Genitourinary Cancer—Kidney and Bladder

GENITOURINARY CANCER—KIDNEY AND BLADDER

5000 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC).

Maha H. A. Hussain, Thomas Powles, Peter Albers, Daniel Castellano, Siamak Daneshmand, Juergen Gschwend, Hiroyuki Nishiyama, Stephane Oudard, Darren Tayama, Nicole N. Davarpanah, Viraj Degaonkar, Yi Shi, Sanjeev Mariathasan, Petros Grivas, Peter H. O’Donnell, Jonathan E. Rosenberg, Daniel M. Geynisman, Jean H. Hoffman-Censits, Daniel Peter Petrylak, Joaquim Bellmunt; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Department of Urology, Heinrich-Heine-University, D¨usseldorf, Germany; Hospital Universitario 12 de Octubre, Madrid, Spain; USC Norris Comprehensive Cancer Center, Los Angeles, CA; Department of Urology, Technical University of Munich, Munich, Germany; University of Tsukuba, Tsukuba, Japan; Georges Pompidou Hospital, Paris, France; Genentech, South San Francisco, CA; Genentech, Inc., South San Francisco, CA; Genentech, San Francisco, CA; University of Washington, Seattle, WA; University of Chicago Comprehensive Cancer Center, Chicago, IL; Memorial Sloan Kettering Cancer, New York, NY; Fox Chase Cancer Center, Philadelphia, PA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Smilow Cancer Center, Yale University, New Haven, CT; Beth Israel Deaconess Medical Center, Boston, MA

Background: Radical surgery 6 cisplatin-based neoadjuvant chemo (NAC) is the mainstay treatment (tx) for MIUC, with no conclusive level 1 evidence for adjuvant chemo (AC). Here we present the primary analysis from IMvigor010, a global, open-label, multicenter, randomized trial of adjuvant atezo (anti– PD-L1; approved in metastatic UC [mUC] settings) in pts with MIUC at high risk of recurrence following primary resection. Methods: Pts with MIUC (bladder, upper tract [UT]), ECOG PS 0-2 and resected tissue for PD-L1 testing on immune cells (IC; VENTANA SP142 assay) were enrolled # 14 wks after radical cystectomy/nephroureterectomy with lymph node (LN) dissection. Pathologic stage: 1) ypT2-4a or ypN+ if pts had NAC or 2) pT3-4a or pN+ if pts did not have NAC. No postsurgical radiation or AC was allowed; if no NAC was given, pts must have been ineligible for or declined cisplatin-based AC. Pts were randomized 1:1 to atezo 1200 mg IV q3w or obs for 16 cycles or 1 y (stratification factors: no. of LNs resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, prior NAC). Disease-free survival (DFS) was the primary endpoint (EP). Final DFS, first interim overall survival (OS; secondary EP) and safety are reported. Results: The ITT population included 809 pts (median follow-up, 21.9 mo). In the atezo and obs arms, respectively, 48% and 47% had NAC; 7% and 6% had UTUC as primary disease; 48% each had LN+ disease. DFS and OS are in Table. Baseline prognostic/clinical factors did not influence DFS tx benefit; stratified HR was 0.81 (95% CI: 0.63, 1.05) in IC0/1 pts (PD-L1 , 5%; n = 417) and 1.01 (0.75, 1.35) in IC2/3 pts (PD-L1 $ 5%; n = 392). 16% of atezo-treated pts had a tx- related G3-4 AE. Skin and gastrointestinal toxicities most commonly led to tx discontinuation. Conclusions: IMvigor010, the first phase 3 adjuvant study of a checkpoint inhibitor in MIUC, did not meet its primary EP of DFS. More tx discontinuation due to AEs was seen vs mUC studies. Safety was generally consistent with previous studies. Clinical trial information: NCT02450331. Research Spon- sor: F. Hoffmann-La Roche Ltd.

Atezo Obs IMvigor010 primary analysis (N = 406) (N = 403) Final DFS No. of Events (%) 212 (52) 208 (52) Median (95% CI), mo 19.4 (15.9, 24.8) 16.6 (11.2, 24.8) HR (95% CI)a 0.89 (0.74, 1.08); P = 0.2446b First interim OS No. of Events (%) 118 (29) 124 (31) Median (95% CI), mo NR NR HR (95% CI)a 0.85 (0.66, 1.09); P = 0.1951c NR, not reached. Data cut off: Nov 30, 2019. a Stratified by nodal status, post- resection tumor stage, PD-L1 status. b 2-sided P value. c DFS, then OS tested hierarchically. OS P value for descriptive purposes.

5001 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426.

Elizabeth R. Plimack, Brian I. Rini, Viktor Stus, Rustem Gafanov, Tom Waddell, Dmitry Nosov, Fred´ ´ eric Pouliot, Denis Soulieres, Bohuslav Melichar, Ihor Vynnychenko, Sergio Jobim Azevedo, Delphine Borchiellini, Raymond S. McDermott, Jens Bedke, Satoshi Tamada, Lina Yin, Mei Chen, L. Rhoda Molife, Michael B. Atkins, Thomas Powles; Fox Chase Cancer Center, Philadelphia, PA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro, Ukraine; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; The Christie NHS Foundation Trust, Manchester, United Kingdom; Central Clinical Hospital With Outpatient Clinic, Moscow, Russian Federation; CHU of Quebec and Laval University, Quebec City, ON, Canada; Centre Hospitalier de l’Universite ´ de Montreal, ´ Montreal, ´ QC, Canada; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine; Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil; Centre Antoine Lacassagne, UniversiteC ´ oteˆ d’Azur, Nice, France; Adelaide and Meath Hospital and University College Dublin, Dublin, Ireland; Eberhard-Karls University Tubingen, ¨ T¨ubingen, Germany; Osaka City University Hospital, Osaka, Japan; Merck & Co., Inc., Kenilworth, NJ; MSD UK, London, United Kingdom; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom

Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here. Methods: Treatment-naive patients (pts) with clear cell aRCC, KPS $70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, toxicity, or withdrawal. Random- ization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world). Primary end points were OS and PFS. Secondary end points were ORR, DOR, and safety. All P values are nominal. A post-hoc exploratory analysis was done to evaluate association of depth of response (maximum reduction from baseline in sum of diameters of target lesions) and OS using landmark analysis up to 6 mo after randomization. Results: 861 pts were randomly assigned (pembro + axi, n = 432; sunitinib, n = 429). Median (range) duration of follow-up for all pts was 27.0 mo (0.1-38.4). Pembro + axi improved OS (HR, 0.68 [95% CI, 0.55-0.85]; P , 0.001; 24-mo OS rate, 74% vs 66%) vs sunitinib. Median (95% CI) OS was not reached with pembro + axi and was 35.7 mo (33.3-NR) with sunitinib. Pembro + axi improved PFS (HR, 0.71 [95% CI, 0.60-0.84]; P , 0.001; 24-mo PFS rate, 38% vs 27%) vs sunitinib. For pembro +axi vs sunitinib respectively, median (95% CI) PFS was 15.4 (12.7-18.9) vs 11.1 mo (9.1-12.5); ORR was 60% vs 40% (P , 0.0001); CR rate was 9% vs 3%; and median DOR was 23.5 mo (range 1.4+ to 34.5+) vs 15.9 mo (range 2.3-31.8+). In general, the pembro + axi benefit was observed in all subgroups tested, including IMDC risk and PD-L1 expression subgroups. Post-hoc landmark analysis at 6-mo showed that pts on pembro + axi with $80% target lesion reduction had OS similar to that of pts with CR per RECIST v1.1 based on Kaplan-Meier curves and HR [95% CI] estimates (0.20 [0.05-0.84] vs. 0.10 [0.01-0.76], respectively) vs pts with 0-30% target lesion reduction. No new safety signals were observed. Con- clusions: Pembro + axi continued to demonstrate superior and durable antitumor activity vs sunitinib in pts with first-line aRCC with a 27-mo median follow up; no new safety signals were observed. Clinical trial information: NCT02853331. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

5002 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC).

Toni K. Choueiri, Daniel Yick Chin Heng, Jae-Lyun Lee, Mathilde Cancel, Remy B Verheijen, Anders Mellemgaard, Lone Ottesen, Melanie M. Frigault, Anne L’Hernault, Zsolt Szijgyarto, Sabina Signoretti, Laurence Albiges; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; CHU Bretonneau Centre, Tours, France; Oncology R&D, AstraZeneca, Cambridge, United Kingdom; Oncology R&D, AstraZeneca, Boston, MA; Oncology R&D, Astrazeneca, Cambridge, United Kingdom; Oncology R&D, AstraZeneca, Cambridge, ME, United Kingdom; Department of Pathology, Brigham and Women’s Hospital, Boston, MA; Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France

Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open- label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven (MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade $3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow- up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade $3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192. Research Sponsor: AstraZeneca.

Savolitinib (n = 33) Sunitinib (n = 27) PFS events, n (%) 17 (52) 20 (74) Median PFS (95% CI), mo 7.0 (2.8, NR) 5.6 (4.1, 6.9) HR (95% CI) 0.71 (0.37, 1.36); p = 0.313 Deaths, n (%) 9 (27) 13 (48) Median OS (95% CI), mo NR (11.9, NR) 13.2 (7.6, NR) HR (95% CI) 0.51 (0.21, 1.17); p = 0.110 ORR n (%) [95% CI] 9 (27) [13.3, 45.5] 2 (7) [0.9, 24.3] All partial responses NR, not reached

5003 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

Phase II study of the oral HIF-2a inhibitor MK-6482 for Von Hippel-Lindau disease– associated renal cell carcinoma.

Eric Jonasch, Frede Donskov, Othon Iliopoulos, Wendy Kimryn Rathmell, Vivek Narayan, Benjamin Louis Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Sarah J. Welsh, Sanjay Thamake, Eric Kristopher Park, Naseem J. Zojwalla, Rodolfo F. Perini, W. Marston Linehan, Ramaprasad Srinivasan; The University of Texas MD Anderson Cancer Center, Houston, TX; Aarhus University Hospital, Aarhus, Denmark; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Vanderbilt University, Nashville, TN; University of Pennsylvania, Phila- delphia, PA; University of Utah, Salt Lake City, UT; Hopitalˆ Europ´een Georges-Pompidou, Paris, France; University of Michigan, Ann Arbor, MI; University of Pittsburgh, Pittsburgh, PA; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Peloton Therapeutics Inc., Dallas, TX, a subsidiary of Merck & Co., Inc., Kenilworth, NJ; Merck & Co., Inc., Kenilworth, NJ; National Cancer Institute, Bethesda, MD; Center for Cancer Research, National Cancer Institute, Bethesda, MD

Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2a transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2a inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788). Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability. Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7- 14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily ($20%) anemia (83.6%; considered an on-target- toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness). Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK-6482 in VHL disease. Clinical trial information: NCT03401788. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

5004 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

Results from a phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer.

Ramaprasad Srinivasan, Sandeep Gurram, Munjid Al Harthy, Eric A. Singer, Abhinav Sidana, Brian M. Shuch, Mark Wayne Ball, Julia C. Friend, Lisa Mac, Erin Purcell, Cathy Vocke, Heidi H Kong, Edward W. Cowen, Peter L. Choyke, Ashkan A. Malayeri, Lori Long, Joanna H. Shih, Maria J. Merino, W. Marston Linehan; Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Bethesda, MD; Dermatology Branch, National Institute of Arthritis and Musculo- skeletal and Skin Diseases, National Institutes of Health, Bethesda, MD; Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; National Institutes of Health, Clinical Center, Radiology and Imaging Sciences, Bethesda, MD; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

Background: HLRCC is a familial cancer syndrome associated with a type 2 papillary RCC (pRCC) variant. HLRCC is caused by germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH). FH inactivation results in VHL-independent upregulation of hypoxia inducible factor, a reliance on aerobic glycolysis, and activation of the NRF2 pathway, features also shared by some sporadic pRCC tumors. We hypothesized that the metabolic alterations underlying these tumors would be susceptible to targeted therapy with a combination of bevacizumab and erlotinib. Methods: Patients with advanced pRCC were eligible to enroll on this phase II study. To enrich for patients with FH deficiency, those with 1) HLRCC and 2) sporadic pRCC were enrolled into parallel, independent cohorts. All patients received bevacizumab 10 mg/kg IV every 2 weeks and erlotinib 150 mg orally daily. Patients who had received no more than two agents targeting the VEGFR pathway were included. Patients remained on treatment until unacceptable toxicity or progression. The primary endpoint was overall response rate (ORR); secondary endpoints were progression free survival (PFS) and duration of response. Results: A total of 83 patients with pRCC, including 42 in the HLRCC cohort and 41 in the sporadic cohort were enrolled on study. The majority of patients were IMDC intermediate risk (53/83, 64%) and 27 (33%) had at least one prior treatment. The ORR was 51% (42/83; 95% CI, 40 – 61) in all patients, 64% (27/42; 95% CI, 49 – 77) in the HLRCC cohort, and 37% (15/41; 95% CI, 24 – 52) in the sporadic cohort. The median PFS was 14.2 months (95% CI, 11.4 – 18.6) in all patients, 21.1 months (95% CI, 15.6 – 26.6) in the HLRCC cohort, and 8.7 months (95% CI, 6.4 – 12.6) in the sporadic cohort. The majority of treatment related adverse events (TRAEs) were grade 1 or 2 with the most common being acneiform rash (92%), diarrhea (77%), proteinuria (71%), and dry skin (61%). Grade $3 TRAEs occurred in 47% of patients, including hypertension (34%) and proteinuria (13%), with one patient (1.2%) with a grade 5 GI hemorrhage possibly related to bevacizumab. Conclusions: The combination of bevacizumab and erlotinib is well tolerated and is associated with encouraging activity in advanced pRCC, particularly in patients with FH deficient tumors. This is the first and largest prospective study in HLRCC and provides the basis for considering bevacizumab and erlotinib as a preferred option in a patient population that has no widely accepted standard. Clinical trial information: NCT01130519. Research Sponsor: U.S. National Institutes of Health, U.S. National Institutes of Health, This research was supported [in part] by the Intramural Research Program of the National Cancer Institute. Funded by the NCI Contract No. [HHSN261200800001E, 75N910D00024, Task Order No. (75N91019F00129)]. Genentech-Roche provided study drug but not funding.

5005 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

Optimized management of nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma (RCC): A response-based phase II study (OMNIVORE).

Rana R. McKay, Wanling Xie, Bradley Alexander McGregor, David A. Braun, Xiao X. Wei, Christos Kyriakopoulos, Yousef Zakharia, Benjamin Louis Maughan, Tracy L Rose, Walter Michael Stadler, David F. McDermott, Lauren C Harshman, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; University of Wisconsin Carbone Cancer Center, Madison, WI; University of Iowa and Holden Comprehensive Cancer Center, Iowa City, IA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; The University of North Carolina at Chapel Hill (UNC-CH) School of Medicine and UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; The University of Chicago, Chicago, IL; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Stanford University School of Medicine, Stanford, CA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-na¨ıve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-na¨ıve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at $ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473. Research Sponsor: BMS.

Ipi Added in NR Arm B Induction Nivo (n=83) (n=57) PR 9 (11%) 2 (4%) uPR 3 (4%) 0 SD 36 (43%) 24 (42%) PD 35 (42%) 23 (40%) Unevaluable 8 (14%)

5006 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-na¨ıve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).

Michael B. Atkins, Opeyemi Jegede, Naomi B. Haas, David F. McDermott, Mehmet Asim Bilen, Charles G. Drake, Jeffrey Alan Sosman, Robert S. Alter, Elizabeth R. Plimack, Brian I. Rini, Michael E. Hurwitz, David J. Peace, Sabina Signoretti, Catherine J. Wu, Paul J. Catalano, Hans J. Hammers; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Dana Farber Cancer Institute, Boston, MA; Penn Medicine Abramson Cancer Center, Philadelphia, PA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Herbert Irving Comprehensive Cancer Center, New York, NY; Vanderbilt University Ingram Cancer Center, Nashville, TN; Northern New Jersey Cancer Center, Englewood, NJ; Fox Chase Cancer Center, Philadelphia, PA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Yale School of Medicine, New Haven, CT; University of Illinois at Chicago, Chicago, IL; Department of Pathology, Brigham and Women’s Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX

Background: Nivolumab (nivo) is FDA approved for pts with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment na¨ıve pts with IMDC intermediate and poor risk RCC. Little information is available on the efficacy and toxicity of nivo monotherapy in treatment na¨ıve RCC or the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment na¨ıve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to Part B. Pathology specimens will be analyzed by immunohistochemistry, quantitative immunofluorescence, WES and RNAseq with results linked to clinical outcome. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 65 (range 32-86 years); 72% male. IMDC favorable 30 (25%), intermediate 79 (65%) and poor risk 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). 117 pts are currently evaluable for response. RECIST defined ORR was: 34 (29.3%)[CR 5 (4.3%), PR 29 (24.8%)], SD 47 (40.2%), PD 36 (30.7%). ORR by irRECIST was 35%. ORR by IMDC was: favorable 12/29 (41.4%), intermediate/poor 22/87 (25.3%) and for SARC 6/22 (27.3%). Median DOR is 13.8 (10.9, NA) mo. Median PFS is 7.4 (5.5, 10.9) mo. 110 pts remain alive. 60 pts (54 PD, 6 pSD) to date were potentially eligible for salvage nivo/ipi (Part B), but 28 did not enroll due to symptomatic PD (17), grade 3-4 toxicity on nivo (8), other (3). 27 of 32 Part B pts are currently evaluable for efficacy and 30 for toxicity. Best response to nivo/ipi was PR (11%), SD (30%), PD (59%). ORR by irRECIST was 19%. Grade 3-5 Treatment-related AEs (TrAE) were seen in 35/123 (28)% on nivo with 1 death due to respiratory failure. Grade 3-4 TrAE were seen in 10/30 (33%) on nivo/ipi with 0 deaths. Correlative studies are pending. Conclusions: Nivo monotherapy is active in treatment na¨ıve ccRCC across all IMDC groups. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi after nivo monotherapy was feasible in 53% of pts with PD/ pSD, with 11% responding. Clinical trial information: NCT03117309. Research Sponsor: Bristol Meyers Squibb.

5007 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC).

Toni K. Choueiri, Harriet M. Kluger, Saby George, Scott S. Tykodi, Timothy M. Kuzel, Ruth Perets, Suresh Nair, Giuseppe Procopio, Michael Anthony Carducci, Vincent Castonguay, Edmund Folefac, Chung-Han Lee, Sebastien J. Hotte, Wilson H. Miller, Shruti S. Saggi, David Gold, Robert J. Motzer, Bernard Escudier; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Yale School of Medicine and Smilow Cancer Center, Yale New Haven Hospital, New Haven, CT; Roswell Park Cancer Institute, Buffalo, NY; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Rush University Medical Center, Chicago, IL; Rambam Health Care Campus, Haifa, Israel; Lehigh Valley Health Network, Allentown, PA; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; Hotel Dieu de Quebec, Quebec, QC, Canada; The Ohio State University Comprehensive Cancer Center, Division of Medical Oncology, Columbus, OH; Memorial Sloan Kettering Cancer Center, New York, NY; Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; Jewish General Hospital, McGill University, Montreal, QC, Canada; Bristol-Myers Squibb, Princeton, NJ; Gustave Roussy, Villejuif, France

Background: The immuno-oncology (I-O) combination nivolumab + ipilimumab (NIVO+IPI) is approved for first-line (1L) and NIVO is approved for second-line treatment post TKI therapy in aRCC. The open- label, randomized, phase 2 Fast Real-Time Assessment of Combination Therapies in Immuno-Oncology (FRACTION-RCC; NCT02996110) platform study has an adaptive design allowing rapid evaluation of I- O therapies, including NIVO+IPI or other investigational combinations. This FRACTION analysis reports preliminary outcomes with NIVO+IPI in aRCC pts after progression on checkpoint inhibitor therapy. Methods: All pts, except 1, had previously received and progressed on checkpoint inhibitor treatment. Pts received NIVO+IPI (NIVO 3 mg/kg + IPI 1 mg/kg Q3W 34, then after 6 weeks, NIVO 480 mg Q4W), up to 2 years or until progression, toxicity, or protocol-specified discontinuation. Primary endpoints were confirmed objective response rate (ORR; per investigator using RECIST v1.1), duration of response (DOR), and progression-free survival probability at week 24. Safety outcomes were reported. Results: 46 pts were randomized to NIVO+IPI. Pts had 0 (n = 1), 1 (n = 10), 2 (n = 12), 3 (n = 10), or $4 (n = 13) prior lines of therapy. All pretreated pts had prior anti-PD-(L)1-, none had prior anti-CTLA-4- therapy, and 37 had prior TKI-based therapy; 45 pts progressed on anti-PD-(L)1 as the most recent therapy. Most pts had clear cell aRCC (n = 44). After a median study follow-up of 8.9 months, ORR was 15.2%; no pts achieved complete response and 7 achieved partial response. DOR ranged from 2–19+ months (n = 7); 5 pts had ongoing response. Six of 7 responders had received $2 prior lines of therapy. Any-grade treatment-related adverse events (AEs) were reported in 36 pts (78.3%; fatigue, rash [both 19.6%], and diarrhea [17.4%] were most common). Grade 3–4 treatment-related AEs were reported in 13 pts (28.3%; diarrhea [8.7%], ↑amylase and ↑lipase [both 6.5%] were most common). Treatment- related immune-mediated AEs of any grade were reported in 22 pts (47.8%; rash [19.6%], diarrhea [17.4%], and ↑alanine aminotransferase [8.7%]). No treatment-related deaths were reported. Updated and expanded results with an additional 3 months of follow-up will be presented. Conclusions: These results suggest that NIVO+IPI may provide durable partial response in some pts with prior progression on checkpoint inhibitors, including some heavily pretreated pts. The safety profile of NIVO+IPI in FRACTION pts was similar to historic data in aRCC with this combination. Clinical trial information: NCT02996110. Research Sponsor: Bristol-Myers Squibb.

5008 Oral Abstract Session, Fri, 8:00 AM-11:00 AM

Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC).

Chung-Han Lee, Amishi Yogesh Shah, James J Hsieh, Arpit Rao, Alvaro Pinto, Mehmet Asim Bilen, Allen Lee Cohn, Christopher Di Simone, David R. Shaffer, Regina Girones Sarrio, Sara Gunnestad Ribe, Jane Wu, Emmett V. Schmidt, Rodolfo F. Perini, Peter Kubiak, Alan D. Smith, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; MD Anderson Cancer Center, University of Texas, Houston, TX; Washington University School of Medicine, St. Louis, MO; Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Hospital Universitario La Paz, Madrid, Spain; Winship Cancer Institute of Emory University, Atlanta, GA; Rocky Mountain Cancer Center, Denver, CO; Arizona Oncology Associates, Tucson, AZ; New York Oncology Hematology, Albany, NY; Medical Oncology Service, Hospital Universitari i Politecnic ` La FE, Valencia, Spain; Sorlandet Hospital Kristiansand, Kristiansand, Norway; Eisai Inc., Woodcliff Lake, NJ; Merck & Co., Inc., Kenilworth, NJ; Eisai Ltd., Hatfield, United Kingdom

Background: LEN, a multikinase VEGFR inhibitor, plus everolimus is approved for advanced RCC after prior VEGF-targeted therapy. PEMBRO, an anti-PD-1 antibody, plus axitinib is approved as first-line therapy of advanced RCC. We report phase 2 results of the RCC cohort of a phase 1b/2 trial (Study 111/ KEYNOTE-146) of LEN + PEMBRO in patients (pts) who progressed after ICI therapy. Methods: We performed a multicenter, open-label study of pts with mccRCC, who previously had disease progression by RECIST (confirmed $ 4 weeks later) during or following ICI therapy. Pts had measurable disease by immune-related RECIST, and $ 1 prior therapy. Pts received LEN 20 mg orally once daily plus PEMBRO 200 mg IV every 3 weeks until disease progression or toxicity. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks. The primary endpoint was objective response rate (ORR) at Week 24 by irRECIST. Results: 104 pts were enrolled. At data cutoff (January 12, 2020), 71 (69%) pts were still on study treatment. Most pts had $2 prior anticancer regimens (58%). 91 of 104 pts were evaluable for response at Week 12 (13 pts NE at Week 12); 46 of 91 pts achieved a confirmed partial response for an ORR of 51% (Table). Median progression-free survival (PFS) was 11.7 months and median duration of response (DOR) was 9.9 months. The most common treatment-related adverse events (TRAEs) were fatigue (49%), diarrhea (44%), proteinuria (37%), hypertension (31%), nausea (31%), dysphonia (29%), stomatitis (29%), and arthralgia (27%). There was 1 grade 5 TRAE (upper gastrointestinal hemorrhage). 43% of pts required dose reduction and 12% of pts discontinued treatment due to TRAEs. Response and safety data will be updated to include all pts evaluable at an April 9, 2020 cut-off. Conclusions: LEN + PEMBRO demonstrated promising antitumor activity in pts with mccRCC with disease progression following ICI therapy. No new safety signals were detected. Efficacy outcomes by investigator review per irRECIST. Clinical trial information: NCT02501096. Research Sponsor: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA.

Parameter LEN + PEMBRO (n=91)a

ORR(week 12), % (95% CI) 51 (39.9–61.2) Disease control rateb, % (95% CI) 91 (83.4–96.1) Median DOR, months (95% CI) 9.9 (6.9–NE) Median time to response, months (range) 1.6 (1.2–7.6) Parameter LEN + PEMBRO (n=103)c Median PFS, months (95% CI) 11.7 (9.5–NE) Median PFS follow-up time, months (95% CI) 5.7 (5.5–7.8) aPatients followed for $12 weeks for response evaluation bComplete response + partial response + stable disease (duration $ 5 weeks) cTotal n as of data cutoff

5009 Clinical Science Symposium, Fri, 8:00 AM-9:30 AM

Biomarker analyses from the phase III CheckMate 214 trial of nivolumab plus ipilimumab (N+I) or sunitinib (S) in advanced renal cell carcinoma (aRCC).

Robert J. Motzer, Toni K. Choueiri, David F. McDermott, Thomas Powles, Jin Yao, Ron Ammar, Simon Papillon-Cavanagh, Shruti S. Saggi, Brent M. McHenry, Petra Ross-Macdonald, Megan Wind- Rotolo; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Barts Cancer Centre, London, United Kingdom; Bristol-Myers Squibb, Princeton, NJ

Background: In CheckMate 214 (NCT02231749), N+I demonstrated superior clinical outcomes vs S in patients (pts) with aRCC. Here, we report exploratory biomarker analyses of pretreatment tumor samples relative to outcomes. Methods: Formalin-fixed, paraffin-embedded aRCC samples were characterized by immunohistochemistry (tumor programmed death ligand 1 [PD-L1], n = 992; PD- L1 combined positive score [CPS], n = 980), whole exome sequencing (WES; tumor mutational burden, indel burden, HLA class I zygosity, and PBRM1 mutation status; n = 481), and RNAseq (n = 213). Gene signature scores were calculated as the median value of Z-scored expression for transcripts. Association with outcome was tested using Fisher s exact test and Cox proportional hazards model. With $ 42 mo follow-up, prolonged progression-free survival (PFS) with N+I ( , or $ 18 mo; n = 82 vs 27, respectively) was analyzed by limma and gene set enrichment analysis of Hallmark gene sets (MSigDB). Results: PD-L1 CPS did not have improved predictive power over tumor PD-L1. The WES-derived biomarkers were not associated with outcomes in pts treated with N+I or S. For the RNAseq cohort, objective response rates (ORR) for pts with $ median scores, and hazard ratios (HR) relative to , median are shown (Table). A higher angiogenesis (Angio) gene signature score was associated with higher ORR and PFS for S; lower Angio score was associated with higher ORR in N+I. Immune signature scores were not predictive for ORR in N+I. Prolonged PFS with N+I ($ 18 mo, n = 27) was associated with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition (EMT) gene sets (both adjusted P = 0.002). Conclusions: The Angio gene signature was associated with ORR for S (high score) and N+I (low score). Prolonged PFS in 27 pts receiving N+I was linked with inflammation (consistent with findings from PD-1 blockade monotherapy), but associated with EMT-related transcripts (in contrast with findings in other tumor types). Further validation of these exploratory analyses will be required. Clinical trial information: NCT02231749. Research Sponsor: Bristol-Myers Squibb.

ORR N+I, ORR S, PFS N+I, PFS S, % % HR (95% CI) HR (95% CI) RNAseq cohort 32 28 (n = 213) Angio1 19a 40a 1.23 (0.791.92) 0.58a (0.370.92) T-effector1 39 27 1.08 (0.691.68) 0.88 (0.551.40) Myeloid1 38 29 0.79 (0.511.23) 1.04 (0.661.65) TIS2 39 29 0.88 (0.571.37) 0.81 (0.511.28) Javelin3 38 30 0.95 (0.611.48) 1.01 (0.641.59) aP , 0.05. 1. Nat Med 24:749; 2. J Immunother Cancer 6:63; 3. J Clin Oncol 37(suppl 15):101.

5010 Clinical Science Symposium, Fri, 8:00 AM-9:30 AM

Immunogenomic characterization of advanced clear cell renal cell carcinoma treated with PD-1 blockade.

David A. Braun, Yue Hou, Ziad Bakouny, Miriam Ficial, Miriam Sant’Angelo, Petra Ross-Macdonald, Opeyemi Jegede, Maxine Sun, Megan Wind-Rotolo, Jean-Christophe Pignon, Donna S. Neuberg, Paul J. Catalano, Gordon J. Freeman, Arlene Sharpe, David F. McDermott, Eliezer Mendel Van Allen, Sabina Signoretti, Catherine J. Wu, Sachet A. Shukla, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Brigham and Women’s Hospital, Boston, MA; Bristol-Myers Squibb, Princeton, NJ; Dana Farber Cancer Institute, Boston, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Harvard Medical School, Boston, MA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Background: Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Further, the common paradigm in solid tumor immunology that pre-existing CD8+ T cell infiltration, in combination with high numbers of nonsynonymous mutations (which, in the context of diverse HLA class I alleles, may be presented as neoantigens) drives response to PD-1 blockade, has not been thoroughly explored in ccRCC. Methods: We analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials (CheckMate 009, CheckMate 010, CheckMate 025) of treatment with PD-1 blockade (n = 362) or mTOR inhibition (as control arm; n = 230) by whole-exome (n = 454) and RNA-sequencing (n = 311), integrated with CD8 immunofluorescence analysis (n = 219), to uncover the immunogenomic deter- minants of therapeutic response and survival. Wilcoxon rank-sum test was used to compare somatic alteration burden between clinical benefit (CB) v.s no CB (NCB); Fisher’s exact test was used to compare mutations and copy number alteration by infiltration state; and hazard ratio (HR) was calculated from Cox PH model for progression-free (PFS) and overall survival (OS) endpoints. All tests were at a significance level of p , 0.05. Results: Conventional genomic markers (tumor mutation burden, p = 0.81; neoantigen load, p = 0.47 for CB vs. NCB) and degree of CD8+ T cell infiltration (p = 0.88 for PFS; p = 0.65 for OS) were not associated with clinical response or altered survival with PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 22% having an immune desert phenotype and 5% with an immune excluded phenotype. Our analysis revealed that CD8+ T cell infiltrated tumors are depleted of clinically favorable PBRM1 mutations (p = 0.013) and enriched for unfavorable chromosomal losses of 9p21.3 (p , 0.001) when compared to non-infiltrated tumors. When found within infiltrated tumors, del(9p21.3) was associated with worse CB rate (36% (9/ 25) for del(9p21.3) vs. 88% (7/8) for wildtype at that locus, p = 0.017) and worse survival (HR = 2.38, p = 0.01 for PFS; HR = 2.44, p = 0.01 for OS) with PD-1 blockade. Conclusions: These data demonstrate how the potential interplay of immunophenotypes with somatic mutations and chromosomal alterations impacts therapeutic efficacy in advanced ccRCC. Research Sponsor: Department of Defense (CDMRP), U.S. National Institutes of Health, Bristol Myers-Squibb.

5011 Clinical Science Symposium, Fri, 8:00 AM-9:30 AM

Tumor, immune, and stromal characteristics associated with clinical outcomes with atezolizumab (atezo) + platinum-based chemotherapy (PBC) or atezo monotherapy (mono) versus PBC in metastatic urothelial cancer (mUC) from the phase III IMvigor130 study.

Matt D. Galsky, Romain Banchereau, Habib Rahman Hamidi, Ning Leng, Will Harris, Peter H. O’Donnell, Edward Ernest Kadel, Kobe Chi Yung Yuen, Dexter Jin, Hartmut Koeppen, Darren Tayama, Enrique Grande, Jose Arranz, Maria De Santis, Ian D. Davis, Eiji Kikuchi, Xiaodong Shen, Aristotelis Bamias, Sanjeev Mariathasan; Mount Sinai Hospital, New York, NY; Genentech, Inc., South San Francisco, CA; University of Chicago Comprehensive Cancer Center, Chicago, IL; Stowers Institute for Medical Research, Kansas City, MO; Foundation Medicine, Cambridge, MA; Genentech, South San Francisco, CA; MD Anderson Cancer Center Madrid, Madrid, Spain; Hospital General Universitario Gregorio Mara~non, Madrid, Spain; LBI-ACR Vienna, Kaiser Franz Josef Hospital, Center for Oncology and Hematology, Vienna, Austria; Monash University Eastern Health Clinical School, Victoria, Australia; Department of Urology, Keio University School of Medicine, Tokyo, Japan; National and Kapodistrian University of Athens, Athens, Greece

Background: Tumor mutational burden (TMB), PD-L1 expression, T-effector gene expression (GE) and a fibroblast TGF-b–response signature (F-TBRS) are associated with clinical outcomes with atezo mono in mUC (Mariathasan, Nature, 2018). Here we explore the potential predictive role of these biomarkers and APOBEC mutagenesis in IMvigor130. Methods: Pts receiving first-line (1L) mUC treatment (tx) were randomized 1:1:1 to atezo + PBC, atezo mono, or placebo + PBC. Coprimary efficacy endpoints were PFS and OS. Planned exploratory biomarker analyses included PD-L1 expression, TMB (Foun- dationOne), and T-effector GE (RNA-seq). Results: The 851 biomarker-evaluable pts (BEP) were representative of the 1200 ITT pts. Biomarker results are shown in Table. PD-L1 IC2/3 was associated with significantly longer OS for atezo mono vs placebo + PBC and a combination of PD-L1 IC2/3, and high TMB (. 10 muts/Mb) identified a pt subset (» 14% of BEP) with particularly favorable outcomes with atezo mono vs placebo + PBC; similar results for PD-L1 and TMB were not seen with atezo + PBC vs placebo + PBC. APOBEC mutagenesis was associated with improved OS with atezo-containing regimens whereas high F-TBRS was associated with inferior OS with atezo mono. Conclusions: These results reinforce the potential predictive nature of biomarkers associated with response/resistance to atezo and highlight potentially distinct biology driving benefit with atezo and atezo + PBC. These findings suggest a possible biomarker-directed approach to 1L mUC tx that warrants mechanistic interrogation and prospective validation. Clinical trial information: NCT02807636. Research Sponsor: F. Hoffmann-La Roche.

Interim OS in ITT pts and BEP. Interim OS HR (95% CI)a; Sample size (n) Atezo + PBC vs PBC Atezo vs PBC ITT 0.83 (0.69, 1.00); n = 1.02 (0.83, 1.24); n = 851 719 BEP 0.84 (0.67, 1.04); n = 0.91 (0.73, 1.15); n = 599 539 PD-L1 IC2/3b 0.73 (0.47, 1.14); n = 0.59 (0.36, 0.96); n = 167 143 TMBhigh (> 10 muts/Mb) 0.82 (0.58, 1.17); n = 0.71 (0.49, 1.03); n = 248 236 PD-L1 IC2/3 + TMBhigh 0.88 (0.48, 1.62); n = 94 0.22 (0.08, 0.63); n = 77 APOBEChigh 0.46 (0.26, 0.84); n = 0.42 (0.23, 0.78); n = 112 109 T-effector GE (top 0.79 (0.51, 1.24); n = 0.58 (0.33, 1.02); n = quartile) 161 132 F-TBRShigh (top quartile) 1.13 (0.73, 1.72); n = 1.92 (1.24, 2.99); n = 155 136 aHRs for the BEP are for descriptive purposes only. b PD-L1 expression on immune cells (IC; VENTANA SP142 IHC assay) $ 5%.

5012 Clinical Science Symposium, Fri, 8:00 AM-9:30 AM

DUTRENEO Trial: A randomized phase II trial of DUrvalumab and TREmelimumab versus chemotherapy as a NEOadjuvant approach to muscle-invasive urothelial bladder cancer (MIBC) patients (pts) prospectively selected by an interferon (INF)-gamma immune signature.

Enrique Grande, Felix ´ Guerrero, Javier Puente, Isabel Galante, Ignacio Duran, Mario Dominguez, Teresa Alonso Gordoa, Javier Burgos, Albert Font, Alvaro Pinto, Mario Alvarez-Maestro, Oscar Reig, Jose ´ Maroto, Xavier Garcia del Muro, Patricia Galvan, Juan Fernando Garcia, Nuria Malats, Aleix Prat, Francisco X. Real, Daniel Castellano; MD Anderson Cancer Center Madrid, Madrid, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital Universitario Clı´nico San Carlos, Madrid, Spain; Hospital Clı´nico San Carlos, Madrid, Spain; Department of Medical Oncology, Hospital Universitario Marques ´ de Valdecilla, Santander, Spain; Hospital Universitario Marques de Valdecilla, Santander, Spain; Hospital Universitario Ramon ´ y Cajal, Madrid, Spain; Hospital Ramon ´ y Cajal, Madrid, Spain; Institut Catalad ` ’Oncologia, Hospital Universitari Germans Trias i Pujol (HUGTiP), Badalona, Spain; Department of Medical Oncology, La Paz University Hospital, Madrid, Spain; Hospital Universitario La Paz, Madrid, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumours Lab, Institut d’Investigacions Biomediques ` August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital de Sant Pau, Barcelona, Spain; Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain; IDIBAPS, Hospital Clinic, Barcelona, Spain; MD Anderson Cancer Center, Madrid, Spain; Spanish National Cancer Research Centre, Madrid, Spain; Department of Medical Oncology, Hospital Clinic, Barcelona, Spain; Centro Nacional de Investigaciones Oncologicas, ´ Madrid, Spain

Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N#1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve $8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro- inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274. Research Sponsor: AstraZeneca.

