in ICI vs 52.3% no ICI), current smoking (42.2% ICI vs 37.9% no ICI, p=0.68), number of comorbidities (29.5% with 3 or more comorbidities in ICI vs. 26.5% in no ICI, p=0.86), baseline oxy- gen use (8.9% ICI vs 10.6% no ICI, p=0.59), age (median 66.4 years [IQR 60.3-73.4] for ICI vs. 66.9 years [IQR 61.1-72.2] no ICI, p=0.89), treatment at an academic center (16.0% ICI vs 15.9% no ICI, p=0.97), or ECOG performance status (59.3% ECOG 0 in ICI vs 62.8% no ICI). Conclusions: In a broad range of academic and community-based practices across a state including 27 sites, only two-thirds of potentially eligible stage III NSCLC patients received adjuvant durvalumab or other ICI agents despite a proven overall survival benefit. Receipt of ICI was not strongly associated with baseline demographic or comorbidity variables. Further work will seek to clarify the patient-level reasons behind non-initiation of adjuvant ICI. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8524 Poster Session

Osimertinib as neoadjuvant treatment for resectable stage II-IIIB EGFR mutant lung adenocarcinoma (NEOS).

Chao Lyu, Wentao Fang, Haitao Ma, Jia Wang, Wenjie Jiao, Rui Wang, Nan Wu, Shi-Dong Xu, Yue Yang; Thoracic Surgery II, Peking University Cancer Hospital, Beijing, China; Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; The First Affiliated Hospital of Suzhou University, Suzhou, China; Beijing Cancer Hospital, Beijing, China; Affiliated Hospital of Qingdao University, Qingdao, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Depart- ment of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, China; Harbin Medi- cal University Cancer Hospital, Harbin, China

Background: Neoadjuvant treatment has demonstrated efficacy in several types of cancer and is increas- ingly used for the treatment of early-stage cancers with the potential of cancer downstaging to enhance complete surgical resection and to improve clinical outcomes. Recent evidences have demonstrated that the neoadjuvant use of first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may provide clinically meaningful improvement in EGFRm non-small cell lung cancer (NSCLC) patients, however, limited data were reported on osimertinib, the third-generation EGFR-TKI, in the neoadjuvant setting. Here we present an interim analysis of osimertinib as neoadjuvant treatment for resectable EGFRm NSCLC. Methods: NEOS is a prospective, multi-center, single-arm study to evaluate the efficacy and safety of osimertinib as neoadjuvant treatment in resectable EGFRm (19del/L858R) lung adenocarcinoma. Eligible patients were treated with osimertinib 80 mg orally per day for six weeks followed by surgery. Assessment of response to neoadjuvant therapy was performed according to RECIST 1.1. The primary endpoint was response rate. Secondary endpoints included safety, R0 surgical resection rate, quality of life, major pathologic response (MPR) rate, pathological complete response (pCR) rate, and N2 downstaging rate. Results: As of Dec. 17, 2020, 18 eligible patients (median age 61 [range 46-73], 27.8% male, 22.2% ECOG PS 1) have been enrolled. Patients with clinical stages IIa, IIb, and IIIa (8th AJCC) accounted for 16.7%, 22.2% and 61.1%, respectively. Half (9/18) of the patients had EGFR exon 21 L858R mutations and the other half (9/18) had EGFR exon 19del mutations. Amongst all 15 patients who completed efficacy assessment after neoadjuvant osimertinib, the response rate (RR) was 73.3% (11/15) and the disease control rate (DCR) was 100% (15/15). R0 surgical resection was performed in 93.3% (14/15) patients. Pathological downstaging occurred in 53.3% (8/15) patients. 42.9% (3/7) of the patients with confirmed N2 lymph nodes experienced downstaging to N0 disease after receiving neoadjuvant osimertinib. One patient was identified with a pCR. Adverse events (AEs) were reported in 66.7% (12/18) of patients, with the most common AE being rash (8/18, 44.4%), oral ulceration (8/18, 44.4%), and diarrhea (5/18, 27.8%). No grade 3-5 AEs or serious AEs were reported. Conclusions: Interim analysis from this study indicated neoadjuvant osimertinib as an effective and feasible treatment in patients with resectable stage II-IIIB EGFRm NSCLC. The trial is ongoing and the final results will be provided in the future. Clinical trial information: ChiCTR1800016948. Research Sponsor: astrazeneca. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8525 Poster Session

Cost evaluation of adjunctive osimertinib use in resected epidermal growth factor receptor-positive non-small cell lung cancer.

Briana Choi, Neda Alrawashdh, Ali McBride, Ivo Abraham; University of Arizona College of Pharmacy, Tucson, AZ; University of Arizona, Tucson, AZ; University of Arizona Cancer Center, Tucson, AZ

Background: About 30% of patients with epidermal growth factor receptor positive (EGFR+) non small cell lung cancer (NSCLC) are eligible for surgical resection. Osimertinib, a first line therapy for advanced EGFR+ NSCLC (stages 1B, 2, 3A), has shown clinical efficacy compared to placebo as an adjunctive therapy post resection. We evaluated the cost effectiveness/utility of this regimen. Methods: A two health state Markov model was built (disease free vs. disease recurrence or death). Disease free survival (DFS) curves were digitized and fitted to exponential function. 3 year timeline as patients received osimertinib for 3 years in published data. US payer perspective and 3% discount rate were applied. Drug costs were per Redbook whole acquisition cost and monitoring costs were from published data (US$ 2020). No adverse events > 5% were reported hence none were included. Life years (LY) and quality adjusted life years (QALY) were estimated for each stage. Incremental cost-effectiveness and utility ratios (ICER/ICUR) for LY and QALY gained were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Results: Shown in the table are BCA and (PSA) results. Using LY as outcome, for stage 1B, incremental DFSLY of 0.40 (0.39) and incremental cost of $500,782 ($501,034) yielded an ICER/DFSLYG of ~$1.3 million (M) (~$1.2 M). For stage 2, incremental DFSLY of 0.79 (0.79) and incremental cost of $503,144 ($503,092) resulted in an ICER/DFSLYG of $636,913 ($638,278). For stage 3A, incremental of DFSLY of 0.18 (0.07) and incremental cost of $322,356 ($293,377) yielded an ICER/DFSLYG of ~$1.2 M (~1.2 M). The incremental costs are the same for QALY outcomes. Using QALY as outcome, for stage 1B, incremental of DFSQALY of 0.26 (0.27) yielded an ICUR/DFSQALY of ~$1.9 M. In stage 2, incremental DFSQALY of 0.53 (0.53) resulted in an ICUR/ DFSQALY of $950,616 ($952,654). For stage 1C, incremental DFSQALY of 0.18 (0.07) yielded an ICUR/DFSQALY of ~$1.8 M (~$3.7 M). Conclusions: The ICERs and ICURs indicate that cost effectiveness varies markedly across stages of disease. Stage 2 showed the lowest cost to outcome association. In general, the cost burden of adjunctive maintenance therapy with osimertinib in resected EGFR+ NSCLC is substantial relative to the observed clinical benefit. The incremental benefit of osimertinib in stage 2b is more evident than the ones in 1B and 3A. Research Sponsor: None.

BCA (PSA). 1B 2 3A Placebo Osimertinib Placebo Osimertinib Placebo Osimertinib

Cost $7,128 $507,910 $6,189 $509,333 $5,048 $327,404 ($7,142) ($508,176) ($6,195) ($509,287) ($5,046) ($298,425) DFS LY 2.31 2.71 (2.71) 1.93 2.72 (2.72) 1.47 1.74 (1.59) (2.32) (1.93) (1.47) DFS QALY 1.55 1.81 (1.82) 1.29 1.82 (1.82) 0.99 1.17 (1.06) (1.55) (1.29) (0.99) ICER/ - $1,263,917 - $636,913 - $1,186,058 DFSLYG ($1,283,518) ($638,278) ($2,496,044) ICUR/ - $1,886,443 - $950,616 - $1,770,236 DFSQALYG ($1,915,699) ($952,654) ($3,725,439) LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8526 Poster Session

Minimal residual disease (MRD) in patients with resected stage I NSCLC: Results of the prospective adjuvant IFCT-0703 trial.

Damien Vasseur, Ce�cile Jovelet, Nathalie Cozic, Julien Mazieres, Fabrice Barlesi, Jaafar Bennouna, Radj Gervais, Lionel Moreau, Henri Berard, Olivier Molinier, Denis Moro-Sibilot, Pierre Jean Souquet, Elodie Amour, Franck Morin, Gerard Zalcman, Jean-Charles Soria, Virginie Westeel, Ludovic Lacroix, Benjamin Besse; Gustave Roussy, Villejuif, France; Biostatistics Unit, Gustave Roussy Cancer Campus, Villejuif, France; Centre Hospitalier Universitaire de Toulouse–Ho^pital Larrey, Toulouse, France; Aix- Marseille University, CEPCM CLIP, Assistance Publique Ho^pitaux de Marseille, Marseille, France; Uni- versity Hospital of Nantes, Digestive Oncology, Nantes, France; Centre Franc¸ois Baclesse, Caen, France; Centre Hospitalier Pneumologie Colmar, Colmar, France; Hopital D’instruction Des Armes Sainte-Anne, Toulon, France; Le Mans Regional Hospital, Le Mans, France; Unite� d’Oncologie Thoraci- que, Service Hospitalier Universitaire Pneumologie Physiologie Po^le Thorax et Vaisseaux, CHU Greno- ble Alpes, Grenoble, France; University Hospital of Lyon-Sud, Lyon, France; IFCT, Paris, France; Clinical Research Unit, Intergroupe Francophone de Cance�rologie Thoracique, Paris, France; Depart- ment of Thoracic Oncology, CIC INSERM 1425, Universite� de Paris, Ho^pital Bichat, Paris, France; Gus- tave Roussy Cancer Campus, Department of Drug Development (DITEP), Villejuif, France; Pneumology, Hopital Jean Minjoz, Besanc¸on, France; Cancer Genetics Laboratory, Departement of Pathology and Medical Biology, Gustave Roussy, Villejuif, France; Department of Medicine and Thoracic Pathology Committee, Gustave Roussy, Villejuif, France

Background: MRD aims to detect circulating biomarkers of micrometastatic disease and ultimately predict recurrences. The IFCT-0703 randomized phase II trial failed to show a benefit of 6 months adjuvant pazopanib (P) vs. placebo after resection of stage I NSCLC (7th TNM edition). The outcome of pts based on their MRD status has been evaluated. Methods: Blood samples were collected in EDTA tubes (Becton Dickinson Company) after surgery (T0), after 3 months (T3) of P or placebo and at the end of treatment (T6). Plasmas were obtained after double centrifugation of total blood. Total nucleic acid was extracted using the Maxwell RSC LV plasma kit (Promega) according to the manufacturer’s protocol. Samples were quantified using the QuBit dsDNA HS Assay kit on a QuBit 3.0 flurometer (Thermo Fisher Scientific). Molecular analysis was performed by next generation sequencing using the Oncomine Lung cfDNA Assay (ThermoFisher Scientific). Two MRD definitions were tested : 1) high level of DNA in the blood or 2) any mutation detected by the standard bioinformatic pipeline was considered present, what- ever the allelic fraction. Results: 143 pts were randomized in 29 centers between March 2009 and Au- gust 2012, 71 and 72 in the placebo and P arms respectively. Among the 119 pts with evaluable T0 samples, 27 pts recurred and 14 died. Median DNA concentration ([DNA]) was 6.6 ng/ml and an increase of [DNA] of 10 ng/ml was found prognostic of poor DFS and OS, HR=1.4, 95%CI [1.14-1.72], p=0.0016 and HR=1.62, 95%CI [1.15-2.30], p=0.0057 respectively. In 81 pts with available T0-T6 samples, [DNA] variation had no different impact on DFS and OS, in the P arm and the placebo arm. ctDNA mutations (ctDNA+) were detected in 31/119 pts. ctDNA+ were more frequent in samples with high DNA quantity (p=0.0002). Genes mutated at T0 were TP53 in 16, NRAS in 6, MAP2K1 in 2, KRAS in 1, EGFR in 5, BRAF in 1, ALK in 2. 29 pts had 1 mutation, 2 had 2 mutations. DFS and OS were similar between pts with or without ctDNA+ : HR= 1.038 (95%CI 0.438-2.456, p=0.93) and 1.193 (95% CI 0.367-3.882, p=0.77) respectively. Among 27 pts with ctDNA+ at T0 and available sample at T6, 23 had no more mutations at T6. Two pts had a ctDNA+ only at T6 (not at T3), one of them had a recurrence at 7 months. Conclusions: Post-operative ctDNA mutations are found in 26.0% of the pts but their positivity had no impact on DFS or OS. In contrast, DFS and OS were poorer in pts with increased plasma DNA concentration. ctDNA mutations status do not recapitulate the complexity of MRD characterization. NGS will be performed on matched tissues in order to refine MRD definition. Clinical trial information: NCT00775307. Research Sponsor: Fondation ARC. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8527 Poster Session

Modeling the cost-effectiveness of adjuvant osimertinib in resected EGFR-mutant non- small cell lung cancer patients.

Christopher Lemmon, Emily Craig Zabor, Nathan A. Pennell; Cleveland Clinic, Cleveland, OH

Background: Adjuvant Osimertinib (Osi) was recently approved for resected EGFR-mutant non-small cell lung cancer (NSCLC) based on disease free survival (DFS) benefits from the ADAURA trial. Prior studies of adjuvant EGFR inhibitors yielding DFS benefits have lacked an overall survival (OS) benefit, leading to debate over early clinical implementation given the associated drug costs. This study aims to evaluate the cost-effectiveness (CE) of Osi in this setting. Methods: We constructed Markov models using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of the use of 3 years of adjuvant Osi versus placebo in the ADAURA patient population of stage IB to IIIA NSCLC patients over a 10-year time horizon. All patients entering the progressive disease (PD) state were assigned for re-treatment with Osi. Cost and utility values were derived from Medicare reimbursement data and literature (Table). A CE threshold of 3 times the GDP per capita was used. Deterministic sensitivity analyses were performed to assess the impact of a range of OS benefit, as the impact of adjuvant Osi on OS has not yet been reported. Results: The incremental cost-effectiveness ratio (ICER) for adjuvant Osi was $317,119.90 per QALY gained. Initial costs of Osi are higher in the first 3 years, but become lower than the placebo group in year 4 onward, with similar costs after year 7. Costs due to PD are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2,388, $379,047, and $502,937, respectively in the placebo group, compared to $505,775, $255,638, and $800,697, respectively in the Osi group. QALYs were higher in the Osi arm throughout. Sensitivity analysis using incremental OS gains reaches the CE threshold of $195,000 between 25-30% OS benefit of Osi over placebo. A 50% discount to the Osi annual cost yielded an ICER of $115,419. Conclusions: 3 years of adjuvant Osi is more cost-effective than placebo if one is willing to pay $317,119 more per QALY gained, with most costs accruing in the first 3 years as drug cost. This strategy became cost-effective with an OS benefit between 25-30% over placebo. Discount to Osi annual costs improves the ICER significantly. True cost-effectiveness of adjuvant Osi will require further study due to immaturity of ADAURA OS data and model limitations. Research Sponsor: None.

Model QALY utility an cost inputs. QALY Utilities NED state (osi/placebo) 0.81/0.83 PD state (CNS+/CNS-) 0.55/0.71 Annual Costs EGFR testing $324.58 Osimertinib cost $222,196 NED state healthcare costs 1914.83 PD diagnostic costs $7,202.88 PD state healthcare costs $1,186.76 Average CNS+ PD lifetime costs $45,081.39 Palliative/end of life cancer costs $78,571.06 Adverse event costs and disutilities also incorporated LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8528 Poster Session

Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.

Yufei Liu, Zhe Zhang, Waree Rinsurongkawong, Xiuning Le, Carl Michael Gay, Matthew S. Ning, John Heymach, Jianjun Zhang, Steven H. Lin; The University of Texas MD Anderson Cancer Center, Houston, TX; Rice University, Houston, TX; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX; UT MD Anderson Cancer Center, Houston, TX; University of Texas MD An- derson 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 and Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Department of Genomic Med- icine, University of Texas MD Anderson Cancer Center, Houston, TX

Background: The use of durvalumab after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients significantly improves overall survival. However, it is unclear whether this benefit ap- plies to all genetic subtypes of lung cancer. We hypothesize that patients with driver mutation NSCLC may derive less benefit from consolidation durvalumab. Methods: Using the Genomic Marker-Guided Therapy Initiative (GEMINI) database at MD Anderson, we identified 134 patients who were treated with chemoradiation followed by durvalumab for NSCLC. We segregated patients with driver mutations to targetable (EGFR, ALK translocation, ROS1 fusion, MET exon 14 skipping, RET fusion, and/or BRAF) (N = 24) and those driven by canonical KRAS mutations (N = 26). The rest (N = 84) had none of these mutations. We gathered demographic, treatment, and outcome data and compared progression- free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We used multivariate regression analysis to account for demographic and treatment variables. Results: For our cohort, median age at diagnosis was 64.8, 52% were female (n = 70), and median follow up was 1.5 years. 86% of patients have a history of smoking (n = 115). 21% had squamous cell histology (n = 28). 2 patients had stage IIA disease, 6 had stage IIB, 48 had stage IIIA, 56 had stage IIIB, 13 had stage IIIC, and 9 had stage IV. 73 patients had progression after durvalumab and 37 patients died. Patients with driver mutations had significantly worse median PFS compared to those without driver mutations (8.9 mo vs 26.6 mo; HR 2.62 p < 0.001). Patients with KRAS mutations had particularly poor PFS (Median 7.9 mo, HR 3.34, p < 0.001), while patients with targetable driver mutations trended to worse PFS (Median 14.5 mo, HR 1.96, p = 0.056). The median OS for the cohort was 4.8 yrs with no significant differences based on driver mutation status. On multivariate analysis, only driver mutation status was associated with PFS, but not OS. For patients with first progression, we found the targetable driver group to have significantly improved time to second objective progression (PFS2) compared to the KRAS (HR 0.28, p = 0.011) or non-mutated group (HR 0.38, p = 0.025). All patients in the targetable driver group received targeted therapy after first progression. Conclusions: Our results suggest that patients with driver mutations have worse PFS compared to patients without these mutations after chemoradiation. How- ever, patients with targetable oncogene driver mutations have significantly improved prognosis after initial progression compared to the other groups, likely due to targeted therapy, suggesting that these therapies, including novel approaches towards KRAS mutants, should be further explored in this setting. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8529 Poster Session

Natural history of curatively resected stage IB-IIIA EGFR mutation (+) NSCLC: Clinicopathologic and molecular prognostic factors (ROOT-EGFR-ADJ).

Hyun Ae Jung, Yeong Jeong Jeon, Jhingook Kim, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park; Division of Hematology-Oncology, Department of Medicine, Sam- sung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Thoracic Surgery, Samsung Medical Center, Sungkyunk- wan University School of Medicine, Seoul, South Korea; Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Background: Surgery is the primary therapy for patients with early-stage NSCLC. However, five-year recurrence rates were 45%, 62%, and 76% for pathologic stage (pStage) IB, II, and III respectively. In the ADARUA study, adjuvant osimertinib significantly improved DFS in patients with completely resected EGFR mutation (+) NSCLC. Though marked improvement of DFS is encouraging, OS is not mature yet and several questions remain unanswered; Does this DFS benefit translate to cure? Do all patients need to receive adjuvant Osiemrtinib? In order to address these questions we reviewed the clinical records of pStage IB-IIIA EGFR mutant NSCLC. Methods: From January 2008 and August 2020, total 2,340 patients with pStage IB-IIIA, non-SQ NSCLC underwent curative surgery at Samsung Medical Center. Using innovative in-house algorithm to retrieve medical big data-based cohort called ROOT (Realtime autOmetically updated data warehOuse in healTh care) detailed clinical data were analyzed to investigate any prognostic factors of recurrence. In order to identify any molecular prognostic factors, we did a comprehensive genomic analysis (WTS/WES)in a subset of patients with matched case-control. Results: Total 1,811 patients with pStage IB-IIIA, non-SQ EGFR mutation (+) NSCLC were included (367 patients : no EGFR mutation test). Median follow-up duration was 38.8 (range: 0.5 -156.2). Pa- tient demographics; Deletion 19 was 52.7%, L858R was 47.3%. Female was 64.7% and never smoker was 72%. Stage IB, IIA, IIIA was 50.4%, 26.5%, and 23.2%. Among them, 6.7% of pStage IB, 72.8% of pStage II, and 88.7% of pStage IIIA received adjuvant chemotherapy. Median DFS were 74.0 months (95% CI 63.2-84.8), 48.6 months (95% CI: 40.2-57.0), and 22.4 months (95%: 19.5-25.3) for pStage IB, II, and IIIA, respectively. The median OS were 132.1 months (95% CI: 101.3-162.8), 124.3 months (95% CI: 61.8-186.9), and 82.1 months (95% CI: 71.2-93.1) for pStage IB, II, and IIIA, respectively. In univariate analysis, pStage, poorly differentiation, histologic subtype (micropapil- lary, solid), lymphatic invasion, vascular invasion, and pleural invasion were related with high recurrence rate statistically. In multivariate analysis, pStage, vascular invasion, and pleural invasion were related with recurrence statistically. To detect molecular factors, 76 patients performed the matched case -control (included pStage, type of EGFR mutation, and sex) analysis (WES/WTS). Conclusions: This study showed that the median DFS of pStage II-IIIA EGFR mutation (+) NSCLC was 31.9 months. With approximately 55% of patients with pStage II-IIIA EGFR mutation (+) NSCLC experienced recurrence at the 3rd year, we need to find the appropriate subset who need 3-year adjuvant osimertinib by comprehensive predictive marker for cure. Updated and detail exploratory biomarker outcome will be presented at the annual meeting. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8530 Poster Session

Molecular characteristics of EGFR exon 19 deletion subtypes in NSCLC patients.

Weiquan Gu, Zhongyu Lu, Shulin Shi, Juan Ma, Guanghua Lu, Wanglong Deng, Ran Ding, Fanfeng Bu; The Thoracic Surgery Department, Foshan First People’s Hospital, Foshan, China; Jiangsu Simcere Di- agnostics Co., Ltd, Nanjing, China; The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China; The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China

Background: EGFR exon 19 deletion mutations are well characterized, known to be activating, and are associated with responses to EGFR tyrosine kinase inhibitors (TKIs). A variety of methods have been developed to identify EGFR mutations. Deletions of EGFR exon 19 are more complex compare to the other because they consist of different subtypes. Methods: In this study, we retrospectively analyzed the different subtypes of EGFR exon 19 deletions using next-generation sequencing(NGS). From May 2019 to December 2020, 3275 patients who were diagnosed with Non-small cell lung cancer (NSCLC)were detected. Results: In this analyzed cohort, the average age of patients was 62 years (range, 24-92 years). Most of the patients were female (61.07%) and were diagnosed with lung adenocarcinoma (82.60%). It is worth noting that the deletions in exon 19 of EGFR were also detected in 35 patients (1.07%) with squamous cell carcinoma and 1 patient (0.03%) with sarcomatoid. The most frequent EGFR exon 19 deletions were delE746-A750 (63.4%), followed by delL747-P753insS (9.7%) and L747-T751 (6.9%). The characteristics of the patients in this study are presented. Significantly, three samples with compound EGFR exon 19 deletions were detected: 1) S1:E746_A750delinsFP+E746_A750del; 2) S2: E746_S752delinsV+L747_P753delinsS; 3) S3:E746_P753delinsVS + L747_P753delinsS. Con- clusions: EGFR exon 19 starting at codon 729 to 761, our data showed the deletions occur throughout almost the entire exon 19 amino acid. As our integrated data results, EGFR exon 19 has many different deletions and insertion subtypes could be defined as 79 subtypes. Among those subtypes,70 were complex with an accompanying insertion. The most frequent deletions were starting at E746 and L747. Based on several clinical researches, different deletion subtypes may have significantly different clinical responses after TKI treatment. However, more clinical research is needed to support this finding. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8531 Poster Session

Seroprevalence and immunological memory against SARS-CoV-2 in lung cancer patients (p): SOLID study.

Mariano Provencio, Delvys Rodriguez-Abreu, Ana Collazo Lorduy, Gloria Ma Serrano, Ana Laura Ortega Granados, Carlos Aguado, Guillermo Lopez Vivanco, Maria Guirado, Anna Estival, Beatriz Jimenez Munarriz, Hugo Arasanz, Juan Coves, Margarita Majem, Bartomeu Massuti, Sergio Vazquez-Estevez, Oscar Juan-Vidal, Clara Lucia, Edel del Barco, Manuel Cobo; Puerta de Hierro Majadahonda University Hospital, Madrid, Spain; Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas De Gran Canaria, Spain; Spanish Society of Medical Oncology (SEOM), Madrid, Spain; Hospital Infanta Leonor, Madrid, Spain; Medical Oncology, Hospital Universitario de Jae�n, Jae�n, Spain; H C San Carlos, Madrid, Spain; H. Universitario De Cruces, Barakaldo, Spain; Clinical Oncology Department, Hospital General de Elche, Elche, Alicante, Spain; Medical Oncology Department, Catalan Institute of Oncology (ICO) Badalona, Hospital Universitari Ger- mans Trias i Pujol, B-ARGO, Barcelona, Spain; HM Hospitales, Madrid, Spain; Hospital de Navarra, Pamplona, Spain; Hospital de Son Llatze�r, Palma De Mallorca, Spain; Department of Medical Oncolo- gy, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Alicante University Hospital Isabial, Alican- te, Spain; Lucus Augusti University Hospital, Lugo, Spain; Hospital Universitario y Polite�cnico La Fe, Valencia, Spain; Hospital Universitari Sant Joan de Reus, Reus, Spain; Hospital de Salamanca, Sala- manca, Spain; UGC Oncolog�ıa Intercentros, Hospitales Universitarios Regional y Virgen de la Victoria de Ma�laga, Instituto de Investigaciones Biome�dicas de Ma�laga (IBIMA), Ma�laga, Spain

Background: Coronavirus disease 2019 (COVID-19) is diagnosed by detecting the virus by reverse transcription polymerase chain reaction (RT-PCR). The majority of p go on to develop antibodies (Ab) against viral proteins. However, it is not known how long these antibodies last nor whether cancer treatments could affect the duration of immune response. The prognosis and greater or lesser vulnerability of the oncological population are also unknown. Methods: This prospective, longitudinal, multicenter se- rological study in the setting of SARS-CoV-2 was carried out in 50 Spanish hospitals. Eligibility criteria was a diagnosis of any thoracic cancer. The first determinations were performed between April 21, 2020 and June 3, 2020, either for p in follow up or in active treatment. Between September 10, 2020, and November 20, 2020, the second antibody (Ab) determination was performed in all previously seropositive p. Clinical and treatment data were collected, as was their clinical situation at study end. Study objectives were to prospectively determine seroprevalence in unselected lung cancer p during the first wave of the pandemic; the natural history of these p; the persistence of immunity more than 4 months after first determination; protection or lack thereof against reinfection after this period, and the nature of such protection; and the influence of treatments on maintenance or loss of immunity. Results: Of 1,500 p studied, 128 were seropositive, representing an overall prevalence of 8.5% seropositivity [95% confidence interval [CI], 7.2%, 10.1%]. Seventy-five percent were in active cancer treatment. COVID-19 infection was suspected in 47.7% [95% CI, 38.8%, 56.6%]. A second determination was performed on average 4.5 months later [IQR: 4; 5] and obtained for 104 of the initially seropositive p (81%). A second determination could not be obtained in 24 p, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% (32/104) of p. The severity of the infection, the need for hospitalization (p: 0.032) and the presence of symptoms at diagnosis (p: 0.02), including fever (p: 0.005) and nasal congestion (p: 0.005), were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Ab loss. At time of last follow-up among those p for whom a second determination was performed, 89% (93 p) had completely recovered from the virus, with no lasting after effects. Only 1 of the 128 (0.78%) seropositive p had died from COVID-19. Conclusions: The prevalence of infection in lung cancer p is similar to that of the general population. Immunity against SARS-CoV-2 does not appear to be compromised by treatment, persisting beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population. Research Sponsor: Roche. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8532 Poster Session

Association of high level of plasma tissue factor activity with venous thromboembolism and early death in lung cancers.

