Genitourinary (Kidney & Bladder)

GENITOURINARY CANCER—KIDNEY AND BLADDER

4500 Oral Abstract Session

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426.

Brian I. Rini, Elizabeth R. Plimack, Viktor Stus, Tom Waddell, Rustem Gafanov, Fre�de�ric Pouliot, Dmitry Nosov, Bohuslav Melichar, Denis Soulieres, Delphine Borchiellini, Ihor O. Vynnychenko, Raymond S. McDermott, Sergio Jobim Azevedo, Satoshi Tamada, Anna Kryzhanivska, Chenxiang Li, Joseph E. Burgents, L. Rhoda Molife, Jens Bedke, Thomas Powles; Vanderbilt-Ingram Cancer Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro, Ukraine; The Christie NHS Foundation Trust, Manchester, United King- dom; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; CHU of Que�bec and Laval University, Que�bec City, ON, Canada; Central Clinical Hospital With Outpatient Clinic, Mos- cow, Russian Federation; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Centre Hospitalier de l’Universite� de Montre�al, Montre�al, QC, Canada; Centre Antoine Lacas- sagne, Universite� Co^te d’Azur, Nice, France; Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine; Adelaide and Meath Hospital and University College Dublin, Dublin, Ireland; Hospital de Cl�ınicas de Porto Alegre, Porto Alegre, Brazil; Osaka City University Hospital, Osaka, Japan; Ivano- Frankivsk National Medical University, Ivano-Frankivsk, Ukraine; Merck & Co., Inc., Kenilworth, NJ; MSD UK, London, United Kingdom; Eberhard Karls Universita€t Tu€bingen, Tu€bingen, Germany; Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, Queen Mary University of London, Lon- don, United Kingdom

Background: In the first interim analysis of the randomized, multicenter, open-label, phase 3 KEYNOTE- 426 study (NCT02853331), treatment with pembro + axi significantly improved OS, PFS, and ORR vs sunitinib monotherapy in treatment-naive advanced ccRCC. Extended follow-up (median, 30.6 mo) continued to demonstrate the superior efficacy of pembro + axi vs sunitinib monotherapy in this patient population. Here, we present the results of the prespecified final analysis with 42.8-mo median follow- up. Methods: Treatment-naive patients (pts) with advanced ccRCC, 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, intolerable toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs Rest of World). Dual primary endpoints were OS and PFS. Secondary endpoints were ORR, DOR, and safety. The protocol-specified final analysis was based on a target of 404 OS events. No formal hypothesis testing was performed because all efficacy endpoints were met previously at the first interim analysis; nominal P values are reported. Results: Overall, 861 pts were randomly assigned to receive pembro + axi (n=432) or sunitinib (n=429). Median duration of follow-up, defined as time from randomization to the database cutoff date, was 42.8 mo (range, 35.6-50.6). At data cutoff, 418 pts had died: 193 (44.7%) of 432 pts in the pembro + axi arm vs 225 (52.4%) of 429 pts in the sunitinib arm. Compared with sunitinib, pembro + axi improved OS (median: 45.7 vs 40.1 mo; HR, 0.73 [95% CI, 0.60-0.88]; P<0.001) and PFS (median: 15.7 vs 11.1 mo; HR, 0.68 [95% CI, 0.58-0.80]; P<0.0001). The 42-mo OS rate was 57.5% with pembro + axi vs 48.5% with sunitinib; the 42-mo PFS rate was 25.1% with pembro + axi vs 10.6% with sunitinib. For pembro + axi vs sunitinib, ORR was 60.4% vs 39.6% (P<0.0001); CR rate was 10.0% vs 3.5%; median DOR was 23.6 mo (range 1.4+ to 43.4+) vs 15.3 mo (range, 2.3-42.8+). Subsequent anticancer therapy was administered to 47.2% of pts in pembro + axi arm vs 65.5% of pts in sunitinib arm. Al- though a similar proportion of pts in each arm received VEGF/VEGFR inhibitors, only 10.2% of pts in the pembro + axi arm received subsequent treatment with a PD-1/L1 inhibitor compared to 48.7% of pts in the sunitinib arm. No new safety signals were observed. Conclusions: With a median follow-up of 42.8 mo, this is the longest follow-up of an anti-PD–1/L1 immunotherapy combined with a VEGF/ VEGFR inhibitor for first-line RCC. These results show that pembro + axi continues to demonstrate superior efficacy over sunitinib with respect to OS, PFS, and ORR, with no new safety signals. Clinical trial information: NCT02853331. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

4501 Oral Abstract Session

CANTATA: Primary analysis of a global, randomized, placebo (Pbo)-controlled, double- blind trial of telaglenastat (CB-839) + cabozantinib versus Pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mRCC) patients (pts) who progressed on immune checkpoint inhibitor (ICI) or anti-angiogenic therapies.

Nizar M. Tannir, Neeraj Agarwal, Camillo Porta, Nicola Jane Lawrence, Robert J. Motzer, Richard J. Lee, Rohit K. Jain, Nancy B. Davis, Leonard Joseph Appleman, Oscar B. Goodman, Walter Michael Stadler, Sunil G. Gandhi, Daniel M. Geynisman, Roberto Iacovelli, Begona Mellado, Robert A. Figlin, Thomas Powles, Lalith V Akella, Keith W. Orford, Bernard Escudier; The University of Texas MD Ander- son Cancer Center, Houston, TX; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; University of Bari ’A. Moro’ and Policlinico Consorziale di Bari, Bari, Italy; Auckland City Hospital, Auck- land, New Zealand; Memorial Sloan Kettering Cancer Center, New York, NY; Massachusetts General Hospital, Boston, MA; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Vanderbilt-In- gram Cancer Center, Nashville, TN; University of Pittsburgh Medical Center, Pittsburgh, PA; Compre- hensive Cancer Centers of Nevada, Las Vegas, NV; The University of Chicago, Chicago, IL; Florida Cancer Specialists, Lecanto, FL; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Hospital Cl�ınic, Provincial de Barcelona, Barcelona, Spain; Cedars-Sinai Medical Center, Samuel Oschin Comprehen- sive Cancer Institute, Los Angeles, CA; St Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom; Calithera Biosciences, Inc., South San Francisco, CA; Gustave Roussy, Villejuif, France

Background: Dysregulated metabolism is a hallmark of RCC, driven by overexpression of glutaminase (GLS), a key enzyme of glutamine metabolism. Telaglenastat (Tela) is an investigational, first-in-class, selective, oral GLS inhibitor that blocks glutamine utilization and critical downstream pathways. Pre- clinically, Tela synergized w/ cabozantinib (Cabo), a VEGFR2/MET/AXL inhibitor, against RCC tumors. In a Ph 1 study cohort, Tela+Cabo showed encouraging safety/efficacy as 2L+ therapy for mRCC. This trial compared Tela+Cabo vs Pbo+Cabo in previously treated pts w/ clear-cell mRCC (NCT03428217). Methods: Eligible pts had 1-2 prior lines of systemic therapy for mRCC, including $1 anti-angiogenic therapy or nivolumab + ipilimumab (nivo/ipi), KPS $70%, measurable disease (RECIST 1.1), no prior Cabo or other MET inhibitor. Pts were randomized 1:1 to receive Cabo (60 mg PO QD) with either Tela (800 mg PO BID) or Pbo, until disease progression/unacceptable toxicity, and were stratified by prior PD-(L)1 inhibitor therapy (Y/N) and IMDC prognostic risk group. Primary endpoint was progression-free survival (PFS; RECIST 1.1) by blinded independent radiology review. The study was designed to detect a PFS hazard ratio (HR) of 0.69 w/ alpha 0.05 and 85% power. Data cutoff date: August 31, 2020. Re- sults: 444 pts were randomized (221 Tela+Cabo; 223 Pbo+Cabo). Baseline characteristics were balanced between arms. Median follow-up was 11.7 mo; 276 pts received prior ICI, including 128 w/ prior nivo/ipi. Median PFS (mPFS) was 9.2 mo for Tela+Cabo vs 9.3 mo for Pbo+Cabo (HR = 0.94; 95% CI: 0.74, 1.21; stratified log-rank P= 0.65) with overall response rates (ORR; confirmed) of 31% with Te- la+Cabo vs 28% Pbo+Cabo, respectively. Overall survival was not mature at data cutoff. In a prespecified subgroup analysis in pts w/ prior ICI, mPFS was numerically longer w/ Tela+Cabo than Pbo+Cabo (11.1 vs 9.2 mo, respectively; unstratified HR = 0.77; 95% CI: 0.56, 1.06). In the Pbo+Cabo arm, mPFS was 9.2 mo for pts w/ prior ICI exposure and 9.5 mo for pts without, and ORR was 32% and 20%, respectively; if ICI included nivo/ipi, ORR was 37%. Rates of adverse events (AEs) were similar between arms.Grade 3-4 AEs occurred in 71% of Tela+Cabo pts and 79% of Pbo+Cabo pts and included hypertension (17% vs 18%) and diarrhea (15% vs 13%). Cabo was discontinued due to AEs in 10% of Tela+Cabo pts and 15% of Pbo+Cabo pts. Conclusions: The addition of Tela did not improve the efficacy of Cabo in mRCC in this study. Tela+Cabo was well tolerated with AEs consistent with known risks of both agents. The study provides valuable insight on efficacy outcomes of a contemporary population of pts w/ mRCC who receive Cabo in the 2/3L setting. Clinical trial information: NCT03428217. Re- search Sponsor: Calithera Biosciences, Inc.