COLD: CT (N = HOT: CT (N = HOT: DU+TRE (N = 16) 22) 23) Pathologic complete 11 (68.8%) 8 (36.4%) 8 (34.8%) response Progressive disease 0 (0.0%) 2 (9.1%) 1 (4.3%) pCRs in PDL1 high (%) 50.0% 60.0% 57.1% pCRs in PDL1 low (%) 90.0 60.0% 14.3% Completed cystectomy 15 (93.8%) 20 (90.9%) 20 (87.0%) Grade 3-4 toxicities 10 (62.5%) 8 (36.4%) 5 (21.7%)

5013 Poster Discussion Session; Displayed in Poster Session (Board #82), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study.

Sumanta K. Pal, Neeraj Agarwal, Yohann Loriot, Cristina Suarez Rodriguez, Parminder Singh, Ulka N. Vaishampayan, Elizabeth Mcilvaine, Dominic Curran, Daniel Castellano, Andrea Necchi; City of Hope Comprehensive Cancer Center, Duarte, CA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Vall d’Hebron Institute of Oncology, Universitat Autonoma ` de Barcelona, Barcelona, Spain; Mayo Clinic, Phoenix, AZ; Karmanos Cancer Institute, Detroit, MI; Exelixis Inc, Alameda, CA; Exelixis, Inc, Alameda, CA; Hospital Universitario 12 de Octubre, Madrid, Spain; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Background: Cabozantinib (C), an inhibitor of MET, AXL, and VEGFR, has been shown to promote an immune-permissive environment and has shown promising clinical activity in combination with immune checkpoint inhibitors (ICIs) in solid tumors including renal cell carcinoma and urothelial carcinoma (UC). ICI monotherapy is approved for patients (pts) with locally advanced or metastatic UC with disease progression after platinum-containing chemotherapy. COSMIC-021, a multi-center phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from Cohort 2 in UC pts with prior platinum-containing chemotherapy. Methods: Eligible pts had ECOG PS 0-1 and had progressed on or after a platinum-containing chemotherapy (including pts with disease recurrences , 12 months after the end of perioperative chemotherapy). Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response (DOR), PFS, and OS. Results: As of Dec 20, 2019, 30 pts with advanced UC were enrolled with a median follow-up of 16.5 mo (range 12, 21). Median age was 66 yrs (range 44, 84), 73% were male, and 60% had ECOG PS 1. Primary tumor sites were bladder (80%), renal pelvis (10%), and ureter (10%); the most frequent metastatic sites included lung (40%) and liver (27%). Fourteen pts (47%) had received $2 prior systemic anticancer therapies. The most common treatment-related AEs (TRAEs) of any grade were asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%). Grade 3/4 TRAEs occurred in 57% of pts, with no grade 5 TRAEs. Confirmed ORR per RECIST v1.1 was 27% (8 of 30 pts), including 2 pts with CR. DCR (CR+PR+SD) was 64%. Median DOR was not reached, with the longest DOR ongoing at 14.3+ mos. Median PFS was 5.4 mo (range 0.0+, 17.3+). Conclusions: C in combination with A demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. Additional cohorts of pts with advanced UC are being explored in the study. Clinical trial information: NCT03170960. Research Sponsor: Exelixis Inc.

5014 Poster Discussion Session; Displayed in Poster Session (Board #83), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Safety and preliminary efficacy of rogaratinib in combination with atezolizumab in a phase Ib/II study (FORT-2) of first-line treatment in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression.

Jonathan E. Rosenberg, Pablo Gajate, Rafael Morales-Barrera, Jae-Lyun Lee, Andrea Necchi, Nicolas Penel, Vittorina Zagonel, Mitchell Robert Sierecki, Ana-Maria Piciu, Peter Ellinghaus, Randy F. Sweis; Memorial Sloan Kettering Cancer, New York, NY; Medical Oncology Department, Ramon ´ y Cajal University Hospital, Madrid, Spain; Vall d’Hebron Institute of Oncology, Vall d’ Hebron University Hospital, Universitat Autonoma ` de Barcelona, Barcelona, Spain; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Medical Oncology, Centre Oscar Lambret, Lille, France; Oncologia Medica 1, Istituto Oncologico Veneto IRCCS Padova, Padua, Italy; Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ; Chrestos Concept GmbH & Co. KG, Essen, Germany; Bayer AG, Berlin, Germany; University of Chicago, Chicago, IL

Background: Programmed cell-death ligand 1 (PD-L1) overexpression is a mechanism for immune escape in UC. Rogaratinib, an oral pan-FGFR1-4 inhibitor, showed promising efficacy in a Phase I study in pts with solid tumors, including UC, with FGFR1-3 mRNA overexpression (Schuler et al. Lancet Oncol 2019). This Phase Ib/II study is evaluating rogaratinib in combination with atezolizumab, a PD- L1 inhibitor, in pts with FGFR-positive, locally advanced or metastatic UC (NCT03473756). We report results from the Phase Ib study. Methods: Cisplatin-ineligible pts with untreated metastatic UC were eligible if high FGFR1 or 3 mRNA was detected by RNA in situ hybridization of archival tissue (RNAscope). Pts were treated at a starting dose of rogaratinib 800 mg p.o. BID and atezolizumab 1200 mg i.v. on day 1 (21-day cycle). Primary objectives were safety, tolerability, and determination of the recommended Phase II dose. Results: 27 pts were treated (rogaratinib 800 mg + atezolizumab, n = 11; rogaratinib 600 mg + atezolizumab, n = 16); 85% were male, median age was 72 years (range 47- 83), 37% had an ECOG PS of 1, and 96% had negative/low PD-L1 expression. Most common treatment-emergent adverse events (TEAEs) were diarrhea (63%), hyperphosphatemia (44%), and urinary tract infection (37%). Dose interruption/reduction due to AEs occurred in 67%/37% of pts; TEAEs lead to discontinuation in 45.5% (800 mg) and 12.5% (600 mg). Most common grade 3/4 TEAEs were increased lipase without pancreatitis (11%), rash, and increased alanine aminotransferase (7% each). Rogaratinib-related unique TEAEs were hyperphosphatemia (44%) and retinal pigment epithelium detachment (4%). The maximum tolerated dose (MTD) was rogaratinib 600 mg BID based on lower overall frequency of AEs. Of 23 evaluable pts (600 mg, n = 13; 800 mg, n = 10), overall 9 (39%) pts had an objective response (RECIST v1.1); 3 (13%) pts had a complete response (600 mg: 2/ 13 pts), 6 (26%) pts had a partial response (600 mg: 5/13 pts), and 6 (26%) pts had stable disease (600 mg: 4/13 pts). Conclusions: Rogaratinib with atezolizumab showed promising efficacy and safety in cisplatin-ineligible pts with tumor FGFR1 or 3 mRNA-positive UC, with nearly all pts demonstrating low or negative PD-L1 expression. Pts are being enrolled at the MTD of rogaratinib 600 mg BID plus atezolizumab. Clinical trial information: NCT03473756. Research Sponsor: Bayer AG. Writing support provided by Complete HealthVizion.

5015 Poster Discussion Session; Displayed in Poster Session (Board #84), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

ERDAFITINIB in locally advanced or metastatic urothelial carcinoma (mUC): Long-term outcomes in BLC2001.

Arlene O. Siefker-Radtke, Andrea Necchi, Se Hoon Park, Jesus ´ Garcı´a-Donas, Robert A Huddart, Earle Frederick Burgess, Mark T. Fleming, Arash Rezazadeh, Begona Mellado, Sergei Varlamov, Monika Joshi, Ignacio Duran, Scott T. Tagawa, Yousef Zakharia, Min Fu, Ademi E. Santiago- Walker, Manish Monga, Anne OHagan, Silvia Mosher, Yohann Loriot, BLC2001 Study Group; The University of Texas MD Anderson Cancer Center, Houston, TX; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Samsung Medical Center, Department of Medicine, Seoul, South Korea; Fundacion Hospital de Madrid, Madrid, Spain; Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Levine Cancer Institute, Charlotte, NC; Virginia Oncology Associates, US Oncology Research, Norfolk, VA; Norton Healthcare, Louisville, KY; Hospital Clı´nic of Barcelona, Institut d’Investigacions Biomediques ` August Pi i Sunyer, Barcelona, Spain; Altai Regional Cancer Center, Barnaul, Russian Federation; Penn State Health Milton S. Hershey Medical Center, Hershey, PA; Department of Medical Oncology, Hospital Universitario Marques ´ de Valdecilla, Santander, Spain; Weill Cornell Medical College, New York, NY; University of Iowa and Holden Comprehensive Cancer Center, Iowa City, IA; Janssen Research and Development, Springhouse, PA; Janssen Research & Development, Spring House, PA; Clinical Oncology, Janssen R&D US, Springhouse, PA; Janssen Research & Development, LLC, Spring House, PA; Janssen Research and Development, San Diego, CA; Institut de Cancerologie ´ Gustave Roussy, Villejuif, France

Background: Erdafitinib (JNJ-42756493; ERDA) is the only pan-FGFR kinase inhibitor with US FDA approval for treatment of adults with mUC with susceptible FGFR3/2 alterations (alt) and who progressed on $ 1 line of prior platinum-based chemotherapy (chemo). Approval was based on data from the primary analysis of the pivotal BLC2001 trial1. Here we report long-term efficacy and safety data from the 8 mg/d continuous dose regimen in BLC2001. Methods: BLC2001 (NCT02365597) is a global, open-label, phase 2 trial of pts with measurable mUC with prespecified FGFR alt, ECOG 0-2, and progression during/following $ 1 line of prior chemo or # 12 mos of (neo)adjuvant chemo, or were cisplatin ineligible, chemo na¨ıve. The optimal schedule of ERDA determined in the initial part of the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERD 8 mg UpT) if a protocol-defined target serum phosphate level was not reached and if no significant treatment-related adverse events (TRAEs) occurred. Primary end point was the confirmed objective response rate (ORR= % complete response + % partial response). Key secondary end points were progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Results: Median follow-up for 101 patients treated with ERDA 8 mg UpT was ~24 months. Confirmed ORR was 40%. Median DOR was 5.98 mos; 31% of responders had DOR $ 1 yr. Median PFS was 5.52 mos, median OS was 11.3 mos. 12-mos and 24-mos survival rates were 49% and 31%, respectively. Median treatment duration was 5.4 mos. The ERDA safety profile was consistent with the primary analysis. No new TRAEs were seen with longer follow-up. Central serous retinopathy (CSR) events occurred in 27% (27/101) of patients; 85% (23/27) were Grade 1 or 2; dosage was reduced in 13 pts, interrupted for 8, and discontinued for 3. On the data cut-off date, 63% (17/27) had resolved; 60% (6/10) of ongoing CSR events were Grade 1. There were no treatment-related deaths. Conclusions: With a median follow-up of 2 yrs, ERDA in mUC + FGFR alt showed a manageable safety profile and consistent efficacy, with median OS of 11.3 mos. 31% had a DOR $12 mos and 31% were alive at 24 mos. ERDA monotherapy vs. immune checkpoint inhibitor (PD-1) or chemo is being further analyzed in a randomized control study (THOR; NCT03390504).Re- ference: Loriot Y, et al. N Engl J Med. 2019;381:338-48. Clinical trial information: NCT02365597. Research Sponsor: Janssen Research and Development.

5017 Poster Discussion Session; Displayed in Poster Session (Board #86), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Final results of PEANUT: Pembrolizumab and nanoparticle albumin-bound paclitaxel (nab- paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).

Patrizia Giannatempo, Giuseppina Calareso, Marco Bandini, Laura Marandino, Daniele Raggi, Elena Far`e, Maurizio Colecchia, Filippo Pederzoli, Andrea Gallina, Russell Madison, Alberto Briganti, Jeffrey S. Ross, Francesco Montorsi, Andrea Necchi; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Radiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Torino, Italy; Fonda- zione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy; Universita ` Vita-Salute San Raffaele, Milan, Italy; Vita Salute San Raffaele University and Urological Research Institute (URI), IRCCS San Raffaele Hospital, Milan, Italy; Foundation Medicine, Inc., Cambridge, MA; Foundation Medicine, Cambridge, MA; Universita Vita Salute San Raffaele, Milan, Italy

Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts received 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression (PD) or unacceptable toxicity. Inclusion criteria were: predominant UC histology, failure of #2 platinum-based CT for metastatic disease. Response was evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers included PD-L1 combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint was the progression- free survival (PFS). The target was to detect an improvement in the median PFS from #3.0 months (H0) to $5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 65 pts: 24% were female, median age was 69 yrs (IQR: 61-73); 25% had failed . 1 prior systemic therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up (FUP) of 5.5 months, 34 pts have relapsed (52.3%). The median PFS was 5 months (95%CI: 3-not reached). The 3-month PFS was 60.7% (95%CI: 49.8-74.1). The confirmed objective response-rate (ORR) was 47.7% (95%CI: 35.2-60.4): 22 partial responses and 9 complete responses (13.8%). The median duration of response was not reached, and 4 pts (6.1%) are long-term responders ( . 12 months). Grade 3 treatment-related adverse events (TRAE) were seen in 20 pts (30.7%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%) and asthenia (33%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. In matched tumor/blood samples, objective responses were seen in 8/10 pts with PI3KCA mutations (80%); 6/10 pts with RB1 alterations (60%); 5/12 pts with DNA damage repair gene alterations (41.7%). Conclusions: Pembro- nab-paclitaxel, the first salvage CT-immunotherapy combination in UC, demonstrated a good tolerability, promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. As more mature data on biomarker selection emerges, this combination warrants additional studies in either second-line or earlier disease settings. Clinical trial information: NCT03464734. Research Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Pharmaceutical/Biotech Company.

5018 Poster Discussion Session; Displayed in Poster Session (Board #87), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Phase II study of nivolumab and ipilimumab for advanced rare genitourinary cancers.

Bradley Alexander McGregor, Matthew T Campbell, Wanling Xie, Subrina Farah, Mehmet Asim Bilen, Guru Sonpavde, Kerry L. Kilbridge, Atish Dipankar Choudhury, Amir Mortazavi, Amishi Yogesh Shah, Aradhana M. Venkatesan, Glenn Bubley, Arlene O. Siefker-Radtke, Rana R. McKay, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; Dana Farber Cancer Institute/Harvard, Boston, MA; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Department of Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA; Lank Center for Genitourinary Malignancy, Dana- Farber Cancer Institute, Boston, MA; Arthur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH; Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Background: Patients with rare genitourinary malignancies (Bladder cancer of variant histologies (BCVH), adrenal tumors, chemotherapy refractory germ cell tumors (CRGCT), penile carcinoma and prostate cancer of variant histology (PCVH)) have poor outcomes. Nivolumab and ipilimumab has demonstrated safety and efficacy in genitourinary malignancies. In this multicenter, single arm, multicohort phase II trial we evaluated the efficacy of nivolumab and ipilimumab in pts with advanced rare genitourinary cancers (NCT 03333616). Herein, we report the results of the fully accrued BCVH, adrenal and other cohorts. Methods: Eligible pts had a metastatic rare genitourinary malignancy, ECOG performance status of 0-2 and no prior immune checkpoint inhibitor exposure; aside from CRGCT pts could be treatment na¨ıve. Eligible pts received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses with continued nivolumab 480 mg IV every 4 weeks. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Results: 56 pts were enrolled at 6 institutions between 4/2018 and 7/2019 in 3 cohorts: BCVH (N = 19), adrenal tumors (n = 18) and other tumors (n = 19). Median follow-up was 9.9 (range , 1~21) months. 28(50%) pts received all 4 doses of nivolumab and ipilimumab. 25 pts received nivolumab maintenance at a median of 4 (range 1-18) cycles. ORR in entire cohort was 16% (n = 9: 2 CR 7 PR, Table); 67% of responders (6/9) maintained response greater than 9 months. Median PFS was 2.8 (2.7-5.2) months. 22 pts (39%) developed treatment-related $ grade 3 toxicity; 23% required high dose steroids ($40 mg prednisone or equivalent) and 15 (27%) pts discontinued treatment due to an AE. Grade 5 toxicity occurred in 3 pts; 1 death was treatment related. Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of pts with rare GU malignancies, especially in BCVH. Biomarkers are being evaluated and an additional cohort exploring the activity in genitourinary tumors with neuroendocrine differentiation is ongoing. This combination warrants further investigation in these pts with substantial unmet needs. Clinical trial information: NCT 03333616. Research Sponsor: BMS.

CR/PR SD PD NE BCVH (n = 19): ORR 37%, 80% CI 22-54% Adenocarcinoma 13 Plasmacytoid 1 Small cell 21 Spindle cell 1 Squamous cell 222 Urachal 121 Adrenal Tumors (n = 18): ORR 6%, 80% CI 1-20% Adrenal cortical carcinoma 178 Paraganglioma 11 Other (n = 19): ORR 5%, 80% CI: 1-19% PCVH 15 Penile Carcinoma 231 CRGCT 14 Other 11 Total 916301

5019 Poster Discussion Session; Displayed in Poster Session (Board #88), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Phase II neoadjuvant (N-) gemcitabine (G) and pembrolizumab (P) for locally advanced urothelial cancer (laUC): Interim results from the cisplatin (C)-ineligible cohort of GU14- 188.

Hristos Z. Kaimakliotis, Nabil Adra, William Kevin Kelly, Edouard John Trabulsi, Richard C. Lauer, Joel Picus, Zachary L Smith, Radhika Walling, Timothy A. Masterson, Adam C Calaway, Michael O. Koch, Elizabeth Sonderman, Pingfu Fu, Gordon Goolamier, Cheryl Eitman, Lee Evan Ponsky, Christopher J. Hoimes; Indiana University Simon Cancer Center, Indianapolis, IN; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA; Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; University of New Mexico Comprehensive Cancer Center, Albu- querque, NM; Washington University in St. Louis School of Medicine, St. Louis, MO; Washington University School of Medicine, St Louis, MO; Community Cancer Center, Indianapolis, IN; Indiana University School of Medicine, Indianapolis, IN; Seidman Cancer Center at University Hospitals Cleveland Medical Center, Cleveland, OH; Department of Population and Quantitative Health Science, Case Western Reserve University, Cleveland, OH; Case Western Reserve University, Cleveland, OH; University Hospitals Seidman Cancer Center, Cleveland, OH; University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; Duke Cancer Institute, Durham, NC

Background: Patients (pts) with laUC who are C-ineligible have inferior survival compared to counterparts who receive C based N-therapy and have a pathologic response at radical cystectomy (RC). Cohort 2 (C2) of the GU14-188 trial is designed to assess the tolerability and efficacy of N- G and P in laUC pts who are C-ineligible. Methods: Eligible pts for C2 were surgical candidates and C-ineligible with cT2- 4aN0M0 bladder UC or mixed histology. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Pts were treated with N- G (1000mg/m2)on days 1, 8, and 15 of a 28 day cycle (cy) for a total of 3 cy, and overlapped with P 200mg every 3wks starting on cy 1 day 8 x 5 doses. Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of pathologic muscle invasive response rate (PaIR, #pT1N0) was assessed at RC and designed for 86% power, 4% significance to detect PaIR difference from 18 to 40%. Molecular subtyping is planned. Results: 37 pts were enrolled to C2 with a median (mdn) age of 72, 70% male, 55% . cT2. C-ineligibility was due to renal function (49%), hearing (30%), neuropathy (12%). Mdn per-pt doses given (intended) for P:5(5) and G:9(9). The PaIR was 51.6% (95%CI 0.35, 0.68), P0 (ypT0N0) rate of 45.2%, and neither correlated with baseline PD-L1 score. Downstage to PaIR occurred in 57% of pts with cT2, and 47% of . cT2. Mdn time to RC from last dose was 5.6wks. Six were not included in the primary analysis: 3 (8.1%) did not have RC due to progression (RFS censored), 2 did not receive required protocol therapy, and 1 withdrew consent. At mdn follow up of 10.8mo (4-24), the estimated 12mo RFS, OS, and DSS is 74.9%, 93.8%, and 100%, respectively. Treatment related AE included grade (gr) 3/4 neutropenia (24%), anemia (13%), and platelets (5%). There were no gr 4 non-heme AE, and of 14 (36%) pts with gr 3, 12 did not preclude RC. Of these, there were 4 gr 3 investigator assessed immune related adverse events (IAirAE) of pneumonitis (5%), colitis (3%), and AST elevation (3%). Though IAirAE improved, protocol therapy was discontinued in 3 pts: 2 did not have RC due to progression. Conclusion: N- G with P in C-ineligible pts with laUC is feasible with manageable toxicity, and has a pathologic downstage rate comparable to standard of care in the C- eligible population. G and P warrants further study with component contribution as a C- free N- option in laUC. Clinical trial information: NCT02365766. Research Sponsor: Merck & Co.

5020 Poster Discussion Session; Displayed in Poster Session (Board #89), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Biomarker analysis and updated clinical follow-up of preoperative ipilimumab (ipi) plus nivolumab (nivo) in stage III urothelial cancer (NABUCCO).

Nick Van Dijk, Alberto Gil Jimenez, Karina Silina, Kees Hendricksen, Laura Smit, Jeantine De Feijter, Maurits L van Montfoort, Annegien Broeks, Yoni Lubeck, Karolina Sikorska, Thierry N. Boellaard, Pia Kvistborg, Daniel J Vis, Erik Hooijberg, Ton Schumacher, Maries van den Broek, Lodewyk FA Wessels, Christian U. Blank, Bas W.G. van Rhijn, Michiel Simon Van Der Heijden; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Experimental Immunology, University Hospital Zurich, Zurich, Switzerland; Netherlands Cancer In- stitute (NKI-AVL), Amsterdam, Netherlands; Antoni van Leeuwenhoek Hospital, Amsterdam, Nether- lands; Netherlands Cancer Institute-The Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Statistics, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; The Netherlands Cancer Institute (NKI), Amsterdam, Netherlands; University of Zurich, Zurich, Switzerland; Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands

Background: Encouraging pathological complete response (pCR) rates were observed in trials testing neoadjuvant pembrolizumab or atezolizumab in urothelial cancer (UC). In cT3-4N0 tumors, pCR to atezolizumab was only 17% and restricted to tumors showing characteristics of preexisting T cell immunity. In NABUCCO, we aimed to increase response to pre-operative checkpoint blockade, particularly in high risk patients (pts), by combining ipi plus nivo in stage III UC. We previously reported pCR in 46% and downstaging to no remaining invasive disease in 58% (ESMO2019). Here, we present biomarker analyses and updated clinical follow-up (FU) data. Methods: Twenty four stage III (cT3-4aN0 or cT2-4aN1-3) UC pts who were unfit to receive cisplatin-based chemotherapy or refused, were treated with ipi 3 mg/kg (day 1), ipi 3 mg/kg + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. The primary endpoint was feasibility (resection , 12 weeks). Efficacy (pCR), safety and biomarker analysis were secondary endpoints. Whole-exome sequencing (WES) was done on baseline tumor samples and local lymph node (LN) metastases showing no response. RNA-seq and multiplex immunofluorescence (mIF) for immune cell markers were done pre- and post-therapy. Results: After a median FU of 15.6 months, 2 pts relapsed (both non-pCR); 1 of these 2 pts died of metastatic disease. Tumors showing complete response (CR, for biomarker analysis defined as pCR, CIS or pTa) had a significantly higher tumor mutational burden than non-CR tumors. CR to ipi+nivo was independent of baseline CD8 T-cell presence. There was no difference between CR and non-CR tumors in baseline immune gene signatures, such as interferon gamma and T-effector signatures. Surprisingly, exploratory gene expression analysis revealed that non-CR was associated with a baseline B cell immune signature, particularly immunoglobulins and genes involved in B cell receptor signaling. CD20 positive cells (by mIF) and presence of tertiary lymphoid structures (TLS) at baseline were also associated with non-CR. Upon treatment with ipi+nivo, early and mature TLS increased significantly in responding tumors. A subset of pts showed CR in the bladder, but non-CR in a local LN tumor focus. WES revealed that these LN metastases were genetically different from the primary tumor bulk. Conclusions: At 15.6 months follow-up, recurrence after pre-operative ipi+nivo was low. Pathological complete response was not restricted to tumors exhibiting preexisting T cell immunity. Clinical trial information: NCT03387761. Research Sponsor: BMS.

5021 Poster Discussion Session; Displayed in Poster Session (Board #90), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

A phase Ib trial of neoadjuvant/adjuvant durvalumab +/- tremelimumab in locally advanced renal cell carcinoma (RCC).

Moshe Chaim Ornstein, Joseph Zabell, Laura S. Wood, Brian Hobbs, Sarah Devonshire, Allison Martin, Kimberly D. Allman, Arpit Rao, Timothy D. Gilligan, Steven Campbell, Venkatesh Krishnamurthi, Brian I. Rini; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; University of Minnesota Department of Urology, Minneapolis, MN; University of Minnesota Department of Hematology, On- cology and Transplantation, Minneapolis, MN; Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, OH; Vanderbilt-Ingram Cancer Center, Nashville, TN

Background: Effective neoadjuvant and adjuvant therapies are lacking in locally advanced RCC. Given robust activity of checkpoint inhibitors in mRCC, a phase Ib trial of perioperative Durvalumab (D) +/- Tremelimumab (T) in locally advanced RCC was conducted (NCT02762006). Methods: Pts with radiographic evidence of high risk localized RCC (clinical stage T2b-4 and/or N1, M0 disease), adequate performance status, and adequate laboratory values were eligible. Primary objective was safety and feasibility of neoadjuvant/adjuvant D +/- T. Results: Twenty-nine pts were enrolled. Cohorts, regimens, and immune-related adverse events (irAE) are detailed in the table. In total, 79% male, median age 61 (range, 42-84), 8%/88%/4% clinical T2/T3/T4, 27% positive clinical lymph nodes (LN+), and median time from neoadjuvant dose to surgery was 7 days. On surgical pathology: 5%/14%/ 77%/5% pathologic T1/T2/T3/T4, and 13% LN+. Median time from treatment to first grade (Gr) .3 irAE or any Gr irAE requiring corticosteroids was 99 days (range, 32-207). There were no treatment- related delays to nephrectomy or surgical complications. Although not meeting the protocol-defined MTD, given higher than expected irAEs, the study was suspended. Conclusions: Perioperative durvalumab in locally advanced RCC appears safe. The addition of tremelimumab is associated with higher rates of toxicity. Updated toxicity will be presented. Clinical trial information: NCT02762006. Re- search Sponsor: AstraZeneca.

Cohorts and toxicity. irAE numbers represent events, not patients. [D = Durva- lumab 1500mg; Gr = grade; T = Tremelimumab 75mg]. Cohort Cohort 1 Cohort 2 Cohort 2a Cohort 3 Number of patients 6 6 8 8 Neoadjuvant Therapy D (x1) D + T (x1) D + T (x1) D + T (x1) D+T (x 1 dose) then D (x 1 Adjuvant Therapy D (x1 dose) D (x1 dose) D (x1 year) year) irAEs Gr 1-2 Gr 3-4 Gr 1-2 Gr 3-4 Gr 1-2 Gr 3-4 Gr 1-2 Gr 3-4 Elevated lipase/amylase 1 1 2121 Rash 1211 Elevated AST/ALT 112 Hyper/Hypo-thyroidism 14 Arthralgia/Myalgia 2 Pruritus 13 Pneumonitis 1 Hypophysitis 1 Parasthesia 11 Hyperglycemia 11 DKA 1 Xerostomia 11 Thrombocytopenia 1 Nephritis 1

5022 Poster Discussion Session; Displayed in Poster Session (Board #91), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816).

Peter C. Black, Catherine Tangen, Parminder Singh, David James McConkey, Scott Lucia, William Thomas Lowrance, Vadim S Koshkin, Kelly Lynn Stratton, Trinity Bivalacqua, Elad Sharon, Wassim Kassouf, Sima P. Porten, Richard Carlton Bangs, Melissa Plets, Seth P. Lerner, Ian Murchie Thompson; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; Mayo Clinic, Phoenix, AZ; Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD; University of Colorado, Denver, CO; University of Utah Hunstman Cancer Institute, Salt Lake City, UT; University of California San Francisco, San Francisco, CA; Memorial Sloan Kettering Cancer Center, New York, NY; Johns Hopkins Hospital, Baltimore, MD; National Cancer Institute, Bethesda, MD; McGill Uni- versity Health Centre, Montreal, ´ QC, Canada; University of California, San Francisco, San Francisco, CA; SWOG, San Antonio, TX; Fred Hutchinson Cancer Research Center, Seattle, WA; Baylor College of Medicine, Houston, TX; CHRISTUS Medical Center Hospital, San Antonio, TX

Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 in NMIBC after BCG therapy, this trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report on the subset with CIS (with or without concomitant Ta/T1) among patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate at 6 months as defined by mandatory biopsy with a null hypothesis of 30% and alternative of 50% with a 1-sided alpha = 0.05 and 96% power. The 3 month CR rate, defined by cytology, cystoscopy and for-cause biopsy, is reported here as a secondary endpoint, in addition to safety. Results: Seventy-five eligible CIS patients were enrolled. Two received no treatment and are not evaluable. Of 73, median patient age was 73.4 years and median number of prior BCG doses was 12. Concomitant Ta/T1 tumor was found in 30 (41.1%) patients, including T1 disease in 16 (21.9%). A CR was observed in 30 (41.1%; 95% CI 29.7%, 53.2%) patients at 3 months and 19 (26.0%; 95% CI 16.5%, 37.6%) at 6 months. Any possibly or probably treatment-related adverse event (AE) was observed in 61 (83.6%) patients. The most frequent AEs were fatigue 36 (49.3%), pruritis 8 (11.0%), hypothyroidism 8 (11.0%), and nausea 8 (11.0%). Grade 3-5 AEs occurred in 9 (12.3%) patients and there was one treatment-related death (myasthenia gravis with respiratory failure and sepsis). Conclusion: The observed response to atezolizumab at 3 and 6 months in patients with BCG-unresponsive CIS was similar to that reported in recent similar trials and meets the benchmark for initial CR defined by the FDA guidance. This trial provided no new safety concerns. The duration of response will determine if this is a suitable treatment option for patients with BCG- unresponsive high risk CIS. Clinical trial information: 02844816. Research Sponsor: U.S. National Institutes of Health, Pharmaceutical/Biotech Company.

5023 Poster Discussion Session; Displayed in Poster Session (Board #92), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Evaluation of predictive biomarkers for nivolumab in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) from the CheckMate-025 (CM-025) trial.

Miriam Ficial, Opeyemi Jegede, Miriam Sant’Angelo, Sonia Moreno, David A. Braun, Megan Wind- Rotolo, Jean-Christophe Pignon, Paul J. Catalano, Maxine Sun, Eliezer Mendel Van Allen, Gordon J. Freeman, Arlene Sharpe, F. Stephen Hodi, Robert J. Motzer, Catherine J. Wu, Michael B. Atkins, David F. McDermott, Sachet A. Shukla, Toni K. Choueiri, Sabina Signoretti; Brigham and Women’s Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Bristol-Myers Squibb, Princeton, NJ; Harvard Medical School, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Depart- ment of Pathology, Brigham and Women’s Hospital, Boston, MA

Background: We previously showed that levels of CD8+ tumor infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+TIM32LAG32) were associated with response to nivolumab (nivo) in pretreated mccRCC pts (Pignon et al, 2019). Here, we sought to validate these findings in a randomized Phase III trial of nivo versus everolimus (evero) (CM-025) and explore the association of the biomarker with transcriptomic profiles. Methods: Tumor tissues from the CM-025 trial were analyzed (nivo arm: n = 116, evero arm: n = 107). Density/percentage of CD8+ PD1+TIM32LAG32 TIC was evaluated by immunofluorescence (IF) and PD-L1 expression on tumor cells (TC) was evaluated by IHC. Linear association with outcomes was assessed using binary logistic (ORR, clinical benefit (CB) defined as CR/ PR and PFS$12 months) and Cox PH (PFS, OS) regression models (1-sided p-values shown). Bulk RNA-seq was performed in a subset of samples (n = 71) and data analyzed using ssGSEA and Gene Signature Scores (GSS). Results: In the nivo arm, density of CD8+ PD1+TIM32LAG32 TIC (IF biomarker) was associated with ORR (OR = 1.43, p = 0.03) and CB (OR = 1.54, p = 0.02) while a trend was observed with PFS (HR = 0.87, p = 0.06). At an optimized cutoff, nivo treated pts with high IF biomarker (24/116, 20.7%) had higher ORR (45.8% vs 19.6%, p = 0.01) and CB (33.3% vs 14.1%, p = 0.03) and longer median PFS (9.6 vs 3.7 months, p = 0.03) than pts with low IF biomarker. A significant interaction between the IF biomarker and treatment was seen for both PFS and OS (2-sided p = 0.02 and 2-sided p = 0.08, respectively; significance determined as p , 0.15). By bulk RNA-seq, several inflammatory pathways (FDR q , 0.1) and inflammatory GSS (FDR q , 0.05) were enriched in the high IF biomarker group. When combined with the IF biomarker, TC PD-L1 expression ($1%) further separated clinical outcomes (ORR, CB and PFS) in the nivo arm. In the evero arm, the IF biomarker was neither prognostic nor predictive of any clinical outcome. Conclusions: High levels of CD8+ PD1+TIM32LAG32 TIC predicted response to nivo (but not to control evero) in mccRCC pts and were associated with activation of inflammatory response. Combination with TC PD-L1 further improved its predictive value, confirming our previous findings (Pignon et al, 2019). Further validation in the setting of first-line anti-PD-1 therapy is ongoing. Research Sponsor: Department of Defense (CDMRP), Pharmaceutical/Biotech Company, U.S. National Institutes of Health.

5024 Poster Discussion Session; Displayed in Poster Session (Board #93), Fri, 8:00 AM-11:00 AM, Discussed in Poster Discussion Session, Fri, 8:00 AM-11:00 AM

Association of gene expression with clinical outcomes in patients with renal cell carcinoma treated with pembrolizumab in KEYNOTE-427.

David F. McDermott, Jae-Lyun Lee, Frede Donskov, Scott S. Tykodi, Georg A. Bjarnason, James M. G. Larkin, Rustem Gafanov, Mark D. Kochenderfer, Jahangeer Malik, Alexandr Poprach, Sabina Signoretti, Razvan Cristescu, Raluca Andreia Predoiu, Andrey Loboda, Yiwei Zhang, Qing Zhao, Alexandra Snyder, Charles Schloss, Rodolfo F. Perini, Michael B. Atkins; Dana-Farber Cancer Center, Harvard Medical School, Boston, MA; University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; Aarhus University Hospital, Aarhus, Denmark; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; The Institute of Cancer Research, London, United Kingdom; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; Oncology and Hematology Associates of Southwest Virginia, Roanoke, VA; Edinburgh Cancer Centre, Western General Hospital, Edinburgh, United Kingdom; Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic; Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Merck & Co., Inc., Kenilworth, NJ; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC

Background: We assessed the association of baseline RNA-sequencing–based gene expression signatures and DNA alterations with response or resistance to pembrolizumab in patients with advanced renal cell carcinoma in cohorts A (clear cell; n = 110) and B (non-clear cell; n = 165) of the phase 2 KEYNOTE-427 study (NCT02853344). Methods: Using RNA-sequencing, we analyzed the association of gene expression signatures (18-gene T-cell–inflamed gene expression profile [GEP]; 10 non–T- cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFb, WNT]) quantifying tumor microenvironment elements (TME) with objective response rate (ORR) and progression-free survival (PFS). Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were analyzed through regression testing of response for association with consensus signatures after adjusting for T-cell–inflamed GEP and International Metastatic RCC Database Consortium scores in the model. P values were adjusted for multiplicity. Using whole exome sequencing, we also summarized the association of renal cell carcinoma driver gene mutations with ORR. Clinical data cutoff: Jan 30, 2019. Results: Patient characteristics for this analysis were comparable to the overall population. In cohort A, T-cell–inflamed GEP (n = 78) was statistically significantly associated with a better ORR (P = 0.021; AUROC = 0.65) but not PFS (P = 0.116). No other TME canonical signatures showed a correlation with ORR or PFS. ORR was estimated for mutations (Table). Conclusions: RNA-sequencing–based, T-cell–inflamed GEP was associated with ORR in patients with clear cell renal cell carcinoma receiving first-line pembrolizumab. Precision was limited by sample size for estimating ORR by specific gene mutation status. Evaluation of tissue-based biomarkers in larger studies are planned. Biomarker analyses from patients in cohort B will also be presented. Clinical trial information: NCT02853344. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

n ORR (95% CI) %, ORR (95% CI) %, Gene (mutant vs non-mutant) mutant non-mutant SETD2 18 vs 58 44 (25-66) 24 (15-37) PBRM1 33 vs 43 30 (17-47) 28 (17-43) VHL 56 vs 20 30 (20-43) 25 (11-47) BAP1 14 vs 62 14 (4-40) 32 (22-45)

5025 Poster Session (Board #94), Fri, 8:00 AM-11:00 AM

CD68+ tumor-associated myeloid cells as the target of adenosine-induced gene products and predictor of response to adenosine blockade with ciforadenant (cifo) in renal cell cancer (RCC).

Martin H Voss, Andrew N. Hotson, Stephen Willingham, Brett Gordon Maxwell Hughes, Jaime R. Merchan, Lawrence Fong, Michael Chu, Saby George, Brian Munneke, Mehrdad Mobasher, Richard A. Miller; Memorial Sloan Kettering Cancer Center, New York, NY; Corvus Pharmaceuticals Inc, Burlingame, CA; Department of Medical Oncology, The Prince Charles Hospital, Department of Medical Oncology, Royal Brisbane & Women’s Hospital, and School of Medicine, University of Queensland, Brisbane, QLD, Australia; University of Miami, Miami, FL; University of California San Francisco, San Francisco, CA; Cross Cancer Institute, Edmonton, AB, Canada; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY

Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as . 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p , 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822. Research Sponsor: Corvus Pharmaceuticals.