Helene Doubre, Isabelle Monnet, Reza Azarian, Philippe Girard, Guy Meyer, Julie Trichereau, Philippe Devillier, Patrick Van Dreden, Louis-Jean Couderc, Christos Chouaid, Marc Vasse; Pneumology, Hopital Foch, Suresnes, France; Pneumology, CHI Creteil, Creteil, France; Pneumology, CH Versailles, Le Ches- nay, France; Thoracic Department,Institut Mutualiste Montsouris, Paris, France; APHP, Paris, France; Direction Recherche Clinique et Innovation, HOPITAL FOCH, Suresnes, France; Upres EA 220, Paris- Saclay University, Pneumology, Hopital Foch, Suresnes, France; Clinical Research Department, Diag- nostica Stago, Gennevilliers, France; Pneumology, HOPITAL FOCH, Suresnes, France; Pneumology, Centre Hospitalier Intercommunal (CHI) Creteil, Cre�teil, France; Biology, Hopital Foch, Suresnes, France

Background: Venous thromboembolism (VTE) is associated with tumor aggressiveness and mortality in cancers. Tissue Factor is the main activator of the coagulation but its variations in lung cancers (LC) have been less studied than D-dimers (DDi). We assessed plasma Tissue Factor Activity (TFa) and DDi and VTE events and mortality in patients with LC. Methods: This prospective study included patients, from 5 hospitals, recently diagnosed LC, without prior VTE or anticoagulant therapy within the last 2 months. Clinical and tumor data, Khorana score (KS), VTE events and overall survival (OS) were assessed (follow up 2 years). Blood samples were collected before any cancer treatment (V1): DDi (Hemo- sIL) and TFa (chromogenic assay, Diagnostica Stago) were analyzed in a central lab. Independent nonparametric tests were used for group comparisons. A relevant clinical threshold of both markers was determined :1500 lg/ml for DDi and 1.2 ng/ml for TFa. Early death was compared using Cox model and Kaplan Meier curves and logrank tests. All tests were two-tailed tests and 0.05 was considered as significant. Results: Between 12/2014 and 01/2017, 302 consecutive patients (pts) were included (mean age 64 years, 61% males, 89% smokers, 85% NSCLC, 67% stage IV). At V1, TFa levels increased with cancer stage (p = 0.004) but not DDi. VTE incidence was 13,9%: 39 events (62% incidental and 51% pulmonary embolism) with 33 events within 6 months. KS failed to predict VTE (KS > 3 in 23% of the pts in VTE group vs 21% of the 302 pts, p = 0.42). DDi and TFa levels were not significantly different in VTE pts than in no VTE pts. But, a TFa > 1.2 ng/ml was significantly predictive in occurrence of VTE within the first 6 months (57.6% of the VTE pts vs 38.8% of no VTE pts, p = 0.04), and also within the first year (p = 0.03). Median OS was 17,6 months (m) in VTE pts and 19.5 m in no VTE pts (p = 0,97). Compared to survivors, higher levels of DDi and TFa were observed for the 38 pts who died within 6 months : 1.82 vs 0.67 lg/ml (p < 0.001) and 1.95 vs 0.33 ng/ml (p < 0.001) respectively. These differences were observed for the 97 pts who died during the first year, too. With thresholds of TFa > 1.2 ng/ml and DDi > 1500 lg/ml, median OS was significantly shorter: 14.4 m vs > 29.8 m ( p < 0,001) and 13.8 m vs 22.6 m (p < 0.001), respectively. Conclusions: High TFa level discriminates a population with high risk to VTE and early death in LC. This biomarker could take place in a predictive score. Clinical trial information: NCT02853188. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8533 Poster Session

Noninvasive identification of emergent mutations following cytotoxic therapy for lung cancer.

Everett James Moding, Angela B. Hui, Yonina R. Murciano-Goroff, Barzin Nabet, Andre Schultz, Yawei Qiao, Bob T. Li, Steven H. Lin, Ash A. Alizadeh, Maximilian Diehn; Stanford University, Stanford, CA; Memorial Sloan Kettering Cancer Center, New York, NY; Department of Radiation Oncology, The Uni- versity of Texas MD Anderson Cancer Center, Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Radiation Oncology, Stanford University School of Medicine, Stan- ford, CA

Background: Lung cancer is the leading cause of cancer death world-wide, and chemotherapy and radiation remain backbones of therapy for patients with locoregionally advanced and metastatic disease. However, the genetic mechanisms that mediate resistance to chemotherapy and radiation are largely unclear due to a lack of available tissue at the time of relapse. We hypothesized that circulating tumor DNA (ctDNA) analysis could identify emergent mutations after chemotherapy and radiation that may lead to treatment resistance. Methods: To identify emergent mutations at the time of progression following an initial response to chemotherapy and/or radiation therapy for lung cancer, we utilized CAncer Per- sonalized Profiling by deep Sequencing (CAPP-Seq) to analyze plasma samples and matched leukocytes collected pre-treatment and at the time of relapse. We analyzed a targeted panel enriched for lung cancer drivers and recurrently mutated genes for 27 patients treated with chemoradiation therapy for locoregionally advanced lung cancer. In addition, we performed ultra-deep whole exome sequencing ( > 2000X deduped depth) of pre-treatment and relapse cell-free DNA for 5 patients treated with combination chemotherapy for metastatic lung cancer. Functional enrichment analysis was performed on emergent mutation gene lists to identify significantly enriched pathways. Results: We identified emergent variants in 6 out of 27 patients using targeted sequencing after chemoradiation therapy. Emergent mutations after chemoradiation were enriched for plasma membrane adhesion molecules such as PCDH17, PCDH10, and FAT3 (adjusted P = 0.03). Using ultra-deep whole exome sequencing, we observed emergent mutations in 3 out of 5 patients treated with combination chemotherapy. After combination chemotherapy, there was a trend towards enrichment in mutations in ATP-binding cas- sette transporters, including ABCA13 and ABCB4 (adjusted P = 0.057). Notably, there were no recurrent emergent mutations within our cohort. Conclusions: Our results suggest that ultra-deep whole exome sequencing can non-invasively identify emergent mutations at the time of progression. Resis- tance to cytotoxic therapy is likely multi-factorial and analysis in expanded cohorts will be helpful to identify recurrently mutated pathways that may contribute to disease progression after an initial response to therapy. Research Sponsor: Conquer Cancer Foundation of the American Society of Clinical Oncology, Pharmaceutical/Biotech Company. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8534 Poster Session

Sequential monitoring of PD-L1 on circulating stromal cells in blood predicts PFS in NSCLC patients undergoing immunotherapy after definitive chemoradiation.

Daniel L Adams, Alexander Augustyn, Jianzhong He, Yawei Qiao, Ting Xu, Zhongxing X. Liao, Kirby J. Gardner, Jillian Moran, Cha-Mei Tang, Steven H. Lin; Creatv MicroTech, Inc., Monmouth Junction, NJ; University of Texas MD Anderson Cancer Center, Houston, TX; Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Creatv MicroTech, Inc., Rockville, MD; The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Cancer Associated Macrophage-Like cells (CAMLs) are circulating stromal cells in the blood of patients (pts) with solid tumors that are phagocytic macrophages that may represent the inflammatory state of the tumor microenvironment. Previously, we demonstrated CAMLs $50mm after chemo-radiation therapy (CRT) in NSCLC is associated with worse progression free survival (PFS) and overall survival (OS). We also showed that PDL1 expression in CAMLs is dynamic & can change with CRT, difficult to assess with repeat biopsies, but possible with liquid biopsy. For this study we evaluated whether CAML properties can predict response to CRT with/without immunotherapy (IMT) agents in unresectable NSCLC. Methods: A single blind multi-year prospective study was undertaken to test the relationship of PDL1 expression and $50mm CAML size to PFS/OS in NSCLC, pre and post CRT with (n = 96) and without (n = 72) anti-PDL1/PD1 IMT. This included atezolizumab (prospective single arm NCT02525757) n = 39, durvalumab n = 52 or pembrolizumab n = 5 both after 2018 FDA approval. We recruited 168 pts with pathologically confirmed unresectable NSCLC prior to CRT. Blood samples 15 mL were taken at baseline (BL), CRT completion (T1), and ~1 month after CRT (T2) (with n = 96 or without n = 72 IMT). Blood was filtered by CellSieve filtration and CAMLs quantified for size ( < 49 mm or $50 mm) and PDL1 expression to evaluate PFS and OS hazard ratios (HRs) by censored univariate and multivariate analysis at 24 months. Results: CAMLs were found in 90% of all samples, average 5.8 CAMLs/15mL. At BL, $50mm CAMLs did not predict PFS in CRT/IMT pts (HR 1.6, p = 0.220) nor CRT alone (HR 1.3, p = 0.593). However, after completion of CRT (T1) $50mm CAMLs predicted PFS in CRT/IMT pts (HR 2.7, p = 0.003) and CRT alone (HR 2.5, p = 0.015). In primary tumor biopsies, PDL1 expression > 1% did not predict CRT/IMT response (PFS HR 1.8, p = 0.262 & OS HR 2.3, p = 0.158). At BL, high CAML PDL1 did not predict PFS in CRT/IMT pts (HR 1.4, p = 0.427) nor CRT alone (HR 1.1, p = 0.982). Further, at CRT completion (T1), high CAML PDL1 only trended for better PFS in CRT/ IMT pts (HR 1.7, p = 0.137), but not CRT alone (HR 1.1, p = 0.972). At T2, however, pts with continuously high CAML PDL1 had significantly better PFS with IMT (HR 3.2, p = 0.002) vs CRT alone (HR 1.4, p = 0.616). While $50mm CAMLs at BL did not predict 24 month progression, $50 mm CAMLs after CRT (with or without 1 cycle of anti-PDL1 IMT) was 84% accurate at predicting progression. Further subtyping and analysis is ongoing to evaluate OS and PDL1 in the CAML populations. Conclusions: Our data suggests that in unresectable NSCLC, $50 mm CAMLs after completion of CRT is prognostic regardless of IMT use. PDL1 expression in CAMLs also appears to predict for response to consolidated IMT after CRT. Additional studies are needed to validate these findings. Research Sponsor: U.S. Nation- al Institutes of Health. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8535 Poster Session

Genomic and immunologic characterization of large-cell neuroendocrine carcinoma of the lung.

Chul Kim, Julie Elaine McGrath, Joanne Xiu, Misako Nagasaka, Patrick C. Ma, Jorge J. Nieva, Gilberto Lopes, Hossein Borghaei, Chukwuemeka Ikpeazu, Taofeek K. Owonikoko, Michael J. Demeure, Antoinette J. Wozniak, Chadi Nabhan, Wolfgang Michael Korn, Stephen V. Liu; Georgetown University, Department of Hematology and Oncology, School of Medicine, Washington, DC; Caris Life Sciences, Phoenix, AZ; Barbara Ann Karmanos Cancer Institute, Detroit, MI; Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA; University of Southern California, Los An- geles, CA; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; Fox Chase Cancer Center, Philadelphia, PA; University of Miami Sylvester Comprehensive Cancer Center, Plantation, FL; Emory University Winship Cancer Institute, Atlanta, GA; Translational Genomics Research Institute, Phoenix, AZ; Hillman Cancer Center University of Pittsburgh, Pittsburgh, PA

Background: Large-cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer with a poor prognosis. Due to its rarity, molecular characterization of LCNEC is not well elucidated. We aim to un- derstand the genomic and immunologic landscape of LCNEC to identify molecular alterations and relevant biological pathways with potential therapeutic value. Methods: Comprehensive profiling including whole exome sequencing (WES), next-generation sequencing (NGS), whole transcriptome sequencing (WTS), and immunohistochemistry (IHC) for PD-L1 was performed (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations. LCNEC was categorized as small cell lung cancer (SCLC)-like LCNEC (TP53/RB1 co-mutated) and non-small- cell lung cancer (NSCLC)-like LCNEC (wild type for one or both of TP53/RB1). Molecular features of LCNEC were compared among the subgroups and with those of SCLC using the v2 test with Benjamini & Hochberg correction. Results: A total of 467 cases of LCNEC were included. Commonly altered genes ($ 5%) included TP53 (79.1%), RB1 (36.8%), SMARCA4 (10.4%), ARID1A (10.3%), KRAS (9.7%), KEAP1 (9.2%), KMT2D (8.7%), STK11 (8.4%), NF1 (7.1%), PTEN (6.1%), and CDKN2A (5.9%). The prevalence of potentially actionable mutations was as follows: EGFR exon 19 deletion (0.48%), EGFR L858R (0.48%), ALK fusion (1.7%), KRAS G12C (2.9%). EGFR exon 19 deletion, EGFR L858R, and ALK fusion were exclusive to NSCLC-like LCNEC tumors. RET fusion, NTRK fusion and BRAFV600E were not detected. Copy number alterations (CNAs) were found in MYC (8.8%), ZNF703 (4.1%), FOXA1 (4.0%), FGFR1 (4.0%), ATK2 (3.9%), CCNE1 (3.7%), FGF19 (3.4%), TNFRSF14 (3.4%), and CCND1 (2.7%). Over-expression of cMET was noted in 10% and PD-L1 expression (by 22C3 pharmDx) of > 1% was noted in 21.5% of samples. WTS detected cMET exon 14 skipping mutations in 2.4% of samples. High tumor mutation burden (TMB; $ 10 Mut/MB) was seen in 40.6%. Among the 467 cases of LCNEC, 112 (24%) were SCLC-like LCNEC and 335 (76%) NSCLC-like LCNEC. Mutations in KRAS (12%), STK11 (11%), CDKN2A (9%), and SMARCA4 (14%) were more common in NSCLC-like LCNEC, compared with SCLC-like LCNEC (p value < 0.05). 442 cases of SCLC were compared with LCNEC tumors. SLFN11:SLFN12 fusion events, detected by WTS, were exclusive- ly seen in SCLC and were not seen in any of the LCNEC cases. Gene expression profiles revealed that 1) B cell infiltration was higher in SCLC-like LCNEC, compared with SCLC, and 2) NK and T cell infiltration was lower, but B-cell infiltration was higher in NSCLC-like LCNEC, compared with SCLC. Conclu- sions: LCNEC displays a broad pattern of genomic alterations that overlap in the SCLC-like subset with the classic alterations in SCLC. The distinct genomic alterations and transcriptomic profiles present op- portunities for therapeutic targeting and inform a future framework for development of therapeutics for LCNEC. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8536 Poster Session

Deep learning to predict subtypes of poorly differentiated lung cancer from biopsy whole slide images.

Gouji Toyokawa, Fahdi Kanavati, Seiya Momosaki, Kengo Tateishi, Hiroaki Takeoka, Masaki Okamoto, Koji Yamazaki, Sadanori Takeo, Osamu Iizuka, Masayuki Tsuneki; Department of Thoracic Surgery, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan; Medmain Inc., Fukuoka, Japan; Department of Pathology, Clinical Research Institute, National Hospi- tal Organization, Kyushu Medical Center, Fukuoka, Japan; Department of Respiratory Medicine, Clini- cal Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan

Background: Lung cancer is the leading cause of cancer-related death in many countries, and its prognosis remains unsatisfactory. Since treatment approaches differ substantially based on the subtype, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC) and small cell lung cancer (SCLC), an accurate histopathological diagnosis is of great importance. However, if the specimen is solely composed of poorly differentiated cancer cells, distinguishing between histological subtypes can be difficult. The present study developed a deep learning model to classify lung cancer subtypes from whole slide images (WSIs) of transbronchial lung biopsy (TBLB) specimens, in particular with the aim of using this model to evaluate a challenging test set of indeterminate cases. Methods: Our deep learning model consisted of two separately trained components: a convolutional neural network tile classifier and a recurrent neural network tile aggregator for the WSI diagnosis. We used a training set consisting of 638 WSIs of TBLB specimens to train a deep learning model to classify lung cancer subtypes (ADC, SCC and SCLC) and non-neoplastic lesions. The training set consisted of 593 WSIs for which the diagnosis had been determined by pathologists based on the visual inspection of Hematoxylin-Eosin (HE) slides and of 45 WSIs of indeterminate cases (64 ADCs and 19 SCCs). We then evaluated the models using five independent test sets. For each test set, we computed the receiver operator curve (ROC) area under the curve (AUC). Results: We applied the model to an indeterminate test set of WSIs obtained from TBLB specimens that pathologists had not been able to conclusively diagnose by examining the HE-stained specimens alone. Overall, the model achieved ROC AUCs of 0.993 (confidence interval [CI] 0.971-1.0) and 0.996 (0.981-1.0) for ADC and SCC, respectively. We further evaluated the model using five independent test sets consisting of both TBLB and surgically resected lung specimens (combined total of 2490 WSIs) and obtained highly promising results with ROC AUCs ranging from 0.94 to 0.99. Conclu- sions: In this study, we demonstrated that a deep learning model could be trained to predict lung cancer subtypes in indeterminate TBLB specimens. The extremely promising results obtained show that if de- ployed in clinical practice, a deep learning model that is capable of aiding pathologists in diagnosing indeterminate cases would be extremely beneficial as it would allow a diagnosis to be obtained sooner and reduce costs that would result from further investigations. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8537 Poster Session

A new model using artificial intelligence to predict recurrence after surgical resection of stage I-II non-small cell lung cancer.

Natalie Lui, Nien Wei, Winston Trope, Shannon Nesbit, Prasha Bhandari, Chin-Hui Lee, Hu Hu, H. Henry Guo, Douglas Z. Liou, Joseph B. Shrager, Leah Monique Backhus, Mark F. Berry, Eric Yang; Stanford University, Stanford, CA; Auspex Diagnostics, Warren, NJ; Georgia Institute of Technology, At- lanta, GA

Background: Five-year survival for stage I-II lung cancer is quite low even after complete surgical resection. Current guidelines recommend adjuvant treatment only for selected patients with stage II or higher disease. A prediction model that identifies patients at high risk of recurrence who may benefit from adjuvant treatment is greatly needed. Many existing prediction models include a small number of genes that were found to be significant in previous studies. We propose using artificial intelligence to analyze a microarray of > 20,000 well-annotated genes to create a model that predicts recurrence after surgical resection of stage I-II lung cancer. Methods: We identified 275 patients who underwent surgical resection for pathologic stage I-II lung adenocarcinoma or squamous cell carcinoma from 2009 to 2019 in our institution’s prospective surgical database. We excluded patients who had follow up time less than 3 years or received adjuvant therapy and had not had a recurrence, as well as patients with missing specimen blocks. Patient characteristics and recurrence information were obtained from chart review. The patients were divided into training (192 patients) and validation (83 patients) cohorts, and the recurrence status for the validation cohort was initially blinded. Gene expression levels were generated using Clariom S human array (ThermoFisher) from 10um sections cut from the formalin-fixed, paraffin- embedded surgical specimen blocks. The artificial intelligence algorithm Support Vector Machine (SVM) was used to create a prediction model for recurrence using the gene expression and recurrence status of the patients in the training cohort. The model was then tested on the validation cohort using Kaplan-Meier analysis and the area under the receiver operator curve (AUROC). Results: The recurrence prediction model separated the validation cohort into 15 (18.1%) patients in the high-risk group and 68 (81.9%) patients in the low-risk group. Kaplan-Meier analysis showed the five-year disease-free survival was significantly higher in the low-risk group compared to the high-risk group (86 vs. 50%, HR = 4.41, p = 0.0025). The AUROC for predicting recurrence was 0.744. Conclusions: Our model uses artificial intelligence to successfully predict recurrence after surgical resection for stage I-II non-small cell lung cancer. With an AUROC of 0.744, our model outperforms previously described models with AUROC up to 0.6. Our model separates patients into high-risk and low-risk groups, which will make management decisions clearer compared to other models that also include an intermediate-risk group. Patients in the low-risk group had 86% five-year disease-free survival; patients in the high-risk group had 50% five-year disease-free survival and may benefit from increased postoperative surveillance or adjuvant therapy. Research Sponsor: Auspex Diagnostics. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8538 Poster Session

Surgical outcomes for early-stage non-small cell lung cancer at facilities with stereotactic body radiation therapy programs.

Yusef Syed, William A. Stokes, Onkar Khullar, Nikhil Sebastian, Manali Rupji, Liu Yuan, Jeffrey D. Bradley, Kristin Ann Higgins, Walter J Curran, Suresh S. Ramalingam, Manu Sancheti, Felix Fernandez, Drew Moghanaki; Emory University, Atlanta, GA; Emory University School of Medicine, At- lanta, GA; Emory University Hospital Midtown, Atlanta, GA; Winship Cancer Institute, Emory University, Atlanta, GA; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA; Winship Cancer Institute of Emory University, Atlanta, GA; Atlanta Veterans Affairs Health Care System, Decatur, GA

Background: Patients undergoing surgery for early-stage non-small cell lung cancer (NSCLC) may be at high-risk for post-operative mortality. Access to stereotactic body radiation therapy (SBRT) offers a less invasive alternative for this population that may facilitate more appropriate patient selection for surgery. Methods: An analysis of all patients with early-stage NSCLC reported to the National Cancer Database between 2004-2015 was performed. Post-operative mortality rates were derived using vital status data. Utilization of SBRT was defined by each facility’s SBRT Experience in years and SBRT-to-Surgery volume ratios, defined by quartiles. Multivariable logistic regression with backward elimination was used to test for independence of associations between exposures of interest and post-operative mortality. In- teraction testing was performed to assess the statistical relationship of covariates found to have independent associations. Results: The study cohort consisted of 202,542 patients who underwent surgical resection of clinical stage T1-T2 NSCLC (AJCC 7th edition). The 90-day post-operative mortality rate de- clined significantly during the study period from 4.6% to 2.6% (p < 0.001). During this period, the proportion of facilities that utilized SBRT increased from 3.3% to 77.5% (p < 0.001) and the proportion of patients treated with SBRT increased significantly from 0.7% to 15.4% (p < 0.001). Lower 90-day post-operative mortality rates were observed at facilities with greater than six years of SBRT experience (OR 0.84, CI 0.76-0.94, p = 0.003) and SBRT-to-Surgery volume ratios above 17% (OR 0.85, CI 0.79-0.92, p < 0.001). Additional covariates associated with 90-day mortality included higher surgical volume, geographic region, year of diagnosis, age, sex, race, insurance status, facility type, Charlson- Deyo score, clinical T stage, histology, anatomic location, surgery type, and prior malignancy. Interac- tion testing between these covariates was negative, demonstrating that higher SBRT Experience and SBRT-to-Surgery volume ratios were independently associated with lower 90-day surgical mortality. Conclusions: Patients who underwent surgery for early-stage NSCLC at facilities with higher SBRT Expe- rience and SBRT-to-Surgery volume ratios had lower rates of post-operative mortality. These findings suggest that the availability of SBRT may be a surrogate for a more comprehensive and safer approach to matching patients to surgery or SBRT. The observation of higher post-operative mortality rates at facilities without an SBRT program deserves further study. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8539 Poster Session

Prognostic value of SUVmax on FDG-PET/CT before and after stereotactic body radiotherapy (SBRT) on recurrence and survival in early-stage non-small cell lung cancer (NSCLC).

Saarang Deshpande, Tarun Kanti Podder, Yuxia Zhang, Yiran Zheng, William Grubb, Michael Kharouta, Philip Aaron Linden, Tithi Biswas; Case Western Reserve University School of Medicine, Cleveland, OH; University Hospitals, Case Medical Center - Seidman Cancer Center, Cleveland, OH

Background: Stereotactic body radiotherapy (SBRT) is the standard of care in medically inoperable early-stage non-small cell lung cancer (NSCLC). Assessment of FDG-PET/CT before and after SBRT may stratify risk of disease recurrence and survival outcomes. Methods: Patients with T1-2N0M0 NSCLC who underwent PET/CT prior to SBRT (50-60 Gy over 3-5 fractions) between 2012 and 2019 were retrospectively identified. Pre-SBRT SUVmax and change in SUVmax at 3 and 6 months after SBRT were assessed as predictors of local control (LC), progression-free survival (PFS), and overall survival (OS). Optimal cutoff points for comparison were determined by receiver operator characteristic (ROC) analysis. Survival analyses were performed with Kaplan-Meier estimates with log rank testing, and Cox proportional hazards models including age, sex, T stage, histology, and performance status. Results: Out of 163 patients identified, 71 (43.6%) underwent repeat PET/CT within 6 months of SBRT completion. Median follow-up was 19 months (range 1 – 94 months). For the whole cohort, 1-year and 2-year LC, PFS, and OS were 95.0% and 80.3%, 75.9% and 47.7%, and 87.1% and 67.0%, respectively. Pre- SBRT SUVmax greater than 12.3 had an aHR of 2.80 (95% CI 1.3 – 6.2, p = 0.011) for PFS. A cut- point of 12.6 for pre-SBRT SUVmax had an aHR of 3.00 (95% CI 1.6 – 5.8, p = 0.003) for OS. Pre- SBRT SUVmax did not significantly predict LC. A 3-month SUVmax decrease of at least 45% was associated with improved LC (aHR = 0.15, 95% CI 0.02 – 0.91, p = 0.018). At 6 months following SBRT, a cutoff point of a 53% decrease in SUVmax was associated with better LC (p = 0.038). Change in SUV- max was not significantly associated with PFS or OS at either time point. Performance status significantly predicted PFS and OS in all models. No other factors were significant. Conclusions: Pre- treatment SUVmax cutoffs can predict PFS and OS in early-stage NSCLC. At both the 3- and 6-month time points following SBRT, cutoff values for change in SUVmax can stratify risk of local recurrence. Re- search Sponsor: None.