4502 Oral Abstract Session

Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC).

Robert J. Motzer, Camillo Porta, Boris Alekseev, Sun Young Rha, Toni K. Choueiri, Maria Jose Mendez- Vidal, Sung-Hoo Hong, Anil Kapoor, Jeffrey C. Goh, Masatoshi Eto, Jinyi Wang, Janice Pan, Alemseged Ayele Asfaw, Cixin Steven He, Kalgi Mody, David Cella; Memorial Sloan Kettering Cancer Center, New York, NY; San Matteo University Hospital Foundation, Pavia, Italy; P.A. Herzen Moscow Oncological Re- search Institute, Moscow, Russian Federation; Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea; Dana-Farber Cancer Institute, Boston, MA; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Hospital Universitario Reina Sof�ıa, Co�rdoba, Spain; Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea; McMaster University Hamilton, Hamil- ton, ON, Canada; ICON Research, South Brisbane & University of Queensland, St Lucia, QLD, Australia; Kyushu University, Fukuoka, Japan; RTI Health Solutions, Research Triangle Park, NC; Eisai Inc., Woodcliff Lake, NJ; Merck & Co., Inc., Kenilworth, NJ; Northwestern University, Chicago, IL

Background: LEN + PEMBRO improved PFS, OS and ORR vs SUN in the first-line treatment of pts with aRCC; LEN + EVE improved PFS and ORR vs SUN (Motzer R et al. NEJM. 2021). We report results of a secondary objective of the CLEAR trial comparing the impact of LEN + PEMBRO or EVE vs SUN, on HRQoL. Methods: Pts (N=1069) were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 wks on/2 wks off). HRQoL was assessed per FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L, at baseline, on day 1 of subsequent 3 wk cycles starting with cycle 2, and at the off-treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized pts with any HRQoL data who received $1 dose of study treatment. No adjustments for multiple testing or estimation were used; P-values and CIs are nominal and descriptive. Results: For comparisons of LEN + PEMBRO vs SUN, overall changes from baseline at mean follow-up (wk 46) favored LEN + PEMBRO with significant differences between treatments for physical functioning (least squares mean difference [LS MD] [95% CI]: 3.0 [0.5, 5.5]) and fatigue (À 2.8 [À 5.5, À 0.1]), dyspnea (À 2.8 [À 5.3, À 0.3]), and constipation (À 2.2 [À 4.2, À 0.2]). LS MD of the FKSI-DRS total score was 0.2 (À 0.4, 0.7). For comparisons of LEN + EVE vs SUN, overall changes from baseline at wk 46 favored SUN with significant differences in overall HRQoL (À 2.8 [À 5.1, À 0.5] assessed by the EORTC QLQ-C30 GHS/QoL scale) and pain (2.8 [0.1, 5.5]), appetite loss (4.2 [1.3, 7.1]), and diarrhea (5.3 [2.6, 7.9]). LS MD of the FKSI-DRS total score was À 0.4 (À 1.0, 0.2). 14 of 18 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in LS MD comparisons. The LEN + PEMBRO arm is favored over SUN for the median time to first deterioration (TTD) for physical functioning, dyspnea, appetite loss and EQ-5D VAS (Table). 15 of 19 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in TTD comparisons. Conclusions: Compared with SUN, pts in LEN + PEMBRO group had similar or better symptoms and HRQoL. Clinical trial information: NCT02811861. Research Sponsor: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Time to first deterioration. Median TTD, wks HR (95% CI) LEN + LEN + LEN + PEMBRO vs LEN + EVE Scale PEMBRO EVE SUN SUN vs SUN

FKSI-DRS total score (3-point MID) 9.1 7.9* 12.1 1.1 (0.9, 1.4) 1.2 (1.0, 1.5) EORTC QLQ-C30: 15.3* 9.4 12.7 0.8 (0.7, 1.0) 1.1 (0.9, 1.3) Physical functioning Pain 7.1 6.1* 9.9 1.1 (0.9, 1.3) 1.3 (1.1, 1.5) Dyspnea 39.3* 18.4 21.1 0.8 (0.6, 1.0) 1.1 (0.9, 1.3) Appetite Loss 18.3* 8.9 9.1 0.8 (0.7, 1.0) 1.2 (1.0, 1.4) Diarrhea 15.4 9.6* 15.1 0.9 (0.7, 1.1) 1.3 (1.1, 1.6) EQ-5D Index 9.1 6.3* 15.0 1.1 (0.9, 1.3) 1.3 (1.1,1.5) EQ-5D VAS (7-point MID) 9.4* 6.4 9.1 0.8 (0.7, 1.0) 1.1 (0.9, 1.3)

*Statistically significant log-rank difference of distribution of TTD (P <0.05) vs SUN.

4503 Oral Abstract Session

Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257.

Matt D. Galsky, Siamak Daneshmand, Kevin G. Chan, Tanya B. Dorff, Jeremy Paul Cetnar, Brock O Neil, Anishka D’souza, Ronac Mamtani, Christos Kyriakopoulos, Philip Garcia, Sudeh Izadmehr, Menggang Yu, Qianqian Zhao, Reza Mehrazin, Sara C Lewis, John Sfakianos, Sumanta K. Pal; Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; USC Norris Comprehensive Cancer Center, Los Angeles, CA; City of Hope, Duarte, CA; Oregon Health and Science University, Portland, OR; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Division of Oncology, USC Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA; University of Pennsylvania Abramson Cancer Center, Philadelphia, PA; Univer- sity of Wisconsin Carbone Cancer Center, Madison, WI; Tisch Cancer Institute, Division of Hematology/ Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY; Icahn School of Medicine at Mount Sinai, New York; University of Wisconsin Department of Biostatistics and Medical Informatics, Madison, WI; University of Wisconsin Madison, Madison, WI; Icahn School of Medicine at Mount Sinai, New York, NY; Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA

Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by (a) lack of prospective studies exclusively testing cisplatin-based neoadjuvant chemotherapy, (b) lack of rigorous methods to define clinical complete response (cCR) and its association with long term outcomes and (c) limited understanding of the role of salvage cystectomy. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder/prostatic urethral biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance; otherwise, patients underwent cystectomy. Coprimary endpoints included (1) cCR rate and (2) ability of cCR to predict 2- year metastasis-free survival (MFS). The key secondary endpoint was the impact of genomic alterations in baseline TURBT (TMB, ERCC2, FANCC, RB1, ATM) on performance of cCR for predicting MFS. The cCR rate coprimary endpoint, and interim analysis of 1-year outcomes, are reported. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%) and 64 (84%) have completed post-cycle 4 restaging; 31/64 achieved a cCR (48%; 95% CI 36%, 61%). The median follow-up of cCR patients is 13.7 months (range, 2.5-24 months). One cCR patient opted for immediate cystectomy (pTaN0M0). Outcomes for the entire cohort are summarized in the table below. Local recurrence has occurred in 8/31 cCR patients and 6 underwent cystectomy (pT0N0 = 1, pTaN0 = 1, pTisN0 =1, pT2N0 = 2, pT4N1 = 1). TMB $ 10 mut/Mb (p=0.02) or mutant ERCC2 (p=0.02) were associated with cCR or pT0. Conclusions: TURBT + gemcitabine, cisplatin, plus nivolumab achieves stringently defined cCR in a large subset of patients with MIBC. 1-year bladder intact survival is possible though the durability of responses, and role of genomic biomarkers in management algorithms, requires longer follow-up. Clinical trial information: NCT03558087. Re- search Sponsor: BMS, Other Foundation.

% at 1 year Group N Estimate 95% CI

Alive Overall 76 92.4% 80.9%, 97.1% cCR 31 100% NA Non-cCR 33 87.7% 66.2%, 95.8% Alive, bladder intact cCR 31 81.2% 60.4%, 91.7% Non-cCR 33 11% 2.9%, 25% Alive, metastasis free cCR 31 100% NA Non-cCR 33 79.5% 57.4%, 90.9% Alive, local recurrence free cCR 31 78% 54.6%, 90.3%

4504 Oral Abstract Session

Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial.