5026 Poster Session (Board #95), Fri, 8:00 AM-11:00 AM

Clinical outcomes and economic burden for bladder cancer patients: An analysis from a Swedish cancer registry.

Joaquim Bellmunt, Thomas Powles, Roger Henriksson, Gary D. Steinberg, Nurgul Batyrbekova, Frida Schain, Sarah Fleming, Waleed Shalaby, Arlene O. Siefker-Radtke; Beth Israel Deaconess Medical Center, Boston, MA; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Umea University, Umea, Sweden; NYU Langone Health, Perlmutter Cancer Center, New York, NY; Scandinavian Development Services, Danderyd, Sweden; Janssen Global Services, Stock- holm, Sweden; Janssen Research & Development, LLC, Raritan, NJ; Janssen Scientific Affairs, LLC, Horsham, PA; The University of Texas MD Anderson Cancer Center, Houston, TX

Background: To investigate the clinical and economic disease burden for patients (pts) with non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC), and metastatic urothelial carcinoma (mUC) using a Swedish bladder cancer registry. Methods: Pts diagnosed with bladder cancer in the Stockholm Gotland region between 2005-2013 were included and followed until May 31, 2015 or until death. MIBC was classified if a T, N, M at diagnosis was T2, T3, T4, N1, N2, N3, or M1, otherwise pts were classified as NMIBC. All diagnostic and therapeutic interventions were captured and differentiated. Inpatient and outpatient healthcare resource utilization (days) and associated costs (US $) were also analyzed. Results: 3587 bladder cancer pts were identified (NMIBC-2728; MIBC-859) with a median observation time of 49.7 (Q1-Q3: 27.8-78.7) versus 17.2 (Q1-Q3: 6.5-39.3) months. 5- year survival for patients with NMIBC at diagnosis was 71.3% (95% CI; 69.5-73.3) and 26.4% (95% CI; 23.4-29.8) for MIBC. By year 1, survival for MIBC-T2, T3, and T4 was 66%, 41.7%, and 28.4%, respectively. Progression from NMIBC to MIBC was estimated in 19.4% (528/2728) of pts. In year 1, 84% (2,275/2,728) of TURBT procedures were performed on NMIBC pts. Over the next 2-10 years of follow-up, 11,035 repeat TURBT procedures were undertaken in this cohort. In the 859 MIBC pts, 607 TURBT procedures and 333 radical cystectomies occurred in year 1. In the same cohort, 28.3% (243/ 859), 15.5% (78/505), and 8.6% (29/338) received systemic chemotherapy in years 1, 2, and 3, respectively. Total health resource utilization (HRU) cost for the NMIBC and MIBC cohorts is provided in Table. Median HRU cost per person-year was estimated at $30,470 for MIBC versus $9,228 for NMIBC in year 1. For MIBC-T2, T3, and T4, median cost per person-year was $30,154, $33,917, and $38,959 in year 1, respectively. Conclusions: This retrospective analysis accomplished its primary purpose to provide a real-world understanding for the clinical and economic impact of bladder cancer over a 10-year period when treatment interventions were relatively consistent. Total HRU Costs for Patients with NMIBC and MIBC per Follow-up Year (Years 1 to 5). Research Sponsor: Janssen.

Diagnosis Follow-up year No. of Patients Person-Years Total HRU Costs (US $) NMIBC 1 2,728 2,632 34,811,317 2 2,531 2,393 14,867,314 3 2,200 1,972 10,188,457 4 1,765 1,574 7,323,923 5 1,399 1,252 5,152,229 MIBC 1 859 666 21,083,790 2 505 418 4,598,487 3 338 280 2,082,339 4 237 203 1,227,474 5 178 156 693,829

5027 Poster Session (Board #96), Fri, 8:00 AM-11:00 AM

Early results of TROPHY-U-01 Cohort 2: Sacituzumab govitecan (SG) in platinum-ineligible patients (pts) with metastatic urothelial cancer (mUC) who progressed after prior checkpoint inhibitor (CPI) therapy.

Daniel Peter Petrylak, Scott T. Tagawa, Rohit K. Jain, Manojkumar Bupathi, Arjun Vasant Balar, Arash Rezazadeh, Saby George, Phillip Lee Palmbos, Luke T. Nordquist, Nancy B. Davis, Nicholas J. Vogelzang, Chethan Ramamurthy, Cora N. Sternberg, Yohann Loriot, Neeraj Agarwal, Quan Hong, Allison Gladden, Charu Kanwal, Trishna Goswami, Petros Grivas; Yale University School of Medicine, New Haven, CT; Weill Cornell Medical College, New York, NY; Lee Moffitt Cancer Center, Tampa, FL; Rocky Mountain Cancer Centers, Littleton, CO; New York University Langone Health, New York, NY; Norton Cancer Institute, Louisville, KY; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Urology Cancer Center and GU Research Network, Omaha, NE; Vanderbilt Ingram Cancer Center, Nashville, TN; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; University of Texas Health Science Center at San Antonio, San Antonio, TX; Weil Cornell Medicine, New York, NY; Institut de Cancerologie ´ Gustave Roussy, Villejuif, France; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Immu- nomedics, Inc., Morris Plains, NJ; University of Washington, Seattle, WA

Background: SG is an antibody-drug conjugate consisting of a humanized monoclonal anti–Trop-2 antibody coupled to the cytotoxic agent, SN-38, via a unique hydrolyzable linker. The epithelial cell surface antigen, Trop-2, demonstrates greater expression between UC vs normal tissue, and is a promising target. In a phase 1/2 basket study (IMMU-132-01), SG showed an overall response rate (ORR) of 31% and manageable toxicity in 45 pts with mUC who had a median of 2 (range 1–6) prior therapy lines (Tagawa 2019 ASCO GU). Recent interim results for cohort 1 of the TROPHY-U-01 study in 35 pts with mUC who progressed on platinum and CPI therapy demonstrated an ORR of 29% in pts with a median of 3 prior treatment lines (range 2–6) (Tagawa 2019 ESMO). The most common grade $3 treatment-related AE (TRAE) was neutropenia. Methods: TROPHY-U-01 (NCT03547973) is a global, open-label, phase 2 trial evaluating the antitumor activity of SG (10 mg/kg, days 1 and 8 of 21- day cycles) in pts with advanced UC with measurable disease and ECOG PS 0 or 1. Cohort 2 includes platinum-ineligible pts who progressed after CPI therapy in the first-line metastatic setting. The primary objective is ORR evaluated with RECISTv1.1 by central review. Secondary objectives include progression-free survival, overall survival, and duration of response. Results: 18 pts with baseline tumor assessment (50% male; median age 79 y [range 57–87], 67% visceral metastases; 28% liver metastases) received a median of 2 (range 1–5) prior therapies. At a median follow-up of 6 months, ORR was 28% (5/18) with 4 confirmed PRs, and 1 PR pending confirmation. The majority of pts (61% [11/18]) had target lesion reduction. The safety profile was consistent with prior reports. Key grade $3 TRAEs were neutropenia (39%), fatigue (33%), diarrhea (28%), leukopenia (22%), anemia (17%), and febrile neutropenia (11%). No events of interstitial lung disease, ocular toxicities, or grade . 2 neuropathy were reported. There were no treatment-related deaths. Conclusions: In cisplatin-ineligible pts, the ORR for currently approved first-line CPI treatments is ~23–29% (Balar 2017 Lancet; Vuky 2018 ASCO). These preliminary data with SG show a manageable safety profile with an encouraging ORR of 28% and support the development of SG in platinum-ineligible pts with mUC who have progressed after CPI therapy. Clinical trial information: NCT03547973. Research Sponsor: Immuno- medics, Inc.

5028 Poster Session (Board #97), Fri, 8:00 AM-11:00 AM

Association of molecular subtypes with pathologic response in a phase II study of co- expression extrapolation (COXEN) with neoadjuvant chemotherapy (NAC) for localized, muscle-invasive bladder cancer (SWOG S1314; NCT02177695).

Seth P. Lerner, David James McConkey, Catherine Tangen, Joshua J Meeks, Thomas W. Flaig, Xing Hua, Siamak Daneshmand, Ajjai Shivaram Alva, M. Scott Lucia, Dan Theodorescu, Amir Goldkorn, Matthew I. Milowsky, Woonyoung Choi, Richard Carlton Bangs, Daniel Gustafson, Ian Murchie Thompson; Baylor College of Medicine, Houston, TX; Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD; SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; Northwestern University, Chicago, IL; University of Colorado Anschutz Medical Campus, Aurora, CO; Fred Hutchinson Cancer Research Center, Seattle, WA; USC Institute of Urology, USC/ Norris Comprehensive Cancer Center, Los Angeles, CA; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, Los Angeles, CA; Division of Medical Oncology, Department of Medicine, Keck School of Medicine and Norris Com- prehensive Cancer Center, University of Southern California, Los Angeles, CA; University of North Carolina Department of Medicine, Division of Hematology/Oncology, Chapel Hill, NC; Bladder Cancer Advocacy Network, Pittsford, NY; Colorado State University, Fort Collins, CO; Christus Santa Rosa Hospital-Medical Center, San Antonio, TX

Background: Cisplatin-based NAC is recommended for patients with MIBC prior to radical cystectomy (RC) but the majority will not have a pathologic response. To identify responders the COXEN gene expression model with chemotherapy-specific scores (for DD-MVAC and GC) was developed and in a prospective rPII clinical trial (SWOG S1314) the GC score was associated with path downstaging in the pooled arms. We investigated RNA based molecular subtypes as additional predictive biomarkers for response to NAC in patients treated in S1314. Methods: Eligibility required cT2-T4a N0 M0, predominant urothelial, . 5 mm tumor, cisplatin eligible, and plan for RC and PLND. 237 patients were randomized between 4 cycles of ddMVAC and GC. Based on Affymetrix transcriptomic data used to assign COXEN scores, we determined subtypes using 3 classifiers: TCGA (k=5), Consensus (k=6), and MD Anderson (MDA; k=3). Primary objective was to assess subtype association with pathologic response to NAC in the pooled arms and to determine any association with COXEN. TCGA and Consensus classifiers were collapsed into 3 groups for ROC analyses. We tested whether each classifier contributed additional predictive power when added to a model based on pre-defined stratification factors (PS 0 vs. 1; T2 vs. T3, T4a). Results: 161 patients had adequate tissue and gene expression results, received at least 3 of 4 cycles of NAC and had pT-N response based on RC. Covariates were 78% PS=0, 89% T2, 84% male, median age 65, 51% randomized to ddMVAC, 49% GC with 33% pT0 and 52% downstaging. Although the TCGA 3 group classifier (Basal-Squamous (BS)/Neuronal, Luminal, Luminal infiltrated) and GC Coxen score yielded the largest AUCs (0.607, 0.610) for pT0 response, neither reached statistical significance (p=0.20, p=0.22). For downstaging (,pT2), the 3 category Consensus classifier (BS/NE-like, Luminal, Stroma-rich) significantly increased the AUC from 0.568 (strat factors alone) to 0.620 (p=0.044). The MDA classifier AUC was 0.640 and the GC Coxen score AUC was 0.626, but neither were significant (p=0.076, p=0.14. The MVAC Coxen score did not improve the AUC beyond the stratification factors. Conclusions: The Consensus classifier, which is based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging when added to clinical stage and PS. With additional followup, we will assess the association of COXEN scores and subtypes with overall survival. Clinical trial information: NCT02177695. Research Sponsor: U.S. National Institutes of Health.

5029 Poster Session (Board #98), Fri, 8:00 AM-11:00 AM

Outcomes and the impact of genomic characteristics on patients with metastatic urothelial carcinoma enrolled in early phase trials.

Omar Alhalabi, Andrew W Hahn, Funda Meric-Bernstam, Aung Naing, Sarina Anne Piha-Paul, Filip Janku, Shubham Pant, Timothy A Yap, David S. Hong, Siqing Fu, Erick Campbell, Hung Le, Amishi Yogesh Shah, Matthew T Campbell, Nizar M. Tannir, Arlene O. Siefker-Radtke, Jianjun Gao, Jason Roszik, Vivek Subbiah; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX

Background: With the recent approvals of checkpoint inhibitors (CPIs), a fibroblast growth factor receptor (FGFR) inhibitor, and an antibody-drug conjugate, patients with platinum-refractory metastatic urothelial carcinoma (mUC) have several treatment options available. However, many patients with platinum-refractory mUC need novel therapies after progressing on current therapies. We assessed the role of early phase trials in treatment of mUC and the impact of genomic alterations on their outcomes. Methods: We retrospectively analyzed medical records of patients with mUC who received an investigational therapy at the phase 1 clinic and had CLIA-certified clinical next generation sequencing. Clinical parameters and mutations were abstracted. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Among the 57 pts enrolled in 41 unique phase 1 trials between 2015 and 2019, 16% (9/57) had variant histology: neuroendocrine carcinoma (n = 3) and urachal carcinoma (n = 6). Median age was 64. Majority were males (72%). 97% received prior platinum therapy and 60% had received prior CPI therapy. Across the pure urothelial carcinoma cohort (n = 48), median PFS was 4.2 months (m), median OS was 9.8 m, and the overall response rate (ORR) was 19%. TP53, FGFR, TERT, and ARID1A alterations (alt) were detected in 54%, 41%, 21% and 17% of UC patients, respectively. Patients harboring a TP53 alt, compared to no alt, had a shorter median PFS of 3.2m vs 9.6 m (HR = 2.738 [1.247 - 6.011], p = 0.0121). On the contrary, median PFS was longer in FGFR alt, compared to no alt, 6.3m vs 3.2m (HR = 0.4662 [0.224 - 0.971], p = 0.0415). Of note, 64% of FGFR alt patients were treated under an early phase FGFR targeting trial. Median OS was numerically longer in FGFR alt and shorter in TP53 alt but did not reach statistical significance (table). Conclusions: Patients with mUC may derive clinical benefit from enrollment in phase I clinical trials. Patients with TP53 alterations had numerically worse outcomes. Patients with mUC should be considered for an FGFR targeting therapy in the setting of an FGFR alteration. Research Sponsor: None.

TP53 alteration vs. no FGFR alteration vs. no UC alteration alteration PFS 4.2 3.2 m vs 9.6 m 6.3 m vs 3.2 m m HR for PFS (95% Confidence -- 2.74 (1.25 - 6.01) 0.4662 (0.224 - Interval) p = 0.01 0.971) p = 0.0415 OS 9.8 5.9 m vs 16.5 m 16.5 m vs 5.3 m m HR for OS (95% Confidence -- 1.52 (0.73 - 3.15) 0.55 (0.26 - 1.17) Interval) p = 0.26 p = 0.12

5030 Poster Session (Board #99), Fri, 8:00 AM-11:00 AM

Pathological response rates and quality of life outcomes of neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle-invasive transitional cell carcinoma of the urinary bladder.

Amarnath Challapalli, Susan Masson, Paul White, Narges Dailami, Sylvia Pearson, Edward Rowe, Anthony Koupparis, Jon Oxley, Janice Ash-Miles, Alicia Bravo, Emily Foulstone, Raj Persad, Amit Bahl; University Hospital Bristol NHS Foundation Trust, Bristol, United Kingdom; Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; Uni- versity of the West of England, Bristol, United Kingdom; University of West of England, Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; North Bristol NHS Trust, Bristol, United Kingdom

Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy, safety and tolerability of cisplatin cabazitaxel combination in this patient group. Methods: A phase 2 single arm trial (Simon 2 stage), to recruit at least 26 evaluable patients was designed with 80% power to detect the primary endpoint, objective response rate (ORR) of . 35%. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging), measured by pathologic staging (T2 or greater at diagnosis, to T1 or less at radical cystectomy). Treatment was with Cisplatin 70mg/m2 and Cabazitaxel 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. Quality of Life (QoL) data were collected at baseline, prior to each cycle of chemotherapy and at 3-5 weeks after 4th cycle of chemotherapy using EQ-5D and EORTC QLQ-C30, BLM30 questionnaires. Results: Objective response was seen in 15 out of 26 evaluable patients, 57.7% and over a third of patients achieved pCR (9/26; 34.6%). 78% (21/27) of patients completed all cycles of treatment, with only 6.7% of the reported adverse events (AEs) being graded 3 or 4. There were 6 treatment related SAEs reported but no SUSARs. In patients who achieved objective response the median progression free (PFS) and overall survival (OS) were not reached (median follow up: 41.5m). In contrast, median PFS (7.2m) and OS (16.9m) were significantly worse (p = 0.001) in patients who did not respond. Response rates for EORTC QLQ-C30, BLM 30 and EQ5D questionnaires was 70.4, 70.4 & 63% respectively, at end of treatment. There was no significant difference in EORTC QLQ C30 summary, global health scores and EQ5D score with treatment. There was a significant decline in mean QLQ C30 domain scores after 1st cycle compared to baseline, but no further deterioration with subsequent cycles of chemotherapy. Conclusions: Cabazitaxel with cisplatin as NAC of MIBC can be considered a safe, well-tolerated and effective regimen with higher pCR rate of 34.6%. This compares favorably to that with Cisplatin/ Gemcitabine (23-26%). Minimal changes in Global Health & EQ5D observed during NAC further demonstrates the excellent tolerability of this regimen and to our knowledge are the first data regarding QoL in NAC in MIBC. These results warrant further evaluation in a larger phase 3 study. Clinical trial information: 2011 004090 82. Research Sponsor: Sanofi.

5031 Poster Session (Board #100), Fri, 8:00 AM-11:00 AM

Assessing the potential cost-effectiveness of the addition of atezolizumab to first-line platinum chemotherapy in advanced urothelial cancer: Implications for value-based pricing.

Ali Raza Khaki, Leonidas Nikolaos Diamantopoulos, Marita Zimmerman, Louis P. Garrison, Petros Grivas; University of Washington, Seattle, WA; Institute for Disease Modeling, Bellevue, WA; VeriTech Corporation, Mercer Island, WA

Background: Data from interim analysis of IMvigor130 trial showed that 1st line treatment of advanced urothelial cancer (aUC) with atezolizumab (Atezo) + platinum-based chemotherapy (PBC) significantly improved progression-free survival (PFS), but not overall survival (OS), vs PBC. Switch maintenance anti-PD(L)1 after completion of PBC as 1st line therapy is an alternate strategy, recently reported to significantly prolong OS. We aimed to compare cost-effectiveness of combined treatment (Atezo+PBC) vs PBC based on IMvigor130. Methods: We used a partitioned-survival model to evaluate the potential cost-effectiveness of treatment with A) Atezo+PBC (gemcitabine with cisplatin or carboplatin) or B) PBC alone with checkpoint inhibitor pembrolizumab at progression (standard-of-care). PFS and OS curves were extracted from IMvigor 130 and parametric models were fit to approximate outcomes with Atezo+PBC with the hazard ratio (HR) from the trial used to project outcomes for PBC alone. We used a health-care payer perspective with a two-year time horizon. Model outputs — costs, life-years, quality- adjusted life years (QALYs) — were used to calculate an incremental cost-effectiveness ratio (ICER). A scenario analysis evaluated the “value-based price” needed for Atezo+PBC to be cost-effective; a one- way sensitivity analysis was also performed. Results: Results of the cost-effectiveness analysis are summarized in the table. The mean projected incremental cost of Atezo+PBC compared to PBC was $59,604 for a mean incremental gain of 0.09 life-years and 0.07 QALYs. This resulted in an ICER of $629,755/life-year and $895,800/QALY, respectively. A 33% reduction would be needed in the price of atezolizumab to make Atezo+PBC cost-effective at an ICER of $150,000/QALY. Results were sensitive to cost of pembrolizumab at progression, the cost of Atezo+PBC, and the OS HR between Atezo+PBC and PBC. Conclusions: Combined chemoimmunotherapy with atezolizumab and PBC would likely not be cost-effective for the first-line treatment of aUC. However, with a price rebate of 33%, it would approach being cost-effective at a widely used cost-effectiveness threshold. Research Sponsor: U.S. National Institutes of Health.

PBC Atezo + PBC Incremental Results Costs per person $92,135 $151,738 $59,604 Life-Years per person 1.27 1.37 0.09 QALYs per person 1.01 1.07 0.07

ICER Life-Years $629,755 QALYs $895,800

5032 Poster Session (Board #101), Fri, 8:00 AM-11:00 AM

Comparative effectiveness of second-line (2L) single-agent atezolizumab (A), nivolumab (N), and pembrolizumab (P) in patients (Pts) with locally advanced or metastatic urothelial cancer (aUC) who progressed on platinum-based systemic chemotherapy (plat-chemo): Results from a real-world dataset.

Umang Swami, Ben Haaland, Benjamin Louis Maughan, Roberto Nussenzveig, John Esther, Adam Kessel, Sumanta K. Pal, Petros Grivas, Neeraj Agarwal; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; University of Utah Huntsman Cancer Institute, Salt Lake City, UT; University of Utah, Salt Lake City, UT; Huntsman Cancer Institute, Salt Lake City, UT; City of Hope Comprehensive Cancer Center, Duarte, CA; University of Washington, Seattle, WA

Background: Five PD-1/L1 inhibitors (PDi) are approved for 2L therapy (Rx) for aUC after progression on plat-chemo, but none compared with each other in randomized trials. Here, we assessed comparative effectiveness of 2L PDi in real-world setting. Methods: Pt level data of Pts with aUC were extracted from Flatiron Health EHR-derived de-identified database. Inclusion criteria: 1L Rx with plat-chemo; receipt of single agent PDi in 2L; initiation of 2L PDi 6 mos before data-cut off. Exclusion criteria: .90 days from diagnosis to date of next visit to ensure active engagement of Pts with data providing site; initiation of 2L after 7/31/2016 to ensure uptake of PDi for aUC. OS was compared from the date of initiation of 2L Rx. Comparative effectiveness was examined by Cox proportional hazards model, stratified by treatment propensity score. Each Pts’ propensity of receiving each 2L PDi was modeled via a random forest based on Pt and disease characteristics potentially driving Rx selection for a PDi (gender, smoking status, race/ethnicity, relapsed vs de novo disease, time between 1L & 2L Rx, cis vs carboplatin in 1L; year of Rx with PDi & following characteristics before 2L Rx: ECOG, Hb, age, ICD codes for liver or CNS mets, albumin & PD-L1 status when available). Results: 703 Pts with aUC who initiated 2L Rx between 8/1/2016 to 10/31/2019 were eligible. 2L Rx were A (n=322), N (n=127) & P (n=254). Durvalumab & avelumab were excluded due to low utilization in this dataset. Median follow up from 2L initiation was 4.8 mos. Median OS (mos; 95% CI) with A (6.4 mos; 5-8.7), N (8 mos; 6.3-11.3) and P (8.5 mos; 6.1-11.6) were similar (propensity stratified log rank p=0.19; simple logrank p=0.34). Over time proportion of Pts receiving 2L A decreased, P increased & N increased then decreased (p,0.001). Propensity stratified comparative effectiveness estimates are below. Conclu- sions: In this real-world cohort of Pts with aUC, OS with 2L Rx with A, N, & P were similar on both univariate and propensity stratified analyses. These results agree with prior trial level meta-analysis (PMID 31200951). Strength of this analysis includes large Pt level data from a real world cohort. Limitations include retrospective nature of this study. Research Sponsor: None.

Propensity stratified pairwise comparative effectiveness estimates. 2L Hazard ratio 95% CI p value NvsA 0.82 0.63-1.08 0.16 PvsA 0.82 0.64-1.05 0.11 PvsN 1.00 0.74-1.34 0.99

5033 Poster Session (Board #102), Fri, 8:00 AM-11:00 AM

Early response marker during pembrolizumab treatment in metastatic urothelial cancer: Temporal shift in peripheral CD4 T cells expressing chemokine receptors.

Maud Rijnders, Hayri Emrah Balcioglu, Debbie Robbrecht, Joost L. Boormans, Maureen J.B. Aarts, Paul Hamberg, Jens Voortman, Hans Westgeest, Ronald De Wit, Martijn P. Lolkema, Astrid Aplonia Maria Van Der Veldt, Reno Debets; Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands; Maastricht University Medical Center, Maastricht, Nether- lands; Franciscus Gasthuis & Vllietland, Rotterdam, Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center, Amsterdam, Netherlands; Amphia Hospital, Breda, Netherlands; Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, Netherlands

Background: Approval of PD1 blockade greatly improved treatment possibilities for patients with platinum-resistant metastatic urothelial cancer (mUC), however the current response rate for pembrolizumab is less than 25%. Since PD-L1 expression does not have predictive value in this setting, the aim of this study was to identify new markers to improve patient selection. Methods: Between Sept 2017 and Jan 2020, 84 mUC patients received pembrolizumab in a prospective biomarker discovery study (NCT03263039). Peripheral blood samples (n = 22) taken prior to and at 6 and 12 weeks after start of treatment were analyzed for frequencies of CD4 and CD8 T cells expressing co-inhibitory, co- stimulatory and chemokine receptors using multiplex flow cytometry. Plasma chemokine levels were determined using ELISA (n = 38), and fresh tumor biopsies obtained prior to and during treatment (n = 26) were analyzed for densities and phenotypes of T cells using multiplex immunofluorescence staining. T cell receptor clonality was analyzed in peripheral blood (n = 10) and tumor biopsies (n = 6) using RNA sequencing. Patients were classified as responder (complete or partial response) or non- responder (progressive disease) according to RECIST v1.1 after 12 weeks of treatment. Results: Longitudinal sampling revealed that upon treatment the frequency of CXCR3+ CD4 T cells decreased in responders, whereas the frequency of CXCR3+ CCR1+ CD4 T cells drastically increased in nonresponders. Before treatment, the frequency of CD4 T cells co-expressing CXCR3 and CCR1 was already decreased in responders. Notably, in responders, the treatment-related decrease in frequency of CD4 T cells expressing chemokine receptors was accompanied by a decrease in the frequency of CD4 T cells expressing the co-inhibitory receptor PD1, whereas an increase in the frequency of CD4 T cells expressing the co-stimulatory receptor 4-1BB was observed. These findings will be complemented with chemokine levels in plasma, contexture of T cells in tumor biopsies, and T cell receptor clonality analysis. Conclusions: mUC patients responding to pembrolizumab treatment demonstrated an on- treatment decrease in frequency of CD4 T cells expressing chemokine receptors that is accompanied by a changed frequency of co-signaling receptor expressing CD4 T cells. These data show that dynamic immune phenotyping can distinguish effective from less effective immune activation by pembrolizumab, and may provide early markers for benefit from PD1 blockade in mUC patients. Research Sponsor: Merck Sharp & Dohme.

5034 Poster Session (Board #103), Fri, 8:00 AM-11:00 AM

First-line pembrolizumab (pembro) monotherapy in advanced non-clear cell renal cell carcinoma (nccRCC): Updated follow-up for KEYNOTE-427 cohort B.

Jae-Lyun Lee, Marek Ziobro, Cristina Suarez, Przemyslaw Langiewitz, Vsevolod Borisovich Matveev, Pawel Wiechno, Rustem Gafanov, Piotr Tomczak, Fred´ ´ eric Pouliot, Frede Donskov, Boris Alekseev, Sang Joon Shin, Georg A. Bjarnason, Daniel Castellano, Xiaoqi Du, Rodolfo F. Perini, Karla Rodriguez- Lopez, David F. McDermott, Michael B. Atkins; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Centrum Onkologii-Instytut im. Marii Sklodowskiej, Krakow, ´ Poland; Vall d’Hebron University Hospital and Institute of Oncology, Barcelona, Spain; Wojskowy Instytut Medyczny Centralny Szpital Medyczny MON, Warsaw, Poland; N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; Hospital No. 1 of the Poznan University of Medical Sciences, Poznan, Poland; CHU of Quebec and Laval University, Quebec City, ON, Canada; Aarhus University Hospital, Aarhus, Denmark; P. A. Herzen Moscow Oncology Research Institute, Ministry of Health of the Russian Federation, Moscow, Russian Federation; Yonsei University College of Medicine, Seoul, South Korea; Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; Hospital Universitario 12 de Octubre, I +12 Research Institute, Madrid, Spain; Merck & Co., Inc., Kenilworth, NJ; Beth Israel Deaconess Medical Center, Boston, MA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC

Background: KEYNOTE-427 (NCT02853344), a single-arm, open-label, phase 2 study, showed antitumor activity with first-line pembro monotherapy in nccRCC (cohort B). Studies of RCC and immune-oncology have shown that depth of tumor response may correlate with long-term benefit. We present the association between depth of response and OS plus updated efficacy and safety data in cohort B. Methods: Pts with histologically confirmed nccRCC, who did not receive prior systemic therapy, and who have measurable disease (RECIST v1.1) received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points were ORR (primary), DOR, and PFS (RECIST v1.1); OS; and safety. Association between depth of response, defined as maximum reduction from baseline in sum of target lesions, and OS was evaluated using a Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: Of 165 pts, 72% had papillary histology, 13% had chromophobe histology, and 16% were unclassified. Median time from enrollment to data cutoff was 18.7 mo (range, 9.9-26.0). ORR was 26.1% (95% CI, 19.5-33.5; 10 CRs, 33 PRs). Median (range) DOR was 15.3 mo (2.8-21.0+); 57.3% had DOR $12 mo. At 18-mo, PFS rate was 18.9% and OS rate was 67.0%. Most pts (58.8%) had some reduction in target lesions. Pts with a . 30% reduction in target lesions had an increased probability of survival (Table). ORR (95% CI) was similar for papillary (28.0% [20.1-37.0]) and unclassified (30.8% [14.3-51.8]) histology but lower for chromophobe (9.5% [1.2-30.4]). OS rates at 18 mo were 70.8%, 66.7%, and 50.0 in the papillary, chromophobe, and unclassified groups, respectively. Treatment-related AEs (TRAEs) occurred in 67.9% of all pts, primarily pruritus (19%), hypothyroidism (14%), and fatigue (14%). Grade 3-5 TRAEs occurred in 14% of pts; 2 pts died of TRAEs (pneumonia and cardiac arrest). Conclusions: First-line pembro monotherapy continued to show antitumor activity in nccRCC with no new safety concerns. In general, for pts who had greater reductions in target lesions, the trend was toward improved OS; pts with reduction of tumor burden $80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Association of Depth of Response and Risk for Death N = 165 n (%) HR (95% CI) Depth of response, % CR 10 (6.1) 0 (0.0-NE) 2100 to 280 12 (7.3) 0 (0.0-NE) < 280 to 260 17 (10.3) 0 (0.0-NE) < 260 to 230 22 (13.3) 0.66 (0.2-2.0) < 230 to 20 36 (21.8) Reference 0to< 20 36 (21.8) 0.96 (0.4-2.3) ‡20 22 (13.3) 1.66 (0.7-3.8)

5035 Poster Session (Board #104), Fri, 8:00 AM-11:00 AM

Atezolizumab (atezo) therapy for locally advanced/metastatic urinary tract carcinoma (mUTC) in patients (pts) with poor performance status (PS): Analysis of the prospective global SAUL study.

Daniel Castellano, Craig Gedye, Giuseppe Fornarini, Andre P. Fay, Jens Voortman, Michal Mego, Aristotelis Bamias, Jason Francis Lester, Robert A Huddart, Michaela Matouskova, Howard Gurney, Begona Mellado, Michael Ong, Filipa Carneiro, Florian Seseke, Laura Milesi, Shahrokh F. Shariat, Simon Fear, Sabine de Ducla, Cora N. Sternberg; Hospital Universitario 12 de Octubre, Madrid, Spain; Calvary Mater Newcastle, Waratah, Australia; Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy; Hospital S~ao Lucas da PUCRS/Grupo Oncoclıńicas, Porto Alegre, Brazil; Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Narodny Onkologicky Ustav, Bratislava, Slovakia; Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece; Velindre Cancer Centre, Cardiff, Wales; Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Fakultni Thomayerova Nemocnice, Prague, Czech Republic; Macquarie University Hospital, Sydney, NSW, Australia; Institut d’Investigacions Biomediques ` August Pi i Sunyer (IDIBAPS), Hospital Clıńic i Provincial, Barcelona, Spain; The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada; Instituto Portuguesˆ de Oncologıádo Porto, Porto, Portugal; Krankenhaus Martha-Maria Halle-Dolau, ¨ Halle, Germany; Asst Papa Giovanni XXIII, Bergamo, Italy; Medical University of Vienna, Vienna, Austria; F. Hoffmann-La Roche Ltd, Basel, Switzerland; San Camillo and Forlanini Hospitals, Rome, Italy and Englander Institute of Precision Medicine, Weill Cornell Medicine (current affiliation), New York, NY

Background: Pts with PS . 1 have a poor prognosis and are often excluded from clinical trials. The single-arm SAUL study (NCT02928406) evaluated atezo in a ‘real-world’ population. Overall, safety and efficacy were consistent with prior trials. However, ECOG PS 2 pts had worse overall survival (OS) but fewer adverse events (AEs) than ECOG PS 0/1 pts [Sternberg, 2019], likely reflecting shorter treatment duration and warranting exploration. Methods: Pts with mUTC received atezo 1200 mg q3w until loss of clinical benefit or unacceptable toxicity. The primary endpoint was safety. Post hoc analyses compared baseline factors, AEs and efficacy in pts with ECOG PS 2 vs 0/1. In this analysis, AE incidences were restricted to the first 45 days of atezo to adjust for differing treatment exposure. Results: None of the baseline factors explored was significantly associated with worse OS or disease control rate (DCR) in ECOG PS 2 pts. However, pts with visceral metastases and ECOG PS 2 had particularly poor outcomes. Safety appeared similar between subgroups. Conclusions: ECOG PS 2 pts have a dismal prognosis. The higher proportion with poor prognostic factors despite similar age in ECOG PS 2 vs 0/1 pts may suggest that poor PS was related to disease rather than comorbidities. Risk/benefit should be considered especially carefully when treating pts with ECOG PS 2 due to high-burden/visceral disease. Clinical trial information: NCT02928406. Research Sponsor: F Hoffmann-La Roche Ltd, Basel, Switzerland.

ECOG PS 2 0/1 Parameter, n (%) (n = 101) (n = 896) Median age, y (range) 69 (43–93) 68 (34–92) Age ‡80 y 10 (10) 68 (8) Male 78 (77) 694 (77) Renal impairment 2 (2) 44 (5) Visceral metastases 52 (52) 322 (36) Low Hb 32 (32) 118 (13) Low albumin 46 (47)a 183 (21)b Low ALP 45 (45)c 207 (23)d PD-L1 IC 2/3 21 (21)e 243 (27)f No prior chemo for mUTC 27 (27) 355 (40) AE, days 1–45 Any G 75 (74) 656 (73) G3/4 43 (43) 216 (24) G5 5 (5) 10 (1) Treatment related 30 (30) 339 (38) Special interest 13 (13) 143 (16) AE leading to atezo withdrawal 2 (2) 25 (3) Median OS, mo (95% CI) 2.3 (1.6–2.6) 10.0 (8.9–11.2) Objective response rate [95% CI] 5(5)[2–11] 130 (15) [12–17] DCRg [95% CI] 14 (14) [8–22] 384 (43) [40–46] an = 97; bn = 873; cn = 100; dn = 889; en = 91; fn = 837. gCR/PR or stable disease for $4 wks G = grade

5036 Poster Session (Board #105), Fri, 8:00 AM-11:00 AM

Impact of renal impairment on clinical outcomes in patients (pts) with locally advanced or metastatic (LA/M) urinary tract carcinoma (UTC) treated with atezolizumab (atezo): Analysis of the international SAUL study.

Margitta Retz, Florian Seseke, Giuseppe Luigi Banna, Ugo De Giorgi, Thomas Powles, Umberto Basso, Raymond S. McDermott, Anna Llado, Wen-Pin Su, Cristina Ligia Cebotaru, Javier Puente, Alvaro Montesa, Jacques De Greve, Zsuzsanna Kahan, Urbano Anido Herranz, Sabine de Ducla, Julie Pavlova, Simon Fear, Cora N. Sternberg; Rechts der Isar Medical Center, Technical University of Munich, Munich, Germany; Krankenhaus Martha-Maria Halle-Dolau, ¨ Halle, Germany; Cannizzaro Hospital, Catania, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Meldola, Italy; Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew’s Hospital, London, United Kingdom; Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy; Adelaide & Meath Hospital, Dublin, Ireland; Istituto Oncologico della Svizzera Italiana (IOSI), Bellinzona, Switzerland; National Cheng Kung Uni Hospital, Tainan, Taiwan; Institutul Oncologic Prof. Dr Ion Chiricut¸a˘ Cluj-Napoca, Cluj- Napoca, Romania; Hospital Clinico San Carlos, Madrid, Spain; Unidad de Investigacion ´ en Tumores Genitourinarios Centro Nacional de Investigaciones Oncologicas ´ (CNIO)-Instituto de Investigacion ´ Biomedica ´ de Malaga ´ (IBIMA), Hospitales Universitarios Regional y V de la Victoria de Malaga, ´ Malaga, ´ Spain; UZ Brussels, Brussels, Belgium; Szegedi Tudomanyegyetem, ´ Altal´ anos ´ Orvostudomanyi ´ Kar, Szent-Gyorgyi ¨ Albert Klinikai Kozpont, Onkoterapias Klinik, Szeged, Hungary; Complejo Hospitalario Universitario de Santiago (CHUS), Santiago De Compostela, Spain; F. Hoffmann-La Roche Ltd, Basel, Switzerland; San Camillo and Forlanini Hospitals, Rome, Italy and Englander Institute of Precision Medicine, Weill Cornell Medicine (current affiliation), New York, NY

Background: Atezo, which targets PD-L1, is an approved therapy for LA/M urothelial carcinoma based on the IMvigor210 and IMvigor211 trials. The single-arm SAUL study (NCT02928406) showed consistent activity and safety in a broader population, including understudied scenarios, eg pts with renal impairment or other IMvigor211 exclusion criteria. Methods: Pts with LA/M UTC received atezo 1200 mg q3w until disease progression or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included overall response rate (ORR) and overall survival (OS). Post hoc analyses explored outcomes in pts classified as: chemotherapy (CT) ineligible (calculated creatine clearance [CrCl] 15– , 30 mL/min); cisplatin ineligible and carboplatin eligible (CrCl 30– , 60 mL/min); or cisplatin eligible (CrCl $60 mL/min). Results: Of 1004 enrolled pts, 46 (5%) were classified as CT ineligible and 420 (42%) as cisplatin ineligible. Results are summarized below. Conclusions: These post hoc analyses suggest pts typically considered cisplatin or CT ineligible are candidates for atezo. Pts with renal impairment achieved similar ORR and DCR to pts with CrCl $60 mL/min, without increased toxicity. Imbalances in pt characteristics may explain numerical differences in OS. Clinical trial information: NCT02928406. Research Sponsor: F Hoffmann-La Roche Ltd, Basel, Switzerland.