Outcome Cutoff value p-value Pre-SBRT SUVmax LC 14.8 0.097 Pre-SBRT SUVmax PFS 12.3 0.011 Pre-SBRT SUVmax OS 12.6 0.003 3-mo SUVmax change LC -45% 0.018 3-mo SUVmax change PFS -50% 0.936 3-mo SUVmax change OS -72% 0.245 6-mo SUVmax change LC -53% 0.038 6-mo SUVmax change PFS -78% 0.317 6-mo SUVmax change OS -40% 0.089 LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8540 Poster Session

Multiomics analysis reveals high-immune infiltration in tumor-adjacent lung tissues affects the prognosis of stage I NSCLC.

Lisa Ying, Dan Su, Zhang Chunliu, Yiping Tian, Jing Bai, Canming Wang, Jianfei Fang, Andrew Futreal, Jianjun Zhang; Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sci- ences (Zhejiang Cancer Hospital);Institute of Basic and CancerMedicine (IBMC), Chinese Academy of Sciences, Hangzhou, China; Institute of Basic and CancerMedicine (IBMC), Chinese Academy of Scien- ces, Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhe- jiang Cancer Hospital), Hangzhou, China; Geneplus-Beijing Institute, Beijing, China; Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospi- tal); Institute of Basic and CancerMedicine (IBMC), Chinese Academy of Sciences, Hangzhou, China; Geneplus-Beijing, Beijing, China; Institute of Basic and Cancer Medicine (IBMC), Chinese Academy of Sciences, Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic and Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX

Background: Along with the wide application of low-dose spiral CT in lung cancer screening, a large number of resectable patients with lung cancer are identified, especially stage I Non-Small Cell Lung Cancer (NSCLC). However, their prognosis varies greatly and 5-year recurrence rate of stage I NSCLC is around 30%. Therefore, it is crucial to explore the potential mechanism of recurrence of early NSCLC. Methods: Eighty-seven patients with stage I NSCLC were enrolled from April 2008 to July 2015, including 79 squamous carcinoma and 28 adenocarcinoma. Frozen tumor tissues and paired tumor-adjacent lung tissues were collected to employ targeted panel sequencing, RNA sequencing and TCR repertoire sequencing. Results: Ninety-five non-silent mutations were detected in tumor-adjacent lung tissues with a median tumor mutation burden of 1.5/Mb, significantly lower than that in tumor tissues (11/Mb), p < 0.05. 42 mutations were specifically detected in the adjacent normal tissues, enriching in the immune response pathways. Comparing with paired tumors, tumor-adjacent lung tissues were found more favorable immune infiltration including higher immune cell activity like CD8+ T cell (0.50 vs 0.43, p < 0.0001), up-regulated immune-associated pathways, higher TCR clonality (0.19 vs 0.18, p < 0.05), less loss of heterozygosity (LOH) of human leukocyte antigen (HLA) (6.25% vs 50%, p < 0.0001) and observed predicted neoantigens expression (1 vs 128, p < 0.01). However, more shared viral-associated TCRs in tumor and tumor-adjacent tissues were found using the GLIPH algorithm. Prognostic analysis showed patients with higher overlap of TCR in tumors and tumor-adjacent lung tissues were prone to recur in five years. Furthermore, patients with higher immune infiltration in tumor-adjacent lung tissues had favorable outcomes than those with lower immune infiltration (HR: 0.37 for DFS, p < 0.05, HR: 0.31 for OS, p < 0.05), irrelevant of the infiltration level in tumor tissues. Conclusions: Immune microenvironment in tumor-adjacent lung tissues plays important roles in progress of stage I NSCLC. Re- search Sponsor: Major Science and Technology Project of Zhejiang Province of China Grants 2020C03023, Public Welfare Technology Foundation of Zhejiang Province of China Grant 2017C34001 and Zhejiang high-level innovative talent program. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8541 Poster Session

Phase II trial of toripalimab plus chemotherapy as neoadjuvant treatment in resectable stage III non-small cell lung cancer (NeoTPD01 Study).

Zerui Zhao, Si Chen, Han Qi, Chao-Pin Yang, Yao-Bin Lin, Jie-Tian Jin, Shan-Shan Lian, Yi-Zhi Wang, Hui Yu, Long Hao; Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, VA, China; Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, Chi- na; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China, Guangzhou, China; Department of Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, China, Guang- zhou, China

Background: Multi-modality treatment provides modest survival benefits for locally advanced non-small- cell lung cancer (NSCLC) patients. Preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC. The current study aimed to investigate the activity and safety of the PD-1 inhibitor, toripalimab, with chemotherapy given as neoadjuvant treatment for resectable stage III NSCLC in Asian population. Methods: Eligible patients recruited were aged 18 years or older with histologically confirmed AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC who deemed surgically resectable. Patients received 3 cycles of neoadjuvant treatment with intravenous toripalimab (240 mg), carboplatin (area under curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for others) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks following the first day of the last cycle of treatment. The primary endpoint was major pathological response (MPR; #10% viable tumor cells). Secondary endpoints included pathological complete response (pCR), R0 resection rate, disease-free survival and safety. Paired primary tumor +/- lymph node and blood samples at baseline and surgery were obtained for exploratory study. This study is registered with ClinicalTrials.gov, NCT04304248. Results: Between August 2019 and July 2020, 33 patients (median age: 61, IQR: 56-66; female: 6, 18.2%) were enrolled and received neoadjuvant treatment. 18 (54.5%) patients had squamous cell lung cancer, and 13 (39.4%) had T3-4N2 stage IIIB disease. Two patients refused surgery and one had progressive disease after treatment. 30 (91.9%) patients underwent resection (median interval between neoadjuvant treatment and surgery: 36.5 days, IQR 30-42.5) and all except one achieved R0 resection (29/30, 96.7%). 20 patients (20/30, 66.7%) had an MPR, including 15 patients (15/30, 50.0%) had a pCR in the per-protocol population. Surgical complications included three arrhythmias, one prolonged air leak, and one chylothorax. 24 patients (80.0%) had pathological downstaging following treatment, and complete lymph node clearances (ypN0) were seen in 70.0% (21/30) of patients. The most common grade 3-4 treatment-related adverse events in the intention-to-treat population were anemia (2, [6.0%]). Severe treatment-related adverse event included one (3.0%) patient with grade 3 peripheral neuropathy (Guillain-Barre� syndrome) and resulted in surgery cancellation. At the time of data cutoff (Feb 7, 2021), the median duration of follow-up was 4.13 months, and there were no treatment-related deaths. Conclusions: Toripalimab plus platinum-based doublet yields a high MPR rate, manageable treatment-related toxicity, and feasible surgical resection in resectable stage III NSCLC. Ongoing analysis of biomarker will be available at the meeting. Clinical trial information: NCT04304248. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8542 Poster Session

Impact of genomic aberrations and additional therapies on survival outcomes of patients with operable non-small cell lung cancer (NSCLC) from the NEOSTAR study.

Nicolas Zhou, Boris Sepesi, Cheuk Hong Leung, Heather Y. Lin, William Nassib William, Annikka Weissferdt, Apar Pataer, Myrna Godoy, Frank V. Fossella, George Blumenschein, Xiuning Le, Anne S. Tsao, Jianjun Zhang, Wayne L. Hofstetter, Stephen Swisher, Ara A. Vaporciyan, J. Jack Lee, Don Lynn Gibbons, John Heymach, Tina Cascone; Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX; Oncology Center, Hospital BP, a Beneficencia Portuguesa de Sa~o Paulo, Sa~o Pau- lo, Brazil; Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Thoracic Imag- ing, The University of Texas MD Anderson Cancer Center, Houston, TX; Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: The NEOSTAR study compared nivolumab (N) vs. nivolumab plus ipilimumab (NI) with major pathological response (MPR; #10% viable tumor) as primary outcome. We report updated rates of treatment failure (TF), including in patients whose tumors harbored genomic aberrations, and outcomes of additional treatments. Methods: Patients (pts) with stage I-IIIA resectable NSCLC (AJCC 7th) were randomized to either neoadjuvant N or NI followed by surgery (n = 44). TF was defined as radiographic and/or biopsy-proven recurrence from primary lung cancer and/or death (treatment or cancer-related). Additional systemic therapy at recurrence included immuno-oncology (IO)-based therapy (IO or chemo-IO), targeted therapy (TT), or chemotherapy. Disease control rate (DCR) was defined as the proportion of pts with radiographic objective responses and stable disease at first restaging. Cox proportional hazards model was used to associate baseline characteristics and time to TF. Results: A total of 44 randomized pts were evaluated, the median follow-up was 35 months (mts) as of February 4, 2021. Among the 12 TF pts (12/44, 27%), 42% (5/12) did not undergo surgery on trial, 9 (9/44, 20%) experienced recurrence and 6 (6/44, 14%) died (1 non-cancer-related, 5 cancer-related). TF was less likely in smokers vs. never smokers (hazard ratio = 0.20, 95% confidence interval = 0.06-0.65, p = 0.007). Among pts with pathological specimen resected on trial, MPR was achieved in 40% (12/30) of non-TF pts. Only 1 (1/7, 14%) TF pt achieved MPR, but died of a non-cancer related cause. TF-free survival rate at 2 years was 92% in MPR and 78% in non-MPR pts. Eight (8/9, 89%) pts had tumors with canonical oncodriver aberrations (5 EGFR mutations, 1 with STK11+ KRAS Q61H mutations, 1 ALK translocation and 1 RET fusions). Of the 9 recurrences, 44% (4/9) were treated with IO therapy, and all 7 pts with targetable aberrations were treated with TT (3 after retreatment with IO therapies). Of the 4 pts re- treated with IO therapy, duration between end of neoadjuvant and retreatment were 20, 17, 23, and 19 mts. Duration from retreatment until progression (PD) were 1, 1, and 2 mts, respectively. Last pt was treated without PD for 2 mts but switched to TT due to discovery of genomic aberration. IO retreatment achieved 25% DCR (1/4). In comparison, the DCR for TT treated pts was 71% (5/7, p = 0.242). Median time to treatment was 21 mts, and median time to PD was not reached. Among 32 non-TF pts, 12 had genomic analysis and 7 aberrations were found in 6 pts (2 STK11, 2 ERBB2, 1 STK11 + 1 KRAS G12C, and 1 KRAS G12C mutation). Conclusions: A 27% TF rate was observed after neoadjuvant IO. TF was less likely to occur in smokers and MPR pts, and 42% of TF pts did not undergo curative-intent surgery on trial. Genomic aberrations were common in pts with recurrence (89%), and treatment with TT achieved 71% DCR vs. 25% DCR with IO-based retreatment. Clinical trial information: NCT: 03158129. Research Sponsor: Conquer Cancer Foundation of the American Society of Clinical Oncolo- gy, Other Foundation, U.S. National Institutes of Health, The University of Texas MD Anderson Cancer Center Lung Cancer Moon Shot Program, The University of Texas MD Anderson Cancer Center Physician Scientist Program. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8543 Poster Session

PIT-2: A multicenter phase II trail of S-1 plus cisplatin with concurrent radiotherapy followed by surgery in stage IIIA (N2) lung squamous cell carcinoma.

Kazuya Takamochi, Masahiro Tsuboi, Morihito Okada, Seiji Niho, Satoshi Ishikura, Shunsuke Oyamada, Takuhiro Yamaguchi, Fumihiro Tanaka, Ichiro Yoshino, Masanori Tsuchida, Satoshi Shiono, Hiroyuki Oizumi, Norihito Okumura, Tomohiro Haruki, Kenji Suzuki; Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan; Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Chiba, Japan; Department of Surgical Oncology, Hiro- shima University, Hiroshima, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Depart- ment of Radiology,Nagoya City University Graduate School of Medical Sciences, Aichi, Japan; Department of Biostatistics, JORTC Data Center, Tokyo, Japan; Tohoku University Graduate School of Medicine, Miyagi, Japan; University of Occupational and Environmental Health, Kitakyushu, Japan; De- partment of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan; Niigata University Medical and Dental Hospital, Niigata, Japan; Department of Thoracic Surgery, Yama- gata Prefectural Central Hospital, Yamagata, Japan; Department of Surgery II, Faculty of Medicine, Ya- magata University, Yamagata, Japan; Kurashiki Central Hospital, Kurashiki, Japan; Division of General Thoracic Surgery, Department of Surgery, Faculty of Medicine, Tottori University, Tottori, Japan

Background: A multicenter phase II study, PIT-2 (Personized Induction Therapy-2), was performed to investigate the efficacy and safety of S-1 plus cisplatin and concurrent thoracic radiation therapy (TRT) followed by surgery in patients with stage IIIA (N2) lung squamous cell carcinoma (LSCC). To date, no clinical trials on the use of induction therapy prior to surgery have focused solely on the treatment of N2 LSCC. Methods: Eligible patients were 20 to 75 years old and had stage IIIA (pathologically proven N2) LSCC, performance status of 0-1, and no prior treatment. The patients received induction therapy consisting of three cycles of S-1 and cisplatin plus concurrent TRT (45 Gy in 25 fractions) followed by surgery. S-1 was administered orally at 40 mg/m2 twice per day, on days 1 through 14 along with an intravenous infusion of cisplatin (60 mg/m2) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, pathological complete remission (pCR) rate, feasibility, and toxicity. Results: Of the 45 patients registered between December 2013 and September 2018, 43 received induction therapy. Of the 43 patients, 39 (91%) underwent surgery (25 lobectomies, 10 bilo- bectomies, three pneumonectomies, and one wedge resection). The complete resection rate was 95% (37/39). Median follow-up time was 35.7 months. The 2-year PFS and OS rates were 67% (90% CI: 54-78%) and 70% (95% CI: 53-81%), respectively. The ORR and pCR rates were 86% (37/43, 95% CI: 76-96%) and 39% (15/39, 95% CI: 23-54%), respectively. Grade (G) 3 or 4 toxicities during the induction therapy in 43 patients included neutropenia (40%), anemia (9%), thrombocytopenia (7%), and hyponatremia (7%). Severe surgical complications in 39 patients included G3/4 pneumonia (5%), G3 bronchopleural fistula (5%), and G3 pleural effusion (5%). No G3/4 intraoperative adverse events occurred. There was no 30-day postoperative mortality and one 90-day postoperative mortality in a patient who underwent right pneumonectomy and developed pneumonia after discharge. Conclusions: In- duction therapy using S-1 plus cisplatin and concurrent TRT followed by surgery is a promising treatment for patients with stage IIIA (N2) LSCC. Clinical trial information: 000012413. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8544 Poster Session

Impact of society and national guidelines on patient selection for lung cancer surgery in the United Kingdom.

Aina Pons, Paulo De Sousa, Chiara Proli, Sarah Ann Booth, Abigail Palmares, Maria Leung, Abdullah Alshammari, Dimitrios Vlastos, Hilgardt Raubenheimer, Anant Patel, Mohan Devbhandari, Eric Kian Saik Lim; Royal Brompton and Harefield Hospitals, London, United Kingdom; Royal Free Lon- don NHS Foundation Trust, London, United Kingdom

Background: In 2010 the British Thoracic Society (BTS) guidelines introduced clinical decision based on patient perception of risk to make surgery more permissive and revised recommendations for broader oncologic criteria such as surgery for N2 disease to improve surgical resection rates. In 2011 the Na- tional Institute for Health and Care Excellence (NICE) guidelines were updated with similar recommendations, but notable disagreement on surgery for N2 disease. We sought to conduct one of the largest cross-sectional studies to ascertain the impact of national clinical guidelines (with conflicting recommendations) on clinician behaviour. Methods: We analysed data from the UK national registry (National Lung Cancer Audit) comprising all patients diagnosed with lung cancer between 2008 to 2013 within England and Wales. Categorical data was summarised as frequency (%) and continuous data was summarised as mean (SD). Linear and logistic regression analyses were used with each year as an independent categorical outcome to determine global and year specific changes in FEV1 and proportions with N2 undergoing surgery respectively. Results: From January 2008 to December 2013, data from 167,192 patients with primary lung cancers were submitted to the NLCA. In 2008, 23,293 new lung cancers were diagnosed in England and Wales increasing annually by 2013 to 29,224. The most common presentation was advanced disease stage IV (49.7%), IIIB (13.2%) and IIIA (12.0%) and early- stage disease was less frequent with presentations IA (7.0%), IB (6.7%), IIA (2.9%) and IIB (4.27%). Lung function tests were undertaken in a subset of 53,905 of all diagnosed patients from 2008 to 2013. The mean FEV1 (SD) increased annually from 67 (22)% in 2008 to 71 (24)% in 2013 (p < 0.001). Overall, 28% (n = 46,742) of the patients were preoperatively staged as N2 disease at diagnosis. The proportion of patients with N2 disease increased from 24 to 29% in this timeframe (P = 0.003). The proportion of patients undergoing surgery for lung cancer increased from 9.5% in 2008 to 20.5% in 2013 (p < 0.001). Mean FEV1 of surgical patients were higher at 79 (22)% than the population average of 69 (23)%, an accepted reflection of surgical selection. Over time, mean FEV1 of surgical patients increased from 76 (22)% in 2008 to 81 (22)% in 2013 (p < 0.001). Of the patients undergoing surgery, the proportion of patients across the 6-year interval were broadly consistent between 8 to 11% without any evidence of trend (P = 0.125). Conclusions: Within 3 years of new clinical guidelines, we did not observe any overall change in selection based on lower levels of lung function and when presented with conflicting recommendation no observable change in attitudes of clinicians on surgery for N2 disease. The observed increase in surgical resection rates is more likely due to (greater access to surgery by) increasing number of surgeons rather than any impact of guideline recommendations. Re- search Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8545 Poster Session

The efficacy of PD-1 antibody sintilimab on ground glass opacity lesions in patients with early-stage multiple primary lung cancer (CCTC-1901, NCT04026841).

Bo Cheng, Bo Cheng, Caichen Li, Yi Zhao, Jianxing He; Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Dis- ease & National Clinical Research Center for Respiratory Disease, Guangzhou, China; The First Affiliat- ed Hospital of Guangzhou Medical University, Guangzhou, China

Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been proven its significant efficacy on advanced non-small cell lung cancer (NSCLC). However, it remains unknown and is of great interest whether the PD-1 antibody affects early-stage lung cancer. Here, we reported the preliminary efficacy and safety outcomes of sintilimab on these early-stage GGO lesions in patients (pts) with multiple primary lung cancer in the CCTC-1901 study, the first trial evaluating PD-1 antibody in preinvasive or low invasive lung cancer worldwide. Methods: This single-center, phase II, Simon’s two-stage design trial included pts who had a pathological diagnosis of resected lung cancer and at least one unresectable GGO lesion suspicious malignant which evaluated by a multidisciplinary team’s consensus. The enrolled pts received 4 cycles of intravenous sintilimab 200 mg every 3 weeks. The primary endpoint is the objective response rate (ORR) of unresectable GGO lesions. For persistent GGO lesions that did not respond to treatment, either observation or second operation was taken. Also, immune biomarkers (T/B/NK subpopulation etc.) were monitored during treatment to validate the immune activity. Results: A total of 36 pts were included, with median age 59.5 (53.5-69), 66.7% females, 80.6% never smokers. All resected lesions were adenocarcinomas, of which 52.8% were EGFR mutated. 49 unresected GGOs (pure 11[22.4%], mixed 38[77.6%]) were defined as target lesions from 36 enrolled pts, with a mean size of 13.20±5.06 mm. The ORR (RECIST v1.1) was 5.6% (2/36, 1 PR and 1 CR); none of the pts had PD. Additionally, 3 non-target lesions (unresected solid lesions) from 3 included pts showed PR after the treatment of sintilimab, and the rest lesions (target or non-target) of 31 pts performed SD. Grade 1-2 fatigue (13, 36%), rash (13, 36%) and arthralgia (8, 22%) were the most common treatment-related adverse events (TrAEs), and no grade 3-5 TrAEs occurred. The proportion of CD8+ T-cell and the ratio of CD8+/CD4+ in 5 patients who showed PR of unresected lesions were significantly higher compared to those with SD lesions at baseline (CD8+ 36.6% vs 24.6%, p < 0.01; CD8+/CD4+ 1.09±0.18 vs 0.64±0.22, p < 0.01). Conclusions: This study is the first to confirm that PD-1 antibody sintilimab has immune-related antitumor activity on GGO-featured lung cancer and could be well tolerated among pts with early-stage lung cancer. Clinical trial information: NCT04026841. Research Sponsor: China National Science Foundation (Grant No. 81871893). LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8546 Poster Session

Doubling of median overall survival in a nationwide cohort of veterans with stage III non- small cell lung cancer in the durvalumab era.

Kamya Sankar, Alex K. Bryant, Michael Green, Nithya Ramnath; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI; Department of Radiation On- cology, Rogel Cancer Center, University of Michigan, Ann Arbor, MI; Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI; Department of Medical Oncology, Veter- ans Affairs Ann Arbor Healthcare System, Ann Arbor, MI

Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p < 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8547 Poster Session

Elderly patients with unresectable stage 3 NSCLC treated with definitive chemoradiation with or without durvalumab: Safety and outcomes.

Malcolm Isaiah Ryan, Jessica Weiss, Aline Fusco Fares, Ming Sound Tsao, Geoffrey Liu, Penelope Ann Bradbury, Natasha B. Leighl, Frances A. Shepherd, Adrian G. Sacher, Sally C. M. Lau; Princess Marga- ret Cancer Centre, Toronto, ON, Canada; University Hospital Network (UHN) Biostatistics Department, Toronto, ON, Canada; Princess Margaret Hospital, Toronto, ON, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Cancer Clinical Research Unit, Princess Margaret Cancer Centre, To- ronto, ON, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada

Background: Recently, it has been demonstrated that the addition of durvalumab after chemoradiation (CRT) in unresectable stage 3 non-small cell lung cancer (NSCLC) significantly improves overall survival (OS). The benefit of CRT in elderly patients is considered controversial given its increased toxicity. As such, CRT followed by durvalumab in elderly patients may be underutilized despite its demonstrated su- periority. The practice pattern at our center is to offer curative treatment unless clearly contraindicated. We sought to investigate the outcomes of elderly patients treated with CRT +/- durvalumab at our center. Methods: We conducted a review of all stage 3 NSCLC patients treated with CRT between 2018 and 2020. Patients were analyzed based on age: < 70 years, $70 years. Endpoints evaluated were treatment patterns, toxicity, progression free survival (PFS) and overall survival (OS). Results: We identified 115 stage 3 patients: 44 patients $70 years (70-89) and 71 patients < 70 years (34-69). Patients were fit: ECOG 0-1 (98%/97%), mean Charlson comorbidity index (CCI) (1.1/0.9) in elderly vs young patients; p > 0.05. All other baseline characteristics including PD-L1 expression were similar. The chemotherapy regimens (platinum in combination with etoposide, paclitaxel or pemetrexed), dose intensity (97% vs 97%) and percentage of planned cycles received (91% vs 96%) were similar. There were 2 treatment related deaths from CRT among the younger cohort and none in the elderly patients. At the completion of CRT, 75% of elderly and 72% of young patients received durvalumab. Clinician/patient preference was the most common reason for not receiving consolidation durvalumab in older patients (55% vs 25%). The median time to starting durvalumab was 43 days in the elderly and 37 days in young patients (p = 0.19). Durvalumab was well tolerated in the elderly and incidence of grade $3 immune-related adverse events was 9% compared to 6% in young patients; p = 0.68. The durvalumab completion rates were 30% in elderly and 24% in young patients; p = 0.22. Median PFS was similar between elderly and young patients (17.9 vs 10.6 months respectively; p = 0.07), even after adjusting for the CCI (HR 0.60; p = 0.07). The 24- and OS rates are also similar (p = 0.93): 77% in elderly and 77% in young patients. Conclusions: Definitive CRT followed by durvalumab can be safely delivered in elderly patients $70 years with comparable outcomes. The non-significant trend towards better PFS in elderly patients suggests that only select fit patients are being referred for treatment. In conclusion, all patients should undergo comprehensive oncologic assessment to determine if curative intent treatment can be delivered to avoid undertreatment of elderly patients. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8548 Poster Session

NRG-RTOG 1106/ACRIN 6697: A phase IIR trial of standard versus adaptive (mid-treatment PET-based) chemoradiotherapy for stage III NSCLC—Results and comparison to NRG-RTOG 0617 (non-personalized RT dose escalation).