Arjun Vasant Balar, Matthew I. Milowsky, Peter H. O’Donnell, Ajjai Shivaram Alva, Marisa Kollmeier, Tracy L Rose, Sean Pitroda, Samuel D. Kaffenberger, Jonathan E. Rosenberg, Kaitlyn Francese, Tsivia Hochman, Judith D Goldberg, Sarah Griglun, Dayna Leis, Gary D. Steinberg, James Wysock, Peter B. Schiff, Nicholas J. Sanfilippo, Samir Taneja, William C. Huang; Perlmutter Cancer Center at NYU Lan- gone Health, New York, NY; University of North Carolina Department of Medicine, Division of Hematolo- gy/Oncology, Chapel Hill, NC; University of Chicago Comprehensive Cancer Center, Chicago, IL; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Memorial Sloan Kettering Cancer Center, New York, NY; The University of North Carolina at Chapel Hill (UNC-CH) School of Medicine and UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; University of Chicago, Chicago, IL; Universi- ty of Michigan, Ann Arbor, MI; Genitourinary Medical Oncology Service, Division of Solid Tumor Oncolo- gy, Memorial Sloan Kettering Cancer Center, New York, NY; New York University School of Medicine, New York, NY; Department of Surgery, The University of Chicago Medicine, Chicago, IL; Department of Urology, New York University School of Medicine, New York, NY; Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY; Weill Cornell Medicine, New York, NY; NYU Langone Health, New York, NY; NYU Langone Medical Center, New York, NY

Background: Trimodality bladder preservation therapy (TMT) is a standard treatment option for clinically localized MIBC with curative intent. Pembro has shown activity in MIBC in the neoadjuvant setting and may combine well with TMT to improve outcomes. This trial evaluated the safety and efficacy of pembro added to TMT in MIBC. Methods: This multicenter phase 2 trial included pts with cT2 – T4aN0M0 MIBC who declined or were ineligible for cystectomy (RC), ECOG PS 0/1, eGFR > 30 cc/min, and no contraindications to pelvic RT or pembro. No perioperative chemotx for MIBC was permitted. Pts received pembro 200 mg x 1 followed 2-3 weeks by maximal TURBT and then whole bladder RT (52 Gy/ 20 fx; IMRT preferred) with twice wkly gem 27 mg/m2 and pembro Q3 wks x 3 treatments. 12 wks post-RT, CT/MR AP, TUR of tumor bed and cytology were performed to document response. Up to 6 pts were enrolled to a safety cohort (SC) followed by 48 pts in efficacy cohort (EC). The primary endpt is 2- yr bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cysto/cytology and CT/MRI. EC had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (RTOG Pooled analysis; Mak JCO 2014). Key secondary endpts were safety, 12 wks CR rate, metastases-free survival and overall survival. Tumor tissue was collected at study entry, maximal TURBT and post-treatment TUR of tumor bed with serial PBMCs for correlative analyses. Results: From 5/2016 to 10/2020, 54 pts (6 SC, 48 EC; 72% M) enrolled at 5 centers; Median age 67 (65-89) for SC and 74 (51-97) for EC. C-stage (74% cT2, 22% cT3, and 4% cT4). 39 (72%) declined RC. All 6 pts in SC and 42/48 (88%) of EC pts completed all study therapy; 1/48 (2%), 2/48 (4%), and 4/48 (8%) discontinued RT/Gem, Gem or Pembro, respectively, most often due to toxicity. As of 1/2021 (median F/U 40.9 mos (38.6-50.8) SC and 11.7 mos (0.6 – 32.2) EC), no recurrences in SC, and 12/48 EC pts had any recurrence (6 NMIBC, 0 MIBC, 2 regional and 4 distant). The estimated 1 yr BIDFS rate is 77% (95% CI: 0.60-0.87). 12 wks CR rate was 100% in SC and 83% for EC (1 PR, 3 NR, 1 Progression, 11 NE; 2 still on active study). In the EC, 35% of pts had a Gr $3 TEAE (Gr 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, thrombocytopenia 2%). Notable Pembro Gr $3 TRAE included 3 pts (6%) Gr 3 GI toxicity and 1 pt Gr 4 colonic perforation. 1 patient died due to fungemia, unrelated to study therapy. Conclusions: Pembro added to hypofractionated RT and twice weekly gem was well-tolerated with promising efficacy in this early analysis. Pembro-related toxicity was consistent with prior monotherapy trials. Selected correlative analyses from serially collected blood and tissue specimens will be presented. Clinical trial information: NCT02621151. Research Sponsor: Merck, U.S. National Institutes of Health.

4505 Oral Abstract Session

Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy (RT) in patients (pts) with localized muscle invasive bladder cancer (MIBC) treated with a selective bladder preservation approach: IMMUNOPRESERVE-SOGUG trial.

Xavier Garcia del Muro, Begon~a P. Valderrama, Ana Medina, M. Andres Cuellar, Olatz Etxaniz, Regina Girone�s Sarrio�, Mar�ıa Jose Juan-Fita, Ferran Ferrer, Isabel Miras Rodr�ıguez, Guillermo Lend�ınez-Cano, Roberto de Haro Piedra, Arturo Candal Gomez, Venancio Chantada Abal, Oscar Buisa�n, Salvador Villa�, Jose� Luis Pontones, Erica Collado, Jose� L. Dom�ınguez-Escrig, Yashmina Murria, Francesc Vigue�s, SOGUG-Spanish Oncology Genitourinary Group; Medical Oncology. Institut Catala� d’Oncologia (ICO) L’Hospitalet del Llobregat, Barcelona, Spain; Department of Medical Oncology, Hospital Universitario Virgen del Roc�ıo, Seville, Spain; Medical Oncology. Fundacio�n Centro Oncolo�gico de Galicia, A Corun~a, Spain; Medical Oncology. Institut Catala� d’Oncologia (ICO) Hospital Germans Trias i Pujol, Badalona, Spain; Medical Oncology Service, Hospital Universitari i Polite�cnic la FE, Valencia, Spain; Medical On- cology Service. Instituto Valenciano de Oncolog�ıa, Valencia, Spain; Radiotherapy Oncology, Institut Catala� d’Oncologia (ICO) L’Hospitalet del Llobregat, Barcelona, Spain; Medical Oncology. Hospital Uni- versitario Virgen del Roc�ıo, Seville, Spain; Urology Service, Uro-Oncology Unit. Hospital Universitario Virgen del Roc�ıo, Sevilla, Spain; Radiotherapy Oncology, Hospital Universitario Virgen del Roc�ıo, Se- ville, Spain; Radiotherapy Oncology, Fundacio�n Centro Oncolo�gico de Galicia, A Corun~a, Spain; Urology Department. Fundacio�n Centro Oncolo�gico de Galicia, A Corun~a, Spain; Urology Department. Institut Catala� d’Oncologia (ICO) Hospital Germans Trias i Pujol, Badalona, Spain; Radiation Oncology Depart- ment, Catalan Institute of Oncology, Badalona, Barcelona, Spain; Oncology Urology Department. Hospi- tal Universitari i Polite�cnic la Fe, Valencia, Spain; Medical Oncology. Hospital Universitari i Polite�cnic la FE, Valencia, Spain; Urology Service, Fundacio�n Instituto Valenciano De Oncolog�ıa (I.V.O.), Valencia, Spain; Radiation Oncology Department, Fundacio�n Instituto Valenciano de Oncolog�ıa (I.V.O.), Valen- cia, Spain; Urologist. Hospital Universitari de Bellvitge, Barcelona, Spain

Background: Bladder-preserving combined-modality therapies constitute an alternative to radical cystectomy for selected pts with MIBC. In preclinical studies, combination of radiation and dual checkpoint blockade appears to activate non-redundant immune mechanisms, potentiating antitumor activity. The purpose of the present study is to explore feasibility, toxicity and activity of this approach in MIBC. Methods: Pts with localized MIBC in clinical stages T2-4a N0 M0, ECOG 0-1, without contraindications to immunotherapy, who either wished for bladder preservation or were ineligible for cystectomy, were included in this phase II study. Treatment consisted of initial transurethral resection (TUR) of the tumor, followed by durvalumab 1,500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam RT was started 2 weeks later, at doses of 46 Gy to minor pelvis and 64-66 Gy to bladder. Pts with either residual or relapsed MIBC were offered salvage cystectomy. The primary endpoint was complete response (CR) defined as absence of MIBC at post-treatment tumor site biopsy. A 2-stage sequential design was used (CR rate P0=5, P1=0.7, a=0.10, b=0.20) requiring at least 6 CR in the first 12 pts to expand to a second cohort of 20 pts. Results: From 1/2019 to 8/ 2020, 32 pts were enrolled at 6 centers. Median age was 71 years (49-91). PS was 0 in 24 pts,1 in 8. 25 were males. Clinical stage was T2 in 28 pts, T3 in 3 and T4a in 1. All pts received at least two immunotherapy cycles. The median dose of RT administered was 64 Gy (60-65). CR at post-treatment biopsy was documented in 26 (81%) pts, 2 pts had residual MIBC and 4 pts were not evaluated due to rejec- tion (1), clinical impairment (1), death from COVID 19 (1) and a suspected treatment-related death from peritonitis (1). After a median follow up of 6.1 months (2.5 - 20.1), 2 pts underwent salvage cystectomy because of MIBC and T1 relapses, respectively. The estimated 6-months rates for disease-free survival (DFS) with bladder intact, DFS and overall survival were 76% (95%CI, 61%-95%), 80% (95%CI, 66%-98%) and 93% (95%CI, 85%-100%), respectively. A total of 31 (97%) pts experienced adverse events related to RT and/or immunotherapy, with diarrhea (41%) and urinary disorders (37.5%) as the most frequent. Grade 3 or 4 adverse events related to therapy were reported in 31% pts, being the most frequent gastrointestinal toxicity (12.5%), acute kidney failure (6%) and hepatitis (6%). Conclusions: A combined-modality approach including durvalumab + tremelimumab with concurrent RT is feasible and safe, showing high efficacy in terms of response and eliciting bladder preservation in a large number of pts. Further research on this approach as an alternative to cystectomy is warranted. Clinical trial information: NCT03702179. Research Sponsor: AstraZeneca, Spanish Oncolo- gy Genitourinary Group (SOGUG).