15– < 30 30– < 60 ‡60 CrCl, mL/min (n = 46) (n = 420) (n = 529) Median age, y (range) 75 (48–92) 72 (40–93) 63 (34–86) Female, n (%) 15 (33) 112 (27) 97 (18) Visceral metastases, n (%) 18 (39) 161 (38) 194 (37) No prior CT for LA/M UTC, n (%) 13 (28) 145 (35) 223 (42) PD-L1 IC 2/3,a n(%) 10 (22) 115 (27) 138 (26) Median atezo duration, mo (range) 3.0 2.8 2.8 (0.0–18.7) (0.0–18.9) (0.0–19.0) Grade ‡3 AEs, n (%) Any 21 (46) 188 (45) 239 (45) Treatment related 3 (7) 51 (12) 73 (14) Special interest 1 (2) 23 (5) 43 (8) AE leading to atezo withdrawal, n 3 (7) 22 (5) 32 (6) (%) Median OS, mo 5.7 8.5 9.4 (95% CI) (3.4–11.0) (7.0–10.8) (8.0–10.4) ORR, n (%) 6 (13) 62 (15) 67 (13) [95% CI] [5–26] [12–19] [10–16] DCR,b n(%) 21 (46) 179 (43) 197 (37) [95% CI] [31–61] [38–48] [33–42] DCR = disease control rate a$5% of tumor immune cells express PD-L1 bComplete/partial response or stable disease for $4wk

5037 Poster Session (Board #106), Fri, 8:00 AM-11:00 AM

Phase I expansion study of cabozantinib plus nivolumab (CaboNivo) in metastatic urothelial carcinoma (mUC) patients (pts) with progressive disease following immune checkpoint inhibitor (ICI) therapy.

Daniel da Motta Girardi, Scot Anthony Niglio, Amir Mortazavi, Primo Lara, Sumanta K. Pal, Biren Saraiya, Lisa M. Cordes, Lisa Ley, Olena Sierra Ortiz, Jacqueline Cadena, Carlos Diaz, Mohammadhadi H. Bagheri, Seth M. Steinberg, Rene Costello, Howard Streicher, John Wright, Howard L. Parnes, Yang-Min Ning, Donald P. Bottaro, Andrea B. Apolo; National Cancer Institute, National Institutes of Health, Bethesda, MD; Arthur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH; University of California, Sacramento, CA; City of Hope Comprehensive Cancer Center, Duarte, CA; Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, Lawernceville, NJ; National Institutes of Health, Bethesda, MD; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD; National Cancer Institute, Bethesda, MD; Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD; Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, MD; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD; NIH/NCI, Bethesda, MD; National Cancer Institute at the National Institutes of Health, Bethesda, MD; U.S. Food and Drug Administration, Silver Spring, MD; Center for Cancer Research, Division of Cancer Treatment and Diagnosis, Bethesda, MD; Genitourinary Malig- nancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

Background: Previous treatment with ICI is more common in clinical practice since recent FDA-approval of 5 ICIs in second-line and 2 in first-line for mUC. There is lack of data regarding the use of ICI after progression on a prior ICI. Cabozantinib has been shown to have immunomodulatory properties and may have synergistic effect with ICI. Methods: This is a phase I expansion cohort of mUC pts, who received prior ICI, treated with Cabozantinib 40mg daily and Nivolumab 3mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary objective was to determine the efficacy and tolerability of CaboNivo. Results: Twenty-nine mUC pts were treated. Median follow-up was 14.1 months (mo). The majority of pts were male (75.8%); 27 were White (93.1%), and 2 were Asian (6.9%). Primary tumor was bladder in 21 pts (72.4%) and upper tract in 8 (27.6%). Twenty-two pts (75.9%) had visceral metastasis (mets), 4 (13.8%) had lymph node only mets and 13 (44.8%) had liver mets. The median number of prior lines of treatment for mUC was 2 (range 0-8) with 17 pts (58.6%) receiving 2 prior lines of treatment. The majority of pts (86.2%) received prior chemotherapy for mUC and all pts received prior ICI. The median number of cycles of prior ICI was 7 (range 1-20) and median time between previous ICI and CaboNivo was 2.5 mo (range 1-18). The best response to previous ICI was partial response (PR) in 1 pt (3.4%), stable disease (SD) in 13 (44.9%), progressive disease (PD) in 14 (48.3%) and one (3.4%) was not evaluable (NE). The overall response rate for CaboNivo was 13.8% with 4 pts achieving PR (13.8%), 15 SD (51.7%), 7 PD (24.2%) and 3 NE (10.3%). Responses were seen in the liver, lung, and lymph nodes. Among 4 pts with PR, 2 were primary refractory to previous ICI and 2 had SD. At cutoff date the median duration of response was not reached and 3 PR were still ongoing: 1 had just began and the other 2 were ongoing at 12.3 and 26.4 mo. Among 15 pts with SD, 4 had SD for more than 6 mo and 2 were still ongoing at 8.1 and 25.1 mo. Median progression-free survival was 3.6 mo (95% CI: 2.1 – 5.3 mo) and median overall survival was 10 mo (95% CI: 5.8 – 16.7 mo). Grade 1/ 2 treatment related adverse events (AEs) occurred in 28 pts (97%) and .Grade 3 (G.3) AEs occurred in 14 pts (48%). The most common G.3 AEs were fatigue (14%), hypophosphatemia (14%), lymphocyte count decrease (14%), hypertension (7%) and hyponatremia (7%). Conclusions: CaboNivo is clinically active and safe in heavily pretreated pts with progressive mUC following ICI. Clinical trial information: NCT02496208. Research Sponsor: U.S. National Institutes of Health.

5038 Poster Session (Board #107), Fri, 8:00 AM-11:00 AM

Infigratinib and treatment response in advanced/unresectable or metastatic urothelial carcinoma in first-line and later-line treatment settings.

Yung Lyou, Petros Grivas, Jonathan E. Rosenberg, Jean H. Hoffman-Censits, David I. Quinn, Daniel Peter Petrylak, Matt D. Galsky, Ulka N. Vaishampayan, Ugo De Giorgi, Sumati Gupta, Howard A. Burris III, Jessica Rearden, Corina Andresen, Hao Wang, Siamak Daneshmand, Dean F. Bajorin, Sumanta K. Pal; City of Hope Comprehensive Cancer Center, Duarte, CA; University of Washington, Seattle, WA; Memorial Sloan Kettering Cancer, New York, NY; Sidney Kimmel Com- prehensive Cancer Center at Johns Hopkins, Baltimore, MD; USC Norris Comprehensive Cancer Center, Los Angeles, CA; Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT; Mount Sinai School of Medicine, New York, NY; Wayne State University, Detroit, MI; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; Huntsman Cancer Institute-University of Utah Health Care, Salt Lake City, UT; Sarah Cannon Research Institute, Nashville, TN; QED Therapeutics Inc., San Francisco, CA; Keck School of Medicine of USC, Los Angeles, CA; Memorial Sloan Kettering Cancer Center, New York, NY

Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 tyrosine kinase inhibitor (TKI), previously reported to be effective and well tolerated in patients with locally advanced/unresectable or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al. Cancer Discovery 2018]. However, this previous study did not examine differences in infigratinib activity based on number of prior lines of treatment (LOT). TKIs studied in other indications (e.g. VEGFRis in renal cell carcinoma) have shown consistent activity in both the first and later LOT. Given the effect seen with other TKIs, we sought to determine if infigratinib showed consistent treatment responses in patients with mUC according to LOT. Methods: Eligible patients had mUC and prior platinum-based chemotherapy unless contraindicated and activating FGFR3 mutations/fusions. Infigratinib was dosed at 125 mg orally daily (3 weeks on/1 week off). The primary endpoint of objective response rate (ORR: partial response [PR] and complete response [CR]) was assessed, as well as disease control rate (DCR: CR + PR + stable disease [SD]). After classification of LOT for each patient, subgroup analysis of response by LOT was performed. Results: 67 patients were enrolled; 81% received $1 prior LOT for mUC. 13 patients (19.4%) received infigratinib as 1st LOT for mUC due to ineligibility to receive platinum-based chemotherapy. ORR for the 67 patients was 25% (95% CI 15.5–37.5) and DCR was 64% (95% CI 51.5–75.5). The ORR with 1st-line infigratinib was 31% (95% CI 9.1–61.4) compared with 24% (95% CI 13.5–37.6) for 2nd and later (salvage) LOT. DCR was 46% (95% CI 19.2–74.9) for 1st-line and 69% (95% CI 54.4–80.5) for $2 LOT. 13 of the 59 patients with urothelial bladder carcinoma (UBC) received 1st-line treatment with an ORR of 31% (95% CI 9.1–61.4) and 46 patients in $2 LOT had an ORR of 20% (95% CI 9.4–33.9). All 8 patients with upper tract urothelial carcinoma (UTUC) received salvage therapy, with an ORR of 50% and a DCR of 100%. An analysis of other outcome measures (e.g. PFS, OS) will be presented. Conclusions: These results indicate that infigratinib has activity in patients with mUC regardless of LOT. Additionally, patients with UTUC showed a trend for better ORR and DCR. Taken together, these results support the ongoing adjuvant PROOF 302 study comparing infigratinib with placebo in patients with resected disease, assessing infigratinib in an even earlier setting in a UTUC-enriched population (NCT04197986). Clinical trial information: NCT01004224. Research Sponsor: QED Therapeutics.

5039 Poster Session (Board #108), Fri, 8:00 AM-11:00 AM

Ipilimumab challenge/re-challenge in metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors treated with cabozantinib+nivolumab (CaboNivo) or cabozantinib+nivolumab+ipilimumab (CaboNivoIpi).

Scot Anthony Niglio, Daniel da Motta Girardi, Amir Mortazavi, Primo Lara, Sumanta K. Pal, Biren Saraiya, Lisa M. Cordes, Lisa Ley, Olena Sierra Ortiz, Jacqueline Cadena, Carlos Diaz, Mohammadhadi H. Bagheri, Seth M. Steinberg, Rene Costello, Howard Streicher, John Wright, Howard L. Parnes, Yang-Min Ning, Donald P. Bottaro, Andrea B. Apolo; National Cancer Institute, National Institutes of Health, Bethesda, MD; Arthur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH; University of California, Sacramento, CA; City of Hope Comprehensive Cancer Center, Duarte, CA; Division of Medical Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, Lawernceville, NJ; National Institutes of Health, Bethesda, MD; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD; National Cancer Institute, Bethesda, MD; Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD; Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, MD; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD; NIH/NCI, Bethesda, MD; National Cancer Institute at the National Institutes of Health, Bethesda, MD; U.S. Food and Drug Administration, Silver Spring, MD; Center for Cancer Research, Division of Cancer Treatment and Diagnosis, Bethesda, MD; Genitourinary Malig- nancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

Background: We investigated challenging/re-challenging pts with ipilimumab (ipi) after progression on CaboNivo or CaboNivoIpi. Methods: In a phase I expansion study, patients with mUC post-platinum chemotherapy and other GU tumors patients who progressed on Cabo 40 mg daily plus nivolumab, 3 mg/kg every 21 days (CaboNivo) alone or with ipi, 1 mg/kg every 21 days for 4 cycles (CaboNivoIpi)-and achieved a PR or SD$6 mo, were challenged/re-challenged with ipi, 1 mg/kg every 21 days for up to 4 cycles. Restaging scans were done every 6 wks for the first 12 wks, then every 8 wks and evaluated by RECIST 1.1. Results: In total, 24 patients were evaluated: 18 pts (8 UC (5 bladder and 3 upper tract), 4 clear cell renal cell carcinoma (RCC), 3 urachal adenocarcinoma (adeno), 2 bladder adeno, and 1 sarcomatoid clear cell RCC) who progressed on CaboNivo were challenged with ipi. In the challenge group, median (m) follow-up was 21.2 months. One pt achieved a PR in the LNs, but was found to have brain metastases before the next restaging, 13 had SD and 4 had PD. Median duration of PR or SD was 3.6 months (95% CI: 1.4 – 7.8 months). The mOS from start of ipi challenge was 13.9 months (95% CI: 5.8 months- not estimable); mPFS was 4.6 months (95% CI: 1.9 – 8.7 months). Grade 1/2 treatment related adverse events (AEs) occurred in all 18 pts (100%) and $Grade 3 (G$3) AEs occurred in 11 pts (61%). The most common G$3 AEs were hypophosphatemia (22%), hypertension (6%), adrenal insufficiency (6%), increased AST (6%), and ALT (6%). Six patients (3 bladder UC, 1 penile squamous cell (SCC) carcinoma, 1 urethral SCC, and 1 clear cell RCC with sarcomatoid features) who progressed on CaboNivoIpi were re-challenged with Ipi. On re-challenge, mfollow-up was 20.9 months. There were no PRs, 3 SDs and 3 PDs. mOS from start of re-challenge was 4.0 months (95% CI: 2.2 – 23.3 months) and mPFS was 1.9 months (95% CI: 1.1 – 2.6 months). Grade 1/2 treatment related AEs occurred in all 6 pts (100%) and $Grade 3 (G$3) AEs occurred in 2pts (33%). G$3 AEs included 1 hypertension (17%) and 1 hyperphosphatemia (17%). Conclusions: Ipi challenge/re-challenge showed low response rates in pts previously treated with CaboNivo or CaboNivoIpi. However, pts treated with CaboNivo who were challenged with ipi had a better OS than patients who had progressed on CaboNivoIpi and were re- challenged with ipi. Larger trials are warranted testing the ipi challenge in pts progressing on CaboNivo. Clinical trial information: NCT02496208. Research Sponsor: U.S. National Institutes of Health.

5040 Poster Session (Board #109), Fri, 8:00 AM-11:00 AM

Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Results of an open-label phase II clinical study Polaris- 03.

Xinan Sheng, Haige Chen, Bin Hu, Xudong Yao, Ziling Liu, Xin Yao, Hongqian Guo, Yi Hu, Zhigang Ji, Hong Luo, Benkang Shi, Jiyan Liu, Jin WU, Fangjian Zhou, Zhisong He, Jinhai Fan, Yiran Huang, Jun Guo; Peking University Cancer Hospital and Institute, Beijing, China; Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China; Liaoning Cancer Hospital & Institution, Shenyang, China; Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China; The First Hospital of Jilin University, Changchun, China; Tianjin Cancer Hospital, Tianjin, China; Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Chinese PLA General Hospital, Beijing, China; Peking Union Medical College Hospital, Beijing, China; Chongqing Cancer Hospital, Chongqing, China; Qilu Hospital of Shandong University, Jinan, China; West China Hospital, Sichuan University, Chengdu, China; Affiliated Cancer Hospital of Harbin Medical University, Harbin, China; Sun Yat-sen University Cancer Center, Guangz- hou, China; Peking University First Hospital, Beijing, China; First Affiliated Hospital of Xi’An Jiao Tong University, Xi’an, China; Peking University Cancer Hospital and Institute, Beijing, China; Peking University Cancer Hospital and Institute, Beijing, China

Background: Patients with advanced metastatic urothelial carcinoma (UC) who experience disease progression after standard therapy have limited treatment options. Phase I study of toripalimab in subjects with heavily pretreated metastatic UC had demonstrated an acceptable safety profile and promising clinical activity. Here we report the safety and efficacy result of toripalimab in a phase II clinical study (POLARIS-03) in Chinese patients with metastatic urothelial carcinoma. (Clinical trial ID: NCT03113266). Methods: Metastatic UC Patients receive toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response is assessed every 8 weeks. Tumor PD-L1 expression and other biomarkers will be evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 204 patients were screened and the study enrollment was completed with 151 patients enrolled from 15 participating centers. The median age was 62 years and 66% were male. 87% patients had visceral metastasis. By the cut-off date of Jan 6, 2020, 92.1% (139/151) patients experienced treatment related adverse event (TRAE) and grade 3 and above TRAE occurred in 35.8% (54/151) patients. Most common TRAE included anemia, triglycerides increased, proteinuria, fatigue, and hyperglycemia. Treatment discontinuation due to a TRAE occurred in 6 (4.0%) patients, while dose delay due to a TRAE occurred in 23 (15.2%) patients. Three patients with major protocol deviations were excluded from efficacy analysis. Among 148 patients assessed by IRC per RECISTv1.1, 2 CR, 36 PR, and 30 SD were observed for an ORR of 25.7% and a DCR of 45.9%. The median DOR was 15.7 months. The median PFS was 1.9 months, and the median OS was estimated 20.8 months. PD-L1 expression results were obtained from 141 patients. PD-L1+ patients (n=46) had significant better ORR than PD-L1- patients (n=95), 41.3% versus 16.8% (p,0.01). Conclusions: Toripalimab has demonstrated encouraging clinical activity in chemo-refractory UC patients with a manageable safety profile. Patients will be continuously monitored for safety and overall survival. Clinical trial information: NCT03113266. Research Sponsor: Shanghai Junshi Bio- science Co., LTD, Shanghai, China.

5041 Poster Session (Board #110), Fri, 8:00 AM-11:00 AM

Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Gu´erin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057.

Arjun Vasant Balar, Ashish M. Kamat, Girish S. Kulkarni, Edward M. Uchio, Joost L. Boormans, Dean F. Bajorin, Mathieu Roumiguie, ´ Eric A. Singer, Laurence Eliot Miles Krieger, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Kijoeng Nam, Jo~ao Paulo Zambon, Ekta Kapadia, Ronald De Wit; Perlmutter Cancer Center, NYU Langone Health, New York, NY; The University of Texas MD Anderson Cancer Center, Houston, TX; Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada; UCI Health, Orange, CA; Erasmus MC, Rotterdam, Netherlands; Memorial Sloan Kettering Cancer Center, New York, NY; Institut Universitaire du Cancer Toulouse Oncopole CHU, Toulouse, France; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Royal North Shore Hospital, Northern Cancer Institute, St Leonards, NSW, Australia; University of Washington, Seattle, WA; National Cancer Center, Goyang, South Korea; University of Tsukuba, Tsukuba, Japan; University of Minnesota, Minneapolis, MN; Merck & Co., Inc., Kenilworth, NJ

Background: Pembro was recently approved for the treatment of HR NMIBC based on results from the phase 2 KEYNOTE-057 (NCT02625961) study. Herein we present safety, efficacy, and posttreatment outcomes with . 2 y follow-up from KEYNOTE-057 cohort A. Methods: Patients with histologically confirmed HR BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors who received adequate BCG therapy and were ineligible for or opted out of radical cystectomy (RC) received pembro 200 mg Q3W for up to 2 y or until disease recurrence, progression, or unacceptable toxicity. The primary end point was complete response rate (CRR). Key secondary end points were duration of response (DOR) and safety. Results: Overall, 102 patients were initially enrolled, and 96 were included in the efficacy analysis. Median time from enrollment to data cut off was 28.4 months (range, 18.2-40.5). CRR was 40.6% (95% CI, 30.7-51.1), and median DOR was 16.2 months (range, 0+ to 30.4+). Among 39 patients with CR, 18 (46.2%) had a DOR $12 months. No patient’s disease progressed to muscle-invasive or metastatic bladder cancer while on study treatment. Median PFS and OS were not reached. At 12 months, PFS was 82.7% and OS was 97.9%. A total of 36 patients (37.5%) underwent RC after discontinuation from study treatment, which included 9 of 22 patients (40.9%) who had recurrence after initial CR and 27 of 57 (47.4%) nonresponders. Of the 36 who underwent RC, 33 (91.6%) had no pathological upstaging to MIBC and 3 (8.3%) had at least pT2 disease at time of RC. For subsequent treatments other than RC, 27 of 96 (28.1%) patients received additional intravesical therapy (eg, BCG, gemcitabine, or mitomycin), 21 of 96 (21.9%) underwent local procedures (eg, TURBT), and 3 of 96 (3.1%) received systemic therapy (eg, pembro). In 102 patients treated with pembro, treatment-related AEs (TRAEs) occurred in 67 (65.7%) patients; most frequently reported TRAEs were fatigue, pruritus, and diarrhea (10.8% each). Grade 3/4 TRAEs occurred in 13 patients (12.7%), and 21 patients (20.6%) experienced immune-mediated AEs. There were no grade 5 TRAEs. Conclusions: After . 2 y of follow-up, durable and clinically meaningful activity of pembro was observed in patients who had HR BCG-unresponsive CIS with or without papillary tumors and who were ineligible for or opted out of RC. Pembro did not seem to limit the opportunity for subsequent therapies, including RC. The safety profile was consistent with what is reported in the literature. Clinical trial information: NCT02625961. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

5042 Poster Session (Board #111), Fri, 8:00 AM-11:00 AM

Thromboembolism (TE) in patients (pts) with bladder cancer treated with checkpoint inhibitors (CPIs).

Iris Yeong- Fung Sheng, Shilpa Gupta, Chandana A. Reddy, Dana E Angelini, Pauline Funchain, Tamara A. Sussman, Joseph Sleiman, Timothy D. Gilligan, Moshe Chaim Ornstein, Alok A. Khorana; Cleveland Clinic, Cleveland, OH; Cleveland Clinic Foundation, Cleveland, OH; Cleveland Clinic Foundation, Avon Lake, OH; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Cleveland Clinic Cancer Center, Cleveland, OH; Cleveland Clinic- Taussig Cancer Institute, Cleveland, OH

Background: Most pts with bladder cancer will be treated with immunotherapy. There is concern for increased TE risk with CPIs in this already high risk population. We present the first analysis of the incidence and outcomes of venous (VTE) and arterial (ATE) thromboembolism in pts with bladder cancer treated with CPIs. Methods: Consecutive pts with bladder cancer treated with CPIs at the Cleveland Clinic from 1/2015 to 12/2019 were identified and TE events noted. Overall survival (OS) was estimated using Kaplan-Meier method and the impact of VTE on OS was evaluated using Cox proportional hazards regression. Results: Of 274 pts, 72% were men (median age 73.3 years, 89% white), 82% had pure UC, 92% had lower tract disease, and 67% had a Bajorin score $1 (median KPS 90, 61% visceral metastases), 59% had prior systemic therapy (median 1, range 0-4) and 36% had prior TE (14% ATE, 19% VTE, 0.4% both). At CPI initiation, 24% were on antiplatelet therapy, and 15% on therapeutic anticoagulation. CPI (median doses 5, range 8.5-59) included: 40% atezolizumab, 3% nivolumab, 57% pembrolizumab. VTE occurred in 14% (n = 37), including 8% DVT, 4% PE, 2% both. DVT locations were 56% lower limb, 26% upper limb, 15% visceral vein, 4% visceral+upper limb. 2% (n = 5) had ATE (1% CVA, 0.4% visceral, 0.4% left subclavian). 92% of VTE and all ATE occurred within 6 months of CPI initiation. The incidence of TE was 10.9% (95%CI 6.6%—15.1%) at 6 months and 19.8% (95%CI 13.3%-26.4%) at 12 months. 82% of VTE (mean 6 days) and all ATE (mean 5 days) resulted in hospitalization. Multivariate analysis showed TE (HR 2.296, 95%CI 1.451- 3.632, p = 0.0004), Bajorin score 1 (HR 1.490, 95%CI 1.036-2.142, p = 0.0315), and Bajorin score 2 (HR 3.50, 95%CI 2.14-5.74, p , 0.0001) were independently associated with worse OS. Conclusions: CPIs in bladder cancer pts are associated with a high TE risk, especially within six months of initiation. TE is associated with worsened survival. Further investigation into the risk factors for CPI- associated TE is needed to identify if benefits exist from thromboprophylaxis. Research Sponsor: None.

5043 Poster Session (Board #112), Fri, 8:00 AM-11:00 AM

Dissecting outcomes of patients (pts) with

Praful Ravi, Gregory Russell Pond, Leonidas Nikolaos Diamantopoulos, Rohit K. Jain, William Paul Skelton, Sumati Gupta, Jonathan David Tward, Kathleen Olson, Parminder Singh, Camilla Marisa Grunewald, Guenter Niegisch, Jae-Lyun Lee, Andrea Gallina, Marco Bandini, Andrea Necchi, Matthew Mossanen, Bradley Alexander McGregor, Catherine Curran, Petros Grivas, Guru Sonpavde; Dana-Farber Cancer Institute, Boston, MA; McMaster University, Department of Oncology, Hamilton, ON, Canada; University of Washington, Seattle, WA; Lee Moffitt Cancer Center, Tampa, FL; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Huntsman Cancer Institute-University of Utah Health Care, Salt Lake City, UT; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Mayo Clinic, Phoenix, AZ; Heinrich-Heine-University, Medical Faculty, Department of Urology, Dusseldorf, ¨ Germany; Department of Urology, Medical Faculty, University of D¨usseldorf, Dusseldorf, ¨ Germany; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Vita Salute San Raffaele University and Urological Research Institute (URI), IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Depart- ment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Brigham and Women’s Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Department of Genitouri- nary Oncology, Dana Farber Cancer Institute, Boston, MA

Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long- term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved , ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate- vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving , ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin- based NAC regimen used was not an independent predictor of recurrence. Research Sponsor: None.

5044 Poster Session (Board #113), Fri, 8:00 AM-11:00 AM

Study EV-103: Durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.

Jonathan E. Rosenberg, Thomas W. Flaig, Terence W. Friedlander, Matthew I. Milowsky, Sandy Srinivas, Daniel Peter Petrylak, Jaime R. Merchan, Mehmet Asim Bilen, Anne-Sophie Carret, Nancy Yuan, Carolyn Sasse, Christopher J. Hoimes; Memorial Sloan Kettering Cancer, New York, NY; University of Colorado Anschutz Medical Campus, Aurora, CO; University of California San Francisco, San Francisco, CA; University of North Carolina Department of Medicine, Division of Hematology/ Oncology, Chapel Hill, NC; Stanford Cancer Institute, Stanford, CA; Smilow Cancer Center, Yale University, New Haven, CT; University of Miami, Miami, FL; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Seattle Genetics, Inc., Bothell, WA; Astellas Pharma, Inc., Northbrook, IL; Duke Cancer Institute, Durham, NC

Background: Platinum chemotherapy is the standard for patients (pts) with metastatic urothelial carcinoma (mUC) in the first line (1L) setting. PD-1/PD-L1 inhibitors, such as pembrolizumab (P), have shown promising durability in this setting for PD-L1 high patients. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with locally advanced or mUC who have previously received a PD-1/PD- L1 inhibitor and a platinum-containing chemotherapy. EV is investigational in the 1L setting. Initial EV + P data were previously presented (Hoimes ESMO 2019); this provides durability data and an update on safety/ORR. Methods: This multicohort study (NCT03288545) evaluated the safety/activity of EV + P. We report a cohort of 1L cisplatin-ineligible patients treated with EV 1.25 mg/kg + P. In each 3-week cycle, EV was administered on Days 1 and 8 and P on Day 1. The primary endpoint was safety/ tolerability; secondary objectives included determination of recommended EV dose, ORR, DCR, DOR/ PFS per RECIST v1.1, and OS. Results: As of 8 Oct 2019, 45 1L or previously untreated mUC pts (median age 69 yr [51–90]) received a median of 9 (range 1-22) cycles of EV + P. The most common treatment-emergent adverse events (AE) were fatigue (58%, 11% $G3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% $G3). One pt died due to an AE reported as related (multiple organ failure). With a median follow-up of 11.5 mo, confirmed investigator-assessed ORR was 73.3% (95% CI, 58.1, 85.4) including 15.6% CRs; DCR was 93.3%. The ORR in pts with liver metastasis was 53.3% (8/15). The ORR in pts with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). Of the 33 responders, 18 (55%) have ongoing responses including 11 responses beyond 10 months. The median DOR was not reached (range 1.2 to 12.9+ mo); the 12- month DOR rate was 53.7% (95% CI, 27.4, 74.1). The median PFS was 12.3 mo (95% CI, 7.98, -); the 12-month PFS rate was 50.1% (95% CI, 33.0, 65.0). The median OS was not reached (range 0.66 to 19.2+ mo); the 12-month OS rate was 81.6% (95% CI, 62.0, 91.8). Conclusions: In 1L cisplatin- ineligible pts with mUC, EV + P, a potential platinum free option, demonstrates promising activity and durability, with a manageable safety profile. Further evaluation of EV + P in mUC and muscle-invasive UC is ongoing. Clinical trial information: NCT03288545. Research Sponsor: Seattle Genetics, Inc, Pharmaceutical/Biotech Company.

5045 Poster Session (Board #114), Fri, 8:00 AM-11:00 AM

Impact of timing of antibiotic use on clinical outcomes in patients with urothelial cancer treated with immune checkpoint inhibitors (ICIs).

Chana Weinstock, Pradeep Bandaru, Laura L Fernandes, Elaine Chang, Andrew Girvin, Shenghui Tang, Sundeep Agrawal, Daniel L. Suzman, Harpreet Singh, Michael Holman Brave, James Xu, Kirsten B. Goldberg, Amna Ibrahim, Marc Robert Theoret, Richard Pazdur, Julia A. Beaver; U.S. Food and Drug Administration, Silver Spring, MD; Palantir Technologies, Washington, DC; Food and Drug Administration, Silver Spring, MD; Palantir Technologies, Menlo Park, CA; Medstar Washington Hosp Ctr, Washington, DC; Johns Hopkins University, Baltimore, MD; U.S. Food and Drug Adminis- tration, Washington, DC; National Cancer Institute at the National Institutes of Health, Bethesda, MD

Background: Although recent evidence has suggested that patients who receive antibiotics (ABX) during the course of ICI treatment might decrease overall survival (OS) (1), our previous analysis did not support a difference in OS in urothelial cancer patients who did and did not use ABX during the course of ICI treatment without regard to timing (2). This updated analysis aims to addresses the question of timing; specifically, use of ABX in the 30-day window pre- or post- initiation of ICI treatment. Methods: We pooled data from 7 trials that led to drug approval and which included 1747 patients with advanced urothelial cancer treated with an ICI. Five trials enrolled patients who received prior platinum and 2 enrolled cisplatin-ineligible patients. Concomitant medication datasets were searched for systemic ABX use. The association between ABX use and survival was evaluated using Kaplan-Meier estimates and Cox proportional hazards regression models stratified by study. Results: Overall, 56% of patients were exposed to antibiotics (ABX+) and 43% were not exposed (ABX-). In an exploratory analysis, median OS was similar between arms: 9.7 vs. 9.3 months in ABX+ vs. ABX- patients, respectively (HR 0.96). However, OS results differed in the 27% of patients who were exposed to antibiotics in the 30- day window pre- or post- initiation of ICI treatment, for whom median OS was 4.7 months vs. 11.5 months in the ABX+ vs. ABX- patients, respectively (HR 1.8). This remained true after controlling for baseline risk prognostic factors (Bajorin and Bellmunt scores). Similar trends were observed for progression-free survival (PFS). Conclusions: Patients treated with ABX while on therapy with an ICI for urothelial cancer had similar OS outcomes to those not treated with ABX. However, in an exploratory analysis looking at ABX use in the 30-day window pre- or post-initiation of ICI treatment, OS appeared decreased in ABX+ vs ABX- patients. Our exploratory analyses appear to show an association of OS/PFS with timing of antibiotics. References: 1) Routy B, Science (2017) 2) Weinstock C, ASCO 2019, abstract. Research Sponsor: None.

ABX+ ABX- ABX+, no window ABX-, no window 630 days 630 days (N= 986) (N= 761) (N=482) (N=1265) Deaths (%) 671 (68%) 511 (67%) 377 805 (63%) (78%) Median OS, months 9.7 (8.2, 11.1) 9.3 (8.1, 10.4) 4.7 (3.9, 11.6 (10.9, (95% CI) 5.9) 13.1) HR (95% CI) 0.96 (0.85, 1.1) ref 1.8 (1.6, ref 2.0) PFS events 826 (84%) 637 (84%) 428 1035 (89%) (82%) Median PFS, months 2.1 (2.1, 2.5) 2.1 (2.0, 2.1) 1.9 (1.7, 2.5 (2.2, (95% CI) 1.9) 2.8) HR (95% CI) 0.94 (0.85, 1.0) ref 1.6 (1.4, ref 1.8)

5046 Poster Session (Board #115), Fri, 8:00 AM-11:00 AM

Detection of urothelial carcinoma using plasma cell-free methylated DNA.

Pier Vitale Nuzzo, Sandor Spisak, Jacob E Berchuck, Sylvan Baca, Keegan Korthauer, Amin Nassar, Sarah Abou Alaiwi, Ziad Bakouny, Ronan Flippot, John A. Steinharter, Catherine Curran, Gwo-Shu Mary Lee, Sushrut Waikar, Mark Pomerantz, Daniel De Carvalho, Guru Sonpavde, Matthew L. Freedman, Toni K. Choueiri; Department of Medical Oncology, Dana-Farber Cancer Institute, Brookline, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Dana–Farber Cancer Institute, Boston, MA; Department of Statistics The University of British Columbia, Vancouver, BC, Canada; Brigham and Women’s Hospital, Boston, MA; Laboratory of Avec Foundation, Hopital Piti- Salpetriere, Paris, France; Dana-Farber Cancer Institute, Boston, MA; Dana Farber Cancer Institute, Boston, MA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Background: Methylation profiling of circulating cell-free DNA (cfDNA) is a promising approach for non- invasive tumor detection due to the presence of tissue-specific epigenetic signatures that are detectable in cfDNA. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMedDIP-seq) is a sensitive, low-input, cost-effective, bisulfite-free approach to profiling cfDNA methylomes, capable of detecting and classifying various tumor types. We tested the feasibility of cfMeDIP-seq to detect urothelial carcinoma (UC) in plasma samples. Methods: We performed cfMeDIP- seq on plasma samples from 43 patients (pts): 18 metastatic UC (UC) pts, 12 pre-cystectomy non- metastatic UC pts, and 13 cancer-free controls. Six (50%) of pre-cystectomy cases were non-muscle invasive UC. cfDNA was immunoprecipitated and enriched using an antibody targeting 5-methylcy- tosine and PCR-amplified to create a sequence-ready library. The top differentially methylated regions (DMRs) between UC and control samples were used to train a regularized binomial generalized linear model using 80% of the samples as a training set. The 20% of withheld test samples were then assigned a probability of being UC or control. This process was repeated 100 times. Results: The average amount (standard deviation) of cfDNA isolated from 1 ml of UC plasma samples was 29.2 (27.4) ng/mL and 8.02 (3.58) ng/mL in cancer-free controls. We identified 9,826 DMRs in plasma samples at an adjusted p-value of , 0.01, which partitioned UC and control samples. Iterative training and classification of held out samples using the top 300 DMRs resulted in a mean AUROC of 0.987. Conclusions: cfMeDIP-seq is an interesting new approach for non-invasive detection of UC. cfMeDIP- seq demonstrates high sensitivity to detect UC across all stages of UC, including non-muscle invasive disease. Research Sponsor: Dana Farber Cancer Institute.

5047 Poster Session (Board #116), Fri, 8:00 AM-11:00 AM

Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)- eligible cohort of HCRN GU14- 188.

Christopher J. Hoimes, Nabil Adra, Mark T. Fleming, Hristos Z. Kaimakliotis, Joel Picus, Zachary L Smith, Radhika Walling, Edouard John Trabulsi, Jean H. Hoffman-Censits, Michael O. Koch, Clint Cary, Robert Abouassaly, Cheryl Eitman, Pingfu Fu, Gordon Goolamier, Adam C Calaway, Lee Evan Ponsky, William Kevin Kelly; Duke Cancer Institute, Durham, NC; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Virginia Oncology Associates, US Oncology Research, Norfolk, VA; Indiana University Simon Cancer Center, Indianapolis, IN; Wash- ington University in St. Louis School of Medicine, St. Louis, MO; Washington University School of Medicine, St Louis, MO; Community Cancer Center, Indianapolis, IN; Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Indiana University School of Medicine, Indianapolis, IN; Glickman Urology and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH; University Hospitals Seidman Cancer Center, Cleveland, OH; Department of Population and Quantitative Health Science, Case Western Reserve University, Cleveland, OH; Case Western Reserve University, Cleve- land, OH; Seidman Cancer Center at University Hospitals Cleveland Medical Center, Cleveland, OH; University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA

Background: Patients (pts) with laUC who are C-eligible for N- therapy may benefit from combination chemo-immunotherapy. Cohort 1 (C1) of the GU14-188 trial is a phase 1b/2 trial designed to assess the tolerability and efficacy of N- gemcitabine (G), C, and P in pts with laUC. The current standard of care is ddMVAC with a pathologic non-muscle invasive rate (PaIR, #pT1N0) of ~44%. Methods: Eligible pts for C1 were surgical candidates and C-eligible with cT2-4aN0M0 bladder UC. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Phase 1b (no DLT) /2 treatments were the same: P 200mg q3wks on day 8 x5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle (cy), for 4 cy; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of PaIR was assessed at RC and designed for 86% power with 4% significance to detect a difference from 23 to 48%. Secondary endpoints include relapse free survival and overall survival. Results: 43 pts were enrolled to C1 with a median (mdn) age 64, 63% male, 51% . cT2. Mdn per-pt doses given (attempted) for: P:5(5), C:4(4), G:8(8). The PaIR was 61.1% (95%CI 0.45, 0.75), P0 (ypT0N0) rate of 44.4%, and did not correlate with baseline PD-L1 score. Downstage to PaIR occurred in 53% of cT2, and 74% of cT3/4. Mdn time to RC from last dose was 5.3wks. Seven were not included in the primary analysis: 4 (9.3%) without RC, 1 progressed, 1 lost to f/u during C1, 1 did not receive required protocol therapy. There was 1 death on post-RC day 9 due to mesenteric ischemia. Of 4 pts who did not have RC, 3 refused and 1 due to gr4 thrombocytopenic purpura; 4pts are alive and without recurrence at mdn f/u of 32mo. One pt with presumed gr3 MI during cy 4 had a negative inpt cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. At mdn f/u of 34.2mo (3.9-47.4), the estimated 36mo RFS, OS, and DSS is 63%, 82%, and 87%, respectively. Conclusion: Neoadjuvant GC with P in laUC has manageable toxicity and has improved pathologic outcomes compared to historic controls. Durable long-term survival in those with- and without -RC is noteworthy in this advanced cohort. KEYNOTE 866, NCT03924856, is a Phase III study of GC with perioperative P. Clinical trial information: NCT02365766. Research Sponsor: Merck & Co.