Feng-Ming Spring Kong, Chen Hu, Randall Ten Haken, Ying Xiao, Martha Matuszak, Vera Hirsh, Daniel A. Pryma, Barry A. Siegel, Daphna Y. Gelblum, James Hayman, Clifford Grant Robinson, Billy W. Loo, Gregory M.M. Videtic, Sergio Faria, Catherine Ferguson, Neal E. Dunlap, Vijayananda Kundapur, Rebecca Paulus, Jeffrey D. Bradley, Mitchell Machtay; Clinical Oncology Department, The University of Hongkong-Shenzhen Hospital, Shenzhen, China; NRG Oncology Statistics and Data Management Cen- ter, Philadelphia, PA; University of Michigan, Ann Arbor, MI; University of Pennsylvania, Department of Radiation Oncology, Philadelphia, PA; McGill University Health Centre, Westmount, QC, Canada; Washington University School of Medicine in St. Louis, St. Louis, MO; Memorial Sloan Kettering Cancer Center, New York, NY; Stanford Cancer Institute, Stanford, CA; Cleveland Clinic Foundation, Cleveland, OH; Georgia Cares Minority Underserved NCORP, Augusta, GA; The James Graham Brown Cancer Cen- ter at University of Louisville, Louisville, KY; Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada; Emory University, Atlanta, GA; Penn State Milton S Hershey Medical Center, Hershey, PA

Background: NRG-RTOG 0617 (R0617) found that non-personalized dose escalation of radiotherapy (RT) with concurrent chemotherapy was deleterious. NRG-RTOG 1106/ACRIN 6697 (R1106) studied adaptive chemoradiotherapy, using tumor and patient individualized RT dose intensification simulta- neously with field reduction, based upon mid-treatment FDG-PET. Methods: The control arms of both studies used 60 Gy (+ weekly carboplatin/paclitaxel). The investigational arm of R0617 used 74 Gy in 37 fractions, with no field/dose adaptation, while R1106 used mid-treatment FDG-PET (after ~40 Gy) to design an individualized dose adaptive RT plan with daily-fraction size 2.2 to 3.8 Gy (up to 80.4 Gy/ 30 fractions), based upon a model of isotoxic lung risk. Nearly all (93%) patients had IMRT. No patients had consolidation immunotherapy. The primary endpoint for R1106 was local-regional-progression freedom (LRPF) assessed by central review. Other endpoints reported here were survival, toxicity, and institution-defined local/regional control. Results: From 2012-2017, 127 patients were enrolled to R1106 (43 in the standard and 84 in the adaptive arms), with a median follow-up of 3.6 years. The median actual RT dose in the adaptive arm was 71 Gy (Q1-Q3 68-76 Gy). The 2-year LRPF was 59.5% versus 54.6% (p=0.66) for standard versus adaptive RT; the 3-year survival rates were 49.1% versus 47.5% (p=0.80). An exploratory analysis of 2-year in-field local primary tumor control and local-regional tumor control (institution-assessed) were 58.5% and 55.6% for standard RT, and 75.6% and 66.3% for adaptive RT, respectively. As shown in the table, there were no significant differences in cardiac or esophageal adverse events between the two arms; the adaptive RT arm had more Grade 3+ respiratory events (23.8% versus 14.3%). Conclusions: NRG-RTOG1106 did not meet its primary endpoint of demonstrating improved LRPF. Unlike R0617, there was no suggestion of a detrimental effect of adaptive dose-intensified RT on survival and cardiac events. Studies to refine personalized RT, especially in the immunotherapy era, should be considered. Outcome comparison between R0617 and R1106. Clinical trial information: NCT01507428. Research Sponsor: This project was supported by grants UG1CA189867 (NCORP), U10CA180822 (NRG Oncology SDMC), U10CA180868 (NRG Oncology Operations), and U24CA180803 (IROC) from the National Cancer Institute (NCI).

R0617 Control Arm R0617 High-dose Arm R1106 Control Arm R1106 Adaptive Arm

3-yr OS 44.5% 31.1% 49.1% 47.5% 3-yr Local-regional failure 47.1% 50.9% 30.0% 30.2% (institution reported) 2-yr In-field primary tumor local NS NS 58.5% 75.6% control (institution reported) 2-yr In-field local-regional control NS NS 55.6% 66.3% (institution reported) Cardiac event Grade 3+ (crude %) 17.9% 19.8% 2.6% 1.3% Pulmonary toxicity 20.6% 19.3% 14.3% 23.8% Grade 3+ (crude %) Esophagitis Grade 3+ (crude %) 5.0% 17.4% 7.9% 3.8% LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8549 Poster Session

The impact of a genomic sequencing classifier (GSC) on clinical decision making in patients with a high-risk lung nodule.

Sonali Sethi, Scott Oh, Alexander Chen, Christina Bellinger, Lori Lofaro, Jennifer Tom, Marla Johnson, Jing Huang, Sangeeta Maruti Bhorade, Giulia Kennedy; Cleveland Clinic, Cleveland, OH; University of California, Los Angeles, Los Angeles, CA; Washington University School of Medicine, St. Louis, MO; Wake Forest School of Medicine, Winston-Salem, NC; Veracyte, Inc., South San Francisco, CA; Vera- cyte, South San Francisco, CA

Background: Current guidelines recommend that patients who have lung nodules with high risk of malignancy (ROM) ( > 65%) should undergo surgical and other ablative therapies. However, prior studies have shown that clinicians may opt for more conservative management in these high-risk patients. Per- cepta Genomic Sequencing Classifier (GSC), a RNA-seq based classifier derived from bronchial epithelial cells to assess risk of lung cancer, was designed to risk stratify lung nodules by both down classifying ROM as a “rule -out“ test with high sensitivity as well as up-classifying ROM as a “rule- in” test with high specificity for malignancy. This study assesses the impact of up-classification of high ROM to very high- risk (ROM > 90%) by Percepta GSC in increasing the number of ablative therapies recommended for high-risk lung nodules. Methods: This prospective randomized decision impact survey included 37 patients from the AEGIS I/ II cohorts and the Percepta Registry who were undergoing work up of a lung nodule and had a high ROM that was up-classified to very high ROM by Percepta GSC. 97 physicians assessed 10 randomly assigned patient cases. They then responded to a survey designed to test the hypothesis that including a Percepta GSC result will increase the recommendation for surgical or other ablative therapy in very high- risk patients as well as their level of confidence of this recommendation. Physicians were first presented with the patient’s clinical information without Percepta GSC and then with Percepta GSC. Results: 97 physicians provided a total of 682 evaluations of 37 patients. In this study, the recommendation for surgical or other ablative therapy increased from 19/341 (5.6%) prior to the Percepta GSC result to 157/341 (46%) after the Percepta GSC result (odds ratio of 4.76, p- value < 0.001). The number of extremely confident recommendations increased from 72/341 (21%) without Percepta GSC to 106/341 (31%) with Percepta GSC. Significantly more physicians had increased confidence in their recommended next step post-Percepta GSC when collapsing the confidence level responses into increased confidence (n = 93) and decreased confidence (n = 44) (p-value = 0.002). Conclusions: Percepta GSC had a quantifiable impact on clinical decision making. It increased the number of surgical and other ablative therapies recommended when patients were re-classified from high to very high- risk of lung cancer with a higher confidence in the recommended next step. By up-classifying nodules from high to very high ROM, Percepta GSC will improve the likelihood and timeli- ness of appropriate therapies and assist clinicians more effectively manage patients to improve patient outcomes. Research Sponsor: Veracyte, Inc. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8550 Poster Session

Patients with early-stage (T1-2N0) adenosquamous lung cancer have worse long-term survival compared to patients with early-stage lung adenocarcinoma or squamous cell histology.

Larisa Shagabayeva, Patel B. Heer, Chi-Fu Jeffrey Yang, Michael Lanuti; Harvard Medical School, Bos- ton, MA; Massachusetts General Hospital, Boston, MA

Background: Survival outcomes for patients with adenosquamous carcinoma of the lung are not well understood by virtue of reduced prevalence. The objective of this study is to compare the long-term survival among patients with adenocarcinoma, squamous cell carcinoma and adenosquamous carcinoma of the lung. Methods: Overall survival of all patients with adenosquamous carcinoma, squamous cell carcinoma, and adenocarcinoma who received guideline-concordant treatment for T1-2N0M0 from 2004- 2017 in the National Cancer Data Base was assessed using Kaplan-Meier analysis, multivariable Cox proportional hazard analysis, and propensity score-matched analysis. Results: Among patients who met study criteria (N = 88,983), there were 2,469 (2.77%) patients with adenosquamous, 60,148 (67.59%) with adenocarcinoma and 26,366 (29.63%) with squamous cell carcinoma histology. In patients who had T1-T2 N0 M0 disease, adenosquamous carcinoma was associated with significantly worse 5-year overall survival (58.9% [95%CI:56.6%-61.1%]) when compared with adenocarcinoma (72.4% [95% CI:72.0%-72.8%]) and squamous cell carcinoma (62.6% [95% CI:61.9%-63.3%]). In multivariable Cox proportional hazards analysis, adenocarcinoma (HR 0.81 [95% CI:0.76-0.87], p < 0.001) and squamous cell carcinoma (HR 0.86 [95% CI:0.80-0.92], p < 0.001) continued to be associated with significantly better survival when compared to adenosquamous carcinoma histology. A propensity score-matched analysis of 1,854 adenocarcinoma and 1,854 adenosquamous patients who were well matched by 17 common prognostic covariates (including tumor size and comorbidities) found that adenosquamous histology (57.2% [95% CI:54.7%-59.6%]) was associated with worse survival when compared to adenocarcinoma (63.0% [95% CI:60.6%-65.4%]). An additional propensity score- matched analysis of 1,852 squamous cell carcinoma and 1,852 adenosquamous patients matched by the same covariates demonstrated that adenosquamous carcinoma (57.1% [95%CI:54.6%-59.6%]) was associated with worse survival when compared with squamous cell carcinoma (64.0% [95% CI:61.5%-66.4%]). Conclusions: Early stage adenosquamous carcinoma of the lung is associated with worse overall survival compared to its individual histologic components of adenocarcinoma or squamous cell carcinoma. These observations in both the unmatched and propensity matched patient cohorts in- voke consideration of multimodality therapy for these early tumors. Research Sponsor: Departmental Funding. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8551 Poster Session

Early candidate nasal swab classifiers developed using machine learning and whole transcriptome sequencing may improve early lung cancer detection.

Peter J. Mazzone, Carla Lamb, Kimberly M. Rieger-Christ, Chakravarthy B. Reddy, Jianghan Qu, Shuyang Wu, Jie Ding, Duncan Whitney, Daniel G. Pankratz, Joshua Babiarz, Lori Lofaro, P. Sean Walsh, Jonathon Wilde, Sangeeta Maruti Bhorade, Jing Huang, Giulia Kennedy, Avrum Spira; Cleveland Clinic, Cleveland, OH; Lahey Hospital and Medical Center, Burlington, MA; University of Utah, Salt Lake City, UT; Veracyte, Inc., San Francisco, CA; Johnson & Johnson, Boston, MA; Veracyte, South San Francisco, CA; Veracyte, Inc., South San Francisco, CA

Background: The goal of lung nodule management is to make an early diagnosis in patients with lung cancer while avoiding unnecessary, costly and potentially harmful procedures in patients with benign lesions. Increased implementation of low dose CT screening will lead to increased numbers of both benign and malignant nodules that will require effective management. We have previously described the feasibility of detecting gene expression changes associated with lung cancer (“field of injury”) in nasal epithelium utilizing whole transcriptome RNA sequencing from non-invasive nasal brush samples. Us- ing this approach, we now report the performance of candidate nasal classifiers that combine both genomic and clinical features to risk stratify lung nodules from ever-smokers to aid in the diagnosis of lung cancer. Methods: Patients from several clinical cohorts who were ever-smokers with a lung nodule < 30 mm and without a history of prior cancer underwent nasal epithelium sampling. All patients had at least one year of follow up or until a final diagnosis of benign or malignant nodule was made. Candidate classifiers were developed using whole-transcriptome RNA sequencing and machine learning. Training of these classifiers included genomic and clinical information (age, sex, pack-years, years-since-quit, nodule size and nodule spiculation). Two decision boundaries were chosen to maximize sensitivity and specificity for low and high-risk nodules, respectively. The performance of these classifiers was evaluated using cross-validation (CV). Results: All candidate nasal classifiers underwent CV assessment on over 700 patients with lung nodules. All candidate classifiers achieved CV performance of > 40% specificity at 95% sensitivity in low- risk nodules and all candidate classifiers achieved CV performance of > 60% sensitivity at 90% specificity in high-risk nodules. The classifiers stratified benign nodules as low- risk with > 95% negative predictive value (NPV), intermediate risk nodules were stratified as 5-65% risk and malignant nodules were stratified as high- risk with > 65% positive predictive value (PPV) in a population with estimated 25% prevalence. This performance was robust across subgroups of age ( < 65 year vs. >65 year), sex, and current versus former smokers. Conclusions: The nasal genomic-clinical candidate classifiers have a high NPV effectively identifying benign nodules when calling them low- risk, thereby, informing decisions to more safely avoid a diagnostic workup. Additionally, the high PPV of these classifiers identifies malignant nodules when calling them high- risk and informs decisions regarding the urgency of a further diagnostic work-up. A nasal genomic-clinical classifier has the potential to serve as a non-invasive tool for lung cancer risk-stratification to help inform decision making in patients with lung nodules. Research Sponsor: Veracyte, Inc. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8552 Poster Session

A comparative analysis of mortality between black and white stage III non–small cell lung cancer patients in the United States.

Elizabeth Blessing Elimimian, Rafael Arteta-Bulos, Hong Liang, Nadeem Bilani, Leah Elson, Diana Saravia, Evan W. Alley; Cleveland Clinic Fl, Weston, FL; St Lukes Mntn States Tumor Inst, Boise, ID; Cleveland Clinic Florida, Weston, FL; University of Pennsylvania, Philadelphia, PA

Background: Lung cancer remains the leading cause of cancer death in the United States (U.S.). For stage III non-small cell lung cancer (NSCLC), concurrent chemotherapy (CT) plus radiotherapy (RT) within 30 days (CCRT) confers a survival benefit. The proportion of Black and White NSCLC patients not receiving CCRT and their outcomes have not been explored. Methods: Stage III NSCLC in Black and White patients diagnosed between 2004 and 2015 from the U.S. NCDB were included. Those with multiple tumors and who received surgery were excluded. Six groups were analyzed: CCRT (0-30 days between CT and RT), SCRT (31-120 days between CT and RT), RT (only RT), CT (only CT), No-RT-nor- CT (didn’t receive RT nor CT), and other (uncategorized). Univariate, multivariate, and Kaplan-Meier analyses were utilized (p<0.05). Results: A total of 22,459 Black (CCRT 42.3%, SCRT 7.6%, RT 13.8%, CT 15.1%, and No-RT-nor-CT 21.2%) and 138,477 White (CCRT 43.9%, SCRT 7.0%, RT 12.7%, CT 14.9%, and No-RT-nor-CT 21.5%) stage III NSCLCs were analyzed. Male gender and White race were positive predictive factors for receiving CCRT (Table). In Black patients SCRT (HR 1.1; 95% CI 1.04-1.17), RT only (HR 1.2; 95% CI 1.81-1.99), CT only (HR 1.4; 95% CI 1.36-1.49), and No RT or CT (HR 2.6; 95% CI 2.49-2.69) was associated with decreased overall survival (OS) compared to CCRT. In White patients, SCRT (HR, 1.0; 95% CI, 0.99-1.03) did not decrease OS compared to CCRT, whereas RT only (HR 1.8; 95% CI, 1.74-1.80), CT only (HR 1.3; 95% CI, 1.29-1.34), and No RT or CT (HR 2.6; 95% CI, 2.59-2.67) were associated with decreased OS. Median OS with CCRT was 18 months for Black patients, versus 16 months for White patients (p<0.0001). Conclusions: OS was highest when CCRT was given. A lower proportion of Black cases were managed with CCRT, but Black patients benefit more from CCRT and had improved OS than White patients. Despite the known benefits of CT and RT in stage III NSCLC, the second largest management cohort received neither RT nor CT. Re- search Sponsor: None.

Factors associated with receiving CCRT versus other treatments a in NSCLC. Gender Race Age Comorbidity Variable Male Female White Black < 65 > 65 0 1 2 3

CCRT N (%) 40753 29591 60841 9503 32493 37851 43470 18703 6103 2068 (56.9) (54.0) (56.0) (53.7) (63.2) (50.5) (57.1) (55.0) (51.5) (46.8) Other 30863 251999 47858 8204 18945 37117 32649 15306 5753 2354 Treatmentsa (43.1) (46.0) (44.0) (46.3) (36.8) (49.5) (42.9) (45.0) (48.5) (53.2) N (%) Odds Ratio 1.121 1 1.158 1 1 0.637 1 0.921 0.809 0.661 (95%CI) (1.095- (1.119- (0.617- (0.897- (0.777- (0.620- 1.148) 1.199) 0.658) 0.946) 0.842) 0.704) Multivariate <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 p-value

aAll other treatments = SCRT + RT Only + CT Only (No-RT-nor-CT excluded). LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8553 Poster Session

Early detection of lung cancer with an incidental lung nodule program (ILNP).

Matthew Smeltzer, Wei Liao, Meghan Meadows-Taylor, Nicholas Faris, Carrie Fehnel, Jordan Goss, Sara C. Williams, Olawale Akinbobola, Alicia Pacheco, Amanda Epperson, Joy Luttrell, Denise McCoy, Keith Tokin, Rob Optican, Jeffrey Wright, Edward Todd Robbins, Shailesh R. Satpute, Parker Harris, Meredith Ray, Raymond U. Osarogiagbon; University of Memphis, School of Public Health, Memphis, TN; Baptist Cancer Center, Multidisciplinary Thoracic Oncology Department, Memphis, TN; Midsouth Imaging and Therapeutics, Memphis, TN; Memphis Lung Physician Foundation, Memphis, TN; Baptist Memorial Hospital, Multidisciplinary Thoracic Oncology Department, Memphis, TN

Background: Lung cancer early detection improves survival, but risk-based low-dose CT screening (LDCT) only identifies a minority of patients. We implemented an ILNP in a community healthcare system, and evaluated its risks and benefits. Methods: Patients with lung lesions on routinely-performed ra- diologic studies were flagged by radiologists and triaged using evidence-based guidelines. We tracked demographics, clinical characteristics, procedures, complications, and health outcomes. We analyzed ILNP subjects’ eligibility for LDCT by National Lung Screening Trial (NLST), Center for Medicaid Serv- ices (CMS), NEderlands Leuvens Screening ONderzoek (NELSON), National Comprehensive Cancer Network (NCCN) Risk Groups 1 and 2 (screening recommended), NCCN Risk Group 3 (screening not currently recommended), and US Preventive Services Task Force (USPSTF) criteria from 2013 and 2020. Statistical analysis used the chi-square test and Kaplan Meier method. Results: From 2015- 2020, 13,710 patients were evaluated in the ILNP program: median age, 64 years; 42% male; 65% White, 29% Black; 667 (4.9%) were diagnosed with lung cancer. Lung cancers diagnosed from ILNP were 39% adenocarcinoma / 20% Squamous Cell with clinical stage distribution 49% I, 8% II, 17% III, and 16% IV. 832 (6.1%) had invasive diagnostic testing- CT-guided biopsy (50%), bronchoscopy (30%), and/or EBUS (26%); 11% of the 832 had >1 invasive diagnostic test. The most common complications from invasive testing were pneumothorax and chest tube placement. Only 11%-20% of all ILNP patients would have been eligible for LDCT. In ILNP patients diagnosed with lung cancer, only 33% were eligible for screening by NLST criteria; the proportion increased substantially when USPSTF 2020 or NCCN Group 2 criteria were applied (Table). Compared to NLST, NCCN Group 2 criteria increased screening eligibility among cancer patients by 22% (from 33% to 55%), while only increasing screening eligibility by 6% (from 8% to 14%) in non-cancer patients. Aggregate 1-year and 3-year survival rates for lung cancer patient diagnosed through ILNP were 76% (95% CI: 73, 80) and 64% (95% CI: 59, 69). Conclusions: The ILNP identified early-stage lung cancer more frequently than most LDCT programs, with promising survival rates. The majority of subjects with lung cancer were not eligible for LDCT, we still need to optimize risk-based screening criteria. Even with new, expanded criteria for LDCT, structured ILNP is necessary to expand early detection of lung cancer. Research Sponsor: None.

Screening Criteria %ILNP Lung Cancer Patients Eligible for LDCT Screening

NLST Criteria 33% CMS Criteria 39% NELSON Criteria 41% USPSTF 2013 41% USPSTF 2020 47% NCCN Group 1 39% NCCN Group 2 55% NCCN Group 3 64% LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8554 Poster Session

Radical surgery in malignant pleural mesothelioma (MPM): An analysis of SEER database.

Qian Wang, Yaning Zhang, Meng Ru, Changchuan Jiang, Jessica Tran, Juan P. Wisnivesky, Rajwanth Veluswamy; Department of Medicine, Icahn School of Medicine at Mount Sinai St Luke’s and West, New York, NY; Department of Surgery Cleveland Clinic, Cleveland, OH; Icahn School of Medicine at Mount Sinai, New York, NY; Yale University, New Haven, NY; Divisions of General Internal Medicine and Pulmonary and Critical Care Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Background: MPM is an aggressive malignancy with poor overall prognosis. A combined treatment approach involving radical surgery (RS), radiation (RT) and chemotherapy (CT) provide improved survival compared to systemic treatment alone. Selecting patients who may benefit from RS is challenging. The NCCN guidelines recommend that up to T3N1M0 (Stage IIIA) epithelioid or biphasic MPM should be considered for multimodality therapy incorporating RS. However, the impact of clinical and pathologic features within each histologic subtype of MPM on RS outcomes is unknown. Methods: MPM patients from the SEER 18 program from 2004-2015 were identified. Cox proportional hazard regression models were used to examine the independent contribution of several clinical and pathologic features on overall survival (OS) in patients who received RS vs those that did not. Results: A total of 5,498 MPM patients were identified, of which 531 underwent RS. Overall, RS was associated with improved OS in the multivariate model adjusting for important clinical and pathological characteristics (Table). When strat- ifying according to histology, epithelioid subtype was linked to improved OS with RS despite of the presence male gender, age > 60 years old, T3, T4 or N2 or above disease; and the OS improved among those who also underwent CT ± RT with RS. Patients with sarcomatoid histology also had OS benefit from RS (HR=0.59, 95%CI: 0.37-0.93), even those that were > 60 years old, but not among those with more advanced disease (T3/4, N2/3). Sarcomatoid patients who received CT ± RT (HR = 0.52, 95%CI: 0.30-0.90) also experienced OS benefit. Among biphasic histology, no OS benefit was found overall (P = 0.11) or within other high-risk clinical features except for those who were treated CT ± RT (HR = 0.64, 95%CI: 0.45-0.90). Conclusions: Our findings demonstrate that the presence of high-risk clinical and pathologic features does not impact OS benefit of RS in epithelioid MPM, however should be considered when deciding on RS in sarcomatoid and biphasic histologies. Poor prognostic histology especially sarcomatoid subtype may experience improved survival with RS if in conjunction with other treatment modalities. Research Sponsor: None.

OS associated with vs without RS by patho-clinical features. All participants Epithelioid Sarcomatoid Biphasic

Overall 0.71 (0.64-0.79) 0.70 (0.60-0.81) 0.59 (0.37-0.93) 0.78 (0.57-1.06) Male 0.73 (0.65-0.82) 0.75 (0.63-0.89) 0.65 (0.41-1.04) 0.77 (0.54-1.09) Age > 60 0.67 (0.60-0.76) 0.65 (0.55-0.76) 0.57 (0.34-0.98) 0.95 (0.68-1.33) T3 0.77 (0.62-0.94) 0.70 (0.52-0.94) 1.31 (0.28-6.09) 1.49 (0.67-3.31) T4 0.71 (0.57-0.88) 0.55 (0.41-0.74) 0.55 (0.25-1.20) 1.02 (0.52-1.99) N2 or N3 0.54 (0.41-0.71) 0.44 (0.30-0.66) 3.58 (0.07-173.5) 2.10 (0.001-NA) CT± RT 0.65 (0.58-0.74) 0.64 (0.54-0.76) 0.52 (0.30-0.90) 0.64 (0.45-0.90) LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8555 Poster Session

Comprehensive molecular profiling of pleural mesothelioma according to histologic subtype.

Ibiayi Dagogo-Jack, Russell Madison, Douglas A. Mata, Alexa Betzig Schrock, Tyler Janovitz, Brennan Decker, Richard S.P. Huang, Douglas I. Lin, Jonathan Keith Killian, Shakti H. Ramkissoon, Ole Gjoerup, Natalie Danziger, Jeffrey Michael Venstrom, Brian M. Alexander, Jeffrey S. Ross; Massachu- setts General Hospital, Boston, MA; Foundation Medicine, Inc., Cambridge, MA; Foundation Medicine, Inc, Cambridge, MA; Foundation Medicine, Boston, MA; Foundation Medicine, Cambridge, MA

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited therapeutic options. Immunotherapy has emerged as an effective therapeutic strategy, particularly in the non-epithelioid MPM subgroup. An improved understanding of the molecular profile of MPM may inform targeted therapeutic approaches and provide insights into factors underlying differential sensitivity to therapies. Methods: We performed comprehensive genomic profiling of MPMs from 980 patients, with histologic subtyping on a subset (n = 340; n = 235 epithelioid, n = 48 sarcomatoid, n = 57 biphasic). Analyses included quantifying tumor mutational burden (TMB), assessing microsatellite instability (MSI), and evaluating PD-L1 expression (Dako 22C3). Results: Median TMB of MPM was 1.74 (0.87- 2.61) mutations per megabase (mut/mb). Median TMB was comparable for non-epithelioid (biphasic, sarcomatoid) vs epithelioid MPM (1.25 mut/mb vs 1.25 mut/mb, p = 0.43). In the overall cohort, inac- tivating alterations in the following genes were most prevalent: CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (35%), and NF2 (33%). MTAP loss co-occurred with CDKN2A and CDKN2B loss in > 99% and 94% of cases, respectively. MTAP loss was observed in 28% of epithelioid vs 46% of non-epithelioid MPMs (p = 0.03). BAP1 alterations were detected in 51% of epithelioid vs 36% of non-epithelioid MPMs (p = 0.81). PD-L1 expression was assessed in 308 MPMs, among which 153 (49%) had PD-L1 $1%, including 35 (11%) with PD-L1 $50%. Among 164 specimens that underwent histologic subtyping and PD-L1 evaluation, PD-L1 was expressed in 46 (71%) non-epithelioid MPMs compared to 49 (51%) epithelioid MPMs (p = 0.03). Given the high prevalence of alterations involving the two genes, we evaluated impact of BAP1 and MTAP status on PD-L1 and TMB. TMB (1.74 mut/mb vs 1.74 mut/mb) and PD-L1 expression (50% vs 54%) were comparable in BAP1-altered vs wildtype specimens. Although TMB was comparable in MTAP-deficient and MTAP-intact tumors (1.25 mut/mb vs 1.74 mut/mb), more tumors with MTAP loss expressed PD-L1 (68% vs 44%, p = 0.0004). Conclusions: Compared to epithelioid MPM, non-epithelioid tumors demonstrate comparable TMB, higher PD-L1 expression, and enrichment for MTAP loss. As MTAP is frequently altered in MPM, further study is indicated to explore the relationship between MTAP status and MPM biology, including sensitivity to therapeutics such as immunotherapy and synthetic lethal approaches. Research Sponsor: Foundation Medicine. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8556 Poster Session

Improved survival among patients with malignant pleural mesotheliomas who develop immune-related adverse events on immunotherapy.