4507 Oral Abstract Session

A randomized phase II study comparing cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma.

Sumanta K. Pal, Amir Mortazavi, Matthew I. Milowsky, Ulka N. Vaishampayan, Mamta Parikh, Yung Lyou, Peng Wang, Rahul Atul Parikh, Benjamin A. Teply, Robert Dreicer, Hamid Emamekhoo, M. Dror Michaelson, Christopher J. Hoimes, Tian Zhang, Sandy Srinivas, William Y. Kim, Glenn Liu, Paul Henry Frankel, Yuijie Cui, Primo Lucky N. Lara; City of Hope Comprehensive Cancer Center, Duarte, CA; Ar- thur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; University of Michigan Cancer Center, De- troit, MI; UC Davis Comprehensive Cancer Center, Sacramento, CA; University of Kentucky Markey Can- cer Center, Lexington, KY; University of Kansas Medical Center, Westwood, KS; University of Nebraska Medical Center, Omaha, NE; University of Virginia Cancer Center, Charlottesville, VA; University of Wis- consin Carbone Cancer Center, Madison, WI; Massachusetts General Hospital, Boston, MA; Duke Can- cer Center, Durham, NC; Duke University Medical Center, Durham, NC; Stanford University Medical Center, Stanford, CA; City of Hope Cancer Center, Duarte, CA; University of California, Sacramento, CA

Background: Cisplatin with gemcitabine (CG) remains the standard upfront chemotherapy regimen for metastatic urothelial cancer (mUC). Preclinical synergy was noted between cisplatin and berzosertib, a selective ATR inhibitor. The current study sought to determine if the combination of berzosertib and CG could improve clinical outcomes in mUC. Methods: An open-label, randomized study was conducted across 23 centers in the United States through the Experimental Therapeutics Clinical Trials Network of the National Cancer Institute. Key eligibility criteria included confirmed mUC, no prior cytotoxic therapy for metastatic disease, $ 12 months since perioperative therapy and eligibility for cisplatin based on standard criteria. Patients (pts) were randomized to receive either CG alone (control arm) or CG plus berzosertib (experimental arm). In the control arm, 70 mg/m2 of cisplatin was given on day 1 and gemcitabine at 1000 mg/m2 on days 1 and 8 of a 21-day cycle. In the experimental arm, 60 mg/m2 of cisplatin was given on day 1, gemcitabine at 875 mg/m2 on days 1 and 8 and berzosertib at 90 mg/m2 on days 2 and 9 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized; 41 pts received CG alone while 46 received CG with berzosertib. Visceral metastases were present in 49% of pts and 52%, 45% and 3% of pts were Bajorin risk 0, 1 and 2, respectively. Median PFS was 8.0 months for both arms (Bajorin risk adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 0.72-2.08). RR was 54%(4 CR, 21 PR) in the CG with berzosertib arm and 63% (4 CR, 22 PR) in CG alone arm (P = 0.66). Median OS was shorter with CG with berzosertib as compared to CG alone (14.4 versus 19.8 months; Bajorin risk adjusted HR 1.42, 95%CI 0.76-2.68). Notably higher rates of grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with CG plus berzosertib compared to CG alone. Higher rates of toxicity-related discontinuation were seen in the experimental arm (24% vs 15%), and the median cumulative cisplatin dose in the experimental arm was 250 mg/m2, as compared to 370 mg/m2 in the control arm (P < 0.001). Conclusions: No improvement in PFS was observed with the addition of berzosertib to CG, and a trend towards inferior survival was observed. These results suggest caution in reducing the starting dose of cytotoxic therapy to accommodate addition of a myelosuppressive agent, as in the experimental arm of this study. Clinical trial information: NCT02567409. Research Sponsor: U.S. National Institutes of Health.

4508 Oral Abstract Session

First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study.

Peter H. O’Donnell, Arjun Vasant Balar, Jacqueline Vuky, Daniel Castellano, Joaquim Bellmunt, Thomas Powles, Dean F. Bajorin, Petros Grivas, Noah M. Hahn, Elizabeth R. Plimack, Jin Zhi Xu, James Luke Godwin, Blanca Homet Moreno, Ronald De Wit; The University of Chicago, Chicago, IL; Perlmutter Cancer Center, NYU Langone Health, New York, NY; Oregon Health and Science University, Portland, OR; Hospital Universitario 12 de Octubre, Madrid, Spain; Beth Israel Deaconess Medical Cen- ter, Harvard Medical School, Boston, MA; Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Memorial Sloan Kettering Cancer Center, New York, NY; University of Wash- ington, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Balti- more, MD; Fox Chase Cancer Center, Philadelphia, PA; Merck & Co., Inc., Kenilworth, NJ; Erasmus MC Cancer Institute, Rotterdam, Netherlands

Background: Pembro was approvedfor cisplatin-ineligible patients with untreated advanced UC based on initial results of the phase 2 KEYNOTE-052 study (NCT02335424), which showed an ORR of 29%. Updated results after up to 5 years of follow-up are presented. Methods: KEYNOTE-052 is a single-arm, multi-site, open-label trial. Patients had advanced or metastatic UC, were cisplatin ineligible (criteria: ECOG PS 2, CrCl $30 to ~60 mL/min, grade $2 peripheral neuropathy/hearing loss, NYHA class III heart failure), and had not previously received chemotherapy for advanced/metastatic disease. Patients received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. PD-L1 status was determined by combined positive score (CPS, number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100); PD-L1–positive was CPS $10. The primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points were duration of response (DOR), OS, and safety. Results: Among 370 enrolled patients, median age was 74 y, 315 (85.1%) had visceral disease, and 43 (11.6%) completed 24 mo of therapy. Median time from enrollment to data cutoff (Sep 26, 2020) was 56.3 mo (range, 51.2-65.3) for all patients and 56.0 mo (range, 51.4- 65.2) for the 110 patients (29.7%) with CPS $10. Confirmed ORR for all patients was 28.9% (95% CI, 24.3-33.8); complete response, 9.5% (n=35); partial response, 19.5% (n=72). Median DOR was 33.4 mo (range, 1.4+ to 60.7+); 44.8% and 39.4% of patients had DOR $36 and $48 mo, (Kaplan- Meier estimates). Median OS was 11.3 mo (95% CI, 9.7-13.1); 24- and 36-mo OS rates were 31.5% and 22.1%. Patients with CPS $10 had better outcomes than patients with CPS <10 (Table). Treat- ment-related adverse events (AEs) occurred in 67.3% of patients; 21.1% of treatment-related AEs were grade $3, including 1 death (myositis). Conclusions: After up to 5 y of follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible patients with advanced UC. These effects were more pronounced in patients with CPS $10. Clinical trial information: NCT02335424. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Efficacy results. CPS <10 CPS $10 Total n=251 n=110 N=370

Confirmed ORR, % (95% CI) 20.7 (15.9-26.3)a 47.3 (37.7-57.0)a 28.9 (24.3-33.8)b DOR, median (range), mo 21.2 (1.6+ to 59.7+)a NR (1.4+ to 60.7+)a 33.4 (1.4+ to 60.7+)b DOR $36 months, % 34.4 57.6 44.8 DOR $48 months, % 27.4 57.6 39.4 OS, median (95% CI), mo 9.7 (7.6-11.5) 18.5 (12.2-28.5) 11.3 (9.7-13.1) OS at 36 months, % (95% CI) 15.4 (11.2-20.1) 35.8 (26.9-44.7) 22.1 (18.0-26.5) a52 responders. b107 responders; 3 had unknown PD-L1 status.

4509 Poster Discussion Session; Discussed in Poster Discussion Session

Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial.