5048 Poster Session (Board #117), Fri, 8:00 AM-11:00 AM

Outcomes of patients (pts) with metastatic urothelial carcinoma (mUC) following discontinuation of enfortumab-vedotin (EV): Emergence of a new unmet need.

Catherine Curran, Gregory Russell Pond, Vera Kazakova, Petros Grivas, Leonidas Nikolaos Diamantopoulos, Ajjai Shivaram Alva, Christopher Su, Rohit K. Jain, Ankita Tandon, Jingsong Zhang, Andrea Necchi, Laura Marandino, Jaime R. Merchan, Trisha M. Plastini, Guru Sonpavde; Dana Farber Cancer Institute, Boston, MA; McMaster University, Department of Oncology, Hamilton, ON, Canada; St. Elizabeth’s Medical Center, Brighton, MA; University of Washington, Seattle, WA; University of Michigan Rogel Cancer Center, Ann Arbor, MI; University of Michigan Cancer Center, Ann Arbor, MI; Lee Moffitt Cancer Center, Tampa, FL; University of South Florida, Tampa, FL; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology, University of Turin, Candiolo Cancer Institute-FPO-IRCCS, Candiolo (TO), Italy; University of Miami, Miami, FL; University of Pennsylvania Health System, Philadelphia, PA; Department of Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA

Background: Enfortumab vedotin (EV) is an antibody drug conjugate recently approved to treat mUC following prior platinum and PD1/L1 inhibitors. The outcomes and patterns of therapy of pts following discontinuation of EV has yet to be studied. We investigated outcomes of pts who completed EV treatment for mUC at multiple institutions in order to identify benchmarks for evaluation of new agents following EV. Methods: Clinical data were obtained from mUC patients who had completed EV treatment from collaborating academic institutions. Descriptive stats were performed to describe the overall dataset and compare patient characteristics and outcomes of those who went on to receive further treatment post-EV and those who did not. Results: Data were available for 63 patients from 6 collaborating institutions: DFCI, University of Michigan, University of Washington, Moffitt Cancer Center, INT Milan and University of Miami. 17 (27%) were female and 46(73%) were male. The median age was 68 (range 43-83. The primary site of malignancy included bladder, upper tract, and other in 43 (68%), 19 (30%), and 1pt (.02%), respectively. The histologies included pure UC and mixed predominant UC in 49 (78%), and 14 pts (22%), respectively. 32 pts (51%) received further therapy after EV and 31pts (49%) did not. Longer duration of prior EV therapy was associated with receipt of post-EV therapy (p=0.0437). Treatments received post-EV were: trial therapy (n=14), PD1/L1 inhibitor (n=7), pemetrexed (n=4), taxane (n=3), carboplatin (n=2) and unknown in 2 pts. Objective response was observed in 3 of 32 pts (9.4%) who received therapy post-EV. The median duration of time from end of EV to death was 24 weeks. The median overall survival (OS) of those who received post-EV therapy and did not receive post-EV therapy was 37.5 weeks and 12 weeks, respectively. Conclusions: Outcomes of mUC following discontinuation of EV are dismal with only 51% receiving subsequent therapy. This study identifies an unmet need setting and establishes benchmarks for the interpretation of activity of new agents evaluated following EV. Research Sponsor: None.

5049 Poster Session (Board #118), Fri, 8:00 AM-11:00 AM

Analysis of chemotherapy-related modulation of the immune microenvironment in muscle invasive bladder cancer.

Elshad Hasanov, William Tabayoyong, Jianfeng Chen, Guoliang Yang, Fengqi Nie, Jieru Meng, Anh Hoang, Yueting Zhu, Eleni Efstathiou, Jolan Bondaruk, Wei-Lien Wang, Charles Guo, Miao Zhang, Bogdan Czerniak, Christopher Logothetis, Ashish M. Kamat, Jianjun Gao; University of Texas MD Anderson Cancer Center, Houston, TX; University of Rochester, Pittsford, NY; The University of Texas MD Anderson Cancer Center, Houston, TX; UT MD Anderson Cancer Center, Houston, TX; Department of Genitourinary Medical Oncology, Division of Cancer Medicine, Houston, TX; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Novel immune checkpoint inhibitors provide significant clinical benefits for patients with metastatic bladder cancer. It is known that chemotherapy administered to muscle invasive patients prior to radical cystectomy (neoadjuvant chemotherapy) improves survival. However, it is unknown whether immune checkpoint inhibitor therapy in combination with chemotherapy can provide further clinical benefits as neoadjuvant therapy. Here, we test the hypothesis that treatment of bladder cancer with certain chemotherapy agents can modulate bladder tumor immune microenvironment (TIME) for optimal combination with immune checkpoint therapy. Methods: Time course and dose response experiments were performed using eight human bladder cancer cell lines (UMUC3, RT4, 253J, RT112, J82, HT1376, T24, and HT1197) and two murine bladder cancer cell lines (MB49, MBT2). Con- ventional chemotherapy agents and combinations (MVAC, GemCis, PemVin) were used to treat bladder cancer cell lines. Flow cytometry analysis was used to measure immune cell subsets and PD-L1 expression. For in vivo studies, the subcutaneous MB49 murine bladder cancer model was used to evaluate responses to chemotherapy and anti-PD-L1 combinations. Pre- and post-treatment bladder tumors from patients who received neoadjuvant MVAC and GemCis are selected to evaluate changes in TIME. Results: Our data demonstrate that chemotherapy agents varies in their ability to up-regulate PD- L1 expression on bladder cancer cell lines. Vinblastine, gemcitabine, and pemetrexed treatment each resulted in significant upregulation of PD-L1 expression. Combination regimens with GemCis or PemVin demonstrated induction of PD-L1 across different cell lines. In in-vivo studies, GemCis + anti-PD-L1 had a synergistic activity in causing tumor regression. We also found that sequential versus concurrent treatment with chemotherapy and anti-PD-L1 had a similar outcome. Tissue analyses show that combination chemotherapies increased CD4 Th cell infiltration while decreasing Treg cells in TIME. Consistent with the in vitro data, PD-L1 expression was also up-regulated with combination treatment. The evaluation of TIME modulation in human bladder tumors treated with neoadjuvant MVAC or GemCis is ongoing. Conclusions: Our data suggest that chemotherapy could favorably modulate TIME and thus, may be combined with immune checkpoint inhibitor to improve antitumor responses in the neoadjuvant setting for patients with muscle invasive bladder cancer. Research Sponsor: MD Anderson Physician Scientist Award, Andrew Sabin Family Foundation Award.

5050 Poster Session (Board #119), Fri, 8:00 AM-11:00 AM

Clinicogenomic predictors of extreme responses to anti-PD1/PDL1 checkpoint inhibitors (CPI) in metastatic urothelial cancer (mUC).

Min Yuen Teo, Karissa Whiting, Jose Mauricio Mota, Han Li, Ashley Marie Regazzi, David B. Solit, David Henry Aggen, Chung-Han Lee, Samuel Aaron Funt, Dean F. Bajorin, Irina Ostrovnaya, Gopa Iyer, Jonathan E. Rosenberg; Memorial Sloan Kettering Cancer Center, New York, NY; Instituto do Cancerˆ do Estado de S~ao Paulo, S~ao Paulo, Brazil; Weill Cornell Medicine, New York, NY; Columbia University Medical Center, New York, NY; Memorial Sloan Kettering Cancer, New York, NY

Background: Only a subset of mUC patients (pts) derives benefit from CPI. We sought to evaluate potential clinical and genomic predictors, with additional focus on extreme outcomes. Methods: CPI- treated mUC with tumor sequencing with MSK-IMPACT (up to 468 genes) were identified. Pre-CPI clinical variables (including hemoglobin [hgb], lymphocyte [lymph], neutrophil [neut] and eosinophil [eos] counts) were extracted. Endpoint was time on treatment (ToT). Poor responders were defined as ToT #9 weeks and overall survival #3 months; exceptional responders had ToT .20 months. A multivariate Cox model for ToT was performed with clinical variables chosen by stepwise selection minimizing Akaike information criterion. Genomic analyses were adjusted for multiple testing. Results: 166/171 identified mUC were evaluable. Median age was 68 years, 78% were male. 72% had bladder primary, while 17%, 35% and 28% had liver, lung and bone metastases (mets). 67% had prior platinum chemo. 24 pts (14%) were poor and exceptional responders, respectively. In univariate analysis, liver mets were associated with shorter ToT while DNA damage repair (DDR) gene alterations, higher body mass index (BMI), eos, hgb and tumor mutation burden (TMB) were associated with longer ToT. No specific genomic alterations achieved q,.05. In multivariate model, prior chemo (HR 1.6, p=.01), liver mets (HR 2.4, p,.01) and high neut were associated with shorter ToT while urethral primary (HR 0.1, p,.01), higher TMB (HR 0.9, p,.01) and higher eos (HR 0.1, p,.01) were independently associated with ToT. Univariate logistic regression to identify poor and exceptional responders are tabulated. Multivariate results will be reported. Conclusions: In addition to validation of various known mUC prognosticators, we observed potential non-linear influence of clinical and genomic factors on extreme outcomes. Research Sponsor: None.

Exceptional responders Poor responders Odds ratio p OR p Liver mets 1.3 ,.01 BMI 1.1 .03 Bone mets 1.2 ,.01 Urethral primary 1.5 .04 Upper tract primary 1.1 .05 DDR alterations 1.2 ,.01 Eos 0.6 .02 TMB 1.01 ,.01 Hgb 0.95 ,.01 Eos 1.6 .01 Neut 1.02 ,.01 NCOR 1.6 q,.01 CDKN2A del 1.2 q=.03 TET1 1.9 q=.01 CDKN2B del 1.2 q=.03 RICTOR 1.6 q=.04

5051 Poster Session (Board #120), Fri, 8:00 AM-11:00 AM

Maintenance oral etoposide (VP-16) after high-dose chemotherapy (HDCT) for patients with relapsed metastatic germ-cell tumors (mGCT).

Bilal Anouti, Reem Akel, Sandra K. Althouse, Rafat Abonour, Mohammad Issam Abu Zaid, Nasser H. Hanna, Lawrence H. Einhorn, Nabil Adra; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN

Background: HDCT and peripheral-blood stem-cell transplant (PBSCT) can cure up to 60% of patients with relapsed mGCT. Maintenance daily oral VP-16 after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the role of maintenance VP-16 post HDCT+PBSCT compared to observation. Methods: The prospectively maintained Indiana University testicular cancer database was interrogated. Patients with relapsed non-seminoma who completed HDCT+PBSCT and achieved serologic remission and hematologic recovery were evaluated. Outcomes of patients who received maintenance VP16 (N = 141) were compared to patients who were observed (N = 252). In this retrospective study, Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Univariable and multivariable cox regression models were used to determine variables associated with PFS. Results: 2-year PFS in the maintenance VP-16 versus observation group was 55% vs. 44% (p = 0.008). 2-year OS was 61% vs. 52% (p = 0.01). A multivariable analysis was performed including the factors: primary tumor site (testis vs. mediastinum), IGCCCG risk, platinum refractory, HDCT line of therapy (2nd vs. $3rd), tumor marker amplitude at HDCT initiation, and receipt of maintenance VP-16 post HDCT vs. observation. Maintenance VP-16 was confirmed as an independent predictor of improved PFS with HR 0.48 [95% CI, 0.35-0.66] (p , 0.001). Conclusions: Maintenance oral VP-16 post HDCT+PBSCT improved PFS and OS. In a multivariable model including known adverse prognostic factors, maintenance VP-16 was an independent predictor of improved PFS. Research Sponsor: Internal funds from Indiana University.

Maintenance etoposide No maintenance etoposide Variable N = 141 N = 252 P Median age 27 31 , 0.001 Primary site -Testis/RP 130 (93%) 233 (92%) 0.93 -Mediastinum 11 (7%) 19 (8%) Metastatic sites -Retroperitoneum 118 (84%) 195 (77%) 0.14 -Pulmonary 111 (79%) 171 (68%) 0.02 -NPVM 62 (44%) 100 (40%) 0.41 -Liver 39 (28%) 54 (21%) 0.16 -Bone 9 (6%) 13 (5%) 0.61 -Brain 36 (26%) 50 (20%) 0.19 IGCCCG Risk -Good 28 (20%) 80 (32%) 0.03 -Intermediate 17 (12%) 23 (10%) -Poor 96 (68%) 146 (58%) Platinum refractory 63 (45%) 95 (38%) 0.17 HDCT line of therapy -2 124 (88%) 206 (82%) 0.11 -‡3 17 (12%) 46 (18%)

5052 Poster Session (Board #121), Fri, 8:00 AM-11:00 AM

Multicenter analysis of serum tumor markers, treatment patterns, and relapse in patients with testicular cancer in clinical stage IS.

Maximilian Peter Johannes Karl Brandt, Christian Guido Ruf, Klaus Peter Dieckmann, Isabella Syring, Christian Ruckes, Andreas Hiester, Peter Albers, Bolenz Christian, Axel Heidenreich, Axel Haferkamp, Friedemann Zengerling, Pia Paffenholz; University Clinic for Urology and Pediatric Urology, Mainz, Germany; Bundeswehrkrankenhaus Ulm, Ulm, Germany; Asklepios Klinik Altona, Hamburg, Germany; Universityclinic Bonn, Bonn, Germany; Mainz University, Mainz, Germany; Department of Urology, Heinrich-Heine-University, Dusseldorf, ¨ Germany; University Clinic Dusseldorf, ¨ Dusseldorf, ¨ Germany; Department of Urology and Pediatric Urology, University Hospital Ulm, University of Ulm, Ulm, Germany; University Hospital of Cologne, Cologne, Germany; Department of Urology and Pediatric Urology, Mainz, Germany; Department of Urology and Uro-Oncology, University Hospital of Cologne, Cologne, Germany

Background: Testicular germ cell tumors (TGCT) in clinical stage I (CSI) are tumors confined to the testis without evidence of metastasis. Around 50% of all TGCT patients present with elevated serum tumor markers (TM) such as alpha-feto protein (AFP), beta-humanochoriongonadotropin (ß-HCG) and lactate- dehydrogenase (LDH). After ablatio testis, TMs usually return to normal according to half-life kinetics, however, in clinical stage IS (CSIS) TMs remain elevated or increase after surgery. Follow-up data on CSIS is scarce and our study aims to assess clinical characteristics and oncologic outcomes in a large TGCT cohort. Methods: In this multicenter study we collected data from 5 tertiary referring hospitals in Germany, included patients with CSIS and evaluated TM levels, treatment and the primary outcome relapse-free survival. False CSIS was defined as documented CSIS but TMs that returned to normal after respective half-life kinetics. Differences between predefined groups (chemotherapy, TM, true/ false CSIS) was analyzed with fisher’s exact and chi-square test. Results: Overall, 2616 patient data files were analyzed. Forty-three patients (1.6%) were documented as CSIS of which 27 (63%) were true and 16 (37%) false CSIS. Six (14%) had seminomas and 37 (86%) non-seminomas. In the true CSIS group AFP, ß-HCG, AFP plus ß-HCG and LDH were elevated in 13, 6, 3 and 2 cases. Four true CSIS patients received surveillance, 21 had 3x or 2x courses of BEP (bleomycin, etoposide and cisplatin) and 2 carboplatin. Within the false CSIS group, 2 patients were treated with surveillance, 10 received 3x BEP, one 3x PEI (cisplatin, etoposide and ifosfamid) and 3 had carboplatin. Chi-Square test revealed no difference between true or false CSIS classification in respect to application of chemotherapy (any chemotherapy, p = 0.83). Relapse-free survival after 5 and 10 years was 88.9% and 77.8%, respectively. Three patients in the true CSIS group relapsed (2 seminomas had carboplatin, 1 non- seminoma had surveillance). All relapses were treated with 3 courses of BEP with no documented death in the CSIS population. Conclusions: Overall, less than 2% of all TGCT were documented CSIS of which 37% were falsely classified. We report a high proportion of relapse-free survival in CSIS treated with surveillance or BEP with a high heterogeneity in treatment patterns. Correct classification of CSIS remains of critical importance to avoid toxicity for patients that could be safely treated with surveillance. Research Sponsor: None.

5053 Poster Session (Board #122), Fri, 8:00 AM-11:00 AM

Outcome of men with HIV-associated germ cell cancer: Results from an international collaborative study.

Marcus Hentrich, Mark Bower, Gedske Daugaard, Annette Dieing, Markus Bickel, Massimiliano Berretta, Florian Lesmeister, Vindi Jurinovic, Albrecht Stohr, ¨ Julia Heinzelbecker, Ivanka Krznaric, Klaus-Peter Dieckmann, Andrea Necchi, Jose ´ Maroto, Jurgen ¨ Rockstroh, Margarida Brito Goncalves, Burkhard Joerg Otremba, Christian Hoffmann; Red Cross Hospital, Uni- versity of Munich, Munich, Germany; Chelsea and Westminster Hosp, London, United Kingdom; Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Hematology and Oncology, Vivantes Klinik am Urban, Berlin, Germany; Infektiologikum, Frankfurt, Germany; National Cancer Institute/IRCSS, Aviano, Italy; Ludwig Maximilian University of Munich, Munich, Germany; Institute for Interdisciplinary Medicine, Hamburg, Germany; Klinik fur ¨ Urologie und Kinder- urologie, Homburg, Germany; Center for Infectious Diseases, Berlin, Germany; Department of Urology, Asklepios Klinik Altona, Hamburg, Germany; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Medical Oncology, Hospital de Sant Pau, Barcelona, Spain; University of Bonn, Bonn, Germany; Instituto Portuguesˆ de Oncologı´a de Lisboa, Lisbon, Portugal; Onkologische Praxis, Oldenburg-Delmenhorst, Oldenburg, Germany; IPM Study Center, Hamburg, Germany

Background: Previous studies showed that men with HIV-associated germ cell cancer (HIV-GCC) have a similar cancer-free outcome compared with their HIV-negative counterparts. However, the overall survival (OS) was inferior and little data is available on treatment and outcome of HIV-GCC in the era of combined antiretroviral therapy (cART). Methods: Men living with HIV aged $ 18 years (yrs) with a diagnosis of histologically proven GCC made from 01/1996 to 07/2018 were included. Primary outcomes were OS and progression-free survival (PFS). Secondary outcomes included characteristics of GCC and HIV-infection, treatment and causes of death. Results: Data of 89 men from 23 institutions and 6 countries with a total of 92 HIV-GCC (2 synchronous and 1 metachronous bilateral GCC) were analysed, among them 64 (70%) seminomas and 28 (30%) nonseminomas. 10/89 (11%) cases were primary extragonadal GCC. Median age was 36 yrs (range, 22-52) and median time from HIV to GCC diagnosis was 5 yrs (range, 0-29). Median CD4 count at GCC diagnosis was 420 cells/ml (range, 3- 1503) and 83% of pts were on cART. Stage I disease was found in 44/80 (55%) gonadal GCC (metachronous bilateral case included). Of 46 cases with stage II/III/extragonadal GCC 78%, 17% and 4% were assigned to the IGCCCG good, intermediate and poor prognosis group, respectively. Of the 44 stage I cases, 22 (50%) were followed by active surveillance, and 11 (25%) received adjuvant chemotherapy (CT) or radiotherapy. Relapses occurred in 14 pts (6 from stage I, 8 in pts primary disseminated GCC) and CT was applied to 13/14 pts, of which 3 received high-dose CT. Overall, 12/89 (13%) pts have died. Causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3) and other (n = 4). After a median follow-up of 6.5 yrs (range, 0.3-20.9), the 5- and 10-year PFS rate was 81% and 73%, and the 5- and 10-year OS rate was 91% and 85%, respectively. There were no significant differences between the good and intermediate prognosis group or between pts with CD4 counts , 200/mlor$ 200/ml. Conclusions: The 5- and 10-year PFS and OS rates of men with HIV-GCC are similar to those reported for HIV-negative GCC. Pts with HIV-GCC should remain on cART and be managed in an identical fashion to HIV-negative pts. Research Sponsor: None.

5055 Poster Session (Board #124), Fri, 8:00 AM-11:00 AM

Prognostic role of early interim [18F] fluoro-deoxy-glucose positron emission tomography in patients with advanced seminoma undergoing standard treatment.

Daniele Raggi, Marco Bandini, Patrizia Giannatempo, Elena Fare, ` Laura Marandino, Maurizio Colecchia, Barbara Padovano, Gianluca Serafini, Alessandra Alessi, Andrea Necchi; Fonda- zione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Torino, Italy; Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy

Background: In patients (pts) with advanced seminoma, efforts are underway to tailor a risk-adapted treatment strategy to the individual pt. Our main objective was to prospectively determine the prognostic value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT2) after two cycles of bleomycin, etoposide and cisplatin (BEP) or EP chemotherapy under standardized treatment and PET evaluation criteria. Methods: Pts with advanced-stage seminoma were treated with BEP or EP according to guidelines. PET/CT examinations were performed at baseline, after two cycles in all pts and after chemotherapy at physician’s choice. PET/CT response was qualitatively evaluated by two independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to the guidelines (at baseline, after treatment, during follow-up). The primary endpoint was the relapse-free survival (RFS). Results: From 01/2009 to 01/2017, 75 consecutive pts were enrolled, of whom 70 were evaluable. The clinical stage was IIA-B and IIC-III in 40% and 60% of the pts, respectively. Eight pts (11.4%) received consolidation radiotherapy. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these pts presented with stage IIC-III. The median follow-up was 79 months. Five-year RFS of PET/CT2-positive pts was 75% (95%CI: 60- 95%) compared with 97.8% (95%CI: 93.7-100%) of PET/CT2-negative pts (p = .002). This significant improvement in RFS was maintained when analyzing only pts with clinical stage IIC-III (p = 0.04) and by excluding those who received consolidation RT (p = 0.02). An increasing linear association was found between the maximum diameter of retroperitoneal lymph nodes and the rate of PET/CT2+. In univariable Cox regression analyses, PET/CT2+ (HR: 12.9, 95%CI: 1.5-106.9, p = 0.02) and elevated HCG levels (HR: 6.3, 95%CI: 1.2-32.3, p = 0.03) were significantly associated with RFS, whereas IGCCCG risk group was not (p = 0.1). PET/CT2 result was also associated with the tumor shrinkage post- BEP (p = 0.009), whereas complete response at CT did not predict the RFS (p = 0.3). Conclusions: No residual FDG-uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, may outperform the utility of standard prognostic risk groups and may be more accurate to predict the RFS compared to standard response criteria. Benchmark RFS estimates for the design of the next clinical trials of chemotherapy de-escalation are offered. Research Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori.

5056 Poster Session (Board #125), Fri, 8:00 AM-11:00 AM

Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.

Eoghan Ruadh Malone, Jeremy Howard Lewin, Lisa Wang, Susan Lau, Robert James Hamilton, Aaron Richard Hansen, Keith Jarvi, Wenjiang Zhang, Eric Xueyu Chen, Philippe L. Bedard; Princess Margaret Hospital, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada; Murray Koffler Urologic Wellness Centre, Joseph and Wolf Lebovic Health Complex, Toronto, ON, Canada; Division of Urologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

Background: Cisplatin is highly curative treatment for testicular cancer. Most survivors develop azo- ospermia immediately after cisplatin with recovery expected in 50% at 2 years and 80% at 5 years. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, however, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. Methods: Testicular cancer survivors previously treated with cisplatin were enrolled, relapsed disease treated with salvage chemotherapy was excluded. Semen samples were collected to assess semen quality. Repeat semen collections were performed if azoo- or oligospermia was noted. Serum and semen Platinum levels were determined using HPLC-tandem mass spectrometry. DNA Fragmentation Index (DFI) was measured. Results: From 11/2017 to 12/2019, 38 pts (median age 32 years; range: 19-52; median BSA 2.03; range: 1.81-2.61) were enrolled, 31 were treated with 3 cycles of Bleomycin, Etoposide, Cisplatin. Median cumulative cisplatin dose was 300 mg/m2 (range: 274-404). Median serum platinum concentration was 0.1 ng/mL (range: 0-22.6) at a median of 11 months (range 0.5-36) post treatment completion. Median semen platinum concentration was 0.5 ng/mL (range: 0.2-28.7) at a median of 14 months (range: 1.3-40) post treatment completion. Semen platinum levels were higher in semen than in blood drawn at the same time (p = 0.03). Semen platinum levels were associated with time from last cisplatin dosing (r = -0.34; p = 0.09) but not cumulative cisplatin dose (r = -0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p , 0.001) but not with semen platinum level (r = -0.15, p = 0.46). DFI was associated with time from last cisplatin dosing (r = 0.55, p = 0.08) but not with semen platinum level (r = -0.32, p = 0.33). In 4 pts with serial semen samples available, semen platinum level decreased with time, sperm concentration and motility increased. Conclusions: Platinum can be detected in semen in long-term testicular cancer survivors at higher levels than matched blood samples. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer, further studies are needed to assess the relationship between platinum persistence in semen and recovery of fertility post chemotherapy. Research Sponsor: Department of Medical Oncology and Hematology Grant (Internal Princess Margaret Hospital).

5057 Poster Session (Board #126), Fri, 8:00 AM-11:00 AM

Model to predict brain metastasis (BM) in patients with metastatic germ-cell tumors (mGCT).

Ryan Ashkar, Sandra K. Althouse, Clint Cary, Timothy A. Masterson, Richard Foster, Nasser H. Hanna, Lawrence H. Einhorn, Nabil Adra; Indiana University Simon Comprehensive Cancer Center, Indian- apolis, IN; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Indiana University School of Medicine, Indianapolis, IN

Background: BM is an independent adverse prognostic factor that can lead to treatment complications and failure in pts with mGCT. We aimed to establish an effective and practical model for prediction of BM in mGCT. Methods: 2,256 consecutive pts with mGCT treated at Indiana University between January 1990 and September 2017 were identified. Pts were divided into 2 categories: BM present (N = 144) and BM absent (N = 2112). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated 50/50 into training and validation datasets with equal numbers of events in each. Results: Baseline characteristics for 2 groups are listed in Table. 2-yr PFS and OS for pts with vs without BM: 17% vs 66% (p , 0.001) and 62% vs 91% (p , 0.001) respectively. Among the 144 pts with BM, 64 (44%) had radiation only (whole-brain radiotherapy or gamma knife), 21 (15%) had BM-surgery only, 14 (10%) had both radiation and BM-surgery. 45 pts (31%) did not receive local therapy for BM. A stepwise selection was used to determine the best model with p , 0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis$40 (1 point), presence of pulmonary metastases (3 points), bone metastasis (1 point), pre- chemotherapy hCG$5000 (1 point), and choriocarcinoma predominant histology (1 point). Patients with 0 points had a 0.4% probability of BM, 1 point: 1%, 2 points: 2.6%, 3 points: 7%, 4 points: 16%, 5 points: 32%, 6 points: 56%, and 7 points: 77%. Details regarding analysis in training and validation datasets will be presented. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence and can be used by clinicians to identify high- risk pts. Research Sponsor: None.

BM present BM absent Variable N = 144 N = 2112 Median age at diagnosis (range) 29 (16-49) 30 (13-75) Primary site -Testis 125 (87%) 1966 (93%) -Retroperitoneum 8 (6%) 81 (4%) -Mediastinum 10 (7%) 57 (3%) Histology -Seminoma 6 (4%) 381 (18%) -Non-seminoma 137 (95%) 1721 (82%) Choriocarcinoma 56 (39%) 90 (4%) Embryonal carcinoma 30 (21%) 667 (32%) Yolk sac tumor 12 (8%) 155 (7%) Teratoma 11 (8%) 223 (11%) Metastatic sites -Retroperitoneal LN 106 (74%) 1788 (85%) -Pulmonary 134 (93%) 828 (39%) -Liver 54 (38%) 202 (10%) -Bone 12 (8%) 54 (3%) Pre-chemo AFP‡1000 ng/mL 21 (19%) 343 (25%) Pre-chemo hCG‡5000 mIU/mL 100 (81%) 336 (25%)

5058 Poster Session (Board #127), Fri, 8:00 AM-11:00 AM

Olaparib as salvage treatment for advanced germ cell tumors after chemotherapy failure: Results of the open-label, single-arm, IGG-02 phase II trial.

Ugo De Giorgi, Giuseppe Schepisi, Giorgia Gurioli, Carmela Pisano, Umberto Basso, Cristian Lolli, Elisabetta Petracci, Chiara Casadei, Sabrina Chiara Cecere, Laura Attademo, Alberto Clemente, Valentina Zampiga, Valentina Galla, Ilaria Cangini, Marilena Di Napoli, Linda Valmorri, Sandro Pignata; Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; National Cancer Institute of Naples, Naples, Italy; Medical Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IOV IRCCS, Padua, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy; Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy; INT, Naples, Italy; Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Srl- IRCCS, Meldola, Italy; Uro-Gynecological Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, IRCCS, Naples, Italy; Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy

Background: Therapeutic options for patients with advanced germ cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. We aimed to evaluate olaparib activity in patients with refractory GCT. Methods: In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ cell cancer IGG-02 study (NCT02533765), patient eligibility included failure after high-dose chemotherapy or after at least 2 different cisplatin- based regimens. Measurements of serum tumor markers and computed tomography were carried out at baseline and every 6 weeks of olaparib treatment. The study primary endpoint was the overall response rate, the study planned to recruit initially 18 patients and not continue further recruitment until one or more responses were observed. Results: Between September 2015 and February 2019, 18 patients, median age 39 years (range, 22-61) were enrolled. The number of prior chemotherapy regimens was: 2 for 3 patients (16.7%), 3 for 5 patients (27.8%), .3 for 10 patients (55.6%). Sixteen cases (89.9%) received prior high-dose chemotherapy with support of hematopoietic progenitor cells. Grade 3-4 adverse events were observed in 5 patients (27.7%). There were no partial responses, 5 cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 7+ months and 13 (72.2%) progressive disease. The 12- week progression-free survival probability was 27.8% [95% confidence interval (CI): 10.1%-48.9%]. The 12-month overall survival probability was 27.8% (95% CI: 10.1%-48.9%). A germline DNA repair profile panel showed only a BRCA1 mutated case associated with a SD lasted 4 months. Conclusions: Olaparib as a single agent has marginal activity in heavily pretreated GCT patients, however, an anecdotic 4-month SD in the only BRCA mutated patient has been reported. Plans for future studies with olaparib are suggested in combination or following salvage chemotherapy in less pretreated and more selected GCT patients. The Study has been conducted with AstraZeneca contribution. Clinical trial information: NCT02533765. Research Sponsor: Astrazeneca.

5059 Poster Session (Board #128), Fri, 8:00 AM-11:00 AM

SBRT versus nephrectomy in the treatment of renal cell carcinoma.

Mausam Patel, Thomas Kim, Chenghui Li, Ahmed Safar, Sanjay Maraboyina; University of Arkansas for Medical Sciences, Little Rock, AR

Background: Stereotactic body radiotherapy (SBRT) is being increasingly used for renal cell carcinoma (RCC) treatment in non-surgical candidates. However, no studies have compared survival between nephrectomy and SBRT. The National Cancer Database (NCDB) database was used to assess overall survival in patients undergoing SBRT vs nephrectomy. Methods: All cases of T1-T4, N0, M0 RCC diagnosed between 2004 and 2016 were extracted from the NCDB. Only patients undergoing either nephrectomy or SBRT, but not both, were included in the final analysis. Primary outcome was overall survival, defined as time in months from diagnosis to death due to any cause. Descriptive statistics were calculated for all variables. Univariate survival analysis was performed using the Kaplan Meier method and log rank test. Multivariate Cox proportional hazards regression models were performed to determine the predictive performance of covariates with respect to overall survival, reported as hazard ratio [HR] with 95% CIs. Nephrectomy patients were propensity score matched to SBRT patients for sub-cohort survival analysis. Comparisons were considered statistically significant at P , 0.05. Results: There were 243,754 patients meeting inclusion criteria with 243,488 undergoing nephrectomy and 266 undergoing SBRT. Five year OS rates were 53% and 80% for SBRT and nephrectomy, respectively (P , 0.001). On multivariate Cox regression, SBRT was associated with an increased risk of death as compared to nephrectomy (HR, 2.05; 95% CI, 1.72 – 2.44; P , 0.001). Sex, race, insurance coverage, comorbidity index, tumor grade, lymphovascular invasion status, T-stage, tumor size, and academic status of treatment facility were also independent predictors of survival. After propensity score matching of 266 SBRT patients to 266 nephrectomy patients, there were no significant differences in baseline characteristics between the groups. However, SBRT continued to demonstrate worse survival and an increased risk of death as compared to nephrectomy (HR, 1.85; 95% CI, 1.41 – 2.44; P , 0.001). Conclusions: Among node-negative, non-metastatic RCC patients, SBRT is associated with inferior survival outcomes as compared to nephrectomy, even after correcting for underlying differences in demographics, tumor characteristics, socioeconomic status, and comorbidities. These results indicate that nephrectomy should remain the standard of care for RCC patients, with SBRT reserved for non-surgical candidates. Research Sponsor: None.

5060 Poster Session (Board #129), Fri, 8:00 AM-11:00 AM

INMUNOSUN-SOGUG trial: A prospective phase II study to assess the efficacy and safety of sunitinib as second-line (2L) treatment in patients (pts) with metastatic renal cell cancer (RCC) who received immunotherapy-based combination upfront.

Enrique Grande, Teresa Alonso Gordoa, Oscar Reig Torras, Emilio Esteban, Daniel Castellano, Xavier Garcia del Muro, Marı´a Jose ´ Mendez Vidal, Jesus ´ Garcı´a-Donas, Jose Angel Arranz, Cristina Suarez Rodriguez; MD Anderson Cancer Center Madrid, Madrid, Spain; Hospital Universitario Ramon ´ y Cajal, Madrid, Spain; Hospital Clinic i Provincial, Barcelona, Spain; Hospital Universitario Central de Asturias, Oviedo, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Institut Catala ` d’Oncologia (ICO Bellvitge), Barcelona, Spain; Hospital Universitario Reina Sofia, Cordoba, ´ Spain; Fundacion Hospital de Madrid, Madrid, Spain; Vall d’Hebron Institute of Oncology, Universitat Autonoma ` de Barcelona, Barcelona, Spain

Background: Immunotherapy (IO)-based combinations have replaced tyrosine kinase inhibitors (TKI) as standard upfront treatment of metastatic RCC pts. Selection of 2L treatment after progression to novel combinations in 1st-line (1L) is mostly based on retrospective series or subgroups analysis of randomized trials. We aim to evaluate the activity and safety of sunitinib in advanced RCC after progression on an IO-based 1L approach. Methods: This is a prospective, non-randomized, open-label and multicenter phase II study. Pts with ECOG 0-2 and locally advanced or metastatic RCC after treatment in 1L with a prior PD-1 and/or PD-L1 and/or CTLA-4 inhibitor were included. Sunitinib was administered at 50 mg/day on a 4/2 schedule until disease progression. Primary endpoint was overall response rate (ORR) by RECIST v 1.1 criteria. Results: Twenty pts were enrolled in the study. Median age was 66 yo, 70% had intermediate prognosis by Heng’s scale, and 88% ECOG 1. 45% of pts received atezolizumab, 30% pembrolizumab, 20% nivolumab and 15% ipilimumab-based regimens as 1L. ORR to 1L treatment was 45%. Median time from end of 1L to sunitinib onset date was 1.1 months (0.3-22.1). Two (10%) pts had partial response with sunitinib and 11 (55%) stable disease for a total disease control rate of 65%. With a median follow-up of 8.8 months, median PFS was 6.8 months (0.0-13.9) and median OS 13.6 months (10.5-16.6). Median duration of treatment was 4 months (0.9-16-2). Most common treatment-related adverse events, all grades, were asthenia (55%), dysgeusia (35%), diarrhea (30%), hypertension (30%), mucosal inflammation (25%), palmar-plantar erythrodysesthesia (25%), anemia (20%), neutropenia (20%) and nausea (15%); grade 3 were asthenia (15%), hypertension (10%) and neutropenia (10%). Conclusions: To our knowledge, the INMUNOSUN trial is the first study to evaluate prospectively the activity of a single agent TKI in a pure 2L setting of metastatic RCC pts treated with an IO-based approach upfront. ORR and PFS with sunitinib seem lower than expected when used as a 1L. Consistency in toxicity profile was observed. Clinical trial information: NCT03066427. Research Sponsor: Pfizer.

5061 Poster Session (Board #130), Fri, 8:00 AM-11:00 AM

Association of neutrophil to lymphocyte ratio (NLR) with efficacy from JAVELIN Renal 101.