Michael Offin, Jacklynn V. Egger, Caroline G. McCarthy, Vasilisa Rudneva, Jason Beattie, Michelle S. Ginsberg, Jennifer L. Sauter, Andreas Rimner, Valerie W. Rusch, Prasad S. Adusumilli, Marjorie Glass Zauderer; Memorial Sloan Kettering Cancer Center, New York, NY

Background: While immune checkpoint inhibitors (ICI) are a standard option for patients with malignant pleural mesotheliomas (MPM), there is limited data on the rate of immune related adverse events (irAEs) and effects on clinical outcomes. Methods: 61 patients with MPM who received ICI between Jan- uary 2016 and October 2020 were assessed and followed through November 2020. irAEs (CTCAE v5.0) were noted along with the time from ICI start to irAE onset. Patients were grouped into irAE ever versus never. Clinicopathologic characteristics, prior treatments, and investigator assessed clinical benefit rate (CBR; partial response [PR] + stable disease [SD]) were compared by Fisher’s Exact and Mann- Whitney Tests. Overall survival (OS) and investigator assessed progression free survival (PFS) from ICI start were compared using Kaplan Meier. In consented patients (n = 56), next generation sequencing (MSK-IMPACT) was performed with HLA genotyping analysis by POLYSOLVER software and alleles for the three major MHC class I (HLA-A, -B, -C) genes were obtained from whole exome recapture. Results: Most patients were male (72%), smokers (55%), > 70 years old (median 72, range 34-90), and had epithelioid histology (67%). No patients had baseline autoimmune disease. The median line of prior systemic therapies to ICI start was 2 (range 1-5). 17 patients (28%) developed an irAE on therapy including 7 (11%) with grade 3 to 5 events (pneumonitis, myositis, pancreatitis, nephritis, encephalitis and adrenal insufficiency). The median time from ICI start to irAE was 2.5 months (range 2 days – 5.8 months). There was no association with dual ICI (n = 6) vs single agent (n = 11) and sooner onset (2.1 vs 4.0 months; p = 0.10) nor higher grade (median grade 2 vs 3; p = 0.31) of irAEs. 1 patient developed grade 5 pneumonitis with onset 2 days after initial dose of dual-ICI. Comparing patients with irAEs to those without, there was no difference in distribution of epithelioid histology (n = 10 vs 31; p = 0.54), median age (71 vs 72 years old; p = 0.43), nor prior thoracic radiation (n = 5 vs 11; p = 0.75).There was no difference in HLA type nor the fraction of HLA alleles of individual genes amongst the groups. Patients who had an irAE were on ICI longer than those that did not (median time on ICI 5.4 vs 0.9 months, respectively; p = 0.02). OS was higher in patients with irAEs compared to those without (21.1 vs 4.7 months; p = 0.003) as was PFS (6.8 vs 1.7 months; p = 0.01). There was a significant increase in the CBR between those that had an irAE (65%; 5 PR, 6 SD) and those that did not (27%; 2 PR, 10 SD; p = 0.006). Conclusions: 28% of patients with MPM who received ICIs developed an irAE and onset tended to be early in the course of treatment. There was no clear predictive clinicopathologic feature that correlated with the occurrence of irAE. There was a significant increase in OS, PFS, and CBR in patients that had an irAE compared to those that did not. Research Sponsor: National Cancer Institute Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748]. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8557 Poster Session

Comprehensive genomic profiling of malignant peritoneal mesothelioma (MPeM) reveals key genomic alterations (GAs) distinct from malignant pleural mesothelioma (MPM).

Lynne O. Chapman, Michael J. Overman, Anneleis Willett, Mark Knafl, Szu-Chin Fu, Anais Malpica, Christopher Scally, Paul F. Mansfield, Aurelio Aurelio Matamoros, Ajaykumar Morani, Scott Eric Woodman, Boris Sepesi, Reza J. Mehran, Cara L. Haymaker, Gauri Rajani Varadhachary, Anne S. Tsao, Keith Fournier, Kanwal Pratap Singh Raghav; Baylor College of Medicine, Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Cancer Center, Houston, TX; Univer- sity of Texas MD Anderson Cancer Center, Houston, TX; Thoracic and Cardiovascular Surgery, The Uni- versity of Texas MD Anderson Cancer Center, Houston, TX; Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: MPeM is a rare and aggressive cancer with very limited treatment options. Lack of dedicat- ed research has impeded improvements in outcomes. Defining prevalent GAs is a critical unmet need for use of targeted therapies in these patients. Although MPeM is notably distinct from MPM vis-a�-vis epidemiologic and clinical attributes, the genomic underpinings of these differences have yet to be established. We aimed at describing a comprehensive genomic profile (CGP) of MPeM in comparison to MPM. Methods: We performed a retrospective comparative analysis between 89 patients with MPeM and 241 patients with MPM (N = 330) who underwent CGP using CLIA certified next-generation sequencing assays. The cohort was generated using mesothelioma patients at MD Anderson Cancer Cen- ter (N = 223) and supplemented by additional mesothelioma patients (N = 107) from a publicly available database from Memorial Sloan Kettering Cancer Center, the MSK-IMPACT database. Essen- tial clinicopathological variables were collected. Descriptive statistics, Fisher’s exact and Mann-Whit- ney tests were used for comparison. Kaplan-meier method and log rank tests were used for overall survival (OS) estimates. Results: MPeM cohort (vs. MPM) had more women (54% vs. 31%, P < 0.001) and younger age at diagnosis (56 vs. 69 years, P < 0.001). Histology was epithelioid, biphasic and sarcomatoid in 86%, 7% and 7% cases, a distribution similar to MPM cohort. At least 1 GA was found in 64 (72% vs. 82% in MPM, P = 0.044) of MPeM patients with a median of 1 (range 1 – 12) (vs. a median of 2, range 1 – 24, P < 0.001) GA per patient. A significantly lower proportion of MPeM patients had $ 3 mutations (14% vs. 26%, OR 2.1, P = 0.028) per patient. The most frequent mutations were present in the following genes: TP53 (24%), BAP1 (16%), NF2 (15%), MET (9%) and TRAF7, KIT and PIK3CA (each 6%). MPeM patients harbored more mutations in MET (9% vs. < 1%, P < 0.001) and TRAF7 (6% vs. < 1%, P = 0.02) but fewer mutations in BAP1 (16% vs. 32%, P = 0.003) and CDKN2B (0% vs. 5%, P = 0.041). The most common copy number variations (CNVs: amplifications or deletions) were seen in BAP1, MCL1, SETD2, WT1 (each 2%) and AURKA (1%) genes. Among genes with CNVs, MPeM had a lower rate of deletions in CDKN2A (1% vs. 6%, P = 0.040). Among more common GAs, only BAP1 mutations appeared to be associated with poor OS (45.7 vs. 127.1 months, HR 2.5, 95%CI: 0.6 – 10.1, P = 0.050) in patients with MPeM. Conclusions: In this large cohort with CGP, we identified potential molecular drivers in MPeM and demonstrated key genomic differences between MPeM and MPM. MPeM is frequently driven by GAs involved in cell cycle control, a potentially targetable pathway. Despite this insight from CGP, a large subset of patients do not have actionable GAs and for these patients, further collaborative trans-“omic” research efforts are needed to advance potential therapeutic options. Research Sponsor: U.S. National Institutes of Health. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8558 Poster Session

A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.

Dean Anthony Fennell, Amy King, Seid Mohammed, Amy Branson, Alastair Greystoke, Sam Moody, Margaret Hutka, Alan G. Dawson, Liz Darlison, Molly Scotland, Vina Bhundia, Amrita Bajaj, Bruno Morgan, Adrian Nicholson, Cassandra Brookes, Aarti Gaba, Peter Wells-Jordan, Catherine Jane Richards, Anne Thomas; University of Leicester and University Hospitals of Leicester, Leicester, United Kingdom; University of Leicester, Leicester, United Kingdom; Leicester Clinical Trials Unit, University of Leicester, Leicester, United Kingdom; Freeman Hospital, Newcastle-upon-Tyne, United Kingdom; Freeman Hospital, Newcastle, United Kingdom; Leicester Royal Infirmary, Leicester, United Kingdom; University Hospitals of Leicester NHS Trust, Leicester, United Kingdom

Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A enco- des the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconsti- tution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirma- tion of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if $ 11 patients had disease control (A’Hern design). Sec- ondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between No- vember 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, > 1 prior systemic therapy 62%. All patients received at least one cycle with 27% complet- ing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): $ grade 3 toxicities affected 5.7% of pts. Conclu- sions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833. Research Sponsor: Mesothelioma Stratified Therapy 2. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8559 Poster Session

Genomic landscape of malignant mesothelioma by site and histology.

Elio Adib, Elie Akl, Amin Nassar, Talal El Zarif, Sarah Abou Alaiwi, David J. Kwiatkowski; The Lank Cen- ter for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Bos- ton, MA; Brigham and Women’s Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Dana-Farber Cancer In- stitute, Boston, MA

Background: Malignant mesothelioma (MM) is a highly lethal tumor that can develop in the pleura, the peritoneum, the pericardium or the testes. While the genomic features of pleural MM have been well- described overall, less is known about the distribution of genetic alterations (GAs) according to histology. In addition, few reports comparing genetic features according to disease site are available. Methods: We identified patients with pleural or peritoneal mesothelioma with mutational analysis through the GE- NIE registry. Patient tumor genetic data were provided by Memorial Sloan-Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Patients with more than one sequenced sample were excluded. We limited our analysis to genes common to all ver- sions of both panels and that were significantly mutated in the TCGA mesothelioma cohort. Mutation and copy number variant (CNV), collectively called GAs, were determined, and were compared using the Fisher’s Exact test and Kruskal-Wallis Test. Comparisons were made both by disease site (pleural vs. peritoneal) and histology for the pleural samples (epithelioid vs. biphasic vs. sarcomatoid). Nominal p-values were obtained, and FDR correction was employed (q<0.1). Results: We identified 439 patients with MM in the GENIE registry who fit the inclusion criteria. The median age was 70.5 years for pleural MM and 60 years for peritoneal MM (Wilcoxon-rank sum test p-value = 3e-9). 72% of patients were male. CDKN2A/CDKN2B GAs (97% and 100% being deletions in CDKN2A and CDKN2B respectively), a described prognostic marker in MM, were more common in pleural than in peritoneal MM. Among pleural MMs, tumors of epithelioid histology had less NF2 GAs than biphasic or sarcomatoid tumors, whereas sarcomatoid tumors had the lowest frequency of BAP1 GAs (Table). Conclusions: Malignant mesotheliomas of different disease sites and/or histologies display distinct patterns of GAs. These findings may contribute in part to differences in response to treatment and survival among these subsets of MM. Research Sponsor: None.

Pleural MM (all Epithelioid Biphasic Sarcomatoid histologies) Peritoneal q- Pleural MM Pleural MM Pleural MM Gene N=366 MM N=73 value N=266 N=76 N=24 q-value

BAP1 162 (44%) 25 (34%) 0.117 120 (45%) 39 (51%) 3 (13%) 0.072 CDKN2A 98 (27%) 7 (10%) 0.004 61 (23%) 25 (33%) 6 (25%) 0.276 CDKN2B 92 (25%) 6 (8%) 0.004 65 (24%) 26 (34%) 7 (29%) 0.276 NF2 96 (26%) 12 (16%) 0.15 54 (20%) 30 (40%) 12 (50%) 0.0005 SETD2 39 (11%) 9 (12%) 0.68 33 (12%) 5 (7%) 1 (4%) 0.276 TP53 30 (8%) 8 (11%) 0.588 22 (8%) 6 (8%) 2 (8%) 0.99 LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8560 Poster Session

Efficacy and safety analysis of anlotinib combined with etoposide plus cisplatin/ carboplatin as first-line therapy for extensive-stage small cell lung cancer (SCLC): The final results from a phase II single-arm trial.

Tiandong Kong, Lu Chen, Fangfang Duan, Xiaoxia Hou, Liuyan Wang, Hanli Zhou, Lanrong Wang, Shanshan Hu, Danna Liu; Cancer Hospital of Henan University/the Third People’s Hospital of Zheng- zhou City, Zhengzhou, China

Background: In recent years, the therapeutic regimens of extensive-stage small cell lung cancer (ES- SCLC) have progressed a lot. The most significant clinical studies include IMpower133 and CASPIAN. However, the relevant results showed that the combination of PD-L1 monoclonal antibody and EC regimen chemotherapy as first-line treatment of small cell lung cancer have a median PFS (progession-free survival) of about 5 months, which is comparable to that of simple chemotherapy. Therefore, the EP/EC is still the standard treatment for extensive-stage small cell lung cancer. Meanwhile, we noticed that anlotinib (multi-target small molecule oral VEGF inhibitor) has a curative effect on patients with extensive-stage SCLC as a third-line or above treatment in the ALTER 1202 study in China. Therefore, we tried to add anlotinib to the first-line treatment with EP/EC regimen in patients with ES-SCLC to observe the efficacy and safety. Methods: Eligible ES-SCLC pts (18~75 years old, initial treatment, no obvious heart, liver and kidney dysfunction) were received anlotinib (12mg QD from day 1 to 14 of a 21-day cycle) + etoposide(100mg/m2, d1~3 of a 21-day cycle)+CBP (AUC = 4~5,d1,Q3W) or DDP (70~75mg/ m2, d1,Q3W) for 4~6 cycles, then anlotinib maintenance (12mg QD from day 1 to 14 of a 21-day cycle) until the disease progresses or intolerable adverse reactions occur. During the treatment, dose reduction of anlotinib was permitted, which could be reduced to 10mg or 8mg if it was intolerable. The main observation endpoints were ORR, PFS and adverse events. Results: Between January 2019 and August 2020, a total of 20 patients with extensive-stage SCLC were enrolled in the study, with an average age of 66.2 ± 8.1(45-75) years old, 17 males (85%) and 3 females (15%). The median PFS was 10 months (95% CI: 7.809-12.191), median OS was 15 months (95%CI:10.639-19.361), ORR (objective remission rate) was 90% and DCR (disease control rate) was 100%. The most common grade 3 or 4 adverse events related to the trial regimen included: neutropenia was 10/20 (50.0%), thrombocytopenia was 5/20 (25.0%), anemia, nausea and fatigue were all 2/20 (10%), hypertension, transaminase el- evation and hoarseness were all 1/20 (5%). Conclusions: Anlotinib combined with EP/EC regimen has better PFS, OS, ORR and DCR for the initial treatment of extensive-stage SCLC, and a manageable safety profile. A randomized, controlled phase III clinical study will be conducted to confirm this conclusion. Clinical trial information: ChiCTR2000035043. Research Sponsor: Tianqing Pharmaceutical Group Co. Ltd. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8561 Poster Session

Real-world evidence of cancer immunotherapy (CIT) combination treatment in first-line (1L) extensive-stage small cell lung cancer (ES-SCLC).

Eric S. Nadler, Anupama Vasudevan, Kalatu Davies, Yunfei Wang, Ann Johnson, Sarika Ogale; Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX; Ontada, The Woodlands, TX; Genen- tech, Inc., South San Francisco, CA

Background: Atezolizumab plus chemotherapy was the first CIT combination regimen approved for 1L treatment of ES-SCLC in 2019. This study investigated patient characteristics and treatment patterns for patients with ES-SCLC receiving this regimen in the real-world community oncology setting. Meth- ods: This was a retrospective study including adult patients diagnosed with ES-SCLC between 01-Oct- 2018 (after IMpower 133 publication in NEJM Sep-2018) and 31-Dec-2019, with follow-up through 31-March-2020 using The US Oncology Network electronic health records data. Descriptive analyses of patient characteristics and treatment patterns were conducted, with Kaplan-Meier (K-M) methods used to assess time to treatment discontinuation (TTD) and time to next treatment/death (TTNT). Re- sults: Of the 408 patients included in this study, 267 (71.4%) received atezo+carboplatin+etoposide (Atezo+Chemo), 80 (21.4%) received carboplatin+etoposide (Chemo only) and the rest received other regimens. The Atezo+Chemo patients in the real-world cohort compared with the IMpower 133 trial (n = 201) were older (median age 68 vs. 64 years) and included fewer males (45% vs. 64%), fewer white race (73% vs. 81%), more patients with brain metastases at baseline (23% vs. 9%), and more patients with worse ECOG (2/3) performance-status score (24% vs. 0%). The median follow-up, TTD, and TTNT in months (mo) for the real-world cohort are presented in the table alongside the best comparable measures reported for the trial. Conclusions: Most patients in this real-world ES-SCLC cohort received the Atezo+Chemo regimen in the 1L setting. While the follow-up was much shorter and patients had worse baseline characteristics (age, brain metastases, ECOG) in the real-world setting compared to the IM- power 133 trial, the real-world median TTD in this descriptive analysis was found to be in line with the median duration of treatment in the trial. Further research with longer follow-up comparing the real- world effectiveness of the CIT and chemo regimens is needed. Research Sponsor: Genentech.

Real-world Cohort: Atezo+Chemo (n = 267) IMpower 133: Atezo+Chemo (Reference) (n = 201)

Median follow-up (FU): 5.45mo (range 0.72, 14.36) Median FU 13.9mo (Data cut-off April 24, 2018) K-M median TTD*: 4.9mo (95% CI 4.2, 5.3) Median duration of treatment: 4.7mo (range:0, 21)† % still on treatment at 6mo (K-M): 35.1% (95% CI 28.4, 41.9) % still on treatment > 6mo: 31.3%† K-M median TTNT: 6.9m0 (95% CI 6.4, 8.2) K-M Median progression-free survival (PFS): 5.2mo (95%CI 4.4, 5.6) % not initiated on 2L at 6mo: 64.5% (95% CI 56.7, 71.3) PFS (RECIST criteria) at 6mo: 30.9% (95% CI 24.3, 37.5)

*From 1L treatment initiation to discontinuation for any cause (including death). Patients who did not discontinue treatment during the study period were censored on the study end date or the last visit date available in the dataset, whichever occurred first. †Not based on K-M. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8562 Poster Session

The clinical efficacy of olaparib monotherapy or combination with ceralasertib (AZD6738) in relapsed small cell lung cancer.

Sehhoon Park, Peter G. Mortimer, Simon Smith, Heejung (Rosa) Kim, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Woong-Yang Park, Se-Hoon Lee, Keunchil Park; Samsung Medical Cen- ter, Sungkyunkwan University School of Medicine, Seoul, South Korea; Early Oncology Clinical Science, R&D Oncology, AstraZeneca, Cambridge, United Kingdom; External R&D, R&D Oncology, AstraZeneca, Seoul, South Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Cen- ter, Sungkyunkwan University School of Medicine, Seoul, South Korea; Samsung Medical Center, Seoul, South Korea; Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea; Divi- sion of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Background: The molecular profiling of small cell lung cancer (SCLC) has demonstrated a high incidence of genomic alterations in cell cycle-related genes and DNA damage and response (DDR) pathways, which correlates with devastating clinical outcomes of SCLC. Using two small molecules targeting the DNA repair pathway, olaparib (PARP inhibitor) and ceralasertib (ATR inhibitor), we evaluated their clinical efficacy in monotherapy or in combination, in relapsed SCLC. Methods: As part of the phase II biomarker-driven umbrella study in SCLC (SUKSES), patients who failed prior platinum-based regimen were enrolled and allocated based on their genomic alterations. Patients with mutations harboring HR pathway gene mutation not limited to BRCA 1 or 2, ATM deficiency or MRE11A mutations were allocated to the olaparib monotherapy (SUKSES-B, NCT03009682). As an biomarker non- matched arm, biomarker unselected patients were also allowed to receive olaparib and ceralasertib arm (SUKSES-N2, NCT0328607). The primary endpoint was objective response rate (ORR), and two-stage Simon’s design was used. Results: Based on pre-defined protocol criteria, both arms terminated at stage 1. In the olaparib monotherapy arm (SUKSES-B, n = 15), ORR was 6.7%, and disease control rate (DCR) was 26.7%, 1 partial response (PR), and 3 stable diseases (SD). Median progression-free survival (PFS) was 1.25 months (95% confidential interval [CI] 1.18–NA), and median overall survival (OS) was 8.56 months (95% CI, 6.62–NA). Adverse events that led to treatment discontinuation (n = 2 total, 13.3%) were drug related grade 3 renal impairment, thrombocytopenia, and grade 2 anemia. A patient with confirmed PR showed a tumor volume decrease of 37% compared to the baseline, and a splicing site mutation in BRCA2 was identified from deep target sequencing. In the olaparib and ceralasertib treatment arm (SUKSES-N2, n = 26), ORR was 3.8% (n = 1) and DCR was 42.3% (n = 11). Median PFS was 2.75 months (95% CI 1.77–5.44), and OS was 7.18 months (95% CI 5.97-10.79). Three patients discontinued treatment due to drug related grade 5 pneumonia, grade 3 drug-induced pneumonitis and grade 2 anemia. The most common adverse events for the combination were anemia (n = 11, 42.3%), followed by thrombocytopenia (n = 6, 23.1%). A patient with confirmed PR with a 43% de- creases in tumor volume compared with baseline had a mutation in TP53. Conclusions: Targeting the DDR pathways with olaparib as single agent or in combination with ceralasertib demonstrated early signal of efficacy in relapsed SCLC patients with a tolerable safety profile. Clinical trial information: NCT03009682, NCT0328607. Research Sponsor: AstraZeneca. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8563 Poster Session

Analysis of homologous recombination DNA repair gene mutation status in patients with metastatic small cell lung cancer treated with cediranib and olaparib on NCI 9881 study.

Joseph W. Kim, Marc R. Radke, Navid Hafez, Hatem Hussein Soliman, Siqing Fu, Shumei Kato, Primo "Lucky" N. Lara, Ulka N. Vaishampayan, Albiruni Ryan Abdul Razak, Dana Backlund Cardin, Pamela N. Munster, Joseph Paul Eder, Yu Shyr, S. Percy Ivy, Patricia LoRusso, Elizabeth M. Swisher; Yale Cancer Center, Yale School of Medicine, New Haven, CT; University of Washington Medical Center, Seattle, WA; Yale University School of Medicine, New Haven, CT; H. Lee Moffitt Cancer Center and Re- search Institute, Tampa, FL; The University of Texas MD Anderson Cancer Center, Houston, TX; Univer- sity of California San Diego, Moores Cancer Center, La Jolla, CA; University of California, Sacramento, CA; University of Michigan Cancer Center, Detroit, MI; Princess Margaret Cancer Centre, Toronto, ON, Canada; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of California San Francisco, San Francisco, CA; Yale University, New Haven, CT; Vanderbilt University Medical Center, Nashville, TN; National Cancer Institute, Rockville, MD; University of Washington School of Medicine, Seattle, WA

Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of homologous recombination DNA repair (HRR) genes and increases sensitivity of tumors to a poly-(ADP-ribose) polymerase (PARP) inhibitor in vitro and in vivo models of breast and ovarian cancer. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumor with a deleterious mutation in HRR genes. We hypothesized that cediranib induces HRR deficient phenotype by suppressing expression of HRR genes and cediranib and olaparib combination (C+O) results in an objectives response in patients with HRR proficient (HRP) advanced solid tumors. Herein, we report the biomarker data from analyses of targeted sequencing of 84 DNA repair (DR) genes with BROCA-HR assay in patients with metastatic small cell lung cancer (mSCLC). Methods: This multi- institutional phase 2 trial enrolled patients with mSCLC previously treated with a platinum-based chemotherapy. Patients received cediranib 30mg orally (po) daily plus olaparib 200mg po twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. A tumor biopsy was obtained from the patients with safely accessible metastatic tumor. HRR deficiency (HRD) was defined as presence of a deleterious mutation in any of the 10 key HRR-related genes per BROCA-HR assay including: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, or RAD51D. Otherwise, the tumors were defined as HRR proficiency (HRP). Results: A total of 25 patients with SCLC received the study treatment. Four- teen patients had available tumor biopsy samples and/or germline available for BROCA-HR. One patient (7%) was determined to have a HRD tumor by a presence of PALB2 mutation. This patient had stable disease as a best overall response but came off study due to unequivocal clinical progression. Thirteen patients (93%) had a HRP tumor. Six of these (46%) patients had PR. Median PFS in patients with HPR tumors was 122 days. The most common gene alterations detected by BROCA-HR assay was TP53 (93%) and RB1 (79%). Other DR gene alterations noted from our study samples were MRE11, CKD12 PALB2, ERCC4, FANCB, and BAP1. Conclusions: HRD was infrequent in our mSCLC samples. C+O resulted in objective responses in 46% of mSCLC patients with HRP tumors. Mutations in TP53 and RB1 were the most common gene alterations. Further investigation in warranted to confirm this observation. Clinical trial information: NCT02498613. Research Sponsor: U.S. National Institutes of Health. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8564 Poster Session

Circulating tumor DNA (ctDNA) mutations may predict treatment response in extensive- stage small cell lung cancer (ES-SCLC) treated with talazoparib and temozolomide (TMZ).

Matthew C Mulroy, Amy Lauren Cummings, Melody A. Mendenhall, David E. Kanamori, Andrew V. Nguyen, David Dae-Young Kim, William E. Lawler, Tirrell T. Johnson, Jennifer Tseng, Sunil Babu, Andrew Bennett Brown, Shaker R. Dakhil, Sidharth Anand, Zev A. Wainberg, Dennis J. Slamon, Edward B. Garon, Jonathan Wade Goldman; UCLA Medical Center, Los Angeles, CA; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; UCLA Medical Center, Santa Monica, CA; Comprehensive Blood & Cancer Center, Bakersfield, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; West Valley Hem. Onc. Med. Grp., Northridge, CA; Virginia K Crosson Cancer Center, Fullerton, CA; MD Anderson Cancer Ctr, Orlando, FL; UF Health Cancer Center Orlando, Orlan- do, FL; Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN; St Barnabas Medcl Ctr, Living- ston, NJ; NSABP/NRG Oncology, and Wichita NCORP via Christi Reg. Med. Ctr, Wichita, KS; University of California, Los Angeles, CA; David Geffen School of Medicine, University of California Los Angeles, Santa Monica, CA; University of California, Los Angeles, Los Angeles, CA

Background: Poly (ADP-ribose) polymerase (PARP) inhibition in combination with TMZ is a promising treatment strategy for ES-SCLC. In SCLC models, talazoparib, a potent PARP inhibitor, exhibits cytotoxic effects by inhibiting PARP proteins 1/2 and trapping PARP on DNA while TMZ potentiates antitumor response by contributing to genomic instability (Wainberg 2016). Prior ctDNA studies in SCLC have suggested that treatment precipitates the appearance of DNA repair alterations (Nong 2018), but it is unknown whether homologous recombination deficiency (HRD) predicts for treatment response with this combination. Methods: Patients (pts) with relapsed or refractory ES-SCLC were treated with oral talazoparib 0.75 mg daily on 28-day cycles and oral TMZ 37.5 mg/m2 on days 1-5 in a phase 2 clinical trial (UCLA/TRIO-US L-07, NCT03672773). ctDNA was collected and assessed based on allele frequency and plasma copy number at baseline and every 8 weeks during treatment with the Guardant360 assay (Redwood City, CA). HRD was defined as a deletion or missense mutation known or likely to result in aberrant expression of ATM or BRCA1/2 (other HRD genes not detected by assay). Response to treatment was defined by RECIST 1.1 criteria. Fisher’s exact tests were used to compare proportions of patients with P-values < 0.05 considered statistically significant (www.r-project.org, Vienna, AU). Results: For 15 evaluable pts in the first Simon stage of this trial, 45 ctDNA samples were collected. The most common baseline genetic alterations were mutations in TP53 (14 pts), BRCA2 (5 pts), ATM (4 pts), and RB1 (3 pts). Of those with > 1 ctDNA timepoint collected, 10/11 (90.9%) pts had $1 new mutation (range 1-19) detected after receiving treatment (range 8-35 weeks), most commonly in ATM (5 pts). Overall, 5 pts had confirmed partial responses (PR), 7 had stable disease, and 3 had progressive disease. Disease control (DC) was associated with the presence of new mutations (P = 0.022) and was more common in those with HRD, with DC in 9/10 (90.0%) HRD pts vs 3/5 (60.0%) pts without HRD. All those with PRs experienced a ctDNA nadir at 8 weeks of treatment with nearly all (4/5, 80.0%) ex- hibiting HRD, 2 at baseline and 2 at 8 weeks of treatment. Conclusions: Mutations in DNA repair genes occur on treatment with talazoparib and TMZ and may associate with disease control. With a response rate of 33% in the first Simon stage of this trial, the TRIO-US L-07 trial exploring the combination of talazoparib and TMZ will be assessed in 13 additional patients, after which additional ctDNA analyses will be performed on the cohort as a whole. Clinical trial information: NCT03672773. Research Spon- sor: Pfizer, U.S. National Institutes of Health. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8565 Poster Session

Cisplatin versus carboplatin for the treatment of limited-stage small cell lung cancer (LS- SCLC).