Chung-Han Lee, Martin H Voss, Maria Isabel Carlo, Ying-Bei Chen, Eduard Reznik, Andrea Knezevic, Robert A Lefkowitz, Natalie Shapnik, Diana Tassone, Chloe Dadoun, Neil J. Shah, Colette Ngozi Owens, Deaglan Joseph McHugh, David Henry Aggen, Andrew Leonard Laccetti, Ritesh Kotecha, Darren R. Feldman, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; Columbia Universi- ty Medical Center, New York, NY; MD Anderson Cancer Center, Houston, TX

Background: Cabozantinib plus nivolumab (CaboNivo) improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell renal cell carcinoma (RCC). (Choueiri, abstract 6960, ESMO 2020) We report the results of a phase 2 trial of CaboNivo in patients (pts) with non-clear cell RCC. Methods: Pts had advanced non-clear cell RCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors, and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC; Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy. Correlative analyses by next generation sequencing were performed and to be presented. Results: A total of 40 pts were treated in Cohort 1, and 7 pts were treated in Cohort 2 (data cutoff: Jan 20, 2021). Median follow up time was 13.1 months (range 2.2 – 28.6). In Cohort 1, 26 (65%) pts were previously untreated, and 14 (35%) pts had 1 prior line: 10 (25%) received prior VEGF-targeted therapy and 8 (20%) received prior mTOR-targeted therapy. ORR for Cohort 1 was 48% (95% CI 31.5–63.9; Table). Median PFS was 12.5 months (95% CI 6.3–16.4) and median OS was 28 months (95% CI 16.3–NE). No responses were seen among 7 patients in Cohort 2 with chromophobe histology (Table). Grade 3/4 treatment emergent adverse events were consistent with that reported in the phase 3 trial; Grade 3/4 AST and ALT were 9% and 15%, respectively. Cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of pts, respectively. Conclusions: CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Clinical trial information: NCT03635892. Research Sponsor: Exelixis, BMS.

Cohort 1: Papillary, Unclassified, Translocation Associated Any Line (N = 40) 1st Line (N = 26) 2nd Line (N = 14) ORR 19 (48%) 14 (54%) 5 (36%) PR 19 (48%) 14 (54%) 5 (36%) SD 20 (50%) 12 (46%) 8 (57%) PD 1 (3%) 0 (0%) 1 (7%)

Cohort 2: Chromophobe Any Line (N = 7)

ORR 0 (0%) PR 0 (0%) SD 5 (71%) PD 1 (14%) Not Evaluable 1 (14%)

4510 Poster Discussion Session; Discussed in Poster Discussion Session

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-nave patients (pts) with advanced non-clear cell renal cell carcinoma (nccRCC) (HCRN GU16- 260-Cohort B).

Michael B. Atkins, Opeyemi Jegede, Naomi B. Haas, David F. McDermott, Mehmet Asim Bilen, Jessica Hawley, Jeffrey A. Sosman, Robert S. Alter, Elizabeth R. Plimack, Moshe Chaim Ornstein, 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; Abramson Cancer Center, University of Pennsylvania (ECOG-ACRIN), 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; Columbia Uni- versity Medical Center, New York, NY; Robert H. Lurie Cancer Center of Northwestern University, Chica- go, IL; John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; Fox Chase Cancer Center, Philadelphia, PA; Cleveland Clinic Cancer Center, Cleveland, OH; Yale School of Medicine, New Haven, CT; University of Illinois at Chicago, Chicago, IL; Brigham and Women’s Hospi- tal, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX

Background: The HCRN GU16-260 trial reported on the efficacy and toxicity of nivo monotherapy in treatment nave clear cell RCC (Cohort A) and the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy (Atkins JCO 2020.38.15_suppl.5006). Limited information is available on the effects of such an approach in pts with advanced nccRCC. Methods: Eligible pts with treatment-nave nccRCC 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 enrolling on Part B for correlative studies. Results: 35 pts with nccRCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 63 (range 35-84 years); 89% male. IMDC favorable 8 (23%), intermediate 18 (51%) and poor risk 9 (26%). Of the 35 pts 19 (54%) had papillary, 6 (17%) chromophobe and 10 (29%) unclassified histology. RECIST defined ORR was 5 of 35 (14.3%) [CR 2 (5.7%), PR 3 (8.6%)], SD 16 (45.7%), PD 14 (40.0%). Immune-related ORR was 8 of 35 (22.9%). RECIST ORR by histology was: papillary - 1/19 (5%); chromophobe - 1/6 (17%); unclassified - 3/10 (30%). 9 pts (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified, 1 papillary) responding. Median PFS was 4.0 (2.7, 4.3) mo. 21 pts remain alive. None of the responders have progressed or died. 28 pts (25 PD, 3 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 12 did not enroll due to symptomatic PD (2), grade 3-4 toxicity on nivo (3), or other including no biopsy tissue (7). In the 16 Part B pts, best response to nivo/ipi was: PR (1, 6%) – (unclassified/non-sarcomatoid); SD (7, 44%); PD (8, 50%). Grade 3 Treatment-related adverse events (TrAEs) were seen in 7/35 (20%) on nivo. Grade 3-5 TrAEs were seen in 7/16 (44%) on nivo/ipi with 1 pt experiencing sudden death. Correlative studies including PD-L1 status, WES and RNAseq are pending. Conclusions: Nivo monotherapy has limited activity in treatment nave nccRCC with most responses (4 of 5) seen in pts with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi was provided in 16 of 28 (57%) pts with PD/pSD on nivo monotherapy, with 1 response observed. Clinical trial information: NCT03117309. Research Sponsor: Bristol Meyers Squibb, Other Government Agency.

4511 Poster Discussion Session; Discussed in Poster Discussion Session

Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.

Cristina Suarez Rodriguez, James Larkin, Poulam M. Patel, Begon~a P. Valderrama, Alejo Rodriguez- Vida, Hilary Glen, Fiona Thistlethwaite, Christy Ralph, Gopalakrishnan Srinivasan, Maria Jose Mendez- Vidal, Abigail Carter, Charlotte Tyson, Aaron Prendergast, Kelly Mousa, Thomas Powles; Vall d’ Hebron University Hospital, Barcelona, Spain; Royal Marsden NHS Foundation Trust, London, United King- dom; Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Hospital Universitario Virgen del Roc�ıo, Seville, Spain; Hospital del Mar, Barcelona, Spain; Beatson West of Scotland Cancer Center, Glasgow, United Kingdom; The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom; St. James’s Institute of Oncology, University of Leeds, Leeds, United Kingdom; Mid Essex Hospital Services NHS Trust, Broomfield, United Kingdom; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Hospital Universitario Reina Sof�ıa, Co�rdoba, Spain; Barts ECMC, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom

Background: Savolitinib is a potent and selective MET inhibitor with activity in MET-driven papillary renal cancer (PRC). Durvalumab is a PD-L1 inhibitor which has been tested in combination with savolitinib in metastatic PRC with response rates of 29% (12/41). Here we describe the efficacy of this combination in MET-driven metastatic PRC. Methods: This single arm phase I/II trial explored durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in metastatic PRC, with a 4wk savolitinib run in. Biomarker analysis results were compared with responses to treatment as planned in the protocol. The analysis presented here focuses on those patients with MET DNA alterations (central analysis:- chromosome 7 gain/MET or HGF amplification/MET kinase domain mutations). Confirmed response rate (RR) (RECIST v1.1), progression-free survival (PFS), tolerability (CTCAE v4.03) and overall survival (OS) were analysed. Results: 42 patients were enrolled in the metastatic papillary cohort, of which 41 patients received treatment. The median follow up was 26.8 months. The confirmed RR was 29% (12/ 41) and median PFS was 4.9 months (95% CI 2.5-10.0). 14/41 (34%) of these patients had MET-driven disease. 71% (10/14) of MET-driven patients had not previously received systemic therapy and 7% (1/14) were PD-L1 positive. IMDC good, intermediate, and poor risk disease occurred in 36% (5/14), 57% (8/14), and 7% (1/14) of MET-driven patients respectively. Confirmed RR in MET-driven patients was 57% (8/14) with duration of response at 9.4 months (95% CI 3.9-Not reached [NR]). Median PFS and OS in MET-driven patients were 10.5 months (95% CI 2.9-15.7) and 27.4 months (95% CI 7.3- NR) respectively. No new safety signals were seen. Conclusions: The combination of savolitinib and durvalumab has clinical activity in MET-driven PRC. A randomised phase III study is planned based upon these data. Clinical trial information: NCT02819596. Research Sponsor: AstraZeneca.

4512 Poster Discussion Session; Discussed in Poster Discussion Session

Vorolanib, everolimus, and the combination in patients with pretreated metastatic renal cell carcinoma (CONCEPT study): A randomized, phase 3, double-blind, multicenter trial.