Mehmet Asim Bilen, Brian I. Rini, Robert J. Motzer, James M. G. Larkin, John B. A. G. Haanen, Laurence Albiges, Lance C. Pagliaro, Eric Voog, Elaine Tat Lam, Nikolai Kislov, Bradley Alexander McGregor, Bo Huang, Alessandra di Pietro, Stan Krulewicz, Toni K. Choueiri; Winship Cancer Institute of Emory University, Atlanta, GA; Vanderbilt University Medical Center, Nashville, TN; Memorial Sloan Kettering Cancer Center, New York, NY; Royal Marsden NHS Foundation Trust, London, United Kingdom; Netherlands Cancer Institute, Amsterdam, Netherlands; Gustave Roussy, Villejuif, France; Mayo Clinic, Rochester, MN; Clinique Victor Hugo, Le Mans, France; University of Colorado Anschutz Medical Campus, Aurora, CO; Yaroslavl Region Clinical Oncological Hospital, Yaroslavl, Russian Federation; Dana-Farber Cancer Institute, Boston, MA; Pfizer, Groton, CT; Pfizer SRL, Milan, Italy; Pfizer, Inc., Collegeville, PA

Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) in treatment-naive patients with advanced renal cell carcinoma (aRCC) demonstrated significantly improved progression-free survival (PFS; hazard ratio [HR], 0.69; 95% CI, 0.56, 0.84; P , 0.001) and higher objective response rate (ORR; 51.4% vs 25.7%) with avelumab + axitinib vs sunitinib (Motzer RJ, et al. N Engl J Med. 2019; 380:1103-15). NLR has emerged as a potential prognostic biomarker in aRCC; elevated NLR is associated with poorer prognosis. Here, we describe the association of NLR with the efficacy of avelumab + axitinib from JAVELIN Renal 101. Methods: We examined baseline NLR and its association with efficacy outcomes. PFS, best overall response (per blinded independent central review using RECIST 1.1), and overall survival (OS) data from the avelumab + axitinib arm from the first interim analysis of JAVELIN Renal 101 were analyzed (data cutoff, June 20, 2018). Multivariate Cox regression analyses of PFS and OS were also conducted. Results: In the avelumab + axitinib arm, patients with , median NLR (N = 217) had longer observed PFS (stratified HR, 0.85; 95% CI, 0.634, 1.153) and longer observed OS (stratified HR, 0.51; 95% CI, 0.300, 0.871) than patients with $ median NLR (N = 217). The ORR was 57.1% in patients with , median NLR vs 47.5% in patients with $ median NLR, with complete response in 5.5% vs 1.4%. Multivariate analysis showed that low NLR was associated with longer PFS and OS by treating baseline NLR as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Low NLR was associated with better observed treatment outcomes in patients with aRCC who received avelumab + axitinib. Clinical trial information: NCT02684006. Research Sponsor: This study was funded by Pfizer, as part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany.

5062 Poster Session (Board #131), Fri, 8:00 AM-11:00 AM

TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC).

Sumanta K. Pal, Bernard Escudier, Michael B. Atkins, Thomas E. Hutson, Camillo Porta, Elena Verzoni, Michael N. Needle, David F. McDermott, Brian I. Rini; City of Hope Comprehensive Cancer Center, Duarte, CA; Gustave Roussy, Villejuif, France; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Baylor Sammons Cancer Center-Texas Oncology, Dallas, TX; Department of Internal Medicine, University of Pavia and Division of Traslational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Aveo Oncology, Cambridge, MA; Beth Israel Deaconess Medical Center, Dana- Farber/Harvard Cancer Center, Boston, MA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Background: Tivozanib (T) is a potent and highly selective VEGFR inhibitor. TIVO-3 is a phase 3 study designed to compare the efficacy and safety of T with those of sorafenib (S) as 3rd and 4th line therapy in patients with metastatic RCC. Methods: Subjects with RCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint inhibitor (CPI); TKI plus other) then randomized in a 1:1 ratio to T or S. Results: The 2 arms were well balanced for demographics and prior cancer history. 60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 26% had prior treatment with a CPI. Patients treated with T demonstrated PFS superiority compared to S, 5.6 (95% CI 7.3 - 5.3) v. 3.9 mos (95% CI 5.6 – 3.7; HR 0.73; p=0.02). ORR was 18% for T compared to 8% for S (p=0.02). 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. The predefined, interim analysis for OS performed two years after enrollment was closed had a HR of 0.99 based on 227 events. The final analysis will be presented based on an estimate of 263 events. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this heavily-treated/ relapsed or refractory RCC population and is better tolerated than S. Final OS data will be updated prior to presentation. Clinical trial information: 02627963. Research Sponsor: AVEO Oncology.

5063 Poster Session (Board #132), Fri, 8:00 AM-11:00 AM

Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes.

Shaan Dudani, Chun Loo Gan, Connor Wells, Ziad Bakouny, Nazli Dizman, Sumanta K. Pal, Lori Wood, Christian K. Kollmannsberger, Bernadett Szabados, Thomas Powles, Benoit Beuselinck, Frede Donskov, Aaron Richard Hansen, Georg A. Bjarnason, Christina M. Canil, Sandy Srinivas, Neeraj Agarwal, Elizabeth Chien Hern Liow, Toni K. Choueiri, Daniel Yick Chin Heng; Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada; Tom Baker Cancer Centre, Calgary, AB, Canada; Queen’s University, Kingston, ON, Canada; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; City of Hope Comprehensive Cancer Center, Duarte, CA; Dalhousie University, Halifax, NS, Canada; BC Cancer-Vancouver Centre, Vancouver, BC, Canada; Barts Cancer Institute, London, United Kingdom; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Division of Medical Oncology and Hema- tology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; Stanford Cancer Institute, Stanford, CA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Peter MacCallum Cancer Centre, Melbourne, Australia; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada

Background: In patients with mRCC, the International mRCC Database Consortium (IMDC) criteria have been validated as a prognostic tool in patients treated with targeted therapy in the 1-4L settings and with 2L Nivolumab (Nivo). However, it is unknown whether the IMDC criteria can be used to risk stratify in recently approved 1L IO combination therapies, including Ipilimumab + Nivolumab (IOIO) and Axitinib + Pembrolizumab/Avelumab (IOVE). We sought to assess the ability of the IMDC criteria to risk stratify with the use of novel 1L IO combinations and provide updated benchmarks for older 1L and 2L treatments. Methods: Patients with mRCC starting systemic therapy between 2010-2019 were identified through the IMDC. IMDC risk score was calculated at the time of starting the line of therapy of interest. The primary endpoint was overall survival (OS) from time of initiating the treatment of interest. Results: From a total of 6596 unique patients, 5043 treated in the 1L setting and 2498 treated in the 2L setting were included in the analysis. Across the entire cohort, median age was 61, 73% were male, 16% had sarcomatoid features, 79% underwent nephrectomy and 88% had clear-cell histology. IMDC risk groups for 1L and 2L treatment were 17%, 57%, 27% and 10%, 60%, 30% for favourable-, intermediate- and poor-risk disease, respectively. IMDC criteria appropriately risk stratified into 3 prognostic groups in 1L IOIO and 1L IOVE combinations, in addition to older treatments: 1L VEGF TT, 2L VEGF TT, 2L Nivo and 2L Everolimus. Results are displayed in Table. Due to the novelty of 1L IO combinations, median follow up time was shorter and thus landmark OS values are presented. Conclusions: IMDC criteria may be used to risk stratify in recently approved 1L IO combination therapies in addition to older 1L and 2L treatments. These data provide contemporary benchmarks for OS that may be used for patient counseling and trial design. Research Sponsor: None.

Favourable- Intermediate- Poor- P-value (log- Risk Risk Risk rank) Median OS (months) by IMDC Risk Group 1L VEGF TT* 47.8 27.2 8.3 ,0.01 (N=4662) 2L VEGF TT† 41.0 21.4 7.0 ,0.01 (N=1230) 2L Nivo (N=586) NR 28.2 6.7 ,0.01 2L Everolimus 21.4 14.7 4.8 ,0.01 (N=682) Landmark OS by IMDC Risk Group 1L IOIO (N=291) 1-year OS 96% 83% 56% ,0.01 2-year OS 76% 65% 44% 1L IOVE (N=90) 0.01 1-year OS 96% 86% 51% 0.01 2-year OS 84% 69% 34% *Sunitinib, Pazopanib, Cabozantinib †Sunitinib, Pazopanib, Cabozantinib, Axi- tinib, Lenvatinib NR = Not Reached

5064 Poster Session (Board #133), Fri, 8:00 AM-11:00 AM

Immunomodulation by HDAC inhibition: Results from a phase I study with entinostat in combination with atezolizumab and bevacizumab in metastatic renal cell carcinoma patients.

Roberto Pili, Nabil Adra, Nur Damayanti, Theodore F. Logan, Vivek Narayan, Paul Monk, S Dropcho, Lina M Sego, Hao Liu, Sandra K. Althouse, Naomi B. Haas; Indiana University, Indianapolis, IN; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Indiana University Simon Cancer Center, Indianapolis, IN; University of Pennsylvania, Philadelphia, PA; Ohio State University, Columbus, OH; Indiana University School of Medicine, Indianapolis, IN; Penn Medicine Abramson Cancer Center, Philadelphia, PA

Background: Immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that the HDAC inhibitor entinostat has synergistic antitumor effect in combination with immunotherapies in preclinical models by inhibiting Tregs and MDSCs function. The combination of atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) is active in renal cell carcinoma (RCC). Thus, we have conducted a Phase I study with entinostat, atezolizumab and bevacizumab in patients (pts) with metastatic RCC. Methods: The primary objective was to evaluate safety and tolerability. The phase I portion included 3 dose levels of entinostat (1 mg, 3 mg or 5 mg, PO weekly) and fixed, standard doses of atezolizumab (1200 mg IV every 21 days) and bevacizumab (15 mg/Kg IV every 21 days). Pts with any histological type and prior therapies were included. Results: Dose levels were completed with up to 1 DLT/dose level. 5 mg was the Phase II recommended dose for entinostat. DLTs included hypertension, encephalopathy, hyponatremia and pruritus. The most common resolved grade 3/4 toxicities were hypophosphatemia (33%), hypertension (17%), and pneumonitis (11%). We have enrolled 18 pts (17 evaluable for ORR by RECIST). 5 pts continue on treatment. 3 pts discontinued treatment because of adverse events, 9 pts for disease progression, and one pt for physician decision. Good risk and intermediate risk pts were 61% and 39%, respectively. Overall ORR was 47.1% (95% CI 23.0-72.2) and median PFS was 7.6 months (95% CI 1.6-16.3). In pts with no prior therapies (12) the ORR was 58.3% (95% CI 27.7-84.8) and median PFS was 13.4 months (95% CI 1.5-28.9). One additional PR was observed by ir-RC but was not confirmed within the data cut-off date of 11/11/19. In pts with prior immune checkpoint inhibitors (ICIs) (5) ORR was 20% (95% CI 0.5-71.6) and median PFS was 7.6 months (95% CI 1.3-NR). Preliminary data show a statistically significant lower % of circulating monocytic MDSC (HLADR21CD11b+CD33highCD14+CD152) and exhausted T cells (CD45+CD3+CD8+TIM3+) following treatment in pts (4) with objective responses as compared to pts (4) with progressive disease. Conclusions: The results from this phase I suggest that the combination of entinostat, atezolizumab and bevacizumab is relatively well tolerated and is active in renal cell carcinoma patients, in both ICIs na¨ıve and resistant disease. A phase II portion of this study is currently accruing patients. Clinical trial information: NCT03024437. Research Sponsor: None.

5065 Poster Session (Board #134), Fri, 8:00 AM-11:00 AM

A phase II multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy.

Patrick Cheung, Samir Patel, Scott A. North, Arjun Sahgal, William Chu, Hany Soliman, Belal Ahmad, Eric Winquist, Francois Patenaude, Tamim Niazi, Daniel Yick Chin Heng, Gerald Lim, Arbind Dubey, Piotr Czaykowski, Rebecca Wong, Anand Swaminath, Scott Carlyle Morgan, Justin White, Sareh Keshavarzi, Georg A. Bjarnason; Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; Division of Radiation Oncology, Cross Cancer Institute; Department of Oncology, University of Alberta, Edmonton, AB, Canada; University of Alberta Cross Cancer Institute, Edmonton, AB, Canada; Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; Princess Margaret Hospital, Mississauga, ON, Canada; London Regional Cancer Program, London, ON, Canada; Oncology Department, McGill University - Segal Cancer Centre, Montreal, QC, Canada; Jewish General Hospital, McGill University, Montreal, QC, Canada; Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Tom Baker Cancer Centre, Calgary, AB, Canada; Cancercare Manitoba, Winnipeg, AB, Canada; CancerCare Manitoba, Winnipeg, MB, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; Ottawa Hospital Research Institute, Ottawa, ON, Canada; Ozmosis Research Inc, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada

Background: SRT is increasingly considered to delay the need to change systemic therapy in metastatic cancer patients who develop oligoprogression. This prospective phase II study evaluated the use of SRT in the setting of mRCC patients who developed oligoprogression while on 1st or 2nd line TKI therapy. Methods: IMDC favourable or intermediate risk mRCC patients (pts) who had previous stability or response on $ 3 months of TKI therapy were eligible if they developed radiographic progression of # 5 metastases. The oligoprogressive tumours were treated with SRT while other metastases which were stable or responding to TKI therapy were left alone. TKI therapy was temporarily stopped during SRT, and the same TKI drug then resumed. Endpoints included local control of the irradiated lesions, progression free survival (PFS), overall survival (OS), and cumulative incidence of changing systemic therapy after study entry. Results: 37 pts (median age 63, IMDC favourable 12, intermediate 25) with 57 oligoprogressive tumours were enrolled. 35 pts were on sunitinib and 2 on pazopanib. Median duration of TKI therapy prior to study entry was 18.6 months. 4 pts had IL-2 therapy prior to a 2nd line TKI. 21 pts had a solitary oligoprogressive tumour, while 17 pts had 2-3 oligoprogressive tumours treated with SRT. Median biological effective dose (BED10) was 72 Gy, corresponding to an SRT dose of 40 Gy in 5 fractions. Irradiated tumour sites were the following: 21 lung/pleural, 15 bone, 7 lymph node, 4 adrenal, 4 liver, 3 brain, 2 spleen, and 1 pancreas. At a median followup of 11.6 (1.8-53.5) months the median PFS from study entry was 9.6 months (95%CI 7.4-20.5) with the vast majority of progression occurring outside of the irradiated areas. The 2-year local control of the irradiated tumours was 96%. The 2-year OS from study entry was 77%. The cumulative incidence of changing systemic therapy was 47% at 1 year and 75% at 2 years, with a median time to a change in systemic therapy of 12.6 months. There were no grade 3-5 SRT related toxicities. Conclusions: To our knowledge, this is the first prospective evaluation of the use of SRT for oligoprogressive metastatic cancer. Local control of irradiated oligoprogressive mRCC tumours was high. After delivering SRT, mRCC patients did not need a change in their systemic therapy for a median of 1 year, effectively increasing the PFS of their TKI therapy. This novel approach should be studied in patients with oligoprogression on immunotherapy. Clinical trial information: NCT02019576. Research Sponsor: Pfizer Canada.

5066 Poster Session (Board #135), Fri, 8:00 AM-11:00 AM

Clinically advanced renal cell carcinoma (RCC) and renal sarcoma (RSC) in young patients: A comprehensive genomic profiling (CGP) study.

Gennady Bratslavsky, Andrea Necchi, Petros Grivas, Oleg Shapiro, Joseph M Jacob, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Erik Abraham Williams, Shakti H. Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Alexa Betzig Schrock, Kimberly McGregor, Venkataprasanth P. Reddy, Brian Michael Alexander, Natalie Danziger, Mehdi Mollapour, Brian M. Shuch, Jeffrey S. Ross; Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; University of Washington, Seattle, WA; SUNY Upstate Medical University, Syracuse, NY; Foundation Medicine, Inc., Cambridge, MA; Foundation Medicine, Cambridge, MA; Foundation Medicine, Inc, Cambridge, MA; University of California, Los Angeles, CA

Background: We queried whether the landscape of genomic alterations (GA) would differ in patients with metastatic RCC under 40 years of age (under40) and patients 40 years of age or older (over40). Methods: FFPE tissues from 2,128 clinically advanced RCC and 25 RSC underwent hybrid-capture based CGP to evaluate all classes of GA. Samples were classified at time of sequencing as the following RCC subtypes: clear cell (ccRCC), papillary (papRCC), chromophobe (chrRCC), medullary (medRCC), collecting duct (cdRC), sarcomatoid (sarcRCC) and NOS (nosRCC). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: The male preponderance increased in the over40 patients. The GA/tumor increased in the over40 cohorts except for medRCC. Similarly, TMB was consistently higher in over40 groups. MSI high status was virtually absent. PD-L1 expression, available only in small subsets, was generally absent although 44% high positive staining in sarcRCC was noteworthy. Differences in GA in under40 vs over40 RCC were seen and included increased PBRM1 and SETD2 GA in over40 vs under40 ccRCC; increased CDKN2A/B and TERT and decreased FH GA in over40 vs under40 papRCC; increased TP53 and decreased VHL, BAP1, SETD2 and PTEN in over40 vs under40 chrRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in over40 vs under 40 sarcRCC; and increased TP53, VHL and TERT in over40 vs under40 nosRCC. Changes in GA in under40 vs over40 medRCC, cdRCC and RSC were noted but insufficient cases prevented further evaluation. Conclusions: When separately evaluated by under/over 40 years of age, CGP of clinically advanced RCC demonstrates differences in genomic landscapes with over40 cases featuring increasing male preponderance, higher GA/tumor, higher TMB and increases in a variety of GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of metastatic RCC. Research Sponsor: Foundation Medicine Inc.

ccRCC pRCC sRCC nosRCC < 40 >40 < 40 >40 < 40 >40 < 40 >40 Cases 55 1,328 26 279 12 131 11 123 Males 64% 71% 62% 76% 67% 69% 82% 72% Median age 35 60 30 64 34 60 34 60 GA/tumor 3.2 3.5 1.9 2.9 3.7 4.7 2.5 4.9 TP53 7% 13% 4% 5% 17% 41% 9% 34% VHL 71% 77% 0% 4% 33% 42% 9% 30% PBRM1 18% 45% 0% 8% 0% 12% 9% 14% SETD2 16% 27% 4% 10% 8% 10% 9% 15% CDKN2A 15% 14% 4% 21% 33% 40% 0% 38% CDKN2B 13% 11% 0% 15% 33% 30% 0% 28% FH 2% .2% 57% 6% 0% 1% 11% 1% PTEN 13% 12% 0% 1% 0% 13% 0% 7% NF2 9% 3% 12% 13% 33% 17% 18% 13% TERT 8% 8% 0% 23% 0% 22% 0% 22% PD-L1 IHC Low/ 17%/ 20%/ 50%/ 12%/ 0%/ 6%/ 0%/ 13%/ High + 0% 4% 0% 10% 0% 44% 33% 17%

5067 Poster Session (Board #136), Fri, 8:00 AM-11:00 AM

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of lenvatinib plus everolimus versus everolimus monotherapy in patients with advanced renal cell carcinoma (RCC).

Chung-Han Lee, Yin Wan, Alan D. Smith, RAN Xie, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; Eisai Inc., Woodcliff Lake, NJ; Eisai Ltd., Hatfield, United Kingdom

Background: In the primary analysis of Study 205 phase II trial (NCT01136733), lenvatinib+everolimus (vs everolimus) significantly prolonged progression-free survival (median PFS; 14.6 vs 5.5 months, HR = 0.40, 95% CI [0.24, 0.68]) in advanced RCC patients who received one prior anti-angiogenic therapy. Overall treatment differences were evaluated in a post hoc analysis using a quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) methodology. Methods: Patients’ survival time was partitioned into three mutually exclusive health states: time spent with grade 3/4 toxicity (TOX), time prior to disease progression and without grade 3/4 toxicity (TWiST) and time post disease progression (REL). Mean time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. Non-parametric bootstrapping method was used to generate 95% CI, which evaluates the between-treatment differences. At base case, utility for TWiST, TOX and REL were assigned as 1.0, 0.5 and 0.5, respectively. A sensitivity analysis was used, applying utilities across the range of 0 (similar to death) to 1.0 (perfect health). A relative gain in Q-TWiST of $10% and $15% has been established in previous literature as clinically important and clearly clinically important, respectively. Results: Patients receiving lenvatinib+everolimus (n = 51) vs everolimus (n = 50) had significantly longer mean time in TWiST (10.9 vs 6.4 months; difference 4.5 [95% CI: 1.4, 7.8]) and numerically longer in TOX (1.9 vs 0.7 months; difference 1.2 [95% CI: -0.3, 3.1]) but shorter in REL (5.8 vs 8.5 months; difference -2.8 [95% CI: -6.2, 0.6]). At base case, lenvatinib+everolimus patients had a significant mean Q-TWiST gain of 3.7 months (14.7 vs 11.0; 95% CI of difference [1.3, 6.3]), with a relative gain of 24% vs everolimus. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 - 0.9) with utility of TOX and REL both set as 0.5, absolute mean Q-TWiST gain ranged from 1.7 to 3.3 months, with a relative gain ranging from 11.0% to 21.2% (all significant). With TWiST utility set as 1.0 and utility of TOX and REL varying from 0 to 1.0, Q-TWiST gain ranged from 1.7 to 5.8 months (mostly significant and became non-significant as the REL utility gets closer to 1.0 and TOX utility gets closer to 0). Conclusions: Within Study 205, lenvatinib+everolimus resulted in a statistically significant and clinically important gain in Q-TWiST vs everolimus alone. Clinical trial information: NCT01136733. Research Sponsor: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

5068 Poster Session (Board #137), Fri, 8:00 AM-11:00 AM

Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC): An international mRCC database consortium (IMDC) analysis.

Daniel Vilarim Araujo,ConnorWells,Aaron RichardHansen,NazliDizman, SumantaK. Pal, Benoit Beuselinck, Frede Donskov, Chun Loo Gan, Flora Yan, Ben Tran, Christian K. Kollmannsberger, Guillermo de Velasco, Takeshi Yuasa, M. Neil Reaume, D. Scott Ernst, Thomas Powles, Georg A. Bjarnason, Toni K. Choueiri, Daniel Yick Chin Heng, Shaan Dudani; Princess Margaret Cancer Centre, Toronto, ON, Canada; Queen’s University, Kingston, ON, Canada; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; City of Hope Comprehensive Cancer Center, Duarte, CA; University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Royal Melbourne Hospital, Melbourne, Australia; University of Texas Southwestern Medical Center, Dallas, TX; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; BC Cancer-Vancouver Centre, Vancouver, BC, Canada; Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Ottawa Hospital Cancer Centre, Ottawa, ON, Canada; Division of Medical Oncology, Department of Oncology, London Regional Cancer Program, London Health Sciences Centre and University of Western Ontario, London, ON, Canada; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Sunnybrook Research Institute, Toronto, ON, Canada; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada

Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as $ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P , 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p , 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p , 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age. Research Sponsor: None.

5069 Poster Session (Board #138), Fri, 8:00 AM-11:00 AM

First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated follow-up for KEYNOTE-427 cohort A.

David F. McDermott, Jae-Lyun Lee, Georg A. Bjarnason, James M. G. Larkin, Rustem Gafanov, Mark D. Kochenderfer, Niels Viggo Jensen, Frede Donskov, Jahangeer Malik, Alexandr Poprach, Scott S. Tykodi, Teresa Alonso Gordoa, Daniel C. Cho, Poul F. Geertsen, Miguel Angel Climent Duran, Christopher Di Simone, Xiaoqi Du, Rodolfo F. Perini, Karla Rodriguez-Lopez, Michael B. Atkins; Dana- Farber/Harvard Cancer Center, Boston, MA; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; Institute of Cancer Research, London, United Kingdom; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; Carilion Clinic, Roanoke, VA; Odense University Hospital, Odense, Denmark; Aarhus University Hospital, Aarhus, Denmark; Edinburgh Cancer Centre, Western General Hospital, Edinburgh, United Kingdom; Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Hospital Uni- versitario Ramon ´ y Cajal, Madrid, Spain; NYU Langone Health, New York, NY; Herlev Hospital, University of Copenhagen, Herlev, Denmark; Instituto Valenciano de Oncologı´a, Valencia, Spain; Arizona Oncology/ US Oncology, Tucson, AZ; Merck & Co., Inc., Kenilworth, NJ; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC

Background: KEYNOTE-427 (NCT02853344), an open-label, single-arm, phase 2 study, showed clinical activity of first-line pembro monotherapy in patients (pts) with ccRCC (cohort A). Previous studies in RCC and immune-oncology suggest depth of response may correlate with long-term benefit. Association between depth of response and OS, along with updated efficacy and safety for cohort A of KEYNOTE-427, are presented. Methods: Pts with histologically confirmed ccRCC, measurable disease (RECIST v1.1), and no prior systemic therapy received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points: ORR (primary), DOR, and PFS (RECIST v1.1); OS, and safety. Association between depth of response (maximum reduction from baseline in the sum of target lesions) and OS was evaluated using Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: 110 pts enrolled; median time from enrollment to data cutoff was 23.1 (range, 16.7-27.5) mo. Overall, 38.2% of pts had favorable and 61.2% had intermediate/poor IMDC risk. ORR was 36.4% (95% CI, 27.4-46.1; 3 CRs, 37 PRs); median (range) DOR was not reached (2.3-23.5+ mo); 64.0% had a DOR $12 mo. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached; 18-mo PFS and OS rates were 26.6% and 80.0%, respectively. 69.1% had some reduction in target lesions. Pts with . 60% reduction in target lesions had a greater probability of survival than pts with a #60% reduction (Table). ORR observed in IMDC favorable and intermediate/poor risk was 31.0% and 39.7%, respectively; 18-mo OS rate was 95.2% for favorable and 70.5% for intermediate/poor IMDC risk. Treatment-related AEs (TRAEs) occurred in 81.8% of pts, primarily fatigue (29.1%) and pruritus (28.2%). Grade $3 TRAEs occurred in 29.1% of pts; 1 pt died of treatment-related pneumonitis. Conclusions: First-line pembro monotherapy was tolerable and showed promising antitumor activity in advanced ccRCC. In general, pts who had greater reductions in target lesions demonstrated a trend toward improved OS; pts with reduction of tumor burden $80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Association Between Depth of Response and Risk for Death N = 110 Depth of response, % n (%) HR (95% CI) CR 3 (2.7) 0 (0.0-NE) –100 to –80 16 (14.5) 0 (0.0-NE) < –80 to –60 13 (11.8) 0.39 (0.04-3.54) < –60 to –30 18 (16.4) 1.57 (0.44-5.65) < –30 to < 0 26 (23.6) Reference 0to< 20 17 (15.5) 1.70 (0.52-5.59) ‡20 14 (12.7) 2.04 (0.61-6.88)

5070 Poster Session (Board #139), Fri, 8:00 AM-11:00 AM

Outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first-line Immuno-oncology (IO) agents who do not meet eligibility criteria for clinical trials.

Chun Loo Gan, Shaan Dudani, Connor Wells, Ziad Bakouny, Nazli Dizman, Sumanta K. Pal, Bernadett Szabados, Lori Wood, Christian K. Kollmannsberger, Neeraj Agarwal, Frede Donskov, Naveen S. Basappa, Georg A. Bjarnason, Francis Parnis, Camillo Porta, Ian D. Davis, Ulka N. Vaishampayan, Ravindran Kanesvaran, Toni K. Choueiri, Daniel Yick Chin Heng; Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada; Queen’s University, Kingston, ON, Canada; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; City of Hope Com- prehensive Cancer Center, Duarte, CA; Barts Cancer Institute, London, United Kingdom; Dalhousie University, Halifax, NS, Canada; BC Cancer-Vancouver Centre, Vancouver, BC, Canada; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Cleveland Clinic, Cleveland, OH; Sunnybrook Research Institute, Toronto, ON, Canada; Adelaide Cancer Centre, Adelaide, Australia; University of Pavia, Pavia, Italy; Monash University Eastern Health Clinical School, Victoria, Australia; Karmanos Cancer Institute, Detroit, MI; National Cancer Centre Singapore, Singapore, Singapore; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada

Background: IO combination therapies [including IOIO and IO/vascular endothelial growth factor inhibitor (IOVE) combinations] in mRCC have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of trial ineligible patients who are treated with first- line IOIO or IOVE combinations are unknown. Methods: Metastatic RCC patients treated with first-line IOIO or IOVE were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria in IO trials) if they had a Karnofsky performance status (KPS) , 70%, no clear-cell component, brain metastases, hemoglobin (Hb) , 9 g/dL, eGFR , 40 mL/min, platelet count of , 100,000/mm3, and/or neutrophil count , 1500/mm3. Time to treatment failure (TTF) and overall survival (OS) were calculated from time of starting first-line IO therapy. Results: Overall, 26% (155/ 592) of patients in the International mRCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Baseline characteristics are listed in Table. The reasons for ineligibility were: no clear-cell component (34%, 53/155), Hb , 9g/dL (28%, 44/155), eGFR , 40 mL/min (19%, 30/155), brain metastases (19%, 29/155), KPS , 70% (14%, 21/155), platelet , 100,000/mm3 (3%, 4/155) and neutrophil count , 1500/mm3 (0%, 0/155). Between ineligible versus eligible patients, the response rate, median TTF and median OS of first-line IOIO or IOVE was 34% vs 46% (p = 0.02), 4.2 vs 9.7 months (p , 0.01), and 25.3 vs 44.4 months (p , 0.01), respectively. When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.50 (95% CI 1.05-2.14). Conclusions: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. These data may guide patient counselling and specific trials addressing the unmet needs of protocol ineligible patients are warranted. Research Sponsor: None.

TRIAL INELIGIBLE TRIAL ELIGIBLE Baseline Characteristics (N = 155) (N = 437) P-VALUE Median Age 62 63 0.24 Male 63% (98/155) 73% (318/437) 0.03 Sarcomatoid histology 25% (29/115) 20% (63/314) 0.25 Nephrectomy 66% (102/155) 75% (326/437) 0.04 IOIO 63% (97/155) 57% (247/437) 0.19 IOVE 37% (58/155) 43% (190/437) Received second line therapy 33% (50/155) 34% (148/437) 0.72 IMDC Risk Group Favorable 11% (15/138) 19% (74/385) , 0.01 Intermediate 47% (65/138) 65% (251/385) Poor 42% (58/138) 16% (60/385)

5071 Poster Session (Board #140), Fri, 8:00 AM-11:00 AM

Characterizing sites of metastatic involvement in metastatic clear-cell, papillary, and chromophobe renal cell carcinoma.

Shaan Dudani, Guillermo de Velasco, Connor Wells, Chun Loo Gan, Frede Donskov, Camillo Porta, Anna Fraccon, Felice Pasini, Jae-Lyun Lee, Aaron Richard Hansen, Georg A. Bjarnason, Benoit Beuselinck, Sumanta K. Pal, Takeshi Yuasa, Nils Kroeger, Ravindran Kanesvaran, M. Neil Reaume, Christina M. Canil, Toni K. Choueiri, Daniel Yick Chin Heng; Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada; Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Queen’s University, Kingston, ON, Canada; Royal Melbourne Hospital, Melbourne, Australia; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; University of Pavia, Pavia, Italy; CDC Pererzoli, Peschiera Del Garda, Italy; Oncologia Medica Ospedale Santa Maria della Misericordia, Rovigo, Italy; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Sunnybrook Research Institute, Toronto, ON, Canada; University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; City of Hope Comprehensive Cancer Center, Duarte, CA; Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Urology, University Medicine Greifswald, Greifswald, Germany; National Cancer Centre Singapore, Singapore, Singapore; Ottawa Hospital Cancer Centre, Ottawa, ON, Canada; Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Depart- ment of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada

Background: There exists considerable biological and clinical variability between histologic variants of metastatic renal-cell carcinoma (mRCC). Data reporting on sites of metastatic involvement in less common histologies of mRCC are sparse. We sought to characterize the frequency of metastatic site involvement across the three most common histologies of mRCC: clear-cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). Methods: Using the International mRCC Database Consortium (IMDC) database, patients with mRCC starting systemic therapy between 2002-2019 were identified and sites of metastases at the time of systemic therapy initiation were documented. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. The primary outcomes were prevalence of metastatic site involvement and overall survival (OS). Patients with mixed histology were excluded. Results: 10,105 patients were eligible for analysis. Median age at diagnosis was 60, 72% were male and 79% underwent nephrectomy. 92%, 7% and 2% of patients had ccRCC, pRCC, and chrRCC, respectively. Frequency of metastatic site involvement across the histologic subtypes is shown in Table. Lung, adrenal, brain and pancreatic metastases were more frequent in ccRCC, lymph node involvement was most frequent in pRCC, and liver metastases were most frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (brain/pleura) and 50 months (pancreas). OS by site of metastatic involvement was compared between histologies for the four most common sites of metastases (lung, lymph nodes, bone, liver). As compared to patients with ccRCC, patients with pRCC had lower OS regardless of site of metastasis (p , 0.05). Power was limited and thus differences in OS between ccRCC and chrRCC were not detectable. Conclusions: Sites of metastatic involvement differ based on histology in mRCC. These data highlight the clinical and biologic variability between histologic subtypes of mRCC and constitute the largest cohorts of patients with metastatic pRCC and chrRCC to report on sites of metastases. Sites of Metastatic Involvement by Histology. Research Sponsor: None.

Metastatic Site ccRCC (N=9252) pRCC (N=667) chrRCC (N=186) P-value Lung 70% 49% 36% ,0.01 Lymph Nodes 45% 69% 51% ,0.01 Bone 32% 29% 33% 0.26 Liver 18% 22% 34% ,0.01 Adrenal 10% 7% 6% 0.02 Brain 8% 3% 2% ,0.01 Pancreas 5% 1% 2% ,0.01 Pleural 4% 3% 0.7% 0.03 Peritoneal 2% 5% 4% ,0.01 Spleen 0.9% 0.6% 0.8% 0.88 Thyroid 0.7% 0.2% 0% 0.25 Bowel 0.7% 0.2% 1.5% 0.24

5072 Poster Session (Board #141), Fri, 8:00 AM-11:00 AM

Baseline and early change of systemic inflammation index (bSII and DSII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with Nivolumab: Final results of the Meet-URO 15 (I-BIO-REC) study.

Sara Elena Rebuzzi, Francesco Atzori, Marilena Di Napoli, Marco Stellato, Marco Messina, Silvia Chiellino, Francesca Vignani, Alessia Cavo, Hector J. Soto Parra, Giandomenico Roviello, Veronica Prati, Davide Bimbatti, Ugo De Giorgi, Melissa Bersanelli, Federico Paolieri, Paolo Andrea Zucali, Emanuela Fantinel, Giuseppe Procopio, Alessio Signori, Giuseppe Fornarini; Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino di Genova, Genoa, Italy; Medical Oncology Department, University Hospital, University of Cagliari, Cagliari, Italy; Uro-Gynecological Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, IRCCS, Naples, Italy; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; UOC Oncologia Fondazione Istituto G. Giglio, Cefal`u (Pa), Palermo, Italy; Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; SCDU Oncologia, AO Ordine Mauriziano, Turin, Italy; Oncology Unit, Villa Scassi Hospital, Genoa, Italy; Medical Oncology, University Hospital Policlinico, Vittorio Emanuele, Catania, Italy; Department of Health Sciences, University of Florence, Firenze, Italy; Medical Oncology, ASL CN 2, Alba e Bra, Alba, Italy; Medical Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IOV IRCCS, Padua, Italy; Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; Medical Oncology Unit, Clinical Cancer Centre, IRCCS-AUSL di Reggio Emilia, Reggio Emilia, Italy; Department of Health Sciences, Section of Biostatistics, University of Genoa, Genoa, Italy; Medical Oncology Unit, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are still needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was collected at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to baseline neutrophil-to-lymphocyte ratio. Secondary analyses included bSII defined as platelet x NLR (cutoff = 1375) and DSII defined as the difference between SII at 2ndcycle and bSII (median used as cutoff = 383). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2nd(67%), 3rd(22%) and . 3rd(11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. SII was available in 404 patients: SII , 1375 (82%) correlated with statistically significant improvement of PFS [10.2 vs 4.1 months, HR 2.06 (1.54-2.76), p, 0.001], OS [46.2 vs 9.5 months, HR 3.16 (2.23-4.49), p, 0.001], ORR (35% vs 21%, p= 0.035) and DCR (67% vs 40%, p, 0.001). DSII was available in 360 patients: DSII , 383 (75%) correlated with statistically significant improvement of PFS [11.3 vs 4.7 months; HR 1.64 (1.23-2.18), p= 0.001] and OS [NR vs 21.1 months; HR 1.76 (1.21-2.56), p= 0.003], ORR (37% vs 24%, p= 0.023) and DCR (68% vs 53%, p= 0.01). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bSII and DSII with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bSII and early DSII with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab. Research Sponsor: None.

5073 Poster Session (Board #142), Fri, 8:00 AM-11:00 AM

Phase I clinical trials as a therapeutic option for patients with metastatic renal cell carcinoma (mRCC).

Andrew W Hahn, Omar Alhalabi, Funda Meric-Bernstam, Aung Naing, Eric Jonasch, Pavlos Msaouel, Sarina Anne Piha-Paul, David S. Hong, Shubham Pant, Timothy A Yap, Erick Campbell, Hung Le, Nizar M. Tannir, Jason Roszik, Vivek Subbiah; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Texas MD Anderson Cancer Center, Houston, TX; Department of Investi- gational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Cancer Center, Houston, TX; Department of Investigational Cancer Ther- apeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Immune checkpoint inhibitors, multi-kinase VEGF agents, and mTOR inhibitors are approved for mRCC. Due to the overlapping mechanisms of action of the twelve approved therapies for mRCC, select patients are referred for phase I clinical trials after progression on multiple lines of treatment. We sought to evaluate the efficacy of phase I trials in patients with mRCC. Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center. Baseline clinical characteristics and outcomes data were retrospectively collected. The historical control was a study of 1112 patients with mRCC who received third-line treatment in the IMDC database (PMID: 27318422). Time to event endpoints were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Between 2014 and 2019, there were 106 cases where 82 patients with mRCC were enrolled in a phase I clinical trials (40 unique trials). 30% (32/108) of the cases were in patients with non-clear cell RCC (nccRCC), and the most prevalent nccRCC histologies were papillary (n = 7) and renal medullary carcinoma (n = 7). The median number of prior systemic therapies was 2 (range 0-9). Across the entire cohort, median PFS was 5.9 months (m), median OS was 31.2 m, and the ORR was 23% (Table). In patients who received at least two prior lines of therapy (n = 70), the median PFS was 4.8 m and median OS was 24.9 m. In patients with metastatic nccRCC, median OS, PFS, and ORR were numerically lower, but statistically did not contradict the supposition that these outcomes did not differ from ccRCC (Table). Conclusions: In the largest pooled phase I clinical trial experience for patients with mRCC, phase I trials may have therapeutic value when compared to historical controls, where median PFS was 3.9 m, median OS was 12.4 m, and ORR was 10.5%. Patients with all histologies of mRCC may derive clinical benefit from phase I clinical trials, yet patients with ccRCC had numerically better outcomes. Patients with mRCC should be considered for phase I clinical trials. Research Sponsor: None.