Ibrahim Azar, Adam Austin, Seongho Kim, Hyejeong Jang, Malini Surapaneni, Daniel Kurtz, Omid Yazdanpanah, Amit Chopra, Syed Mehdi, Hirva Mamdani; Wayne State University & Karmanos Cancer institute, Detroit, MI; Albany Medical College, Albany, NY; Karmanos Cancer Institute/Wayne State Uni- versity, Detroit, MI; Karmanos Cancer Institute, Detroit, MI; Barbara Ann Karmanos Cancer Institute, Detroit, MI; Wayne State University, Detroit, MI; Stratton Veterans Affairs Medical Center, Albany, NY

Background: Standard of care therapy for LS- SCLC is concurrent chemo-radiation (CRT) with a platinum-etoposide backbone. Cisplatin is traditionally the preferred platinum agent in the curative intent setting. Data comparing the efficacy of the less toxic carboplatin to cisplatin in LS-SCLC are lacking. Methods: Data from the National VA Cancer Cube were collected. Pathologically confirmed cases of LS- SCLC that received concurrent CRT with platinum-based multiagent chemotherapy were included. In- terval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Survival curves were compared by a Wald test. Results: 801 LS-SCLC patients who received carboplatin-based therapy (Carbo-SCLC) and 1018 who cisplatin-based therapy (Cis-SCLC) were included in the analysis. Median OS with Carbo-SCLC and Cis- SCLC were 2.13 years (95% CI 1.97-2.31) and 2.24 years (95% CI 2.09-2.4), respectively (HR=1.04;95% CI, 0.94-1.16; p=0.46). Subset analysis showed similar median OS for Carbo-SCLC and Cis-SCLC in patients with ECOG-PS of 0, 1 and 2, as well as patients in their 50s, 60s and >70. Multivariable regression analysis accounting for age and ECOG-PS shows a HR of 0.99 (95% CI 0.86- 1.14; p=0.91). Conclusions: Concurrent CRT with carboplatin-etoposide was associated with similar OS compared to cisplatin-etoposide in LS-SCLC, irrespective of PS and age. Carboplatin’s advantageous toxicity profile and comparable OS indicate that it is an acceptable choice of platinum for LS- SCLC. Re- search Sponsor: None.

Median OS in years (95% CI). Carboplatin Cisplatin Total population 2.13 (1.97-2.31) 2.24 (2.09-2.40) ECOG-PS 0 2.60 (2.18-3.11) 2.74 (2.35-3.16) ECOG-PS 1 2.15 (1.86-2.48) 2.15 (1.88-2.43) ECOG-PS 2 1.62 (1.28-2.05) 1.95 (1.51-2.47) Age 50-59 2.75 (2.15-3.52) 2.89 (2.44-3.39) Age 60-69 2.32 (2.07-2.59) 2.22 (2.02-2.42) Age>70 1.78 (1.57-2.01) 1.82 (1.56-2.10) Stage I 2.35 (1.88-2.93) 2.85 (2.28-3.49) Stage II 2.48 (2.05-3.01) 2.70 (2.25-3.17) Stage III 2.04 (1.85-2.24) 2.09 (1.92-2.27) LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8566 Poster Session

Application value of plasma exosomal long RNA in SCLC diagnosis and prognosis.

Chang Liu, Jialei Wang, Shenglin Huang, Hui Yu, Zhengfei Zhu, Min Fan; Fudan University Shanghai Cancer Center, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

Background: Little research has focused on blood exosomal transcription profile in small cell lung cancer (SCLC). The aim of this study is to identify plasma exosomal specific transcriptional profile in SCLC and explore the application value of plasma exosomal long RNA (exLR) in SCLC diagnosis and prognosis. Methods: This study included 81 healthy people and 40 SCLC patients receiving standard first-line chemotherapy with etoposide and carboplatin/cisplatin. The efficacy was evaluated by progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). 19 Patients who achieved complete response (CR) or partial response (PR) as best response during the first-line therapy and had not progressed within the following 90 days after the end of first-line therapy were defined as chemosen- sitive. 21 Patients who achieved stable disease (SD) as best response or received progressive disease during the first-line therapy or within the following 90 days after the end of first-line therapy were defined as chemoresistant. Baseline plasma samples were collected from 40 SCLC patients (17 patients’ samples after 2 courses were collected) and 81 healthy people. Plasma exosomes were isolated and pu- rified; exosomal RNA were extracted for high-throughout sequencing analysis. Results: We obtained plasma exLRs profiles from 81 healthy control samples and 57 SCLC samples (baseline samples from 40 patients plus samples collected by 17 patients after 2 courses). Bioinformatics analysis found that exLRs were significantly different between the SCLC and the healthy control group; between the chemo- sensitive and the chemoresistant group; between the baseline samples and the paired samples after 2 courses. For 40 SCLC patients receiving first-line chemotherapy, ORR was 65.0%, DCR was 90.0% and mPFS was 6.0 months (95% CI, 4.3-7.7 months). Multivariate analysis showed that baseline brain metastases and baseline bone metastases were independent predictors of poor PFS; and 223 genes were independent predictors of PFS. There were 10 genes (AC107954.1, H2AFZP2, CALB2, IFITM9P, GFPT2, PLA1A, CHST10, AC021231.2, SETP20, HILPDA) intersected in differentially expressed genes between the SCLC and the healthy control group, differentially expressed genes between the che- mosensitive and the chemoresistant group and independent predictors of PFS. These 10 genes were highly expressed in both the SCLC group and the chemoresistant group, and their high expression was an independent risk factor for poor PFS. Conclusions: This study firstly identified the plasma exLRs profiles in SCLC patients, verified the feasibility and value of identifying biomarkers based on exLRs profiles in SCLC diagnosis and prognosis. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8567 Poster Session

Imfirst: A phase IIIb, safety, single arm study of carboplatin (CB) or cisplatin (CP) plus etoposide (ET) with atezolizumab (ATZ) in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) in Spain—Primary safety results of the induction phase.

Maria Rosario Garc�ıa Campelo, Manuel Domine, Javier De Castro, Alberto Moreno, Santiago Ponce Aix, Edurne Arriola, Enric Carcereny, Margarita Majem, Gerardo Huidobro Vence, Emilio Esteban, Jose Fuentes Pradera, Bartomeu Massuti, Ana Laura Ortega, Guillot Mo�nica, Juan Felipe Cordoba, Natalia Fernandez, Ruben Alonso, Leonardo Crama, Natalia Lerones, Manuel Cobo; Complejo Hospitalario Uni- versitario A Coruna Hospital Teresa Herrera-Materno Infantil, A Coruna, Spain; Instituto de Inves- tigacio�n Sanitaria, Hospital Fundacio�n Jime�nez D�ıaz, Madrid, Spain; Hospital Universitario La Paz, Madrid, Spain; Hospital Universitario Reina Sof�ıa, Co�rdoba, Spain; Hospital Universitario 12 de Octu- bre, Madrid, Spain; Hospital Del Mar, Barcelona, Spain; Medical Oncology Department, Catalan Insti- tute of Oncology, Hospital Germans Trias i Pujol, B, ARGO Group Badalona Applied Research Group in Oncology, Badalona, Spain; Hospital De Sant Pau, Barcelona, Spain; Complejo Hospitalario Universi- tario de Vigo, Vigo, Spain; Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain; Hospital Universitario Virgen de Valme, Sevilla, Spain; Alicante University Hospital Isa- bial, Alicante, Spain; Complejo Hospitalario de Jae�n, Jae�n, Spain; Hospital Son Espases, Palma De Ma- llorca, Spain; Hospital Universitario Arnau De Vilanova, Lleida, Spain; Hospital Universitario Lucus Augusti, Lugo, Spain; Hospital San Pedro de Alca�ntara, Caceres, Spain; Roche Farma SA, Madrid, Spain; Roche Far.a S.A:, Madrid, Spain; Hospital Regional Universitario de Malaga, Malaga, Spain

Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator�s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up. Research Sponsor: Roche Farma S.A.

Treatment related AEs Grade 1-2 Grade 3-4

Neutropenia 5 (4.3%) 6 (5.1%) Thrombocytopenia 3 (2.6%) 4 (3.4%) Platelet Count Decreased 3 (2.6%) 3 (2.6%) Anaemia 11 (9.4%) 2 (1.7%) Febrile Neutropenia 0 (0%) 2 (1.7%) Alanine Aminotransferase Increased 7 (6.0%) 2 (1.7%) Gamma-Glutamyltransferase Increased 4 (3.4%) 2 (1.7%)

Regarding the immune-mediated AEs (IMAEs), there were two pts (2.6%) with grade 1 and 2 hyperthyroid- ism. One patient had a grade 2 increase in Alanine Aminotransferase. One patient presented grade 4 hepato- toxicity and another one had grade 3 pneumonitis. All patients with IMAEs were treated accordingly. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8568 Poster Session

Penpulimab plus anlotinib as second-line treatment for the small cell lung cancer after failure of platinum-based systemic chemotherapy.

Changgong Zhang, Sheng Yang, Jianhua Chen, Huijuan Wu, Jun Wang, Yingping Li, Liying Gao, Zhongyao Jia, Yan Sun, Jun Zhao, Xin Lin Mu, Chunmei Bai, Rui Wang, Kailiang Wu, Qiang Liu, Xiaoping Jin, Xiaowen Tan, Yuankai Shi; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Bei- jing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China; Gansu Provincial Cancer Hospital, Lanzhou, China; Gansu Cancer Hospital, Lanzhou, China; Linyi People’s Hospital, Linyi, China; Beijing Cancer Hospital, Beijing, China; Peking University People’s Hospital, Beijing, China; Department of Oncology, Peking Union Medical College Hospital, Beijing, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medi- cal College, Fudan University, Shanghai, China; Shenyang Chest Hospital, Shenyang, China; Akeso Bio- pharma, Inc., Zhongshan, China; Department of Clinical Medicine, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, China

Background: Combined therapy of an immune checkpoint inhibitor with a targeted anti-angiogenic agent had been proved to be effective for lung cancer. Penpulimab (AK105) was engineered to eliminate FccR binding and antibody-dependent cell-mediated cytotoxicity (ADCC)/ antibody-dependent celluar phagocytosis (ADCP) completely, where ADCC/ADCP effects could induce T-cell apoptosis and clear- ance and therefore compromise anti-tumor activity. Penpulimab demonstrated a slower programmed death-1(PD-1) antigen binding off-rate, which resulted in better cellular activity and higher receptor oc- cupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1. These structural differentiations enhance the anti-tumor activity of penpulimab and improve its safety. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors a and b, and c-kit. Anlotinib has been approved by National Medical Products Ad- ministration as the treatment for small cell lung cancer (SCLC) patients, who had progressed/relapsed on or after at least two regimens of chemotherapy. Here we report the results of one cohort which received penpulimab plus anlotinib in a Phase II study. Methods: In Cohort 4 of an open-label, multi-center, multi-cohort Phase II study evaluating the efficacy and safety of penpulimab plus anlotinib in pts with advanced head, neck or chest tumors(NCT04203719), the SCLC patients, who failed to platinum- based systemic chemotherapy treatment, received penpulimab (200 mg IV Q3W) and anlotinib (12/10 mg PO 2 weeks on/1 week off). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints were disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival. Results: 20 patients (median age was 61 [range:37–75] years old, Eastern Cooperative Oncology Group performance status 0/1 [5%/95%], male/female [65%/35%]) were enrolled and received combination therapy (17 received 12 mg anlotinib, 3 received 10 mg anlotinib; and all received 200 mg penpulimab). At data cut-off (Jan 25, 2021), the confirmed ORR was 50.0% (10/ 20, 1 complete response and 9 partial response) and DCR was 75.0% (15/20). 9 PFS events (45%) had occurred, and the median PFS was 4.7 months (95% CI: 3.6-not reached). Grade 3 treatment-related adverse events (TRAEs) occurred in 30% (6/20, 2 hypertension, 1 hypertriglyceridaemia, 1 gamma-glutamyltransferase increased, 1 palmar-plantar erythrodysaesthesia syndrome and 1 hyponatraemia) of patients, No Grade 4 or 5 TRAEs had occurred. Conclusions: Penpulimab plus anlotinib showed favorable antitumor activity and an acceptable safety profile in SCLC patients who failed to platinum-based systemic chemotherapy. This new combination therapy warrants further evaluation for the treatment of SCLC. Clinical trial information: NCT04203719. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8569 Poster Session

Chemoimmunotherapy for the treatment of extensive-stage small cell lung cancer (ES- SCLC) in patients with an Eastern Cooperative Group (ECOG) performance status (PS) of two or greater.

Daniel Almquist, Blake Langlais, Nathan Y Yu, Terence Tai Weng Sio, Panos Savvides, Ping Yang, Steven E. Schild, Aaron Scott Mansfield, Vinicius Ernani; Mayo Clinic, Phoenix, AZ; The James Ohio State University Comprehensive Cancer Center, Columbus, OH; Mayo Clinic, Rochester, MN; Mayo Clin- ic Arizona, Phoenix, AZ; Emory Univ, Atlanta, GA

Background: Immune checkpoint inhibitor (atezolizumab or durvalumab) combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES- SCLC). The phase III clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC, excluded patients with an Eastern Cooperative Group (ECOG) Performance Status (PS) of Two or Greater. Therefore, data on efficacy of this combination in this subgroup of ES-SCLC patients whose performance status two or greater is limited. Methods: A retrospective analysis was performed of patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, ECOG-PS, date of diagnosis, date of progression, whole brain radiation, CNS involvement, liver involvement, stereotactic body radiation, chest consolidation, platinum sensitivity, lines of therapy and last follow up date were extracted. Overall Survival (OS) and progression free survival (PFS) for ECOG-PS 2-3 were compared to patients with an ECOG-PS 0-1. Results: A total of 84 patients were identified with a median age of 68.2 (48-88) years old. Of these, 54 patients were identified with an ECOG-PS 0-1 and 30 patients with an ECOG-PS 2-3. The median PFS for the ECOG PS 0-1 cohort was 5.2 months (95% CI 4.6-6.1) while the median PFS for the ECOG-PS 2-3 cohort was 6.0 months (95% CI 4.2-7.7; logrank p = 0.93). The median OS for the ECOG-PS 0-1 cohort was 10.8 months (95% CI 8.5-12.9) while the median OS for the ECOG-PS 2-3 cohort was 10.3 months (95% CI 6.0-14.1; logrank p = 0.39). Hazard ratios of ECOG-PS 0-1 versus 2-3 showed no ten- dency of increased PFS or OS for either group within cox proportional hazards models. Forty-three percent of ECOG-PS 0-1 achieved a partial response (PR) and 57% of patients who had ECOG-PS 2-3 also achieved a PR (Fisher’s exact p = 0.23). A complete response was found in 4% of ECOG-PS 0-1 compared to 3% in the ECOG-PS 2-3 cohort. For patients who responded to initial therapy, 46% of ECOG- PS 2-3 patients had a platinum sensitive relapse while only 33% of ECOG-PS 0-1 were still platinum sensitive at the time of relapse. Five ECOG-PS 2-3 patients were able to receive a second-line therapy. Conclusions: To our knowledge, this is the first study to evaluate chemoimmunotherapy in the subgroup of ES-SCLC patients with an ECOG-PS 2 or greater. This retrospective study demonstrated no significant difference in PFS, OS, and ability to achieve a least a PR in ECOG-PS 2-3 cohort when compared to ECOG-PS 0-1. Therefore, chemoimmunotherapy should not be reserved for only an ECOG-PS of 0-1 but should be considered for all treatment eligible patients. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8570 Poster Session

A phase I trial of plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer (SCLC): Big Ten Cancer Research Consortium (BTCRC- LUN17-127) study.

Jyoti Malhotra, Nasser H. Hanna, Alberto Chiappori, Lawrence Eric Feldman, Naomi Fujioka, Igor I. Rybkin, Shadia Ibrahim Jalal, Malini Patel, Dirk Moore, Chunxia Chen, Salma K. Jabbour; Rutgers Can- cer Institute of New Jersey, New Brunswick, NJ; Indiana University Melvin and Bren Simon Cancer Cen- ter, Indianapolis, IN; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; University of Illinois Hospital & Health Sciences System, Chicago, IL; Univ of Minnesota, Minneapolis, MN; Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI; Indiana University Simon Cancer Center, Indianapolis, IN; Rutgers Cancer Institute of New Jersey, New Bruswick, NJ; Biometrics, Rutgers Can- cer Institute of New Jersey, New Brunswick, NJ; Department of Radiation Oncology, Rutgers Cancer In- stitute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ

Background: Plinabulin (BPI-2358) is a vascular disrupting agent with immune-enhancing function by inducing dendritic cell maturation and decreasing regulatory T cells. Preclinical studies report that plinabulin potentiates the cytotoxicity of dual checkpoint inhibition (CPI) with nivolumab and ipilimumab. Plinabulin may also reduce immune-related AEs from CPI through its phosphodiesterase-4 (PDE4) inhibitory activity which is associated with anti-inflammatory effects. We report initial results from a Phase I study assessing plinabulin in combination with nivolumab and ipilimumab. Methods: In this dose-escalation phase I study, patients with extensive-stage SCLC who had progressed on or after prior platinum-based chemotherapy (±CPI) were enrolled using a 3+3 design. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg) and plinabulin (as per dose escalation schema) IV on day 1 of each 21 day cycles. After completion of 4 cycles, patients continued therapy with nivolumab (240 mg) and plinabulin every 2 weeks till progression or intolerable toxicity. Patients were evaluable for DLT if they received at least 2 cycles of therapy; DLT period was defined as the first 6 weeks from C1D1. Sec- ondary endpoints were ORR, PFS and frequency of irAEs. Correlative analysis included inflammatory biomarkers: hsCRP, ESR, SAA and haptoglobin. Results: Between 9/2018 and 11/2020, 17 patients were enrolled (1 patient withdrew consent before treatment, 16 were evaluable for safety). Median age was 59 years (range 43 to 78); 9 patients were male and 10 had received prior CPI. Eight patients were treated at dose-level 1 of plinabulin (20 mg/m2) and 8 patients at 30 mg/m2 of plinabulin (level 2); dose-level 2 was determined to be RP2D. There were 2 DLTs; 1 at dose-level 1 (grade 3 altered mental status lasting < 24 hours) and 1 at dose-level 2 (grade 3 infusion reaction). The most common treatment-related AEs (all grades) were nausea (10; 63%), infusion reaction (8; 50%), vomiting (7; 44%), diarrhea (7; 44%) and fatigue (6, 32%). Seven patients (44%) had at least one grade 3 or higher treatment-related AE; there were no treatment-related deaths. Two patients (13%) had grade 3 or higher irAE requiring steroids (1 colitis, 1 transaminitis); both at dose-level 1. At data cutoff (12/30/20), there were 3 PRs in CPI naïve patients (3/6; 50%) and 2 PRs in evaluable CPI-resistant patients (2/7; 29%). In the two CPI-resistant patients with confirmed response, the tumor reduction was 68% and 52%. Con- clusions: Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated. A phase 2 study in CPI-experienced patients with relapsed SCLC is planned to confirm the preliminary signals of clinical activity and reduced immune toxicity. Clinical trial information: NCT03575793. Re- search Sponsor: BeyondSpring Pharmaceuticals, Bristol Myers Squibb. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8571 Poster Session

A randomized phase II/III study comparing carboplatin and irinotecan with carboplatin and etoposide for the treatment of elderly patients with extensive-disease small cell lung cancer (JCOG1201/TORG1528).

Tsuneo Shimokawa, Yuki Misumi, Hiroaki Okamoto, Yukio Hosomi, Isamu Okamoto, Hiroshi Tanaka, Shinji Atagi, Toyoaki Hida, Koichi Goto, Hiroaki Akamatsu, Kaoru Kubota, Kazuhiko Nakagawa, Hidehito Horinouchi, Masahiko Ando, Ryunosuke Machida, Junko Eba, Tomoko Kataoka, Yuichiro Ohe; Department of Respiratory Medicine, Yokohama Municipal Citizen’s Hospital, Yokohama-Shi, Japan; Yokohama Municipal Citizens Hospital, Yokohama, Japan; Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Koma- gome Hospital, Tokyo, Japan; Kyushu University Hospital, Fukuoka, Japan; Department of Respiratory Medicine, Niigata Cancer Center Hospital, Niigata, Japan; Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan; Department of Thoracic Oncolo- gy, Aichi Cancer Center Hospital, Nagoya, Japan; National Cancer Center Hospital East, Kashiwa, Ja- pan; Osaka Police Hospital, Osaka, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Kindai University Hospital, Osaka, Japan; National Cancer Center Hospital, Tokyo, Japan; Nagoya University Hospital, Nagoya, Japan; Japan Clin- ical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan; Na- tional Cancer Center Japan, Tokyo, Japan; Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

Background: Carboplatin and etoposide is the current standard treatment for elderly extensive-disease small-cell lung cancer (ED-SCLC). The purpose of this study is to evaluate the efficacy and safety of carboplatin and irinotecan compared with carboplatin and etoposide in elderly Japanese patients with ED- SCLC in a randomized phase II/III design. Methods: Eligibility included histologically or cytologically proven SCLC, no previous systemic chemotherapy, performance status of 0 to 2, and aged 71 years or older. Patients received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on day 1 to 3) (CE) every 3 weeks for 4 cycles or carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on day 1 and 8) (CI) every 3 weeks for 4 cycles. In the phase II part, the primary endpoint was the objective response rate of the CI arm and the secondary endpoint was adverse events. In the phase III part, the primary endpoint was overall survival, and the secondary endpoints were progression-free survival, objective response rate, adverse events, and symptom score. This study was designed to confirm the su- periority of CI arm in terms of overall survival over CE arm. The median survival time with CI arm was ex- pected to be increased by 3.5 months with hazard ratio (HR) of 0.750 (10.5 vs. 14.0 months). The sample size was set at 250 to observe the required number of events of 227 with one-sided alpha level of 0.05, a power of 70%, an accrual period of 6.5 years, and a follow-up period of 1.5 years. Results: Be- tween December 2013 and June 2019, 258 patients were randomized (CE arm, 129 patients; CI arm, 129 patients). The median age was 75 (range, 71-90). The characteristics of the patients were well balanced between CE arm and CI arm. Overall survival, progression-free survival, and objective response rate of CE arm vs. CI arm were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.848 (95% CI, 0.650-1.105)) (one-sided P=0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 months (95% CI, 4.5-5.2) (HR, 0.851 (95% CI, 0.664-1.090)) (two-sided P=0.21), and 59.7% (77 of 129) vs. 64.3% (83 of 129), respectively. Symptom score showed no significant difference between the arms. Higher incidences of myelosuppression of grade 3 or worse occurred with CE arm, whereas higher incidences of gastrointestinal toxicity of grade 3 or worse occurred with CI arm. Three treatment-related deaths including lung infection in CE arm and lung infection and sepsis in CI arm were observed. Conclusions: Ef- ficacy tended to be favorable in carboplatin and irinotecan arm, but there was no statistically significant difference. These results indicate that carboplatin and etoposide is a still standard treatment in elderly Japanese patients with ED-SCLC. Clinical trial information: 000012605. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8572 Poster Session

Combination of quantitative features from H&E biopsies and CT scans predicts response to chemotherapy and overall survival in small cell lung cancer (SCLC).

Cristian Barrera, Mohammadhadi Khorrami, Prantesh Jain, Pingfu Fu, Kate Butler, Abdullah Osme, Paula Toro, Vidya Sankar Viswanathan, Satyapal Chahar, Afshin Dowlati, Anant Madabhushi; Case Western Reserve University, Cleveland, OH; University Hospitals-Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH; University Hospitals, Cleveland, OH; Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH; Case Western Reserve Univer- sity, Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH

Background: Small Cell Lung Cancer (SCLC) is an aggressive malignancy with a rapid growth, and Che- motherapy remains mainstay of treatment. Identifying therapeutic targets in SCLC presents a chal- lenge, partially due to a lack of accurate and consistently predictive biomarkers. In this study we sought to evaluate the utility of a combination of computer-extracted radiographic and pathology features from pretreatment baseline CT and H&E biopsy images to predict sensitivity to platinum-based chemotherapy and overall survival (OS) in SCLC. Methods: Seventy-eight patients with extensive and limited-stage SCLC who received platinum-doublet chemotherapy were selected. Objective response to chemotherapy (RECIST criteria) and overall survival (OS) as clinical endpoints were available for 51 and 78 patients respectively. The patients were divided randomly into two sets (Training (Sd), Validation (Sv)) with a constraint (equal number of responders and nonresponders in Sd)—Sd comprised twenty-one patients with SCLC. Sv included thirty patients. CT scans and digitized Hematoxylin Eosin-stained (H&E) biopsy images were acquired for each patient. A set of CT derived (46%) and tissue derived (53%) image features were captured. These included shape and textural patterns of the tumoral and peritumoral regions from CT scans and of tumor regions on H&E images. A random forest feature selection and linear regression model were used to identify the most predictive CT and H&E derived image features associated with chemotherapy response from Sd. A Cox proportional hazard regression model was used with these features to compute a risk score for each patients in Sd. Patients in Sv were stratified into high and low- risk groups based on the median risk score. Kaplan-Meier survival analysis was used to assess the prognostic ability of the risk score on Sv. Results: The risk score comprised nine CT (intra and peri-tumoral texture) and six H&E derived (cancer cell texture and shape) features. A linear regression model in conjunction with these 15 features was significantly associated with chemo-sensitivity in Sv (AUC = 0.76, PRC = 0.81). A multivariable model with these 15 features was significantly associated with OS in Sv (HR = 2.5, 95% CI: 1.3-4.9, P = 0.0043). Kaplan-Meier survival analysis revealed a significantly reduced OS in the high-risk group compared to the low-risk group. Conclusions: A combined CT and H&E tissue derived image signature model predicted response to chemotherapy and improved OS in SCLC patients. Image features from baseline CT scans and H&E tissue slide images may help in better risk stratification of SCLC patients. Additional independent validation of these quantitative image-based biomarkers is warranted. Research Sponsor: U.S. National Institutes of Health. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8573 Poster Session

Myasthenia gravis-associated thymoma and myasthenia gravis-free thymoma have distinct somatic mutation and gene expression profiles.