Xinan Sheng, Dingwei Ye, Ai-Ping Zhou, Xin Yao, Hong Luo, Zhisong He, Zengjun Wang, Yingchao Zhao, Zhigang Ji, Qing Zou, Chaohong He, Jianming Guo, Xinhua Tu, Ziling Liu, Benkang Shi, Ben Liu, Peng Chen, Qiang Wei, Fang-Jian Zhou, Jun Guo; Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China; Fudan University Shanghai Cancer Center, Shanghai, China; Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China; Tianjin Cancer Hospital, Tianjin, China; Department of Urology Sur- gery, Chongqing Cancer hospital, Chongqing, China; Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, Beijing, China; Jiangsu Province Hospital, Nanjing, China; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wu- han, China; Peking Union Medical College Hospital, Beijing, China; Department of Urology Surgery, Jiangsu Cancer Hospital, Nanjing, China; Department of Urology Surgery, Henan Cancer Hospital, Zhengzhou, China; Zhongshan Hospital, Fudan University, Shanghai, China; Jiangxi Province Tumour Hospital, Nanchang, China; The First Hospital of Jilin University, Changchun, China; Qilu Hospital of Shandong University, Jinan, China; The First Affiliated Hospital, Zhejiang University School of Medi- cine, Hangzhou, China; Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China; West China Hospital, Sichuan University, Chengdu, China; Sun Yat-sen University Cancer Center, Guang- zhou, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Bei- jing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China

Background: The combination of agents targeting both VEGF- and mTOR-mediated pathways has been investigated in renal cell carcinoma (RCC). We conducted the CONCEPT study to assess vorolanib, everolimus, or their combination as second-line treatment in Chinese patients (pts) with metastatic RCC. Methods: Pts with cytologically or histologically confirmed RCC who had disease progression after one prior VEGFR-TKI were eligible for participation in the study. They will be randomized by 1:1:1 ratio to receive matching placebo plus vorolanib or everolimus, or the combination. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results: Between November 2016 and June 2019, 399 pts (133 pts in each group) were enrolled. At the data cutoff (October 23, 2020), the median PFS in combination group was significantly longer than that in single-agent everolimus group (10.0 months [95% CI, 8.2-10.4] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.70 [95% CI, 0.52-0.94]; P = 0.0171), while the median PFS was similar between single-agent vorolanib group and single-agent everolimus group (6.4 months [95% CI, 4.6-8.3] vs. 6.4 months [95% CI, 4.7-8.3]; HR = 0.94 [95% CI, 0.69-1.24]; P = 0.6856). An objective response was achieved by 33 (24.8%) of 133 pts allocated vorolanib plus everolimus compared with 11 (8.3%) of 133 who received single-agent everolimus and 14 (10.5%) of 133 pts assigned single-agent vorolanib. OS was immature with no significant difference between pts assigned vorolanib plus everolimus (30.4 months [95% CI, 16.5-NE]) and those allocated single-agent everolimus (25.4 months [95% CI 19.4-NE]) or single-agent vorolanib (30.5 months [95% CI, 22.8-NE]). Treatment-related adverse event (TRAE) occurred in 132 (99%) of 133 pts with vorolanib plus everolimus, 127 (96%) of 133 pts with single-agent vorolanib and 131 (99%) of 133 pts with single-agent everolimus, respectively. Grade 3 or higher TRAEs occurred in fewer patients who received single-agent vorolanib (52 [39%]) than in those who received single-agent everolimus (71 [53%]) or vorolanib plus everolimus (96 [72%]). Safety profiles of both agents were consistent with previous studies. Conclusions: This is the first phase 3 study of combination of mTOR- and VEGF-targeted agents in second-line treatments. Vorolanib plus everolimus showed a PFS benefit for patients with metastatic RCC who have progressed after one previous VEGF-targeted therapy with a safe tolerance profile. Clinical trial information: NCT03095040. Research Sponsor: Betta pharmaceuticals.

4513 Poster Discussion Session; Discussed in Poster Discussion Session

First results of a randomized phase IB study comparing nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma.

Luis A Meza, Nazli Dizman, Paulo Gustavo Bergerot, Tanya B. Dorff, Yung Lyou, Paul Henry Frankel, Valerie Mira, Marian Llamas, Joann Hsu, Zeynep Busra Zengin, Nicholas Salgia, Sabrina Salgia, Jasnoor Malhotra, Neal Shiv Chawla, Alex Chehrazi-Raffle, John D Gillece, Lauren J Reining, Jeffrey M. Trent, Sarah K Highlander, Sumanta K. Pal; City of Hope Comprehensive Cancer Center, Duarte, CA; City of Hope, Duarte, CA; Univ of California Irvine, Orange, CA; City of Hope Cancer Center, Duarte, CA; City of Hope National Medical Center, Duarte, CA; Translational Genomics Research Institute, Flag- staff, AZ; Translational Genomics Research Institute, Phoenix, AZ; Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA

Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/ kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111. Research Sponsor: None.

4514 Poster Discussion Session; Discussed in Poster Discussion Session

Outcomes of patients who progressed while receiving avelumab + axitinib (A + Ax) and received subsequent treatment (Tx) in JAVELIN Renal 101.

Laurence Albiges, Martin H Voss, Brian I. Rini, Gwenaelle Gravis, Marc-Oliver Grimm, Paul D. Nathan, Georg A. Bjarnason, Yoshihiko Tomita, Konstantin Penkov, Bradley McGregor, Bo Huang, Despina Thomaidou, Mariangela Mariani, Alessandra Di Pietro, Toni K. Choueiri; Department of Cancer Medi- cine, Gustave Roussy Cancer Campus, University of Paris Sud, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Vanderbilt-Ingram Cancer Center, Nashville, TN; Institut Paoli-Calm- ettes, Aix-Marseille Universite�, Marseille, France; Department of Urology, Universitaetsklinikum Jena, Jena, Germany; Mount Vernon Cancer Centre, Northwood, United Kingdom; Sunnybrook Research In- stitute, Toronto, ON, Canada; Niigata University Graduate School of Medical and Dental Sciences, Nii- gata, Japan; Private Medical Institution Euromedservice, Saint-Petersburg, Russian Federation; Dana- Farber Cancer Institute, Boston, MA; Pfizer, Groton, CT; Pfizer Hellas, Athens, Greece; Pfizer srl, Milan, Italy; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background: There are limited data on the outcomes of patients receiving second-line (2L) therapy following immunotherapies plus tyrosine-kinase inhibitors in the first-line (1L). We describe the outcomes of patients with advanced renal cell carcinoma (aRCC) who had received 1L A + Ax in the phase 3 JAVE- LIN Renal 101 trial and went on to receive subsequent Tx. Methods: At the cutoff date for the third interim analysis (April 28, 2020), patients who received 1L A + Ax (n = 442) and received any subsequent lines of Tx were assessed. We report the overall survival (OS), progression-free survival on next-line systemic therapy (PFS2) per type of Tx, and duration of 2L Tx. Results: Anticancer drug therapies were received by 204/442 patients following A + Ax Tx. Of patients who received a follow-up anticancer drug Tx, 163/204 received a single agent (SA), and 41/204 received a combination Tx (CT) regimen. The most common 2L SA was cabozantinib (60/163), and the most frequent 2L CT was everolimus + lenvatinib (12/41). OS, PFS2, and duration of treatment (DOT) for the various subgroups are summarized in the table below. Analyses on additional subgroups will also be presented. Conclusions: In patients with aRCC who received 2L CT following 1L treatment with A + Ax, long-term OS and PFS2 were observed. Clinical trial information: NCT02684006. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

2L SA 2L SA cabozantinib 2L combination (n = 163) (n = 60) (n = 41)

18-mo OS (95% CI), % 75.8 (68.4, 81.7) 68.3 (55.0-78.5) 85.3 (70.2-93.1) 36-mo OS (95% CI), % 44.1 (35.9, 52.0) 36.9 (24.2-49.7) 63.4 (45.7-76.6) mOS (95% CI), mo 30.4 (24.7, NE) 26.2 (21.3, 34.1) NE (30.4 to NE) 18-mo PFS2 (95% CI), % 56.2 (48.0, 63.6) 52.6 (39.2-64.4) 65.9 (49.3-78.2) mPFS2 (95% CI), mo 20.4 (17.6, 23.0) 18.2 (14.7-22.6) 24.1 (17.7 to NE) mDOT (95% CI), mo 11.1 (8.4, NE) 19.1 (7.3 to NE) 12.9 (7.4 to NE) mOS, median overall survival; mPFS2, median progression-free survival on next-line therapy; mDOT, median duration of treatment; NE, not estimable.

4515 Poster Discussion Session; Discussed in Poster Discussion Session

Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and brain metastases: results from the CheckMate 920 trial.