All mRCC nccRCC ccRCC HR P value ORR 22% 17% 24% - - CR 2% 0% 3% PR 20% 17% 21% SD 49% 30% 57% - - PD 29% 53% 19% - - PFS (95% CI) 5.9 m 2.5 m 7.3 m 1.39* 0.19 (4.8-9.3 m) (2.1-9.3 m) (5.5-12.4 m) (0.86-2.25) OS (95% CI) 31.2 m 23.9 m 31.6 m 1.26* 0.44 (24.9-38.7 m) (11.4-NR) (27.6-41.5 m) (0.71-2.23) Table legend: * = HR is for nccRCC versus ccRCC.

5074 Poster Session (Board #143), Fri, 8:00 AM-11:00 AM

CT-based radiomic classifier of primary renal tumors to distinguish between metastatic and non-metastatic disease.

Sam O Kleeman, Michael Grant, Kathrine Sofia Rallis, Anna Wozniak, Alfred So, Resha Tejpaul, Nicholas Heller, Christopher J. Weight, Katherine Ordidge, Axel Bex, Anju Sahdev, Thomas Powles; Barts Health NHS Trust, London, United Kingdom; Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom; Department of Urology, University of Minnesota, Minneapolis, MN; Department of Computer Science, University of Minnesota, Minne- apolis, MN; Royal Free London NHS Foundation Trust, London, United Kingdom; Barts Cancer Institute, Queen Mary University London, London, United Kingdom

Background: Existing clinicopathological tools are unable to accurately identify renal cell carcinoma (RCC) patients who will develop metastases after surgery. As a result, it is unclear how long and how often to follow-up patients post-operatively. Tumor macropathology, as assayed by CT scanning, represents the sum product of tumor biology and microenvironment. We hypothesized that quantitative tumor features extracted from CT scans (termed radiomics) could discriminate between metastatic and non-metastatic RCCs. Methods: This retrospective study incorporated three cohorts of clear-cell RCC patients (n = 279, from TCGA, CPTAC and KiTS19 datasets) treated with nephrectomy. The study cohort was sub-divided into metastatic (n = 54, M1 at diagnosis or recurrence after surgery), high metastatic risk/HMR (n = 85, N1, T3-4, T2G3/4, T1G4) or low metastatic risk/LMR (n = 140, absence of these features) subsets. 3D primary tumor segmentation of arterial contrast CT scans was performed by trained investigators. Features were extracted using pyRadiomics 2.2.0 (n = 839) with gray value and voxel size normalization. For random forest (RF) model training, the cohort was randomly split into training (75%) and validation (25%) sets. Results: Multidimensional clustering of radiomic features by t-SNE analysis showed that metastatic and HMR tumors predominantly cluster together, while LMR tumors cluster separately. Consistent with this, there were no differentially regulated radiomic features (DR-features) between HMR and metastatic tumors. In contrast, we identified 26 DR-features (adjusted p-value , 0.05) between presumed-metastatic (n = 139, HMR and metastatic tumors) and LMR tumors, which were then used as input to a RF binary classifier. In the training set, the trained classifier discriminated between presumed-metastatic and LMR tumors with bootstrapped AUC = 0.81. In the validation set, the classifier discriminated subsets with AUC = 0.80. Conclusions: High-risk and metastatic tumors have similar radiomic properties, suggesting common biology driving metastasis in RCC. We propose a novel radiomic classifier that accurately distinguishes between presumed- metastatic and low-risk tumors. Further work will assess whether this tool can identify patients with micrometastatic disease at diagnosis, who may benefit from adjuvant therapy or closer, long-term surveillance. Research Sponsor: None.

5075 Poster Session (Board #144), Fri, 8:00 AM-11:00 AM

A phase II study of the selective MET kinase inhibitor INC280 in advanced papillary renal cell cancer.

Paul Denis Leger, Daniel da Motta Girardi, Munjid Al Harthy, Julia C. Friend, Lisa Mac, Erin Purcell, Cathy Vocke, Sandeep Gurram, Maria J. Merino, Peter Choyke, W. Marston Linehan, Ramaprasad Srinivasan; National Institutes of Health, Bethesda, MD; National Cancer Institute, National Institutes of Health, Bethesda, MD; Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Bethesda, MD; NIH, Bethesda, MD; Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD; National Cancer Institute at the National Institutes of Health, Bethesda, MD

Background: There are currently no approved systemic agents for patients with advanced type 1 papillary renal cell carcinoma (pRCC). Type 1 pRCC can occur in a hereditary form with germline alterations of MET (hereditary papillary RCC: HPRC) or in a sporadic form. Both hereditary and sporadic forms have similar histologic features and somatic MET alterations have been found in 15-20% of patients with sporadic pRCC. Furthermore, gain of chromosome 7, where MET and the gene for its ligand HGF are located, has been reported in a majority of patients with type 1 pRCC and may represent an alternative means of activating the MET pathway. This is a phase II study evaluating the activity of INC280, a highly selective and potent MET inhibitor, in patients with pRCC. Methods: Patients with advanced type 1 pRCC were treated with INC280 at a starting dose of 600mg PO twice daily (capsules). Later in the study course, the capsules were replaced with exposure-equivalent tablets (400mg PO twice daily). Eligible patients had an ECOG PS 0-2, no active brain metastases, and less than 4 prior lines of therapy. The primary endpoint was overall response rate (ORR) assessed by RECIST 1.1. Secondary endpoints included progression-free survival, disease control rate, and tolerability. Explor- atory endpoints included the correlation between MET alteration/copy number gain and response to INC280. Results: Twenty subjects were enrolled from January 2014 to October 2019. Median age was 62 years, 60% of patients were classified as IMDC good risk and 40% as IMDC intermediate risk. Three patients (15%) achieved a confirmed partial response and seven (35%) had stable disease, including 4 (20%) who maintained stable disease for over 6 months. The most common treatment-related adverse events (AEs) were of grade 1-2 including nausea (85%), increased creatinine(70%) diarrhea(60%), fatigue(55%), limb edema(40%), increase in amylase(20%), triglycerides(20%), LFTs(20%), lipase(10%) and leukopenia(10%). INC280-related Grade 3-4 AEs included asymptomatic increased lipase (20%), increased LFTs (10%), increased amylase(5%), leukopenia (5%), lymphopenia (5%) and syncope (5%). Conclusions: INC280 demonstrated clinical activity in patients with advanced type 1 pRCC with an acceptable toxicity profile. The correlation between the presence of MET alteration and/or copy number gain and response to INC280 is under evaluation. Research Sponsor: Novartis, Other Government Agency.

5076 Poster Session (Board #145), Fri, 8:00 AM-11:00 AM

Genomic and transcriptomic correlates of clinical benefit from immunotherapy and targeted therapy among patients with metastatic renal cell carcinoma (mRCC).

Nicholas Salgia, Nazli Dizman, Yung Lyou, Paulo Gustavo Bergerot, Joann Hsu, Sara Ann Byron, Jeffrey M. Trent, Sumanta K. Pal; City of Hope Comprehensive Cancer Center, Duarte, CA; Translational Genomics Research Institute, Phoenix, AZ

Background: Previous studies have delineated PBRM1 alterations as a prognostic indicator for response to nivolumab in mRCC (Miao et al Science 2018). However, further clinically-relevant biomarkers remain elusive in mRCC. Herein, we utilized genomic profiling to detect correlates of clinical benefit (CB) among patients (pts) with mRCC receiving VEGF-directed targeted therapy, immunotherapy, or both. Methods: Pts with mRCC who underwent clinical tumor-normal whole exome and whole tran- scriptome RNA sequencing (Ashion Analytics, Phoenix, AZ) were retrospectively identified at a single institution. Pts’ demographics and clinical variables including treatment type, treatment response, and survival outcomes were collected from an institutional mRCC database. Pts who had received immunotherapy or VEGF-directed therapy (or both) were eligible for analysis. CB was defined as pts who experienced a complete response, partial response, or maintained stable disease for at least 6 months on therapy. Two-tailed Fisher’s exact test was used to assess characteristics of genomic alterations and clinical benefit. Results: Out of 155 mRCC pts with genomic profiling, 58 pts with evaluable response and sufficient follow-up information were included in the analysis. The median age of the cohort was 63 years and 74% were male. The majority (81%) had clear cell histology. 43 pts received targeted therapy and 32 received immunotherapy (17 pts received both). No singular gene was associated with clinical benefit in the targeted therapy cohort. PBRM1 loss of function mutations were more frequent in pts on immunotherapy who experienced CB (p . 0.05). TERT promoter mutations were enriched in pts who experienced no CB on immunotherapy (p = 0.04). Differential gene expression analysis of the transcriptomes found 135 genes that were significantly upregulated in TERT-mutated samples, including SST, CYSLTR2, WNK2, and PTGES (adjusted p-value , 0.05). ENRICHR analysis found that MYC and KAT2A were key transcription factor pathways significantly enriched in pts with TERT mutation who experienced no CB from immunotherapy. Conclusions: These data support previous observations regarding the prognostic nature of PBRM1 in mRCC and offer novel findings associating TERT mutations with a lack of CB from immunotherapy. Our transcriptomic analysis implies that MYC- targeting agents and epigenetic modifiers (directed at KAT2A) could overcome immunotherapy resistance. Research Sponsor: None.

5077 Poster Session (Board #146), Fri, 8:00 AM-11:00 AM

Use of immune checkpoint inhibitors (ICIs) after prior ICI in metastatic renal cell carcinoma (mRCC): Results from a multicenter collaboration.

Praful Ravi, Charlene Mantia, Christopher Su, Karl Sorenson, Nityam Rathi, Ziad Bakouny, Neeraj Agarwal, Brian Addis Costello, Rana R. McKay, Vivek Narayan, Ajjai Shivaram Alva, Bradley Alexander McGregor, Xin Gao, David F. McDermott, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; University of Michigan Cancer Center, Ann Arbor, MI; Mayo Clinic, Rochester, MN; University of Utah Huntsman Cancer Institute, Salt Lake City, UT; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; University of Pennsylvania, Philadelphia, PA; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single- agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had $grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. Research Sponsor: None.

ICI-1 ICI-2 Partial response (PR) 23/64 (36%) 14/60 (23%) Stable disease (SD) 28/64 (44%) 23/60 (38%) Progressive disease (PD) 13/64 (20%) 23/60 (38%)

5078 Poster Session (Board #147), Fri, 8:00 AM-11:00 AM

Randomized prospective trial assessing Bifidobacterium-containing probiotic supple- mentation in metastatic renal cell carcinoma (mRCC) patients receiving vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs).

Nazli Dizman, Joann Hsu, Paulo Gustavo Bergerot, John D Gillece, Megan Folkerts, Lauren J Reining, Jeffrey M. Trent, Sarah K Highlander, Sumanta K. Pal; City of Hope Comprehensive Cancer Center, Duarte, CA; Translational Genomics Research Institute, Flagstaff, AZ; Translational Genomics Re- search Institute, Phoenix, AZ

Background: Studies suggest a link between the gut microbiome and mRCC outcomes, including evidence that mRCC patients (pts) possess a lower abundance of Bifidobacterium spp compared to healthy adults (Pal et al Clin Cancer Res 2015). The aim of this study was to assess if Bifidobacterium- containing probiotics could modulate the gut microbiome and impact rates of clinical benefit (CB) from VEGF-TKIs. Methods: Pts initiating VEGF-TKI therapy for mRCC were randomized to probiotic supple- mented (PSu) or probiotic restricted (PRe) treatment arms. Pts in the PSu arm consumed two 4 oz servings of Activia daily. Stool samples were collected prior to therapy and at wks 2, 3, 4 and 12. Gut microbiota composition was assessed using whole genome shotgun metagenomic sequencing (Zhu et al Microbiome 2018). The primary endpoint was change in Bifidobacterium spp with therapy. Micro- biome composition was compared across pts with CB (complete/partial response or stable disease) versus no CB (NCB). Results: In total, 20 pts were enrolled. The most frequent VEGF-TKIs were cabozantinib (45%), sunitinib (25%) and lenvatinib (25%). Median progression-free survival (PFS) was 6.5 months (95%CI 0.3-12.9) and CB rate was 75%. Bifidobacterium animalis, the active ingredient of Activia, reached detectable levels in all pts in the PSu arm, but was only detectable in one pt in the PRe arm. CB rate was not significantly different in PSu vs PRe arms (70% vs 80%, p . 0.05), and there was no difference in PFS. LDA effect size (LEfSe) analysis of MetaPhIAn2 data captured 25 enriched species demonstrating an LDA score . 3 in either CB or NCB. Of those with high LDA scores, Barnesiella intesitinihominis and Akkermansia municiphila were the most significant members (p = 7.4 x 1026 and p = 5.6 1023, respectively). While 92% of B. intestinihominis positive pts obtained a CB, only 50% of B. intestinihominis negative pts obtained CB (p = 0.036). Conclusions: This is the first prospective randomized study demonstrating modulation of the gut microbiome with probiotics in mRCC. While microbiome modulation by probiotics did not increase CB rates as intended, consecutive stool specimens allowed us to identify an association between B. intesitinihominis, A. municiphila and CB with VEGF-TKIs. In addition to the previously documented association between A. municiphila and immunotherapy outcome (Routy et al. Science 2018), this species may predict activity with VEGF- TKIs. Clinical trial information: NCT02944617. Research Sponsor: Pfizer Inc.

5079 Poster Session (Board #148), Fri, 8:00 AM-11:00 AM

Prediction of watchful waiting in newly diagnosed metastatic clear cell renal cell carcinoma patients with a good or intermediate prognosis.

Sarah Verhoeff, Suzanne C van Es, Sjoerd G. Elias, Sophie Gerritse, Lindsay Angus, Sjoukje Oosting, Sandra Heskamp, Adrienne H. Brouwers, Anne I.J. Arens, Catharina Wilhelmina Menke, Otto S. Hoekstra, Gerben J.C. Zwezerijnen, Astrid Aplonia Maria Van Der Veldt, Peter Mulders, Winette T.A. Van Der Graaf, Elisabeth De Vries, Wim J.G. Oyen, Erik H.J.G. Aarntzen, Carla M.L.- Van Herpen; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Medical Oncology, University Medical Center Groningen, Groningen, Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands; Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Radboudumc, Nijmegen, Nether- lands; Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, Netherlands; Radboud University Medical Center, Nijmegen, Netherlands; Amsterdam UMC Location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands, Amsterdam, Netherlands; Department of Radiology and Nuclear Medicine, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam, Netherlands; Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands; Institute of Cancer Research and The Royal Marsden NHS Trust Foundation, London, United Kingdom; The Department of Radiology and Nuclear Medicine, Rijnstate, Arnhem, Netherlands

Background: In metastatic clear cell renal cell carcinoma (mccRCC), the number of International Metastatic Database Consortium (IMDC) risk factors plus metastatic sites may identify patients with rapid or slow disease progression in a period of watchful waiting (WW) (median WW of 8.4 vs 22.2 months; Rini et al. Lancet Oncol. 2016). We aimed to validate this and prospectively assess the added value of baseline PET with [18F]FDG and [89Zr]Zr-DFO-girentuximab to predict the WW- period in the multicenter IMaging PAtients for Cancer drug selecTion (IMPACT)-RCC cohort study. (NCT02228954). Methods: Between February 2015 and March 2018, 40 treatment-na¨ıve mccRCC patients with a good (n=13) or intermediate prognosis (n=25) according to IMDC, were enrolled. Following baseline CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab-PET, CT scans (RECIST1.1) were acquired at 2, 4, 6, 9, 12 months and thereafter every 4 months. Primary endpoint was time to radiological and/or clinical disease progression, requiring systemic treatment. Patients were assigned to a favorable (,2 IMDC risk factors and ,3 metastatic sites) or unfavorable for WW-group (all others; Rini et al). Maximum standardized uptake values (SUVmax) were measured in PET-positive lesions measuring $10mm, or 15mm in lymph nodes. High and low-uptake groups were defined based on median geometric mean (gm) SUVmax across patients. A one-sided test was used to validate observations by Rini et al; other tests were two-sided. Results: The median WW-period was 9.3 months in the unfavorable WW-group (n=19) vs 20.4 months in the favorable WW-group (n=21) (HR 1.89 95%CI 0.94-3.89; p=0.037), confirming observations of Rini et al. Patients with high [18F]FDG uptake had a median WW-period of 8.5 months compared to 25.2 months in the low-uptake group (HR 4.08 95%CI 1.89-9.28; p=0.0002). Patients with high [89Zr]Zr-DFO-girentuximab uptake had a median WW- period of 10.7 versus 16.4 months in the low-uptake group (HR 1.37; 95%CI 0.69-2.76; p=0.37). [18F]FDG uptake groups improved a Cox-model for WW based on the prognostic groups of Rini et al (p=0.0015); [89Zr]Zr-DFO-girentuximab did not (p=0.98). Conclusions: The IMPACT-RCC study validated the observations by Rini et al. and shows that adding baseline [18F]FDG PET further improves the prediction of the duration of the WW-period in mccRCC patients. Clinical trial information: NCT02228954. Research Sponsor: Dutch Cancer Society (Alpe d’HuZes Grant RUG 2012-5400).

5080 Poster Session (Board #149), Fri, 8:00 AM-11:00 AM

Axitinib plus pembrolizumab in patients with advanced renal cell carcinoma: Long-term efficacy and safety from a phase Ib study.

Michael B. Atkins, Igor Puzanov, Elizabeth R. Plimack, Mayer N. Fishman, David F. McDermott, Daniel C. Cho, Ulka N. Vaishampayan, Saby George, Jamal Christo Tarazi, William Duggan, Rodolfo F. Perini, Kathrine C. Fernandez, Toni K. Choueiri; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Vanderbilt University Medical Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; Moffitt Cancer Center, Tampa, FL; Beth Israel Deaconess Medical Center, Boston, MA; Perlmutter Cancer Center New York University Langone Health, New York, NY; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Roswell Park Comprehensive Cancer Center, Buffalo, NY; Pfizer Oncology, San Diego, CA; Pfizer Inc., Groton, CT; Merck & Co., Inc., Kenilworth, NJ; Pfizer Inc., Cambridge, MA; Dana-Farber Cancer Institute, Boston, MA

Background: Axitinib (AXI) plus pembrolizumab (pembro) showed superior overall survival (OS), progression-free survival (PFS) and response rate compared with sunitinib in a randomized Phase 3 trial in advanced renal cell carcinoma (RCC). Here, we report long-term efficacy and safety data of the combination AXI/pembro from the Phase 1 trial, with almost 5 years of follow-up. Methods: 52 treatment-na¨ıve patients with advanced RCC were enrolled between 23 September 2014 and 13 October 2015, and were treated with oral AXI 5 mg twice daily and intravenous pembro 2 mg/kg every 3 weeks. Planned treatment duration was 2 years for pembro and not limited for AXI. Based on International Metastatic Database Consortium (IMDC) criteria, 46.2%, 44.2% and 5.8% of patients were reported as having favourable, intermediate and poor risk. Results: At data cut-off date (July 3, 2019), median OS was not reached; 38 (73.1%) patients were alive. 14 (26.9%) patients had died, none were related to treatment. The probability of being alive was 96.1% (95% CI 85.2–99.0) at 1 year, 88.2% (95% CI 75.7– 94.5) at 2 years, 82.2 % (95% CI 68.5– 90.3) at 3 years, and 66.8 % (95% CI 49.1–79.5) at 4 years. Median PFS was 23.5 (95% CI 15.4–30.4) months. Median duration of response was 22.1 (95% CI 15.1–not evaluable) months. Median time on treatment with the combination AXI/pembro was 14.5 months (n=52), median time on pembro after AXI discontinuation was 9.0 months (n=10), and median time on AXI after pembro discontinuation was 7.5 months (n=11). After stopping study treatment, 22 patients received subsequent systemic therapy, including nivolumab and cabozantinib (n=6 each). Grade 3/4 AEs were reported in 38 (73.1%) patients. 20 (38.5%) patients discontinued either drug due to AEs: 17 (32.7%) patients discontinued AXI, and 13 (25.0%) patients discontinued pembro with 10 (19.2%) discontinuing both drugs. Dose reduction of AXI due to AEs was reported in 16 (30.8%) patients. The most common AEs reported were diarrhea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%), and dysphonia (48.1%). Increased alanine aminotransferase and aspartate aminotransferase occurred in 44.2% and 36.5% of patients, respectively. With this longer follow-up, there were no cumulative AEs or new AEs. OS by IMDC risk group will be presented. Conclusions: In patients with advanced RCC with almost 5 years of follow-up, the combination of AXI/pembro continues to demonstrate clinical benefit with no new safety signals. Clinical trial information: NCT02133742. Research Sponsor: Pfizer.

5081 Poster Session (Board #150), Fri, 8:00 AM-11:00 AM

FDA pooled analysis of time to treatment discontinuation (TTD) in frontline advanced renal cell carcinoma trials.

Elaine Chang, Yutao Gong, Chana Weinstock, Laura L Fernandes, Jessica Hawley, Thomas Gwise, Meredith M. Regan, Toni K. Choueiri, Brian I. Rini, David F. McDermott, Michael B. Atkins, Daniel L. Suzman, Amna Ibrahim, Shenghui Tang, Marc Robert Theoret, Paul Gustav Kluetz, Richard Pazdur, Julia A. Beaver; U.S. Food and Drug Administration, Silver Spring, MD; Columbia University Medical Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Johns Hopkins University, Baltimore, MD; Food and Drug Administration, Silver Spring, MD; National Cancer Institute at the National Institutes of Health, Bethesda, MD

Background: Time to treatment discontinuation (TTD) has been proposed as a potential pragmatic real- world data (RWD) endpoint, and was closely correlated with progression-free survival (PFS) in pooled analyses of non-small cell lung cancer (NSCLC) and breast cancer trials across therapeutic classes (Blumenthal, Ann Onc 2019; Gao, SABCS Abstract P5-14-02). Methods: We analyzed data from all randomized patients (pts) in the phase 3 trials submitted to FDA 2016-18 evaluating a combination therapy (Rx) of an immuno-oncology agent and another systemic Rx (IO-X) versus sunitinib (SUN) for treatment-na¨ıve advanced renal cell carcinoma (RCC). Protocols specified treatment until progression, but treatment beyond progression was allowed. TTD was defined as the time from the start of Rx to time of treatment discontinuation of both drugs in combination Rx or SUN. We measured TTD in treatment- defined subgroups (IO-X and SUN) and across all pts, and pt-level correlation (Pearson’s r) between TTD and PFS and between TTD and overall survival (OS). We also determined rates of disparity between TTD and PFS greater than 3 months. Results: Of 3758 pts (IO-X, n=1878; SUN, n=1880), 3190 pts (85%) had a TTD event, and 1899 pts (51%) had a PFS event. Median TTD was longer among pts receiving IO-X than SUN (12.3 versus 8.0 months). Regardless of drug class, more pts had early (TTD shorter than PFS by $ 3 months) TTD events than late TTD (13.4% versus 6.4%, overall). We found higher correlation between TTD and PFS in pts receiving SUN (r = 0.89) than pts receiving IO-X (r = 0.72). Overall, TTD was more closely associated with PFS (r = 0.80) than with OS (0.61). Conclusions: Observed correlations of TTD to PFS were stronger compared to the correlation of TTD to OS. This may be expected because OS is farther removed in time from TTD than is PFS. In contrast to TTD in NSCLC, more than twice as many pts in RCC trials had early TTD than late TTD, regardless of Rx group, which may indicate earlier discontinuation with combination Rx due to additive toxicity. Limitations include the censoring of PFS and OS and the post-hoc nature of this analysis. Research Sponsor: FDA.

IO-X SUN All N 1878 1880 3758 Median PFS, mo (95% CI) 15.0 (13.9, 12.5 (11.5, 13.8 (12.7, 15.3) 13.8) 14.2) Median TTD, mo (95% 12.3 (11.5, 8.0 (7.8, 9.0) 9.8 (9.3, 10.6) CI) 12.9) Corr PFS:TTD (95% CI) 0.72 (0.69, 0.89 (0.88, 0.80 (0.79, 0.74) 0.90) 0.81) TTD – PFS ‡ 3mo 8.2% 4.6% 6.4% PFS – TTD ‡ 3mo 17.5% 9.4% 13.4% Median OS, mo (95% CI) 24.4 (23.5, 22.2 (21.4, 23.5 (22.6, 25.2) 23.2) 24.1) Corr OS:TTD (95% CI) 0.56 (0.53, 0.65 (0.62, 0.61 (0.59, 0.59) 0.67) 0.63)

5082 Poster Session (Board #151), Fri, 8:00 AM-11:00 AM

Immune infiltration and angiogenesis as markers of outcome in the post-nephrectomy setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).

A. Ari Hakimi, Martin H Voss, Fengshen Kuo, Andrew W. Silagy, Mahtab Marker, Albert Reising, John Millholland, Timothy An-thy Chan, Paul Russo, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; Novartis Oncology, East Hanover, NJ; Novartis Pharmaceuticals Cor- poration, East Hanover, NJ; Novartis Pharmaceutical Corp, East Hanover, NJ

Background: Defined stromal and immune features of the tumor microenvironment (TME) have proven relevant for outcomes with systemic therapy in advanced clear cell renal cell carcinoma (ccRCC). We hypothesized that these may matter beyond therapeutic applications and could be relevant much earlier in the disease course. We sought to study the TME in high risk ccRCC patients undergoing definitive surgery. Methods: Clinical, pathologic, immunohistochemical, and whole-genome microarray data were acquired on 236 out of 769 patients in the Placebo arm of PROTECT trial (NCT01235962 - pazopanib vs placebo). Transcriptomic scores assessing angiogenesis and myeloid infiltration with individual annotations above/below median were used to categorize patients into four groups (angiogenesis high vs. low; myeloid high vs. low). We tested categorical association with disease free (DFS) and overall survival (OS) using logrank testing and assessed interdependence with relevant clinicopathologic variables, including the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Tumors from236 patients were available for analysis. Overall, 37% developed metastatic recurrence and 81% were alive at last follow up. On univariate analysis increasing tumor stage, higher UISS score, and angiogenesis/myeloid subgroups (high – H and low – L) were associated with worse DFS and OS (all p values ,0.05). On multivariate analysis TME subgroups remained significant for worse DFS and OS (Table). Conclusions: Microenvironmental subgroups stratified into angiogenic and myeloid expression profiles carry independent prognostic significance and should be further explored to guide future biomarker-directed adjuvant trials. Clinical trial information: NCT01235962. Research Sponsor: Novartis, Philantropic.

Variable Level HR Lower 95% CL Upper 95% CL P Angio_Myeloid_Grp H_L REF H_H 3.75 1.72 8.21 ,0.001 L_H 6.44 3.06 13.54 ,0.001 L_L 2.12 0.89 5.05 0.09 Stage T2 REF T3 1.54 0.80 2.94 0.2 T4 8.69 2.66 28.36 ,0.001 UISS Group 2 REF 3 0.56 0.24 1.31 0.18 4 .. . .

5083 Poster Session (Board #152), Fri, 8:00 AM-11:00 AM

Patient preferences and expectations of systemic therapy in renal cell carcinoma.

Dena Battle, Cristiane Decat Bergerot, Pavlos Msaouel, Eric Jonasch, Tian Zhang, Daniel J. George, Michael D. Staehler; KCCure, Alexandria, VA; Universidade Federal de S~ao Paulo (UNIFESP), S~ao Paulo, Brazil; The University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Cancer Center, Houston, TX; Duke Cancer Institute, Durham, NC; Duke University School of Medicine, Durham, NC; University Hospital Munich-Grosshadern, Ludwig Maximilian University, Munich, Germany

Background: In metastatic renal cell carcinoma, the systemic therapy landscape has expanded to include multiple VEGF inhibitors, immunotherapies, and combination therapy. Little is known about patient expectations and preferences when making decisions about systemic therapy. We sought to gather independent data from online kidney cancer patient communities to assess patient perspectives on what matters most when considering treatment options. Methods: The KCCure online survey was performed between August 1, and September 30, 2019. Patients were recruited via the KCCure website, social media channels (Twitter, Facebook) and through fliers distributed at cancer centers. Those who agreed to participate were surveyed for demographics (age, gender, race, income, country) and clinical characteristics (date of the diagnosis, disease stage, treatment history). Key questions focused on treatment selection and side effect management. Results: Out of 1,136 patients responding, 411 patients were on systemic therapy with a median age of 57 years (range 28-86). 223 (54%) of patients on systemic therapy were male. Patients were primarily from the U.S. (83%). Median duration on therapy was 24.7+/- 1.9 months. When asked to select the most important outcome for treatment selection, 58.8 % of patients chose complete response, followed by tumor control (10.2%), low risk of toxicity (5.7%) and the chance to discontinue therapy (3.7%). Patients ranked cost as the least important factor in selecting treatment (2.9%). 10.9% preferred infusion therapy and 42.1% oral therapy, whereas 47% were indifferent about the route of administration. Even if it would be safe to discontinue therapy, 62.8% of patients would be anxious about cancer progression. 23.2% would rather stay on treatment and 39.3% would want increased scanning intervals. Only 34.4% of patients would look forward to having more time off therapy. When asked to define treatment success, 86.3% selected reduction in tumor size, followed by stable disease (71.7%), freedom from symptoms (35.1%) and better quality of life (47.7%). Conclusions: Patients rank efficacy as the most important outcome when considering treatment options. Toxicity, time off therapy and cost are not significant priorities for patients. Further data is warranted investigating the impact of communicating treatment options, potential discontinuation of therapy and resulting expectations. Research Sponsor: None.

5084 Poster Session (Board #153), Fri, 8:00 AM-11:00 AM

Patient-reported use of marijuana and cannabinoid (CBD) oil in patients with renal cell carcinoma undergoing systemic therapy.

Dena Battle, Cristiane Decat Bergerot, Pavlos Msaouel, Tian Zhang, Daniel J. George, Michael D. Staehler; KCCure, Alexandria, VA; Universidade Federal de S~ao Paulo (UNIFESP), S~ao Paulo, Brazil; The University of Texas MD Anderson Cancer Center, Houston, TX; Duke Cancer Institute, Durham, NC; Duke University School of Medicine, Durham, NC; University Hospital Munich-Grosshadern, Ludwig Maximilian Univer- sity, Munich, Germany

Background: The use of cannabis and cannabinoid related products has become increasingly common among cancer patients. We sought to gather independent data from online kidney cancer patient communities to assess frequency of use of marijuana and CBD-oil and estimate influence on treatment duration and side-effects. Methods: The KCCure online survey was performed between August 1, and September 30, 2019. Descriptive statistics were used to characterize patients who self-report using marijuana, their systemic treatments, and interactions with their oncologists. Results: Out of 1,136 patients responding, 411 patients were on systemic therapy with a median age of 57 years (28-86). Of the 441 patients with systemic therapy, 223 patients (54%) were male. There was no difference in gender distribution or race among patients who reported using or not using marijuana and or CBD oil. 93 patients (21%) reported using marijuana or CBD oil and 35 patients (8.5%) reported using both. Patients using marijuana and/or CBD oil had a median age of 55.7 +/- 1.1 years compared with patients not using (65.1 +/- 6.9 years). The median treatment duration was 23.9+/-2.4 months for patients using marijuana and/or CBD oil versus 26.4+/- 1.9 months for patients not using these supplements (p=0.437). Patients using marijuana and/or CBD oil were more likely to have bothersome side effects from therapy (p=0.001) and were less likely to talk to their doctor about their situation (p=0.044). The median NCCN distress score in patients using marijuana and/or CBD oil was 49.5+/-25.7 versus 51.4+/-24.0 (p n.s.). No correlation was seen with the use of steroids, anti-diarrhea drugs, anti-nausea- drugs, hormone substitution or other drugs used to manage side effects. Conclusions: Marijuana and/or CBD oil are used by a significant number of patients. No benefit/harm on treatment duration and use of concomitant drugs to control side effects and severity was seen. Patients using marijuana and/or CBD oil were more likely to report bothersome treatment related side effects and were more willing to report their side effects to their provider. As cannabinoids become more mainstream and legal in a number of states, more research is needed to better understand the impact these supplements may have on patients. Research Sponsor: None.

5085 Poster Session (Board #154), Fri, 8:00 AM-11:00 AM

Camrelizumab plus famitinib malate in patients with advanced renal cell cancer and unresectable urothelial carcinoma: A multicenter, open-label, single-arm, phase II trial.

Yuan-Yuan Qu, Hongqian Guo, Hong Luo, Qing Zou, Ninazeng Xing, Zhongquan Sun, Xuepei Zhang, Shujie Xia, Chaohong He, Hailiang Zhang, Jinling Cai, Xiao Zhang, Quanren Wang, Dingwei Ye; Fudan University Shanghai Cancer Center, Shanghai, China; Nanjing Drum Tower Hospital, Nanjing, China; Chongqing Cancer Hospital, Chongqing, China; Jiangsu Cancer Hospital, Jiangsu, China; Jiangsu Cancer Hospital, Nanjing, China; Shanghai Huadong Hospital, Shanghai, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Shanghai General Hospital, Shanghai, China; Cancer Hospital of Henan Province, Zhengzhou, China; Jiangsu Hengrui Medicine Co., Ltd, Shanghai, China

Background: Camrelizumab (SHR-1210) is a humanised anti-PD-1 antibody. Famitinib malate is a tyrosine kinase inhibitor (TKI) against VEGFR-2, PDGFR, c-kit, and FGFR. This is an ongoing, open label, multi-center Phase II study to assess the preliminary efficacy and safety of camrelizumab in combination with famitinib malate in patients (pts) with genitourinary cancers and gynecologic cancers. Here we just report genitourinary cancers results. Methods: Eligible pts were aged 18 or older, who had advanced clear-cell renal-cell carcinoma with their primary tumour resected or unresectable urothelial carcinoma, had an ECOG performance status of 0-1and measurable disease. Previous system treatments were allowed (excluding prior PD-1/PD-L1 inhibitors or famitinib treatment). Famitinib 20 mg was administered orally once daily with SHR-1210 200 mg given intravenously every 3 weeks. We assessed antitumour activity and safety in all pts who received at least one dose treatment. The primary end point was objective response rate (ORR) per RECIST v1.1. Results: From 23 Jan 2019 to 24 Jun2019, 35 pts were enrolled (25 with RCC, 10 with UC). Median previous treatment line was 1 (range, 1-4), and 50.0% of pts had received $2 prior therapies in RCC, all pts received one or more-line therapies in UC. At the data cut-off date (Dec 31, 2019), after at least 6 months follow-up, 22 (63%) pts were still receiving study treatment. The most common reason for discontinuing treatments was disease progression (n = 10). 16 pts achieved a confirmed response, all were partial response, with 8 additional . 24 weeks stable disease. the ORR was 52.0% (13/25, 95% CI 31.3% to 72.2%) in RCC and 30.0% (3/10) in UC, the disease control rate was 84.0% (21/25) in RCC and 70.0% in UC. 13/16 confirmed PR pts were still on treatment, the median duration of response is not reached. The most common grade 3-4 treatment-related AEs (TRAEs) were hypertension (17.1%), proteinuria (11.4%), platelet count decreased (8.6%), hand-foot syndrome (8.6%) and anemia (5.7%). Immune-related adverse events were observed in 7 pts (20%) of 35 pts, 1 pt (2.9%) with grade 3 enteritis. Conclusions: The camrelizumab with famitinib combination appeared to show encouraging activity in pts with heavy- treated RCC and UC, and the safety profile of the combination seemed to be manageable and consistent with that of each drug alone. This combination represented a novel potential treatment option for these settings and warranted further investigation. Clinical trial information: NCT03827837. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd.

5086 Poster Session (Board #155), Fri, 8:00 AM-11:00 AM

Tipifarnib, a farnesyltransferase inhibitor, for metastatic urothelial carcinoma harboring HRAS mutations.

Jiyun Lee, Hana Kim, Antonio Gualberto, Catherine Rose Scholz, Se Hoon Park; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Kura Oncology, Cambridge, MA; Samsung Medical Center, Department of Medicine, Seoul, South Korea

Background: Tipifarnib is a farnesyltransferase inhibitor known to block RAS signaling and attenuate cancer cell proliferation. We tested the activity and safety of tipifarnib in patients with previously treated urothelial carcinoma (UC) carrying HRAS mutations. Methods: In a prospective phase II clinical trial, genetic screening was performed in 224 UC patients; those with missense HRAS mutations or STK11:rs2075606 received study treatment. Eligible patients received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-d treatment cycles. The primary endpoint was progression-free survival at 6 mo (PFS6). With two-stage design, at least 18 patients were required. Results: Among the 224 patients screened, we found 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11: rs2075606 carriers. In 21 patients enrolled, 14 and 7 patients had HRAS mutations and STK11:rs2075606, respectively. The most frequent adverse events included fatigue and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as a STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. Response rate was 24% (4 missense and one nonsense frameshift HRAS mutation); no response observed in UC patients with wild type HRAS tumors. Conclusions: Oral tipifarnib showed a manageable safety profile and encouraging anti-tumor efficacy against treatment-refractory UC containing HRAS mutations. Clinical trial information: NCT02535650. Research Sponsor: Kura Oncology.

5087 Poster Session (Board #156), Fri, 8:00 AM-11:00 AM

Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).

Petros Grivas, Joseph M Jacob, Oleg Shapiro, Andrea Necchi, Ethan Sokol, Jonathan Keith Killian, Douglas I. Lin, Shakti H. Ramkissoon, Eric Allan Severson, Richard Huang, Brian Michael Alexander, Jeffrey Venstrom, Venkataprasanth P. Reddy, Kimberly McGregor, Julia Andrea Elvin, Alexa Betzig Schrock, Natalie Danziger, Jeffrey S. Ross, Gennady Bratslavsky; University of Washington, Seattle, WA; SUNY Upstate Medical University, Syracuse, NY; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Foundation Medicine, Inc., Cambridge, MA; Foundation Medicine, Cambridge, MA; Foundation Medicine, Inc, Morrisville, NC; Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD

Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 127 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (19%) adenocarcinomas (UrthAC) and 13 (9%) clear cell (UrthCC) were evaluated along with a control cohort of 2,130 bladderUC cases. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Age was similar in all 4 groups. GA in PIK3CA were the most frequent potentially targetable GA; MTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2(6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Higher TMB was seen in UrthUC and UrthCC compared to UrthAC and UrthSCC, possibly reflecting their higher GA/tumor status and suggesting potential for immunotherapy benefit. MSI high status was absent throughout. The bladderUC cases had similar genomic pattern as UrthUC with significantly lower frequency of HPV16/18 positive cases. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials. Research Sponsor: Foundation Medicine Inc.