Yi Zhang, Xiaomo Li, Gaojun Lu, Tonghui Ma, Kejian Shi; Thoracic Surgery Department, Xuanwu Hospi- tal, Capital Medical University, Beijing, China; Genetron Health (Beijing) Technology, Co. Ltd., Beijing, China

Background: A significant proportion of thymoma patients have concurring autoimmune diseases such as myasthenia gravis (MG). However, the molecular signature of myasthenia gravis-associated thymoma (MGT) is largely unknown. Genomic and transcriptomic profiling of MGT may provide valuable insight to the etiology of MGT and facilitate the development of effective therapeutic approaches. Methods: To study the molecular signature of MGT, 26 thymoma patients were divided into two subgroups according to their clinical presentations. One group included 16 thymoma patients associated with MG (MGT) and the other group had 10 patients without MG (MGF). We profiled the genomic and transcriptomic changes of tumor samples from both subgroups with whole exome sequencing (WES) and RNA sequencing (RNA-seq). Results: The WES results indicated that more genes were mutated in the MGF subgroup than the MGT group, although the difference between two subgroups was not statistically significant. There were only five mutated genes (NBPF1, HRAS, ATAD3B, IFITM3 and MUC4) appeared total mutation frequency exceeded 10%. NBPF1 is the most frequently mutated gene, seen in 25% of the MGTs (4/16) and 10% (1/10) of the MGFs. Neuroblastoma breakpoint family member 1 encoded by NBPF1 was involved in several cancer types including gastric cancer and neuroblastoma, but there is no report on the link of NBPF1 with thymoma or MG. Recent studies showed that NBPF1 is a negative regulator of Akt-p53-Cyclin D and PI3K/mTOR signal pathways. Recurrent mutations in HRAS was only observed in MGFs but not MGTs. Genes mutated in more than one patient were NBPF1, ATAD3B, RPDM9, LOC642131, ADAM21, CGNL1, MUC4 and MUC2 in the MGT subgroup, while only three genes HRAS, CSPG4 and IFITM3 were mutated in more than one patient in the MGF subgroup. More- over, RNA-seq data identified 106 significantly differentially expressed genes, including 54 upregu- lated and 52 downregulated genes in the MGT subgroup, further pathway enrichment analysis revealed that the Hippo, Wnt, TGF-b and focal adhesion signaling pathways were significantly downregulated in the MGT subgroup compared with the MGF subgroup. Conclusions: Our findings provide new insights for the etiology of thymoma with and without MG. mTOR signaling pathway is a key regulator of immune response. Importantly, the protein level of some components in the mTOR pathway was reduced in MG caused-atrophic muscle. Further investigation is warranted to examine the functional roles of NBPF1 in mTOR signaling regulation and the etiology of MG-associated thymoma. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8574 Poster Session

First long-term results on efficacy and safety of long-acting pasireotide in combination with everolimus in patients with advanced carcinoids (NET) of the lung/thymus: Phase II LUNA trial.

Eric Baudin, Alfredo Berruti, Mario Giuliano, Wasat Mansoor, Catalin Bobirca, Erik Houtsma, Niamh Fagan, Kjell E. Oberg, Piero Ferolla; Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Medical Oncology, University of Brescia, Spedali Civili Hospi- tal, Brescia, Italy; Department of Clinical Medicine and Surgery, University of Naples Federico II, Napo- li, Italy; The Christie NHS Foundation Trust, Manchester, United Kingdom; Novartis Pharma AG, Basel, Switzerland; Uppsala University Hospital, Uppsala, Sweden; Umbria Regional Cancer Network, Peru- gia, Italy

Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI <70%. PAS +EVE combination showed clinical benefit in terms of PFS and BPFS compared to PAS and EVE alone as shown in Table. At least one dose reduction of PAS or EVE was reported in >50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. Research Sponsor: None.

PAS EVE PAS + EVE N=41 N=42 N=41

Duration of exposure, weeks (range) 38.9 (4.0-295.6) 26.9 (1.0-224.1) 49.0 (4.0-307.9) Median PFS, mo, (95% CI) 8.51 (5.68-14.03) 12.48 (5.55-20.21) 16.53 (11.10-23.26) Median BPFS, mo, (95% CI) 2.89 (2.79-5.49) 2.86 (2.79-3.52) 5.62 (3.19-8.31) LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8575 Poster Session

Cancer activation pathways of thymic epithelial tumors (TETs) by targeted gene expression analysis.

Jose Carlos Benitez, Bastien Job, Vincent Thomas de Montpreville, Ludovic Lacroix, Patrick Saulnier, Riad Arana, Olivier Lambotte, Foundation Cancer and Autoimmune/inflammatory diseases Relationships, Sacha Mussot, Olaf Mercier, Elie Fadel, Jean-Yves Scoazec, Benjamin Besse; Gustave Roussy, Villejuif, Paris, YT, France; Department of Bioinformatics, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France; Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; Can- cer Genetics Laboratory, Departement of Pathology and Medical Biology, Gustave Roussy, Villejuif, France; Gustave Roussy Cancer Campus, Biopathology, Villejuif, Cedex, France; Department of Patholo- gy, Institut d’oncologie thoracique, Ho^pital Marie-Lannelongue, Plessis-Robinson, France; Internal Medicine Department, Ho^pital du Kremlin-Bice^tre, Assistance Publique-Ho^pitaux de Paris, Le Kremlin Bice^tre, France; Cancer and Autoimmune/Inflammatory Diseases Relationships Foundation, Paris, France; Department of Thoracic Surgery, Institut d’oncologie thoracique, Ho^pital Marie-Lannelongue, Le Plessis-Robinson, France; Marie Lannelongue, Le Plessis Robinson, France; Gustave Roussy, Ville- juif, France; Department of Medicine and Thoracic Pathology Committee, Gustave Roussy, Villejuif, France

Background: TETs are rare malignancies of the anterior mediastinum. Clinical behavior varies from mild thymoma (T) A to aggressive thymic carcinoma (TC). The biology of TETs is poorly understood and knowledge of the transcriptomic fingerprint of T and TC is limited. Additionally, up to 30% of patients (pts) will develop associated autoimmune disorders (AIDs). We aimed to characterize the main cancer activation pathways of the TET subgroups. Methods: We selected a representative balanced set of Ts and TCs to analyze 24 main cancer activation pathways using HTG Oncology biomarkers panel (2562 genes) by RNA sequencing. Tumor representative paraffin-embedded blocks were macrodissected for gene expression analysis. We analyzed epidemiologic, clinical and pathological characteristics of pts with TET’s and correlated with genes expression based on cancer Hallmarks. Results: From January 2010 to December 2019, 219 pts were included in the cohort. Molecular results of 194 pts were available. Median age at diagnosis was 56 (9-83) years. 54.1% were women. 65/194 (33.5%) reported AIDs. T B2 was the most frequent (n=41, 21.1%), followed by B1, AB, B3, TC and A. RNA expression analysis identified 2 main clusters, corresponding mainly to T (cluster 2) and TC (cluster 1) respectively (p<0.0001) (Table). Tumors of cluster 1 (TCs predominant) shown activated pathways (MYC [gene ratio= 0.5]; p<0.0001). In cluster 2 (T predominant), activated pathways differed among subgroups: B1 (E2F[0.5], G2M checkpoint [0.45]; p<0.001), B2 (E2F [>0.4]; p<0.0001). Routes were mostly suppressed: A (MYC [>0.5], E2F[>0.4], G2M checkpoint[>0.45], mitotic spindle[>0.35], MTOR [<0.35]; p<0.001), AB (INFa [>0.5], inflammatory response [>0.45], INTÇ [0.45], NFkb [>0.4], MTOR[>0.4]; p<0.001), B1 (EMT [0.6], angiogenesis [>0.5], INFa [0.5], homeostasis [0.5], NFkb [0.5], INTÇ [>0.45], myogenesis [<0.4]; p<0.0001), B2 (INFa [>0.65], INTÇ [>0.5], NFkb [0.5], EMT [0.45], inflammatory response [<0.4]; p< 0.0001), B3 (EMT [0.6], MYC [0.45]; p<0.001). Among pts reporting AIDs 61 and 4 were associated to cluster 2 and 1, respectively (p=0.017). Conclu- sions: We describe differential molecular characteristics among histological subgroups in 2 clusters. The analysis suggests new therapeutic venues. Additional analysis will be presented on outliers and response to treatment. Research Sponsor: None.

Correlation between histological subgroups and molecular clusters (K means used for all subgroups). Histological subtype Cluster (n) Thymoma A 1 2 Thymoma AB 1 16 Thymoma B1 1 34 Thymoma B2 2 34 Thymoma B3 1 40 Thymoma B1/B2 4 29 Thymoma B2/B3 2 6 Thymic Carcinoma 0 2 p-value < 0.01 16 4 LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8576 Poster Session

A phase II study of palbociclib for recurrent or refractory advanced thymic epithelial tumor (KCSG LU17-21).

Myung-Ju Ahn, Hyun Ae Jung, Miso Kim, Joo-Hang Kim, Yoon Hee Choi, Jinhyun Cho, Ji Hyun Park, Keon Uk Park, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park; Samsung Med- ical Center, Seoul, South Korea; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Seoul National Uni- versity Hospital, Seoul, South Korea; CHA Bundang Medical Center, CHA University, Seongnam, South Korea; Division of Hematology-Oncology, Department of Internal Medicine, Dongnam Institute of Ra- diological and Medical Sciences, Busan, South Korea; Inha University Hospital, Incheon, South Korea; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Department of Hemato-Oncology, Keimyung University Dongsan Medical Center, Daegu, South Korea; Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Background: Thymic epithelial tumors (TETs) are rare but the most common tumor of the anterior mediastinum. Platinum-based combination chemotherapy is standard of care which is associated with a 50%-90% overall response rate (ORR) in metastatic disease. However, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with cell cycle including pRB, p16INK4A, and cyclin D1 are commonly observed in TETs. Based on these results, we conducted a phase II trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. Methods: This is a phase II multicenter, open-label, single arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapy. Patients receive oral palbociclib 125mg daily for 21 days followed by a 7-day break. The primary endpoint was the progression-free survival (PFS) rate at 6 months (H0 = 30% vs H1 = 48%). Results: Between August 2017 and October 2019, 48 patients were enrolled. The median number of previous chemotherapy was 1 (range: 1-4) and 21 (43.7%) of 48 patients received thymectomy. By WHO classification, Type A (n = 1), Type B1 (n = 2), Type B2 (n = 8), Type B3 (n = 13), Type C (n = 23), and unknown (n = 1). With medial follow-up of 14.5 months (range 0.8-38.2), the median cycle of palbociclib was 10 (range 1-40). The PFS at 6 months was 60% and the median PFS was 11.0 months (95% CI: 4.6-17.4). Six of 48 patients (12.5%) achieved partial response. The median overall survival was 26.4 months (95% CI: 17.4-35.4). The most common adverse events of any grade included neutropenia (62.5%), anemia (37.5%) and thrombocytopenia (29.1%). Conclu- sions: Palbociblib monotherapy is well tolerable and encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy. Updated results will be presented. Clinical trial information: NCT03219554. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8577 Poster Session

Cell-free circulating tumor DNA (cfDNA) analysis of advanced thymic epithelial tumors (TETs).

Hiba I. Dada, Leylah Drusbosky, Giuseppe Giaccone; Guardant Health, Inc., Redwood City, CA; Weill Cornell Medical Center, New York, NY

Background: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelial cells of the thymus. Thymomas tend to be slowly growing, whereas thymic carcinomas are more aggressive and of- ten metastasize wildly. TETs have a very low tumor mutational burden (TMB). cfDNA has been used in several tumor types to describe the molecular characteristics and select treatment options, especially in absence of tissue availability. There is no information on the cfDNA detected in TETs. The purpose of this study was to identify common genomic alterations occurring in circulating tumor DNA (ctDNA) in patients with advanced TETs, detected using a cfDNA assay. Methods: We retrospectively evaluated 157 TET samples from the Guardant Health database between November 2017 – November 2020. The cfDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes using a commercially available liquid biopsy assay (Guardant360; Guar- dant Health, Redwood City, CA). We evaluated the frequency of genomic alterations based on diagnosis, age, and sex. Results: In this cohort, 66% of the patients had thymic carcinoma and 34% had thymoma. The median age was 60 years, and 59% of patients were male. 126 patients (80%) of this cohort had $1 somatic alteration detected. The most prevalent mutations detected are TP53 (55%), KIT (13%), EGFR (12%), BRCA2 (11%), PIK3CA (10%), ARID1A (10%), ATM (10%), KRAS (9%), APC (9%), and BRAF (9%). Mutations were more commonly observed in thymic carcinomas than thymomas, but statistical significance was not reached due to the small sample size. Frequencies of the observed genomic alterations are shown in the table below. Conclusions: This study confirms that advanced stage TETs shed tumor DNA into the circulation that can be picked up in the majority of patients, using a solid tumor platform, despite the low TMB typically observed in these tumors. This assay can potentially be used to monitor response to therapy. A more targeted gene panel, enriched for genes commonly mutated in TETs (e.g. GTF2I, BAP1, CYLD) might provide further insights in the future in the management of TETs. Research Sponsor: None.

Thymic Carcinoma Thymoma

Amp 12.7% 10.7% Fusion 0.4% 0.0% Indel 9.2% 5.3% Missense 59.4% 58.7% Nonsense 2.8% 6.7% Splice 2.8% 2.7% Synonymous 12.7% 16.0% LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8578 Poster Session

Outcomes of thymic epithelial tumors (TETs) with pleural metastases: Real-world insight from RYTHMIC.

Jean-Michel Maury, Jose Carlos Benitez, Marie Eve Boucher, Eric Dansin, Mallorie Kerjouan, Laurence Bigay-Game, Eric Pichon, Francois Thillays, Pierre-Emmanuel Falcoz, Lyubimova Svetlana, Youssef Oulkhouir, Calcagno Fabien, Luc Thiberville, Christelle Cle�ment Duchene, Virginie Westeel, Pascale Missy, Pascal Alexandre Thomas, Thierry Molina, Nicolas Girard, Benjamin Besse; Department of Tho- racic Surgery Lung and Heart Lung Transplantation, Lyon, France; Gustave Roussy, Villejuif, Paris, YT, France; Medical Oncology Department, Gustave Roussy, Villejuif, France; Department of Medical On- cology, Centre Oscar Lambret, Lille, France; CHU Rennes, Rennes, France; Centre Hospitalier Universi- taire, Hopital Larrey, Toulouse, France; Centre Hospitalier Universitaire, Tours, France; ICO Rene� Gauducheau, Pays-De-La-Loire, France; Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France; Centre Hospitalier Universitaire de Montpellier, Montpellier, France; Centre Hospitalier Unver- sitaire CAEN, Caen, France; Department of Medical Oncology, University Hospital, Besanc¸on, France; Centre Hospitalier Unversitaire Rouen, Rouen, France; Institut de Cance�rologie de Lorraine, Nancy, France; Pneumology, Hopital Jean Minjoz, Besanc¸on, France; Intergroupe Francophone de Cance�rologie Thoracique, Paris, France; Centre Hospitalier Universitaire Marseille, Marseille, France; Hotel Dieu, Paris, France; Institut Curie, Paris, France; Department of Medicine and Thoracic Pathology Commit- tee, Gustave Roussy, Villejuif, France

Background: TETs are rare and potentially aggressive malignancies with high associated prevalence of autoimmune disorders (AIDs). The pleura is the main metastatic site at relapse, referred as Masaoka- Koga stage (MK) IVa. The benefit of surgical management is unknown, so we have collected outcomes of patients with MK IVa TETs in a large prospective database. Methods: RYTHMIC (Re�seau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically discuss every case of TETs. The database, hosted by IFCT (Intergroupe Francophone de Cance�rologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in RYTHMIC national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of patients (pts) with MK IVa TETs. Results: From January 2012 to December 2019, 2909 pts were included in the database, including 182 MK IVa (6.2%). The median age at diagnosis was 63.5 (range 9 to 91). 58/182 (32%) pts reported AIDs, 76% myasthenia gravis. 129/182 pts had synchronous pleural metastasis. 118/182 (65%) tumors were resected, of them 10 (8.4%) had only pericardial metastases. Thymoma (T) B2 rate was 35.6%, B3 17.8% and thymic carcinoma (TC) 13.5%. Induction chemotherapy (CT) was given in 46 (39%) T and 10 (8%) TC with response rate of 50% and 70% respectively. Thymectomy was performed in addition to pleurectomy in 44 pts (37.2%), pericardiectomy in 68 (57.6%), lung resection in 80 (67.8%) or pneumonectomy in 15 (12.7%). Node resection was performed in 57.6% (n = 67), 12 (18%) were positive. The complete resection rate assessed by surgeons was 57% with a median of 15 (0 to 28) resected pleural metastasis. Intrapleural chemotherapy was added for 19 (16%) pts. No mortality was reported 90 days after surgery procedure. Median follow-up was 36 months. Pleural recurrence was seen in 47 (72%) pts. Median disease-free survival (DFS) was 39 vs 16 months in resected vs not resected tumors (p < 0.0001), 5-years overall survival (OS) was 88 vs 66% (p = 0.28), respectively. Risk of relapse decreased by 60% with surgery (HR = 0.4, 95CI (0.25-0.62); p < 0.0001). Con- clusions: The prevalence of MK IVa in our cohort was 6.2%. Surgery appears to be a safe and valid option for pts with MK IVa TET at diagnosis. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

8579 Poster Session

Clinicogenomic characterization of metastatic thymic epithelial tumors.

Fatemeh Ardeshir-Larijani, Milan Radovich, Bryan P. Schneider, Patrick J. Loehrer; Indiana University, Melvin and Bren Simon Cancer Center, Indianapolis, IN; Indiana University Simon Cancer Center, Indi- anapolis, IN; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN

Background: Thymic epithelial tumors (TET) are one of the rarest adult malignancies. Overall, patients have favorable survival outcomes, however a small subset develop metastatic disease. Genomic characterization of this very rare, clinically aggressive TET subset is lacking. Herein, we evaluated the clinical and genomic characteristics of metastatic TET (mTET) compared to a large cohort (n = 117) of primary TET (pTET) from The Cancer Genome Atlas (TCGA). Methods: From 2015 to 2020, 52 pts with mTET underwent clinical CLIA-based sequencing using either whole-exome (n = 35), panel-based testing (n = 13) and/or liquid biopsy (n = 22). The specimen was taken from a metastatic organ (n = 34) or relapsed primary mediastinal mass (n = 14); 4 pts had liquid bx only. Data on pTET was derived from the TCGA. Kaplan-Meier and log-rank test was used for assessment of PFS, OS. Results: The median age was 56 yrs in mTET (range 32-74) vs. 60 yrs (range 17-84) in TCGA data. The M/F (%) was 40/60 in mTET and 48/52 in TCGA, respectively. Of note, 13 mTET pts had other types of cancer prior or concurrent with TET diagnosis (4-breast, 2-bladder, 5-other) in which radiotherapy (n = 4) and/or chemotherapy (n = 3) was administered prior to TET diagnosis. In our cohort, 19 pts had stage IVA and 33 pts had stage IVB (most common metastatic site was liver in 17 pts). WHO histologic classification was: A = 1, A/B = 3, B1 = 4, B2 = 10, B3 = 12, TC = 18, TC with neuroendocrine feature = 3, and lymphoepithelial carcinoma = 1. WHO B3 and TC histologies were more common in our cohort of mTET than in the TCGA cohort (63% (33/52) vs. 17% (20/117), respectively). Pts with TC had worse mOS compare to thymoma (109m vs. 163m, HR = 2.78, P = 0.04). The most common genomic alteration in mTET was TP53 (n = 17, 33%) compared to 3% in TCGA. This was followed by CDKN2A (n = 5, 10%), PIK3CA (n = 4, 8%), CDKN2B (n = 3, 6%) and NF1 (n = 3, 6%). All TP53 missense mut functionality was analyzed with pol- yphen-2 software and 91.6% (22/24) had 98-100% damaging probability. 70% of pts that harbored TP53 muts were TC (41%) or B3 (29%) histology. Clinically actionable genomic alterations targetable with available or investigational agents (e.g. high TMB; gain-of-function mutations in PIK3CA, CDK4, and mTOR; loss-of-function mutations in NF1) were seen in 23% (12/52) of pts. Conclusions: Patients with mTET are associated with more aggressive WHO histology (B3 and TC). Greater frequency of TP53 mutations are observed in mTET compared to pTET. Clinically actionable genomic alterations are frequently seen in mTET suggesting value in the routine sequencing of these patients. Research Sponsor: None. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8580 Poster Session

Phase 3 study of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib versus concurrent chemoradiation therapy followed by durvalumab in unresectable, locally advanced, stage III non-small cell lung cancer: KEYLYNK-012.

Salma K. Jabbour, Byoung Chul Cho, Emilio Bria, Terufumi Kato, Jaishree Bhosle, Justin F. Gainor, Noemi Reguart, Luhua Wang, Daniel Morgensztern, Ellen Gurary, Tanya B. Ashraf, Humberto Lara- Guerra, Martin Reck; Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Universita� Cattolica del Sacro Cuore, Rome, Italy; Kanagawa Cancer Center, Yokohama, Japan; Lung Unit, Royal Marsden Hospital, Sutton, Surrey, United Kingdom; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Hospital Cl�ınic de Barcelona, Barcelona, Spain; Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Hospital, Shenzhen, China; Washington University School of Medicine, St. Louis, MO; Merck & Co., Inc., Kenilworth, NJ; Lung Clinic Grosshansdorf, Airway Re- search Center North (ARCN), member of the German Center for Lung Research (DZL), Grosshansdorf, Germany

Background: Pembrolizumab, an anti–PD-1 antibody is standard of care therapy for metastatic non–- small-cell lung cancer (NSCLC) as monotherapy and in combination with chemotherapy. Durvalumab, an anti–PD-L1 antibody, is approved for unresectable, stage III NSCLC without disease progression following concurrent chemoradiation therapy (CCRT). Early trials of pembrolizumab in combination with chemoradiotherapy, either concurrently or as consolidation, showed acceptable tolerability and promising PFS in patients with unresectable stage III NSCLC. Early data suggest the combination of poly(ADP- ribose) polymerase (PARP) plus anti–PD-(L)1 inhibition can enhance treatment effects. KEYLYNK-012 (NCT04380636) is evaluating pembrolizumab plus CCRT followed by pembrolizumab with/without the PARP inhibitor olaparib vs CCRT followed by durvalumab in patients with unresectable, locally advanced, stage III NSCLC. Methods: This global phase 3, randomized, placebo- and active-controlled, double-blind study is enrolling patients aged $18 y with previously untreated, pathologically confirmed, stage IIIA–C NSCLC, an ECOG PS of 0 or 1, and a tumor sample available for PD-L1 evaluation. Patients are randomized 1:1:1 to CCRT (platinum-doublet chemotherapy [cisplatin plus pemetrexed or etoposide; or carboplatin plus paclitaxel] plus radiotherapy 60 Gy over 6 wks [cycles 2–3]) with pembrolizumab 200 mg Q3W (groups A and B) or CCRT alone (group C) for 3 cycles. This is followed by pembrolizumab 200 mg Q3W for 17 cycles plus placebo (group A) or olaparib 300 mg BID (group B); or durvalumab 10 mg/kg Q2W for 26 cycles (group C). Randomization is stratified by disease stage (IIIA vs IIIB/IIIC), tumor histology (squamous vs nonsquamous), PD-L1 tumor proportion score ($50% vs < 50%) and region (East Asia vs North America/Western Europe/UK vs other). PFS (RECIST v1.1 by blinded independent central review [BICR]) and OS are dual primary endpoints. Secondary endpoints include ORR, duration of response, safety and tolerability, and quality-of-life outcomes. Tumor response will be evaluated per RECIST v1.1 by BICR after CCRT and at regular intervals throughout the study until disease progression, new cancer therapy, study withdrawal, or death. AEs will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Enroll- ment began July 6, 2020 and is ongoing at 204 sites in 24 countries. Clinical trial information: NCT04380636. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8581 Poster Session

A phase III clinical trial of adjuvant chemotherapy versus chemoimmunotherapy for stage IB-IIIA completely resected non-small cell lung cancer (NSCLC) patients nadim-adjuvant: New adjuvant trial of chemotherapy versus chemoimmunotherapy.