Hamid Emamekhoo, Mark R Olsen, Bradley Curtis Carthon, Alexandra Drakaki, Ivor John Percent, Ana M. Molina, Daniel C. Cho, Johanna C. Bendell, Lucio N. Gordan, Arash Rezazadeh Kalebasty, Daniel J. George, Thomas E. Hutson, Edward Arrowsmith, Joshua Zhang, Jesus Zoco, Jennifer L. Johansen, David Leung, Scott S. Tykodi; University of Wisconsin School of Medicine and Public Health, Madison, WI; Oklahoma Cancer Specialists and Research Institute, Tulsa, OK; Emory University Hospi- tal Midtown, Atlanta, GA; University of California Los Angeles, Los Angeles, CA; Florida Cancer Special- ists, Port Charlotte, FL; Weill Cornell Medicine, New York, NY; New York University Langone Health, New York, NY; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; Florida Cancer Specialists North/Sarah Cannon Research Institute, Gainesville, FL; Norton Cancer Institute, Louisville, KY; Duke University Medical Center, Durham, NC; Texas A&M College of Medicine, Bryan, TX; Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Chattanooga, TN; Bristol Myers Squibb, Princeton, NJ; Syneos Health, Braine L’alleud, Belgium; Bristol-Myers Squibb, Princeton, NJ; Universi- ty of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA

Background: Combination therapy with nivolumab plus ipilimumab (NIVO+IPI) has demonstrated long- term efficacy and tolerability in patients with previously untreated advanced renal cell carcinoma (aRCC). Previous phase 3 clinical trials of patients with advanced or metastatic cancers have mostly excluded patients with brain metastases. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NI- VO+IPI treatment in patients with aRCC with a high unmet medical need. We present updated safety and efficacy results for the cohort of patients with aRCC of any histology and brain metastases from CheckMate 920 (NCT02982954). Methods: Patients with previously untreated advanced/metastatic aRCC of any histology, with asymptomatic brain metastases (not currently receiving corticosteroids or radiation), and Karnofsky performance status $ 70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks � 4 doses followed by NIVO 480 mg every 4 weeks for # 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade $ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 28 treated patients with brain metastases, 85.7% were men; median (range) age was 60 (38–87) years, and 14.3% had sarcomatoid features. With 24.5 months minimum follow-up of the 28 patients enrolled, median duration of therapy (range) was 3.4 (0.0–23.3) months for NIVO and 2.1 (0.0–3.3) months for IPI. No grade 5 im- AEs occurred. Grade 3–4 imAEs by category were diarrhea/colitis (7.1%), hypophysitis (3.6%), rash (3.6%), hepatitis (3.6%), and diabetes mellitus (3.6%). Of the 25 patients who were evaluable for ORR, the ORR was 32.0% (95% CI, 14.9–53.5). No patients achieved complete response, 8 achieved partial response, and 10 patients had stable disease. Median time to response (range) was 2.8 (2.4–3.0) months. Median duration (range) of response was 24.0 (3.9–not estimable [NE]) months; 4 of 8 responders remain without reported progression. Of 28 patients, 7 (25%) had intracranial progression. Median PFS (n = 28) was 9.0 (95% CI, 2.9–12.0) months. Median OS (n = 28) was still not reached (95% CI, 14.1 months–NE). Conclusions: In patients with previously untreated aRCC and brain metastases, a population with high unmet medical need that is often underrepresented in clinical trials, the approved treatment regimen of NIVO+IPI followed by NIVO for aRCC showed no new safety signals and continues to show encouraging antitumor activity with longer follow-up. Clinical trial information: NCT02982954. Research Sponsor: Bristol Myers Squibb.

4516 Poster Discussion Session; Discussed in Poster Discussion Session

Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis.

Jaleh Fallah, Haley Gittleman, Chana Weinstock, Erik Bloomquist, Elaine Chang, Daniel L. Suzman, Sundeep Agrawal, Amna Ibrahim, Shenghui Tang, Richard Pazdur, Julia A. Beaver, Laleh Amiri- Kordestani; U.S. Food and Drug Administration, Silver Spring, MD

Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non- metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating. Re- search Sponsor: None.

Prior No Prior Nephrectomy Nephrectomy Pts with stage IV RCC at initial dx (N = 849) (N = 523) (N = 326) HR (95% CI)

Age, mean (SD) 59.8 (9.3) 62.3 (10.3) Months from diagnosis to randomization, 3.4 (1.9, 8.0) 1.5 (1.0, 2.5) median (IQR) Death events N (%) 139/523 (27%) 134/326 (41%) Favorable risk 9/44 (20%) 10/37 (27%) 0.69 (0.28, 1.72) Intermediate risk 93/397 (23%) 80/200 (40%) 0.47 (0.35, 0.64) Poor risk 37/82 (45%) 44/87 (51%) 0.84 (0.54, 1.30) Median OS (unadjusted HR) NR (31.8, NR) 24.5 (19.6, NR) 0.53 (0.42, 0.68) Median OS (HR adjusted for age and prognostic NR (31.8, NR) 25.2 (19.8, NR) 0.59 (0.46, 0.75) risk group)

4517 Poster Discussion Session; Discussed in Poster Discussion Session

Neoadjuvant atezolizumab (A) with gemcitabine and cisplatin (GC) in patients (pts) with muscle-invasive bladder cancer (MIBC): A multicenter, single-arm, phase 2 trial.

Samuel Aaron Funt, Michael Lattanzi, Karissa Whiting, Hikmat A. Al-Ahmadie, Colleen Quinlan, Min Yuen Teo, Jeffrey Kamradt, Maged F. Khalil, Irina Ostrovnaya, Asia S. McCoy, Grace Hettich, Marwah Jihad, Edmund Folefac, William C. Huang, Dean F. Bajorin, Gopa Iyer, Bernard H. Bochner, Arjun Vasant Balar, Amir Mortazavi, Jonathan E. Rosenberg; Memorial Sloan Kettering Cancer Center, New York, NY; Hartford HealthCare Medical Group, Hartford, CT; Lehigh Valley Hosp Network, Allen- town, PA; The Ohio State University Comprehensive Cancer Center, Division of Medical Oncology, Co- lumbus, OH; NYU Langone Medical Center, New York, NY; Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY; Perlmutter Cancer Center at NYU Langone Health, New York, NY; Arthur G. James Cancer Hospital, Ohio State Uni- versity Wexner Medical Center, Columbus, OH

Background: Neoadjuvant GC is standard for pts with MIBC and can result in pathologic downstaging to non-MIBC ( < pT2N0) at radical cystectomy (RC), which correlates with improved survival. Based on the known activity of A in metastatic BC (mBC), we tested the combination of GC+A as neoadjuvant therapy for MIBC in a phase II trial (NCT02989584). Methods: Eligible pts with MIBC (cT2-T4aN0M0) received a single dose of A (1200 mg IV) and, two weeks later, began C (as either 70mg/m2 IV on D1 or 35 mg/m2 on D1,D8), G (1000 mg/m2 on D1,D8), and A (1200 mg IV on D8) every 21 days for 4 cycles followed by RC. Pts were also able to receive one additional dose of A 3 weeks after the last dose of A and prior to RC. The primary endpoint was proportion of pts with < pT2N0. Pts were considered not evaluable for the primary endpoint if they received less than 2 cycles due to withdrawal of consent or unrelated adverse events (AEs). Secondary endpoints included the proportion of pts with pT0N0, recurrence-free survival (RFS), and safety. We prespecified null and alternate < pT2N0 rates of 35% and 55%, respectively, with the null being rejected if at least 19 of 39 pts achieved < pT2N0. Pretreatment tumors underwent centralized PD-L1 staining (SP142; positive if $5% of immune cells). Results: Be- tween Feb 2018 and May 2020, 44 pts were enrolled from five institutions. Five pts were not evaluable (withdrawal of consent before C3, n = 4; unrelated AEs during C1, n = 1). Of the 39 evaluable pts (cT2N0 79%, cT3N0 18%, cT4N0 3%), 1 pt refused surgery and was considered a non-responder. The primary endpoint was met, with 27 of 39 pts (69%) < pT2N0 at RC, including 15 (38%) pT0N0. All pts achieving < pT2N0 are alive and disease free. The median RFS was not reached with a median follow-up of 16.7 months (range: 7.7-33.2). The median time from last dose of chemotherapy to RC was 7.8 weeks (range 5.1 – 17). The most common grade 3-4 treatment related AEs were due to chemotherapy and were neutropenia (36%), lymphopenia (16%), and anemia (11%). Possible grade 3-4 immune related AEs included 2 pts with asymptomatic grade 3 pancreatic enzyme elevation, 1 pt with grade 3 pancreatitis, and 1 pt with hepatitis requiring steroids. Only 4 of 39 (10%) pts had PD-L1 positive tumors, which is low compared to mBC (25% positive; Powles et al. Lancet 2017) and MIBC (40% positive; Powles et al. Nature Med 2019) cohorts also tested with the SP142 clone. All 4 pts with PD-L1 positive tumors achieved < pT2N0. Twelve of 12 (100%) non-responding pts were PD-L1 negative and 23 of 27 (85%) responding pts were PD-L1 negative (p = 0.3). Conclusions: Neoadjuvant GC+A is an effective and safe regimen for the treatment of pts with MIBC. The PD-L1 positivity rate was low compared with other studies and was not predictive of pathologic downstaging. Additional interrogation of the genomic and host immune factors mediating response and resistance to GC+A is ongoing. Clinical trial information: NCT02989584. Research Sponsor: Genentech/Roche, Conquer Cancer Foundation of the American Society of Clinical Oncology.

4518 Poster Discussion Session; Discussed in Poster Discussion Session

PrE0807: A phase Ib feasibility trial of neoadjuvant nivolumab (N) without or with lirilumab (L) in cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC).