UrthUC UrthSCC UrthAC UrthCC BladderUC Number of Cases 49 31 34 13 2,130 Males/Females 78% M/22% F 55% M/45% F 29% M/71% F 9% M/91% F 75%M/25%F Median age (range) 67 (44-87) 61 (40-76) 64 (22-83) 60 (33-71) 67 (19-88) HPV16/18 14% 23% 0% 0% 2% GA/tumor 6.9 10.8 5.6 4.1 7.7 Top Untargetable GA TP53 43% TP53 52% TP53 79% CDKN2A 23% TP53 59% TERT 30% CDKNA 32% CDKN2A 29% MYC 23% TERT 72% CDKN2A 28% TERT 21% SMAD4 24% TP53 23% CDKN2A 37% CDKN2B 22% MYC 16% KRAS 24% VEGFA 15% CDKN2B 29% CCND1 16% FAT1 14% MYC 18% ARID1A 15% CCND1 14% Top Potentially PIK3CA 22% PIK3CA 29% PTEN 15% PIK3CA 31% PIK3CA 21% Targetable GA FGFR3 12% EGFR 10% ERBB3 12% PTCH1 8% FGFR3 14% BRCA2 8% PTEN 7% PIK3CA 12% TSC2 8% BRCA2 10% PTEN 8% ERBB2 3% ERBB2 12% MET 8% PTEN 10% ERBB2 6% FGFR1 3% NF1 9% ERBB2 7% TSC1 4% FGFR3 3% BRCA2 6% TSC1 8% BRCA1 4% TSC2 3% EGFR 3% BRCA1 3% KIT 2% FGFR2 3% BRAF 3% KIT 1% Median TMB (mut/Mb) 5.2 4.3 4.3 5.0 7.0 TMB>10/20 mut/Mb 22%/10% 23%/6% 9%/0% 9%/0% 36%/11%

5088 Poster Session (Board #157), Fri, 8:00 AM-11:00 AM

Impact of human papillomavirus (HPV) infection on the outcome of perioperative treatments for penile squamous-cell carcinoma (PSCC).

Patrizia Giannatempo, Marco Bandini, Yao Zhu, Dingwei Ye, Antonio Augusto Ornellas, Nick Watkin, Michael Ager, Oliver W. Hakenberg, Axel Heidenreich, Daniele Raggi, Friederike Haidl, Laura Marandino, Filippo Pederzoli, Alberto Briganti, Francesco Montorsi, Juan Chipollini, Mounsif Azizi, Maarten Albersen, Philippe E. Spiess, Andrea Necchi; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Vita- Salute San Raffaele University, Milan, Italy; Fudan University Shanghai Cancer Center, Shanghai, China; Hospital Mario ´ Kr¨oeff and Brazilian Cancer Institute, Rio De Janeiro, Brazil; St. George’s University Hospitals, NHS Foundation Trust, London, United Kingdom; University Hospital Rostock, Rostock, Germany; University Hospital of Cologne, Cologne, Germany; Department of Urology and Uro- Oncology, University Hospital of Cologne, Cologne, Germany; Fondazione IRCCS Istituto Nazionale dei Tumori, Torino, Italy; Universita ` Vita-Salute San Raffaele, Milan, Italy; Universita Vita Salute San Raffaele, Milan, Italy; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Moffitt Cancer Center and Research Institute, Tampa, FL; UZ Leuven, Leuven, Belgium; Moffitt Cancer Center, Tampa, FL

Background: PSCC patients (pts) with palpable inguinal lymph node (ILN) disease have a poor overall survival (OS). Multimodal perioperative treatments are usually offered despite the lack of clinically meaningful efficacy. Pending the availability of novel effective systemic therapy, the optimization of conventional treatments in better selected pts is needed. Methods: Within an international, multicenter database of 924 PSCC pts who received ILN dissection from USA, Europe, Brazil and China, 494 had information on HPV, and 52 (10.5%) had HPV+ PSCC, predominantly assessed with immunohistochemistry (53%). Multivariable logistic regression analyses evaluated the association between pt factors and HPV status. Multivariable Cox analyses (MVA) assessed predictors of overall mortality (OM), including HPV status, pathologically-involved ILN ratio (ILNR), extranodal extension, margin status, vascular invasion (VI), perioperative RT (pRT) and perioperative chemotherapy (pCT). Comparisons between HPV status and ILNR were performed using interaction tests. Kaplan-Meier method was used to define the OS benefit related in HPV-stratified sub-groups. Results: Median age at diagnosis was 58yrs. Overall, pCT and pRT were used in 227 (46%) and 50 (10%) pts. The median follow-up was 62 months. Neither clinical factors nor country were associated with HPV status. On MVA, ILNR (HR: 1.01, p = 0.01) and extranodal extension (HR: 1.5, p = 0.02) were statistically significantly associated with OM, but HPV was not (p = 0.2). However, in the subgroup of pts who received pRT, HPV status was associated with favorable OM (HR: 0.11, 95%CI: 0.03-0.5, p = 0.004) together with negative VI (p = 0.03), and the use of adjuvant CT (p = 0.04). A significant interaction was found on OM between HPV+ status and increasing ILNR, with a cutoff at 50% (p = 0.05). Results are limited by their retrospective nature and small numbers in each subgroup. Conclusions: In the largest available dataset of ILND for PSCC, we observed that pRT seemed to be more effective in the subgroup of HPV+ PSCC. These results should be considered as hypothesis-generating and may inspire both the future prospective trials or the ongoing InPACT study. Research Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori.

5089 Poster Session (Board #158), Fri, 8:00 AM-11:00 AM

A pooled analysis of the efficacy and safety of cabozantinib post immunotherapy in patients with advanced renal cell carcinoma.

Mototsugu Oya, Satoshi Tamada, Katsunori Tatsugami, Noboru Nakaigawa, Takahiro Osawa, Hiro-Omi Kanayama, Chihiro Kondoh, Naoto Sassa, Kazuo Nishimura, Masahiro Nozawa, Naoya Masumori, Yasuhide Miyoshi, Akiko Kimura, Shingo Kuroda, Robert J. Motzer, Toni K. Choueiri, Yoshihiko Tomita; Department of Urology, Keio University School of Medicine, Tokyo, Japan; Department of Urology, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Urology, Graduate School of Medicine Science, Kyushu University, Fukuoka, Japan; Department of Urology, School of Medicine, Yokohama City University, Kanagawa, Japan; Department of Renal and Genitourinary surgery, Hokkaido University, Hokkaido, Japan; Department of Urology, Graduate School, The University of Tokushima, Tokushima, Japan; Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan; Department of Urology, Graduate School of Medicine, Nagoya University, Aichi, Japan; Department of Urology, Osaka International Cancer Institute, Osaka, Japan; Department of Urology, Faculty of Medicine, Kindai University, Osaka, Japan; Department of Urology, School of Medicine, Sapporo Medical University, Hokkaido, Japan; Department of Urology and Renal Transportation, Medical Center, Yokohama City University, Kanagawa, Japan; Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, Osaka, Japan; Biostatistics, Takeda Development Center, Takeda Pharmaceutical Company Limited, Osaka, Japan; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Department of Urology, Department of Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Background: While studies have demonstrated survival benefits of first-line regimens including immuno-oncology agents (IO) in advanced renal cell carcinoma (aRCC), optimal treatment following IO is unknown. In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients (pts) with aRCC, after VEGFR-TKI therapy. The Japanese phase II C2001 study (NCT03339219), targeting a population similar to that of METEOR, showed similar efficacy and safety results. Here, we present a post-hoc pooled analysis of pts who had received prior IO therapy from METEOR and C2001. Methods: A pooled analysis was performed in pts who received 60mg/day of oral cabozantinib once daily enrolled in the METEOR or C2001. Patients were divided into two groups with previous IO treatment (pre-w/ IO subgroup) or without previous IO treatment (pre-w/o IO subgroup). Analyses of ORR, PFS, OS, and safety were performed as measures of clinical outcome in each subgroup. Results: 365 pts (pre-w/ IO subgroup: 33 pts, pre-w/o IO subgroup:332 pts) were included for efficacy analysis and 366 pts (pre-w/ IO subgroup: 33 pts, pre-w/o IO subgroup:333 pts) for safety analysis. Minor differences in baseline characteristics were noted between the analysis subgroups but are not expected to substantially affect efficacy outcomes. The ORR was 21.2% (95% CI: 9.0-38.9%) for pre-w/ IO subgroup, and 17.2% (95% CI: 13.3-21.7%) for pre-w/o IO subgroup. PFS rate and OS rate at 6 months pre-w/ IO was 65.5%, 90.8% and pre-w/o IO was 58.3%, 90.6%, respectively. Although there were some differences in the safety profile, almost all AEs were manageable by dose modifications. There were no differences in AEs associated with IO treatment, such as pneumonitis, endocrinolopathy or infusion related reaction. No new safety signals were noted in any subgroups. Conclusions: Safety and treatment efficacy of cabozantinib were maintained in the pooled analysis of pts from METEOR and C2001 irrespective of prior IO treatment. Funded by Takeda Pharmaceutical Company Limited, Tokyo, Japan. Clinical trial information: NCT03339219, NCT01865747. Research Sponsor: Takeda Pharmaceutical Company Limited and Exelixis, Inc.

TPS5090 Poster Session (Board #159), Fri, 8:00 AM-11:00 AM

A phase II, randomized study of nivolumab (NIVO), NIVO plus linrodostat mesylate, or NIVO plus intravesical bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non- muscle invasive bladder cancer (NMIBC): CheckMate 9UT.

Noah M. Hahn, Sam Chang, Maxwell Meng, Neal D. Shore, Badrinath R. Konety, Gary D. Steinberg, Juergen Gschwend, Hiroyuki Nishiyama, Joan Palou, John A Taylor, Alexandre Lambert, Li Zhu, Toshiki Maeda, Bradley Raybold, Bruce S. Fischer, Chandrika Jeyamohan, Dimitrios Zardavas, Fred Witjes; Departments of Oncology and Urology, Johns Hopkins School of Medicine, Baltimore, MD; Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN; Department of Urology, University of California, San Francisco, CA; Carolina Urologic Research Center, Myrtle Beach, SC; University of Minnesota, Minneapolis, MN; NYU Langone Health, Perlmutter Cancer Center, New York, NY; Department of Urology, Technical University of Munich, Munich, Germany; University of Tsukuba, Tsukuba, Japan; Department of Urology, Fundacio ´ Puigvert, Autonomous University of Barcelona, Barcelona, Spain; Department of Urology, University of Kansas Medical Center, Kansas City, KS; Bristol-Myers Squibb, Princeton, NJ; Department of Urology, Radboud University Medical Centre, Nijmegen, Netherlands

Background: Immune checkpoint inhibitors, including NIVO (anti–PD-1), have demonstrated favorable tolerability and efficacy profiles, ushering in a new treatment (tx) paradigm for advanced bladder cancer (advBC). However, an unmet need exists for new effective tx options in earlier stages of disease, specifically for patients (pts) with BCG-unresponsive, high-risk NMIBC. Increased IDO and PD-L1 expression in NMIBC tumors (Inman, et al. Cancer 2007; Hudolin, et al. Anticancer Res 2017), support the combination of anti–PD-1 and IDO1 inhibition in NMIBC. Linrodostat mesylate, a selective, potent, once-daily IDO1 inhibitor, has demonstrated clinical activity in combination with NIVO in pts with immunotherapy-naive advBC who received $ 1 prior line of therapy (objective response rate, 37%; Tabernero, et al. J Clin Oncol 2018;36(suppl) [abstr 4512]). Furthermore, high levels of PD-L1 expression have been reported in patients not responding to BCG tx. These findings provide a rationale for investigation of NIVO 6 linrodostat 6 intravesical BCG therapy in BCG-unresponsive high-risk NMIBC. Here we describe a phase 2, randomized, open-label study assessing the safety and efficacy of NIVO 6 linrodostat 6 intravesical BCG in pts with BCG-unresponsive, high-risk NMIBC (NCT03519256). Methods: Pts aged $ 18 years with BCG-unresponsive (per February 2018 FDA guidance), high-risk NMIBC, defined as carcinoma-in-situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions, will be enrolled. Pts must have urothelial carcinoma as the predominant histological component ( . 50%). Key exclusion criteria include locally advanced or metastatic BC, upper urinary tract disease within 2 years, prostatic urethral disease within 1 year, and prior immunotherapy. Using a novel adaptive-type design, pts will be randomized to 1 of 4 tx arms with NIVO 6 linrodostat 6 BCG. Primary endpoints include proportion of pts with CIS with complete response (CR) and duration of CR in pts with CIS. Secondary endpoints are progression-free survival and safety. This global study in 14 countries is underway, with a target enrollment of 436 pts. Clinical trial information: NCT03519256. Research Sponsor: Bristol Myers Squibb.

TPS5091 Poster Session (Board #160), Fri, 8:00 AM-11:00 AM

A phase III randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) 6 linrodostat mesylate, followed by adjuvant postsurgical NIVO 6 linrodostat, in cisplatin-eligible muscle invasive bladder cancer (MIBC).

Guru Sonpavde, Andrea Necchi, Shilpa Gupta, Gary D. Steinberg, Juergen Gschwend, Michiel Simon Van Der Heijden, Audrey Richiero, Alexandre Lambert, Bradley Raybold, Srikanth Gajavelli, Dimitrios Zardavas, Matt D. Galsky; Department of Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Cleveland Clinic Foundation, Cleveland, OH; NYU Langone Health, Perlmutter Cancer Center, New York, NY; Department of Urology, Technical University of Munich, Munich, Germany; Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Bristol-Myers Squibb, Princeton, NJ; Department of Medicine, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY

Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible, muscle invasive BC (MIBC), the recommended tx is cisplatin-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC). However, since only » 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, supporting the therapeutic pursuit of the PD-1/PD-L1 axis. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. Linrodostat mesylate, a selective, potent, once-daily oral IDO1 inhibitor that works to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had $ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + linrodostat in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC 6 NIVO 6 linrodostat followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged $ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance $ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + linrodostat (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320. Research Sponsor: Bristol Myers Squibb.

TPS5092 Poster Session (Board #161), Fri, 8:00 AM-11:00 AM

Study EV-103: New randomized cohort testing enfortumab vedotin as monotherapy or in combination with pembrolizumab in locally advanced or metastatic urothelial cancer.

Nataliya Mar, Terence W. Friedlander, Christopher J. Hoimes, Thomas W. Flaig, Mehmet Asim Bilen, Arjun Vasant Balar, Elizabeth Henry, Sandy Srinivas, Jonathan E. Rosenberg, Daniel Peter Petrylak, Earle Frederick Burgess, Jaime R. Merchan, Scott T. Tagawa, Anne-Sophie Carret, Joyce Leta Steinberg, Marya F. Chaney, Matthew I. Milowsky; UC Irvine Medical Center, Orange, CA; University of California San Francisco, San Francisco, CA; Duke Cancer Institute, Durham, NC; University of Colorado Anschutz Medical Campus, Aurora, CO; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Perlmutter Cancer Center at NYU Langone Health, New York, NY; Loyola University Medical Center, Maywood, IL; Stanford Cancer Institute, Stanford, CA; Memorial Sloan Kettering Cancer, New York, NY; Smilow Cancer Center, Yale University, New Haven, CT; Levine Cancer Institute, Atrium Health, Charlotte, NC; University of Miami, Miami, FL; Weill Cornell Medical College, New York, NY; Seattle Genetics, Inc., Bothell, WA; Astellas Pharma, Inc., Northbrook, IL; Merck & Co., Inc, Kenilworth, NJ; University of North Carolina Department of Medicine, Division of Hematology/Oncology, Chapel Hill, NC

Background: Cisplatin-based chemotherapy is the standard for first-line (1L) patients (pts) with locally advanced/metastatic urothelial cancer (LA/mUC). PD-1/PD-L1 inhibitors have promising durability of responses but 1L use is restricted to pts ineligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS $10) or pts ineligible for platinum-containing chemotherapy regardless of PD-L1 status. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with LA/mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. In the ongoing phase 1b/2 study EV-103/KEYNOTE-869 (NCT03288545), the safety and antitumor activity of EV are investigated as monotherapy (mono) (for the first time in the 1L setting) and in combination with PD-1 inhibitor pembrolizumab (P) +/- chemotherapy in UC. An initial analysis of EV (1.25 mg/kg) + P (200 mg) (both drugs in investigational use here) in this study showed a 73.3% confirmed ORR in 45 1L cisplatin-ineligible LA/mUC pts (dose-escalation + expansion Cohort A) (Rosenberg ASCO 2020). Methods: A new Cohort K randomized 1:1 to 1.25 mg/kg EV mono or 1.25 mg/kg EV + 200 mg P provides additional information on EV + P and the contribution of activity from EV in cisplatin-ineligible pts with LA/mUC in the 1L setting. This cohort will enroll 150 adults ($18 years) with LA/mUC and measurable disease per RECIST v1.1, and exclude pts with prior systemic treatment for LA/mUC, active CNS metastases, ongoing sensory or motor neuropathy (Grade $2), or uncontrolled diabetes. Cisplatin- ineligibility in this study is based on $1 of the following: ECOG of 2, creatinine clearance of $30 and , 60 mL/min, or hearing loss/dysfunction. In each 3-week cycle of this study, EV is administered on days 1 and 8, and P on day 1. The primary endpoint is ORR per RECIST v1.1 by BICR. Secondary endpoints include ORR per RECIST v1.1 by investigator assessment, DOR, DCR, PFS per RECIST v1.1 by BICR and investigator assessment, OS, safety, and tolerability. Sample size is not based on power calculation for formal hypothesis testing but is selected based on ORR estimate precision based on 95% CIs. Efficacy is summarized by treatment arm with no formal statistical comparisons between arms. The study opened in Oct 2017. Cohort K opened in Jan 2020. Clinical trial information: NCT03288545. Research Sponsor: Seattle Genetics, Astellas, Merck.

TPS5093 Poster Session (Board #162), Fri, 8:00 AM-11:00 AM

Phase III study of pembrolizumab (pembro) plus chemoradiotherapy (CRT) versus CRT alone for patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-992.

Arjun Vasant Balar, Nicholas D. James, Shahrokh F. Shariat, Neal D. Shore, Michiel Simon Van Der Heijden, Andrew James Weickhardt, Xiao Fang, James Luke Godwin, Ekta Kapadia, Jeff M. Michalski; NYU Langone Health Perlmutter Cancer Center, New York, NY; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom; Medical University of Vienna, Vienna, Austria; Carolina Urologic Research Center, Myrtle Beach, SC; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Olivia Newton-John Cancer Wellness & Research Centre, Heidelberg, VIC, Australia; Merck & Co., Inc., Kenilworth, NJ; Washington University in St. Louis School of Medicine, St. Louis, MO

Background: Pembro has shown clinical activity across many stages of bladder cancer (BC), including metastatic BC, MIBC, and NMIBC. Current NCCN and AUA/ASCO/ASTRO/SUO guidelines recommend CRT as a bladder-preserving treatment option for selected pts with MIBC. This phase 3 study was designed to investigate the safety and efficacy of pembro + CRT in pts with MIBC who opt for bladder preservation. Ongoing phase 2 studies (NCT02662062; NCT02621151) have shown that pembro + CRT may be a promising therapeutic option in MIBC. Methods: KEYNOTE-992 (NCT04241185) is a phase 3, global, multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC. Adults ($18 years) opting for bladder preservation with histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC after maximal TURBT are eligible. An estimated 636 pts will be randomly assigned 1:1 to receive CRT + either pembro 400 mg IV every 6 weeks (Q6W) or placebo. Treatment will continue with pembro or placebo Q6W for up to 9 doses. CRT regimens will be decided by the investigator before randomization. Accepted radiotherapy regimens are conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Accepted concurrent radiosensitizing chemotherapy regimens are cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluoro- uracil (500 mg/m2 on days 1-5 and days 22-26) + mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly). Randomization will be stratified by ECOG PS (PS 0/1 vs 2), PD-L1 combined positive score ( , 10 vs $10), T stage (T2 vs T3/4), and geographic region (US vs Europe vs rest of world). Pts must provide tissue for biomarker analysis. Efficacy will be assessed by cystoscopy (6 biopsy), CT or MRI (with blinded independent central review), and urine cytology at 10 weeks after CRT, then Q12W up to the end of year 2, and then Q24W thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastasis, radical cystectomy, or death from any cause. Key secondary end points are OS, metastasis-free survival, time to occurrence of NMIBC, and safety. Clinical trial information: NCT04241185. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

TPS5094 Poster Session (Board #163), Fri, 8:00 AM-11:00 AM

Phase III study of the hypoxia-inducible factor 2a (HIF-2a) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).

Toni K. Choueiri, Laurence Albiges, Li Fan, Rodolfo F. Perini, Naseem J. Zojwalla, Thomas Powles, Brian I. Rini; Dana-Farber Cancer Institute, Boston, MA; Gustave Roussy, Villejuif, France; Merck & Co., Inc., Kenilworth, NJ; Peloton Therapeutics Inc., Dallas, TX, a subsidiary of Merck & Co., Inc., Kenilworth, NJ; Barts Cancer Institute, London, United Kingdom; Vanderbilt University Medical Center, Nashville, TN

Background: In RCC, the Von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2a. HIF-2a is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A (VEGFA), cyclin D1, and CXCR4. MK- 6482 is a potent and selective small molecule inhibitor of HIF-2a, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged $18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received #3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor ($2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

TPS5095 Poster Session (Board #164), Fri, 8:00 AM-11:00 AM

PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations.

Siamak Daneshmand, Petros Grivas, Srikala S. Sridhar, Shilpa Gupta, Joaquim Bellmunt, Guru Sonpavde, Mark T. Fleming, Seth P. Lerner, Yohann Loriot, Hao Wang, Hiywot Takkele, Corina Andresen, Jessica Rearden, Craig Berman, Sumanta K. Pal; Keck School of Medicine of USC, Los Angeles, CA; University of Washington, Seattle, WA; Princess Margaret Cancer Centre, Toronto, ON, Canada; Cleveland Clinic Foundation, Cleveland, OH; Beth Israel Deaconess Medical Center, Boston, MA; Department of Genitourinary Oncology, Dana Farber Cancer Institute, Boston, MA; Virginia Oncology Associates, Hampton, VA; Baylor College of Medicine, Houston, TX; Institut Gustave Roussy, Paris, France; QED Therapeutics Inc., San Francisco, CA; City of Hope Comprehensive Cancer Center, Duarte, CA

Background: Radical surgery 6 cisplatin-based (neo)adjuvant chemotherapy (NAC) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients are unable to receive NAC due to cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a FGFR1–3 selective oral tyrosine kinase inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in patients with high-risk invasive urothelial carcinoma and susceptible FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo- controlled, phase III study of approx. 218 patients. Adults with high-risk invasive UTUC or UBC with susceptible FGFR3 genetic alterations (i.e. activating mutations, gene fusions or translocations) who are #120 days following surgical resection and ineligible for or refusing cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin-based NAC are eligible. Those who received non cisplatin-based NAC are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Patients receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low- risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include quality of life, pharmacokinetics, cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. The study was initiated in late 2019 and is expected to end in 2024. Clinical trial information: NCT04197986. Research Sponsor: QED Therapeutics.

TPS5096 Poster Session (Board #165), Fri, 8:00 AM-11:00 AM

Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients.

Jones Nauseef, Panagiotis J. Vlachostergios, Ana M. Molina, David M. Nanus, Cora N. Sternberg, Timothy D McClure, Douglas Scherr, M. Laura Martin, Giorgio Inghirami, Olivier Elemento, Scott T. Tagawa, Bishoy Morris Faltas; NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY; Weill Cornell Medicine, New York, NY; Sandra and Edward Meyer Cancer Center, New York, NY; Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY; Department of Urology, Weill Cornell Medicine, New York, NY; Department of Urology, Weill Cornell Medical College & New York-Presbyterian Hospital, New York, NY; Weill Cornell Medical College, New York, NY; University of Turin, Torino, Italy; Department of Physiology and Biophysics, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY

Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trials information: NCT03837821. Clinical trial information: NCT03837821. Research Sponsor: Lilly.

TPS5097 Poster Session (Board #166), Fri, 8:00 AM-11:00 AM

Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy as bladder- sparing therapy in patients with localized muscle invasive bladder cancer: A SOGUG study.

M. Andres Cuellar, Ana Medina, Regina Girones, B.P. Valderrama, Albert Font, MJ Juan-fita, Guillermo de Velasco, Ferran Ferrer, Francesc Vigues, ´ Xavier Garcia del Muro; Catalan Institute of Oncology, Barcelona, Spain; Centro Oncologico de Galicia, A Coru~na, Spain; Hospital Universitario La Fé, Valencia, ` Spain; Department of Medical Oncology, Hospital Universitario Virgen del Rocıó, Seville, Spain; Institut Catalad ` ’Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain; Fundacion ´ Instituto Valenciano de Oncologıá, Valencia, Spain; Medical Oncology Department, Hospital Uni- versitario 12 de Octubre, Madrid, Spain; Instituto Catalan Oncologia, Barcelona, Spain; Hospital Universitario de Bellvitge, Barcelona, Spain; Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain

Background: Several studies have shown that long-term bladder preservation is feasible in selected patients with muscle-invasive bladder cancer, using a multimodal treatment, including transurethral resection (TUR), radiotherapy and chemotherapy. Durvalumab, a fully human monoclonal antibody against PD-L1, has shown activity in patients with advanced pretreated urothelial cancer. A preclinical study showed that the combination of radiation, anti-CTLA4 and anti-PD-L1 overcome- adaptive immune resistance and has superior activity than either therapy alone (Twyman-Saint Victor et al. Nature 2015). The purpose of the present study is to explore feasibility, toxicity and activity in terms of response and bladder preservation of the integration of TUR, immune double checkpoint inhibition with durvalumab and tremelimumab (a fully human monoclonal antibody against CTLA-4), and radiotherapy in the treatment of localized muscle-invasive. Methods: This is a multicenter prospective phase II study of multimodal therapy in patients with localized urothelial carcinoma of the bladder in clinical stages T2-4a N0 M0, ECOG 0- 1, without contraindications to immunotherapy, who either wish for bladder preservation or are ineligible for cystectomy. The primary endpoint is pathological response (#T1) at post-treatment biopsy. A 2-stage sequential design (response rate P0=5, P1=0.7, a=0.10, b=0.20) requires at least 6 responses in the first 12 pts to expand to a second cohort of 20 patients. The treatment consists of initial TUR of the tumor, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam radiotherapy is started 2 weeks later, at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. Patients with pathological response will be candidates to bladder preservation, whereas those with residual muscle invasive tumor will be candidates to salvage cystectomy. At present time, prespecified activity goal for the first stage of accrual was met; second stage accrual began in December 2019. Clinical trial information: NCT03702179. Research Sponsor: None.

TPS5098 Poster Session (Board #167), Fri, 8:00 AM-11:00 AM

Hcrn GU15-215: A phase II trial of atezolizumab (atezo) and bevacizumab (bev) in cisplatin-ineligible patients (pts) with advanced/unresectable urothelial cancer (UC).

Arjun Vasant Balar, Samuel Aaron Funt, Shilpa Gupta, Arkadiusz Z. Dudek, Alejandro Recio Boiles, Daniel A. Vaena, Deepak Kilari, Jonathan E. Rosenberg; Perlmutter Cancer Center at NYU Langone Health, New York, NY; Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Health Partners Cancer Care Center, St. Paul, MN; University of Arizona College of Medicine, Tucson, AZ; University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, Iowa City, IA; Medical College of Wisconsin, Milwaukee, WI; Memorial Sloan Kettering Cancer, New York, NY

Background: Atezolizumab is a standard of care in selected cisplatin-ineligible pts with advanced UC. VEGF targeted therapies have activity in advanced UC and may lead to immune synergy when combined with anti-PD-1/L1 therapy. This phase II study is investigating the combination of bevacizumab and atezolizumab in untreated cisplatin-ineligible pts with advanced UC. Methods: HCRN GU15-215 (NCT03272217) is a phase 2, multicenter single arm trial to evaluate the efficacy and safety of atezolizumab and bevacizumab in pts with advanced UC. Cisplatin-ineligible pts (defined as any of estimated CrCl , 60 cc/min, Grade $ 2 hearing loss or neuropathy, ECOG PS 2 or solitary kidney) with untreated, histologically confirmed locally advanced or metastatic UC irrespective of PD-L1 expression status and with sufficient pre-treatment tumor tissue available for biomarker analysis are eligible. Pts who have received perioperative chemotherapy are eligible, however prior treatment with a checkpoint inhibitor is excluded. Pts with NYHA Class II or greater heart failure, significant cerebrovascular or cardiac disease within 3 months, uncontrolled HTN, persistent gross hematuria, and GI obstruction or perforation within 6 months are excluded. 70 pts will receive treatment with atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 21 days. All pts will undergo an on-treatment biopsy before cycle 2 if safe and feasible. Peripheral blood samples and stool samples will be collected before treatment and on-treatment for immune-relevant biomarker analyses. Cross-sectional imaging will be performed every 9 weeks on therapy for the first 12 months and then every 12 weeks thereafter to assess for response. Subjects will be eligible to continue treatment until RECIST v1.1 defined progression or unacceptable toxicity for up to 24 months. The primary endpoint is overall survival rate at 1 year and will be analyzed by the Kaplan Meier method. Key secondary endpoints include objective response rate, duration of response, disease control rate, progression-free survival and safety and toxicity as defined by CTCAE version 4.0. Clinical trial information: NCT03272217. Research Sponsor: Genentech.

TPS5099 Poster Session (Board #168), Fri, 8:00 AM-11:00 AM

A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914).

Axel Bex, Paul Russo, Yoshihiko Tomita, Viktor Grunwald, ¨ Luz-Margarita Ramirez, Brent M. McHenry, Robert J. Motzer; The Netherlands Cancer Institute, Amsterdam, Netherlands; Memorial Sloan Kettering Cancer Center, New York, NY; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; University Hospital Essen, Essen, Germany; Bristol-Myers Squibb, Prince- ton, NJ

Background: Surgery is standard treatment for nonmetastatic renal cell carcinoma (RCC). Unfortu- nately, patients (pts) with stage II or III RCC have high risk of relapse with 5-year disease-free survival rates of ~51%–56%; prevention of recurrence is an unmet need. In CheckMate 214, first-line nivolumab plus ipilimumab (NIVO+IPI) demonstrated significant overall survival improvements in pts with advanced/metastatic RCC, with a manageable safety profile. Moreover, while not yet confirmed in randomized controlled trials, evidence suggests that anti-PD-(L)1 monotherapy may provide sufficient clinical activity in some pts with advanced RCC. These findings indicate a potential for improved clinical outcomes in the early-stage adjuvant RCC setting. As such, the phase 3, double-blind CheckMate 914 study will evaluate NIVO and NIVO+IPI vs placebo in pts with high risk of relapse after nephrectomy (NCT03138512). Methods: Key inclusion criteria: radical or partial nephrectomy with negative surgical margins . 4 weeks and #12 weeks before randomization; predominantly clear cell histology; pathologic TNM staging T2a (grade [G] 3 or 4), T2b (any G), T3 (any G), or T4 (any G) N0M0, or any T (any G) N1M0; Eastern Cooperative Oncology Group performance status #1; no clinical/radiological evidence of macroscopic residual disease or distant metastases post-nephrectomy; and tumor tissue obtained #3 months pre-enrollment. Key exclusion criteria: conditions requiring corticosteroid or immunosuppressive systemic treatment, autoimmune disease, prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways, and prior systemic treatment for RCC. In part A, pts are randomized 1:1 to receive NIVO+IPI or placebo infusions; in part B, pts are randomized 1:1:2 to receive NIVO+IPI, placebo infusions, or NIVO with IPI placebo. All treatments are given for 24 weeks or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Stratification factors: TNM staging and type of nephrectomy procedure. Primary endpoint: disease-free survival per blinded independent central review (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo). Secondary endpoints: overall survival (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo and NIVO+IPI vs NIVO), disease-free survival (part B: NIVO+IPI vs NIVO), and safety. Enrollment in the study is ongoing. Total target enrollment across parts A and B is 1600 pts. Clinical trial information: NCT03138512. Research Sponsor: Bristol-Myers Squibb.

TPS5100 Poster Session (Board #169), Fri, 8:00 AM-11:00 AM

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).

Tian Zhang, Karla V. Ballman, Atish Dipankar Choudhury, Ronald C. Chen, Colleen Watt, Yujia Wen, Ardaman Shergill, Tyler J. Zemla, Hamid Emamekhoo, Ulka N. Vaishampayan, Michael J. Morris, Daniel J. George, Toni K. Choueiri; Duke Cancer Institute, Durham, NC; Weill Cornell Medicine, New York, NY; Dana-Farber Cancer Institute, Boston, MA; University of Kansas, Kansas City, KS; Alliance for Clinical Trials in Oncology, Chicago, IL; Univ of Chicago, Chicago, IL; University of Illinois at Chicago, Chicago, IL; Mayo Clinic, Rochester, MN; University of Wisconsin School of Medicine and Public Health, Madison, WI; Karmanos Cancer Institute, Detroit, MI; Memorial Sloan Kettering Cancer Center, New York, NY; Duke University School of Medicine, Durham, NC; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status . 70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through May 2020 will be presented. Clinical trial information: NCT03793166. Research Sponsor: U.S. National Institutes of Health.

TPS5101 Poster Session (Board #170), Fri, 8:00 AM-11:00 AM

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG- ACRIN EA8143).

Naomi B. Haas, Maneka Puligandla, Mohamad E. Allaf, David F. McDermott, Charles G. Drake, Sabina Signoretti, David Cella, Rajan T. Gupta, Brian M. Shuch, Primo Lara, Anil Kapoor, Daniel Yick Chin Heng, Bradley C. Leibovich, M Dror Michaelson, Toni K. Choueiri, Michael A.S. Jewett, Deb Maskens, Lauren C Harshman, Viraj A. Master, Michael Anthony Carducci; Abramson Cancer Ctr, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; James Buchanan Brady Urological Institute, Dept. of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Herbert Irving Comprehensive Cancer Center, New York, NY; Department of Pathology, Brigham and Women’s Hospital, Boston, MA; Robert H. Lurie Compre- hensive Cancer Center, Northwestern University, Chicago, IL; Duke University Medical Center, Durham, NC; Institute of Urologic Oncology (IUO), Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA; University of California, Sacramento, CA; Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; Department of Medical Oncology, Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Mayo Clinic, Rochester, MN; Massachusetts General Hospital, Boston, MA; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Kidney Cancer Canada, Toronto, Canada; Stanford University School of Medicine, Stanford, CA; Winship Cancer Institute of Emory University, Atlanta, GA; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD

Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage $T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (#3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 2020, 396 patients have been enrolled. Clinical trial information: NCT03055013. Research Sponsor: U.S. National Institutes of Health.

TPS5102 Poster Session (Board #171), Fri, 8:00 AM-11:00 AM

A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk.

Toni K. Choueiri, Laurence Albiges, Thomas Powles, Christian Scheffold, Fong Wang, Robert J. Motzer; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Gustave Roussy, Villejuif, France; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Exelixis, Inc., Alameda, CA; Memorial Sloan Kettering Cancer Center, New York, NY

Background: Cabozantinib (C) inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab (N) and as part of a triplet combination with N and the CTLA-4 inhibitor ipilimumab (I) in patients (pts) with advanced renal cell carcinoma (aRCC) (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS $70%, adequate organ and marrow function and age $18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219. Research Sponsor: Exelixis Inc.

TPS5103 Poster Session (Board #172), Fri, 8:00 AM-11:00 AM

A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).

Marit Ahrens, Bernard Escudier, Ekaterini Boleti, Marc-Oliver Grimm, Marine Gross-Goupil, Philippe Barthelemy, Gwenaelle Gravis, Jens Bedke, Philipp Ivanyi, Andrej Panic, Stefanie Zschaebitz, Sylvie Negrier, Begona Mellado, Anika Biel, Tom Waddell, Pablo Maroto, Margitta Retz, Martin Boegemann, Arndt Hartmann, Lothar Bergmann; Medical Clinic II, University Hospital, Frankfurt Am Main, Germany; Gustave Roussy, Villejuif, France; Royal Free London NHS Foundation Trust, London, United Kingdom; Department of Urology, University of Dresden, Dresden, Germany; Bergonie Institute, Cancer Center, Bordeaux, France; Hopitauxˆ Universitaires de Strasbourg/ICANS Strasbourg, Strasbourg, France; Institut Paoli Calmettes, Marseille, France; Eberhard-Karls University Tubingen, ¨ Tubingen, ¨ Germany; Dept. Hematology, Hemostaseology, Oncology & Stem Cell Transplantation, Hanover Medical School, Hannover, Germany; Clinic for urology, University Hospital, Essen, Germany; Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany; Departement of Medical Oncology, Centre Leon ´ B´erard, Lyon, France; Translational Genomics and Targeted Therapeutics in Solid Tumours Lab, Institut d’Investigacions Biomediques ` August Pi i Sunyer (IDIBAPS), Barcelona, Spain; University Hospital Duesseldorf, Duesseldorf, Germany; Royal Marsden Hospital, Sutton, United Kingdom; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Department of Urology, Klinikum rechts der Isar, TU Munchen, ¨ Munich, Germany; University Hospital Muenster, Munster, ¨ Germany; Institute of Pathology, Universitatsklinikum Erlangen, Friedrich-Alexander-Universitat Erlangen-Nurnberg, ¨ Erlangen, Germany; University Hospital Frankfurt, Frankfurt, Germany

Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky . 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non- papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423. Research Sponsor: Goethe University, Frankfurt, Germany, Pharmaceutical/Biotech Company.