Virginia Calvo, Manuel Domine, Ivana Sullivan, Jose-Luis Gonzalez-Larriba, Ana Laura Ortega, Reyes Bernabe�, Maria Angeles Sala, Begona Campos, Javier De Castro, Paloma Mart�ın-Martorell, Joaquim Bosch-Barrera, Xabier Mielgo, Laia Vila�, Joaquin Casal, Silver Ros, Maite Martinez Aguillo, Airam Padilla, Sergio Sandiego, Jonathan Aires Machado, Mariano Provencio-Pulla; Instituto Investigacion Sanitaria Puerta de Hierro-Segovia de Arana, Hospital Universitario Puerta de Hierro-Majadahonda, Ma- drid, Spain; Instituto de Investigacio�n Sanitaria, Hospital Fundacio�n Jime�nez D�ıaz, Madrid, Spain; De- partment of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Hospital Clinico San Carlos, Madrid, Spain; Complejo Hospitalario de Jae�n, Jae�n, Spain; Hospital Universitario Virgen del Roc�ıo, Seville, Spain; Hospital Universitario de Basurto, Bilbao, Spain; Hospital Universitario Lucus Augusti, Lugo, Spain; Translational Oncology Unit at Medical Oncology Division, Hospital Universitario La Paz, IdipAZ, Madrid, Spain; Hospital Clinic Universitario de Valencia, Valencia, Spain; Medical On- cology Department, Catalan Institute of Oncology, Girona, Spain; Hospital Universitario Fundacio�n Alcorco�n, Alcorco�n, Spain; Parc Tauli�University Hospital, Parc Taul�ı Institute of Research and Innova- tion I3PT, Barcelona Autonomous University, Spain, Sabadell, Spain; Hospital Alvaro Cunqueiro de Vigo, Vigo, Spain; Hospital Clinico Universitario Virgen de la Arrixaca, Murcia, Spain; Complejo Hospi- talario De Navarra, Pamplona, Spain; Hospital Universitario Nuestra Sen~ora de Candelaria, Santa Cruz de Tenerife, Spain; IVO, Valencia, Spain; Department of Clinical Oncology, University Hospital San Pe- dro de Alca�ntara, Ca�ceres, Spain

Background: The results of current studies are considered acceptable evidence to support the hypothesis of efficacy of the proposed combination of immunotherapy with chemotherapy (CT-IO) in patients with NSCLC stages Ib-IIIA candidates for adjuvant treatment. Methods: This is an open-label, randomised, two-arm, phase III, multi-centre clinical trial. Primary objective and endpoint: The primary objective is disease free survival (DFS) defined time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time Sample size: 210 patients NSCLC stages Ib-IIIA (Experimental Arm (Adjuvant Che- motherapy-Inmunotherapy + maintenance adjuvant Inmunotherapy): 105 patients, Control Arm (Adju- vant Chemotherapy): 105 patients Treatment Patients randomised to the experimental arm will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) as adjuvant treatment followed by maintenance adjuvant treatment for 6 cycles with Nivolumab 480 mg Q4W (+/- 3 days). Patients randomized to the control arm will receive Paclitaxel 200mg/m2 + Car- boplatin AUC5 for 4 cycles every 21 days (+/- 3 days) followed by 2 observation visits. Total trial duration: 6.5 years, 3.5 years of recruitment, 1 year of adjuvant treatment or observation and 2 years of follow up. The start date was January 2021. The estimated primary completion date is June 2027. Clinical trial information: NCT04564157. Research Sponsor: BMS. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8583 Poster Session

A randomized phase II trial of adjuvant pembrolizumab versus observation following curative resection for stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm: Big Ten Cancer Research Consortium BTCRC-LUN18-153.

Greg Andrew Durm, Muhammad Furqan, Lawrence Eric Feldman, Malini Patel, Richard Delmar Hall, Shadia Ibrahim Jalal, Thomas J. Birdas, Kenneth Kesler, Karen Marie Rieger, DuyKhanh Ceppa, Nasser H. Hanna; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Universi- ty of Iowa Hospitals and Clinics, Iowa City, IA; University of Illinois Hospital & Health Sciences System, Chicago, IL; Rutgers Cancer Institute of New Jersey, New Bruswick, NJ; University of Virginia, Char- lottesville, VA; Indiana University Dept of Cardiosurgery, Indianapolis, IN

Background: There are approximately 35,000 cases of stage I lung cancer in the United States each year. While these patients have better 5-year overall survival (OS) rates than their counterparts with locally advanced and metastatic disease, there is still considerable room for improvement. Based on a recent publication validating the 8th edition of the TNM classification, the 5-year OS for node-negative pathologically-staged NSCLC between 1-4cm ranges from 73-86%, and recurrence rates for resected stage I NSCLC can range from 18-38%. Previous studies looking at adjuvant chemotherapy in this setting have shown no benefit for stage IA tumors, and the current standard of care is observation alone. Checkpoint blockade with PD-1/PD-L1 inhibitors has shown considerable activity in NSCLC including in metastatic disease, as consolidation in stage III disease after chemoradiation, and in studies evaluating neoadjuvant immunotherapy. Given this activity and their favorable safety profile, we designed a study of adjuvant PD-1 inhibition following resection in stage I NSCLC. Methods: This study is a randomized phase II multicenter trial of adjuvant Pembrolizumab versus observation alone following complete resection of stage I NSCLC with tumors between 1-4cm. The trial will enroll 368 patients randomized 1:1 to either Pembrolizumab 400mg IV every 6 weeks for up to 9 cycles or observation alone with scheduled CT scans and routine clinical follow-up. Stratification factors include PD-L1 $50% vs. < 50% and tumor size of 1-2cm vs. > 2-4cm. The lead site is Indiana University, and the trial will be conducted through the Big Ten Cancer Research Consortium. The primary endpoint is disease free survival (DFS), and secondary endpoints include OS, DFS at 1-, 2-, and 3-year time points, and toxicity. The trial opened to accrual at the lead site in May 2020, and there are currently 6 patients enrolled. Clinical trial information: NCT04317534. Research Sponsor: Merck. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8584 Poster Session

Randomized phase III Trial of MEDI4736 (durvalumab) as concurrent and consolidative therapy or consolidative therapy alone for unresectable stage 3 NSCLC: A trial of the ECOG- ACRIN Cancer Research Group (EA5181).

John M. Varlotto, Zhuoxin Sun, Suresh S. Ramalingam, Heather A. Wakelee, Christine M. Lovly, Kurt R. Oettel, Gregory A. Masters, Nate Pennell; Edwards Comprehensive Cancer Center, Huntington, WV; IBCSG Statistical Center, Boston, MA; Winship Cancer Institute of Emory University, Atlanta, GA; Stan- ford Cancer Institute, Stanford, CA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN; Gundersen Lutheran Hospital/Clinic, La Crosse, WI; Helen F Graham Cancer Center, Newark, DE; Cleveland Clinic, Cleveland

Background: Platinum-based concurrent chemoradiation(CRT) followed by one year of the human im- munoglobulin G1 kappa (IgG1j) monoclonal antibody, durvalumab, which blocks the interaction of PD- L1 with its receptors PD-1 and CD80, is the standard of care for locally advanced, unresectable non- small cell lung cancer (NSCLC). Early studies have noted the feasibility of concomitant administration of radiotherapy and immune checkpoint inhibition in NSCLC. EA5181 will evaluate the use of concomitant durvalumab with chemo-radiotherapy for locally advanced NSCLC. Methods: EA5181 is a randomized, multi-center, phase III study for patients with unresectable Stage III NSCLC comparing the efficacy of CRT with concomitant durvalumab to CRT, followed by one year of durvalumab. Eligibility criteria include: an ECOG PS of 0-1, adequate pulmonary function (FEV1 and DLCO both > 40%), no history of auto-immune disease and no past chemotherapy or RT for this lung cancer. Stratification factors include age, sex, stage, and planned concurrent chemotherapy type. Eligible patients with be randomized 1:1 to receive 60Gy RT (2Gy fractions) CRT and durvalumab (Arm A) or 60Gy CRT (Arm B). Investigators will be allowed to choose from three different chemotherapy options: cisplatin/etoposide q 28 days, Pemetrexed/cisplatin q 21 days, and weekly paclitaxel/Carboplatin. Arm A will use 750mg fixed of durvalumab (considered equivalent to 10mg/kg) on days 1, 11, and 21 of RT. Assuming no disease progression, patients in both arms will be followed by monthly (q28 days) fixed dose of 1500mg durvalumab for one year which will be given optimally within 14 days of radiation or when (non)hematologic toxicity is < Grade 2. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, incidence of local/distant progression and toxicity. The target sample size is 660 patients, anticipated to recruit over 55 months, with follow up for an additional 42 months. This provides approximately 82% power if the true hazard ratio for overall survival was 0.75 or less, with 2-sided alpha of 0.05, and assuming a median survival of 42.5 months in the control arm. The study was activated on 04/09/20 and has currently accrued 90 patients on 02/03/21. Clinical trial information: NCT04092283. Research Sponsor: Astra Zeneca. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8585 Poster Session

Thoracic radiotherapy PLUS durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy: Employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy—The TRADE-hypo trial.

Farastuk Bozorgmehr, Jessica Juergens, Michaela Hammer-Hellmig, Christian Meyer Zum Bueschenfelde, Johannes Classen, Juergen Alt, Marcus Stockinger, Matthias Ulmer, Arndt-Christian Mu€ller, Philipp Schu€tt, Michael J. Eble, Juergen R. Fischer, Christian A. Lerchenmuller, Tobias R. Overbeck, Henning Pelz, Bernd Schmidt, Thomas Wehler, Johannes Krisam, Michael Thomas, Stefan Rieken, TRADE-Hypo Investigators; Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germa- ny; City of Cologne Municipal Hospitals, Lung Hospital Cologne Merheim, Department of Pneumology, Cologne, Germany; City of Cologne Municipal Hospitals, Department of Radiation Oncology, Cologne, Germany; ViDia Christliche Kliniken Karlsruhe, Department of Hematology, Oncology, Immunology and Palliative Medicine, Karlsruhe, Germany; ViDia Christliche Kliniken Karlsruhe, Department of Radiation Oncology, Karlsruhe, Germany; University Medical Center Mainz, Department of Hematology, Medical Oncology & Pneumology, Mainz, Germany; University Medical Center Mainz, Department of Radiation Oncology, Mainz, Germany; Klinikum Ludwigsburg, Department of Hematology, Medical Oncology and Palliative Medicine, Ludwigsburg, Germany; RKH Klinikum Ludwigsburg, Department of Radiation On- cology, Ludwigsburg, Germany; Onkodoc GmbH Guetersloh, Gu€tersloh, Germany; Rheinisch-Westfaeli- sche Technische Hochschule Aachen, Department of Radiation Oncology, Aachen, Germany; Lungenklinik Lo€wenstein, Department of Thoracic Oncology, Lo€wenstein, Germany; Group Practice of Hematology and Oncology, Muenster, Germany; University Medical Center Go€ttingen, Department of Hematology and Medical Oncology, Goettingen, Germany; Ambulantes Therapiezentrum Ha€matologie & Onkologie Offenburg, Offenburg, Germany; DRK Kliniken Berlin Mitte, Department of Internal Medi- cine, Pneumology and Sleep Medicine, Berlin, Germany; Evangelisches Krankenhaus Hamm gGmbH, Department of Hematology and Oncology, Hamm, Germany; University Hospital of Heidelberg, Institute of Medical Biometry and Informatics, Heidelberg, Germany; Internistische Onkologie der Thoraxtumo- ren, Thoraxklinik im Universita€tsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; University Medical Center Go€ttingen, Department of Radiation Oncology, Goettingen, Germany

Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide highlighting the importance of improving current therapeutic options. In particular, elderly and frail patients are not only underrepresented in clinical trials, but also frequently do not receive standard treatment regimens due to comorbidities. For example, patients with unresectable stage III NSCLC who are unfit for chemotherapy (CHT) do not benefit from the recent seminal therapy algorithm change for this disease, i.e. consolidation therapy with the immune checkpoint inhibitor (ICI) durvalumab after combined radiochemotherapy (RChT). Instead, these patients are treated with radiotherapy only, raising the serious concern of undertreatment. This issue is addressed by the TRADE-hypo clinical trial that investi- gates a novel therapy option for NSCLC stage III patients not capable of receiving CHT. To this end, thoracic radiotherapy (TRT) is administered together with durvalumab, employing the synergism created by the combination of restoring anti-tumor immune response by the ICI with the induction of immuno- genicity by irradiation. The latter effect has been suggested to be further boosted by hypofractionated radiotherapy, which could also be more practicable for the patient. Taken these considerations into account, the TRADE-hypo trial addresses safety and efficacy of durvalumab therapy combined with either conventional or hypofractionated TRT. Methods: The TRADE-hypo trial is a prospective, randomized, open-label, multicentric phase II trial. Eligible patients are diagnosed with unresectable stage III NSCLC and not capable of receiving sequential RChT due to high vulnerability as reflected by a poor performance status (ECOG 2 or ECOG1 and CCI$ 1) and/or high age ($ 70)]. Two treatment groups are evaluated: Both receive durvalumab (1,5000 mg, Q4W) for up to 12 months. In the CON-group this is combined with conventionally fractionated TRT (30 x 2 Gy), while in the HYPO-group patients are treated with hypofractionated TRT (20 x 2.75 Gy). In the HYPO-arm, a safety stop-and-go lead-in phase precedes full enrollment. Here, patients are closely monitored with regard to toxicity (i.e., pneumonitis grade $ 3 within 8 weeks after TRT) in small cohorts of 6. The primary objective of the trial is safety and tolerability. As a primary efficacy endpoint, the objective response rate after 3 months will be evaluated. Further endpoints are additional parameters of safety and efficacy, as well as the comprehensive collection of biomaterials to be analyzed regarding treatment-induced changes and potential novel biomarkers. As of February 10, 2021, 9 patients of planned 88 patients have been enrolled in the TRADE- hypo trial. Clinical trial information: NCT04351256. Research Sponsor: AstraZeneca. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8586 Poster Session

DREAM3R: Durvalumab with chemotherapy as first-line treatment in advanced pleural mesothelioma—A phase 3 randomized trial.

Patrick M. Forde, Anna K. Nowak, Peey-Sei Kok, Chris Brown, Zhuoxin Sun, Valsamo Anagnostou, Kenneth John O’Byrne, Sonia Yip, Alistair Cook, Willem Joost Lesterhuis, Brett Gordon Maxwell Hughes, Nick Pavlakis, Julie R. Brahmer, Hedy L. Kindler, Anne S. Tsao, Marjorie Glass Zauderer, Suresh S. Ramalingam, Martin R. Stockler; Johns Hopkins University School of Medicine, Sidney Kim- mel Comprehensive Cancer Center, Baltimore, MD; Sir Charles Gairdner Hospital, Perth, WA, Australia; Liverpool Cancer Therapy Centre, Liverpool, Australia; University of Sydney, Sydney, NSW, Australia; IBCSG Statistical Center, Boston, MA; St James’s Hospital, Dublin, Ireland; Sydney Catalyst Transla- tional Cancer Research Centre, Sydney, Australia; University of Western Australia, Perth, WA, Australia; National Centre for Asbestos Related Diseases, University of Western Australia, Nedlands, Australia; Department of Medical Oncology, Royal Brisbane & Women’s Hospital, and School of Medicine, Univer- sity of Queensland, Brisbane, QLD, Australia; Northern Cancer Institute, St Leonards, Sydney, Austra- lia; University of Chicago, Chicago, IL; The University of Texas MD Anderson Cancer Center, Houston, TX; Memorial Sloan Kettering Cancer Center, New York, NY; Winship Cancer Institute of Emory Univer- sity, Atlanta, GA; NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia

Background: Standard first line treatment for unresectable malignant pleural mesothelioma (MPM) is platinum-based chemotherapy with pemetrexed. Two recent, single-arm, phase 2 trials (DREAM1 and PrE05052) combining the PD-L1 inhibitor durvalumab and standard first line cisplatin and pemetrexed (CP) exceeded pre-specified criteria for proceeding to phase 3. DREAM3R aims to determine the effectiveness of adding durvalumab to first line CP chemotherapy in advanced MPM. Methods: Treatment- naïve patients with advanced MPM will be randomised (2:1) to EITHER durvalumab 1500 mg every 3 weeks plus doublet chemotherapy (cisplatin 75 mg/m2 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target sample size is 480 patients (320 durvalumab, 160 control) recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival is 0.70, with 2-sided alpha of 0.05, assuming a median survival of 15 months in the control group. Key inclusion criteria: MPM of any histological subtype; measurable disease as per RECIST 1.1 modified for mesothelioma (mRECIST 1.1) without prior radiotherapy to these sites; ECOG PS 0-1; and, adequate hematologic, renal, and liver function tests. Key exclusion criteria: prior systemic anticancer treatment for MPM; diagnosis based only on cytology or fine needle aspiration biopsy; contraindi- cation to immunotherapy; and conditions requiring immunosuppressives or corticosteroids. Stratification: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), and region (USA vs. ANZ). The primary endpoint is overall survival. Secondary endpoints include progression-free survival; objective tumour response (by mRECIST 1.1 and iRECIST); adverse events; health-related quality of life; and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DREAM and PrE0505 studies, PD-L1 expression, tumour mutation burden, nuanced genomic characteristics, and HLA subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. Clinical trial information: NCT04334759. and ACTRN 12620001199909. Research Sponsor: AstraZeneca. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8587 Poster Session

KEYLYNK-013: A phase 3 study of pembrolizumab in combination with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib versus concurrent chemoradiation therapy in patients with newly diagnosed limited-stage SCLC.

Andreas Rimner, W. Victoria Victoria Lai, Raffaele Califano, Salma K. Jabbour, Corinne Faivre-Finn, Byoung Chul Cho, Terufumi Kato, Jinming Yu, Li Yu, Bin Zhao, Maria Catherine Pietanza, Lauren Averett Byers; Memorial Sloan Kettering Cancer Center, New York, NY; The Christie NHS Foun- dation Trust, Manchester, United Kingdom; Department of Radiation Oncology, Rutgers Cancer Insti- tute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ; The Christie NHS Foundation Trust & The University of Manchester, Manchester, United Kingdom; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; Kanagawa Cancer Center, Yokohama, Japan; Radiation Oncology, Shandong Cancer Hospital, Jinan, Shandong, China; Merck & Co., Inc., Kenilworth, NJ; MD Anderson Cancer Center, Houston, TX

Background: Concurrent chemoradiotherapy with etoposide and platinum (carboplatin/cisplatin) plus the anti–PD-1 antibody pembrolizumab (pembro) has shown antitumor activity and acceptable safety in patients with limited-stage small-cell lung cancer (LS-SCLC). The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has shown clinical activity in combination with checkpoint inhibitors in patients with SCLC. KEYLYNK-013 (NCT04624204) is a randomized, placebo-controlled, double-blind phase 3 trial of pembro plus concurrent chemoradiation therapy followed by pembro with or without olaparib in patients with newly diagnosed LS-SCLC. Methods: Eligible patients are those aged $18 years with previously untreated LS-SCLC, ECOG PS 0/1, and adequate pulmonary function. Patients are randomized 1:1:1 to receive pembro 200 mg Q3W (groups A and B) or pembro placebo (saline) Q3W (group C) during the chemoradiation phase. All patients also receive 4 cycles of chemotherapy (etoposide 100 mg/m2 on days 1, 2, and 3 of each cycle and investigator’s choice of carboplatin AUC 5 mg/ mL/min or cisplatin 75 mg/m2 on day 1 of each cycle) with definitive thoracic radiotherapy (total dose of 45 Gy in 30 fractions twice daily over 3 weeks or 66 Gy in 33 fractions once daily over 6.5 weeks starting on day 1 of cycle 2). After chemoradiation, prophylactic cranial irradiation is strongly recommended for patients with CR/PR or at investigator’s discretion for patients with SD. Postchemoradiation patients receive pembro 400 mg Q6W plus olaparib placebo (group A), or pembro 400 mg Q6W plus olaparib 300 mg BID (group B), or pembro placebo plus olaparib placebo (group C) for 9 cycles/12 months. Randomization is stratified by ECOG PS (0 vs 1), SCLC stage (I/II vs III), radiation fractionation (twice vs once daily), and region (east Asia vs North America/western Europe/UK/Australia vs rest of world). Tumor imaging occurs at baseline, within 12 weeks of cycle 1 day 1, followed by Q9W to the end of year 2, Q12W in year 3, Q16W in year 4, every 6 months in year 5, and annually thereafter. Imag- ing is assessed per RECIST v1.1 by blinded independent central review. AEs are monitored from randomization to 30 days after cessation of study treatment (90 days for serious AEs) and graded per NCI- CTCAE v5.0. Health-related quality of life is assessed using EORTC-QLQ-C30 and QLQ-LC13. Primary endpoints are OS and PFS per RECIST v1.1 by blinded independent central review. OS and PFS are estimated by the Kaplan-Meier method. Between-group differences will be evaluated with stratified log- rank tests and Cox proportional hazard models with Efron’s method of tie handling. Secondary endpoints include ORR, duration of response, safety, and patient-reported outcomes. The study began enrollment in December 2020. Clinical trial information: NCT04624204. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8588 Poster Session

A phase I, open-label, dose-escalation trial of BI 764532, a DLL3/CD3 bispecific antibody, in patients (pts) with small cell lung carcinoma (SCLC) or other neuroendocrine neoplasms expressing DLL3.

Martin Wermke, Enriqueta Felip, Valentina Gambardella, Yasutoshi Kuboki, Daniel Morgensztern, Zohra Oum’Hamed, Junxian Geng, Matus Studeny, Taofeek K. Owonikoko; Department of Thoracic On- cology, Carl-Gustav-Carus Dresden University Hospital, Dresden, Germany; Department of Medical On- cology, Vall d’Hebron University Hospital, Barcelona, Spain; Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain; Department of Experi- mental Therapeutics, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; Washington Uni- versity School of Medicine, St. Louis, MO; Boehringer Ingelheim France S.A.S., Reims, France; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; Boehringer Ingelheim International GmbH, Ingelheim, Germany; Winship Cancer Institute, Emory University, Altanta, GA

Background: First-line standard of care for pts with metastatic SCLC and neuroendocrine carcinoma (NEC) is platinum-based chemotherapy ± immunotherapy. While the addition of anti-PD1 antibodies has improved outcomes, nearly all pts relapse and prognosis is poor. There is a major unmet need for additional treatment (tx) options. BI 764532 is a delta-like ligand 3 (DLL3)/CD3 T cell engaging bispecific antibody. DLL3 is expressed on the cell surface of many SCLC and NEC tumors, but not on normal cells. In preclinical studies, BI 764532 induced cytotoxicity of DLL3-positive cells and showed anti-tumor activity in animal models. Methods: NCT04429087 is a first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic SCLC, large cell neuroendocrine lung carcinoma, NEC or small cell carcinoma of any other origin. Pts must have failed on or be ineligible for available standard therapies (including $1 line of platinum-based chemotherapy). Tumors must be positive for DLL3 expression (archived tissue/in-study fresh biopsy) according to central review. Pts must have $1 evaluable lesion (modified RECIST 1.1) outside of CNS and adequate liver, bone marrow and renal organ function. Main exclusion criteria: previous tx with T cell engagers or DLL3-targeted therapies; persistent toxicity from previous tx that has not resolved to # CTCAE grade 1; immunodeficiency or receiving immunosuppressive therapy #7 days, prior anti-cancer therapy #3 wks/5 half-life periods or extensive field radiotherapy #2 wks of first dose of BI 764532. The main objective of phase Ia is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 764532, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy. The phase Ib objectives, endpoints and design will be specified after availability of phase Ia results. The trial will assess #3 dosing regimens: Regimen A (fixed iv dose once every 3 wks); Regimen B1 (fixed iv dose once every wk); Regimen B2 (step-in dose[s] followed by fixed-dose weekly doses; optional). Tx will continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or a maximum tx duration of 36 mos, whichever occurs first. For Phase Ia, ~160 pts will be screened and 110 pts accrued. As of Feb 2021, pts are being recruited and treated in early dose escalation cohorts. Clinical trial information: NCT04429087. Re- search Sponsor: Boehringer Ingelheim. LUNG CANCER—NON-SMALL CELL LOCAL-REGIONAL/SMALL CELL/OTHER THORACIC CANCERS

TPS8589 Poster Session

Trial in progress: A multicenter phase Ib/II study of pelcitoclax (APG-1252) in combination with paclitaxel in patients with relapsed/refractory small-cell lung cancer (R/R SCLC).

Angel Qin, Gregory Peter Kalemkerian, Jyoti D. Patel, Nisha Anjali Mohindra, Jennifer W Carlisle, Jacob Sands, Zhicong He, Robert Winkler, Zhiyan Liang, Vakessa Hammock, Riccardo Bombelli, Ming Lu, Yang Xu, Tommy Fu, Cunlin Wang, Dajun Yang, Yifan Zhai; University of Michigan, Ann Arbor, MI; Uni- versity of Michigan Cancer Center, Ann Arbor, MI; Lurie Cancer Center, Northwestern University-Fein- berg School of Medicine, Chicago, IL; Winship Cancer Institute of Emory University, Atlanta, GA; Dana- Farber Cancer Institute, Boston, MA; Jiangsu Ascentage Pharma Pty Ltd, Sydney, Australia; Ascentage Pharma Group Inc., Rockville, MD; State Key Laboratory of Oncology in South China Collaborative Inno- vation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Background: Increased expression of BCL-2, BCL-xL, and MCL-1 allows certain tumors to evade apoptosis. Pelcitoclax is a novel, dual BCL-2/BCL-xL inhibitor with strong single-agent antitumor activity against tumor cells addicted to BCL-2, BCL-xL, and BCL-w, and exhibits even broader antitumor activity when administered with chemotherapy. Pelcitoclax reduces tumor growth in SCLC and other human cancer xenograft models, with manageable effects on platelet counts. Preliminary findings from the first-in-human study suggested promising antitumor activity and a favorable safety profile. Methods: This open-label study is evaluating the safety and preliminary efficacy of pelcitoclax combined with paclitaxel in adults with R/R SCLC that has progressed on or after initial treatment. Prior treatments may include platinum-based therapy (± thoracic radiation), immunotherapy, or chemotherapeutic agents other than paclitaxel. Eligible patients have an ECOG performance status of 0-2; adequate organ function; no known bleeding diathesis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, serious gastrointestinal bleeding, or concomitant use of most anticoagulants; and no residual grade $ 2 adverse events from previous treatment. In the phase Ib study, the pelcitoclax maximum tolerated dose is being determined using a time-to-event continual reassessment method. In this phase, pelcitoclax is administered by IV infusion over 30 minutes on Days 1, 8, and 15 at dose levels of 80, 160, and 240 mg per week, with fixed-dose paclitaxel 80 mg/m2 on Days 1 and 8 of a 21-day cycle. In addition to a baseline scan within 4 weeks before study entry, computed tomography will be performed every two cycles to evaluate antitumor response. Treatment will continue until disease progression, unacceptable toxicity, consent withdrawal, or administrative discontinuation. The primary endpoint of this phase includes dose-limiting toxicity by NCI CTCAE v5.0 over 21 days. After determination of the recommended phase II dose of pelcitoclax in the phase Ib study, the efficacy of pelcitoclax with paclitaxel will be determined in the phase II study using a Simon two-stage design, with overall response rate as the primary endpoint. Other study endpoints in the phase II study include pharmacokinetics of pelcitoclax with paclitaxel, as well as progression-free and overall survival. As of February 8, 2021, 15 of 58 patients had been enrolled. Internal study identifier APG1252SU101. Clinical trial information: NCT04210037. Research Sponsor: Ascentage Pharma Group Corp Limited (Hong Kong).