Petros Grivas, Jun Yin, Vadim S Koshkin, Suzanne Cole, Rohit K. Jain, Robert Dreicer, Jeremy Paul Cetnar, Debasish Sundi, Benjamin Adam Gartrell, Matt D. Galsky, Colin M Sievers, Noah M. Hahn, Michael Anthony Carducci; University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA; Dana-Farber Cancer Institute, Boston, MA; University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; UT Southwestern Medical Center, Dallas, TX; Lee Moffitt Cancer Center, Tampa, FL; University of Virginia, Charlottesville, VA; Oregon Health and Science University, Portland, OR; Ohio State University, Columbus, OH; Monte- fiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; Division of Hematology and Medi- cal Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Seattle Cancer Care Alliance, Seattle, WA; Departments of Oncology and Urology, Johns Hopkins School of Medicine, Baltimore, MD; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD

Background: Neoadjuvant cisplatin-based chemotherapy (CT) prior to radical cystectomy (RC) improves overall survival (OS) in MIBC, but about half of pts are cisplatin-unfit or refuse it. Neoadjuvant immune checkpoint inhibitors can induce high pathologic complete response rate (ypT0N0). The combination of anti-PD-1 (N) and anti-KIR (L) is hypothesized to be safe and have significant activity based on the complementary and possibly synergistic roles in regulating adaptive and innate immune response in MIBC. Methods: This is a phase Ib multi-institutional trial in pts with localized MIBC treated with 2 neoadjuvant doses (4 weeks apart) of N alone (480 mg) in cohort 1 or N (480 mg) + L (240 mg) in cohort 2 prior to RC without adjuvant therapy (NCT03532451). Cohorts were enrolled sequentially and were not randomized. Key eligibility criteria included stage cT2-4aN0-1M0, $20% tumor content at TURBT and cisplatin-ineligibility (Galsky criteria) or refusal. Primary endpoint was safety manifested as rate of $G3 treatment related adverse events (TRAE) assessed in each cohort with CTCAE v5.0. Key secondary endpoints included the % of pts who had RC > 6 weeks after last neoadjuvant dose due to TRAE, CD8+ T cell density at RC, ypT0N0 and < ypT2N0 rates, CD8+ T cell density change between TURBT and RC, recurrence-free survival (RFS) and biomarkers in tumor tissue, blood and urine. Results: Among 43 pts enrolled (13 cohort 1, 30 cohort 2), median age was 75 (51-89), 67% were men, all had PS ECOG 0-1. Pts were cisplatin-ineligible due to impaired renal function (47%) and hearing loss (37%), while 14 % refused cisplatin. At baseline, 37 pts had cT2 stage, 2 had cN1 and 3 cNx. In cohort 1 and 2, 13 and 29 pts, respectively, completed intended neoadjuvant treatment, and 41/43 underwent RC (12/13 cohort 1, 29/30 cohort 2). One pt progressed to metastatic disease prior to RC (cohort 1) and 1 with- drew consent prior to being treated (cohort 2). Additionally, 1 patient was found to have cervical cancer at RC. Median time from last neoadjuvant dose to RC was 27 (95%CI: 24-29) days. There was no RC delayed > 6 weeks from treatment completion due to TRAE. G3 TRAEs occurred in 0% with N and 6.7% (90%CI 1.2-19.5%) in N+L (1: arthralgia, 1: gout, 2: hip pain) that all resolved. No G4/5 TRAEs occurred. Of 40 pts with MIBC and RC, ypT0N0 rates for N and N+L were 8% and 18%, while < ypT2N0 rates were 17% and 29%, respectively. Data on RFS and OS, and biomarker data were not yet mature. Conclusions: Neoadjuvant N alone and N+L combination prior to RC were safe, feasible and well tolerated in cisplatin-ineligible pts with MIBC, but ypT0N0 rates were unexpectedly low, especially with N alone. Two phase 3 trials (NCT03661320; NCT04209114) are evaluating the peri-operative role of N + chemotherapy +/- Linrodostat in cisplatin-fit and N +/- Bempeg in cisplatin unfit patients and are also assessing biomarkers. Clinical trial information: NCT03532451. Research Sponsor: Bris- tol Myers Squibb.

4519 Oral Abstract Session

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

Arjun Vasant Balar, Victor Moreno, Eric Angevin, Hui Kong Gan, Maria Vieito, Antoine Italiano, Riccardo Danielli, Erminia Massarelli, Frans Opdam, Michael Jon Chisamore, Debra Rogan, Xiao Ji, Courtney Henry, Catherine Elizabeth Ellis, Marc S. Ballas, Axel Hoos, Francesco Ricci; Perlmutter Cancer Center at NYU Langone Health, New York, NY; START Madrid-FJD, University Hospital Fundacion Jimenez Di- az, Madrid, Spain; Gustave Roussy Institut de Cance�rologie, Villejuif, France; Department of Medical Oncology, Austin Hospital, Melbourne, VIC, Australia; Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital (HUVH), Barcelona, Spain; Institut Bergonie�, Bordeaux, France; Universi- ty Hospital of Siena, Siena, Italy; City of Hope Cancer Center, Duarte, CA; The Netherlands Cancer Insti- tute, Amsterdam, Netherlands; Merck & Co., Inc., Kenilworth, NJ; GlaxoSmithKline, Research Triangle Park, Durham, NC; GlaxoSmithKline, Collegeville, PA; Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France

Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell deplet- ing mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNc, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, #6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–nave pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–nave pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received $2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received $1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for $9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade $3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–nave R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955. Research Sponsor: Study 204691 (NCT02723955) funded by GSK in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Ken- ilworth, NJ, USA.

4520 Poster Discussion Session; Discussed in Poster Discussion Session

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Analysis of clinical and genomic subgroups from the JAVELIN Bladder 100 trial.

Thomas Powles, Daniel P. Petrylak, Se Hoon Park, Srikala S. Sridhar, Claudia Caserta, Antoine Thiery Vuillemin, Hyo Jin Lee, Joaquim Bellmunt, Yoshiaki Yamamoto, Jeanny B. Aragon-Ching, Bo Huang, Keith A. Ching, Craig B. Davis, Alessandra Di Pietro, Yohann Loriot, Petros Grivas; Barts Cancer Insti- tute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew’s Hos- pital, London, United Kingdom; Yale Cancer Center, New Haven, CT; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea; Princess Margaret Cancer Centre, University Health Net- work, Toronto, ON, Canada; Medical Oncology Unit, Azienda Ospedaliera S. Maria, Terni, Italy; Univer- sity Hospital of Besancon, Dept. of Oncology, Besancon, France; Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, South Korea; Department of Medical On- cology, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, MA; Yamaguchi Uni- versity Hospital, Ube, Yamaguchi, Japan; Inova Schar Cancer Institute, Fairfax, VA; Pfizer, Groton, CT; Pfizer, New York, NY; Pfizer, La Jolla, CA; Pfizer srl, Milan, Italy; Gustave Roussy, INSERMU981, Uni- versite� Paris-Saclay, Villejuif, France; University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC that had not progressed on 1L platinum-based chemotherapy (HR, 0.69 [95% CI: 0.56, 0.86; 1-sided P= 0.0005]). We report post hoc analyses in previously unreported clinical and genomic subgroups. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin, and were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). The primary endpoint was OS, in all randomized pts and pts with PD-L1+ tumors (Ventana SP263 assay). In this exploratory analysis, we analyzed OS in disease stage and site subgroups, in pts with PD-L1+ tumors who received 1L gemcitabine + carboplatin, and in genomic subtypes (RNAseq whole-transcriptome profiling of tumor tissue) defined using data from The Cancer Genome Atlas (TCGA 2017). Interaction tests were not performed. Results: Prolonged OS was observed in the avelumab + BSC arm vs the BSC alone arm in pts with upper or lower tract tumors, metastatic or locally advanced (LA) and unresectable disease (prior to chemotherapy), and lymph node-only disease post-chemotherapy (Table). OS was also prolonged with avelumab + BSC in pts in PD-L1+ tumors who had received 1L gemcitabine + carboplatin, consistent with findings in the overall population. In genomic subtypes, the OS benefit for avelumab + BSC was apparent across TCGA subtypes except luminal. Conclusions: An OS benefit was seen for avelumab 1L maintenance + BSC vs BSC alone across subgroups of interest. Results are consistent with previously reported findings, further supporting avelumab 1L maintenance as a standard of care for pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

Pts, n Median OS (95% CI), months Avelumab + Subgroup BSC BSC Avelumab + BSC BSC HR (95% CI)

Upper tract 106 81 19.9 (15.3, NE) 17.4 (12.8, 0.89 (0.578, 33.0) 1.373) Lower tract 244 269 22.5 (19.0, 14.1 (11.8, 0.62 (0.477, 28.3) 17.9) 0.802) Metastatic disease 216 215 18.2 (13.8, 14.1 (11.7, 0.88 (0.678, 20.3) 17.3) 1.147) LA and unresectable disease 133 133 NE (25.3, NE) 17.9 (13.5, NE) 0.40 (0.265, 0.617) Lymph node-only disease* 48 39 NE (23.8, NE) NE (10.7, NE) 0.55 (0.259, 1.152) 1L gemcitabine + carboplatin, 74 54 24.0 (18.6, NE) 16.1 (9.4, NE) 0.67 (0.393, PD-L1+ tumor 1.137) TCGA: basal squamous 45 44 24.0 (16.0, NE) 17.9 (12.7, NE) 0.62 (0.326, 1.187) TCGA: luminal 30 25 23.8 (12.5, NE) NE (14.3, NE) 1.01 (0.403, 2.509) TCGA: luminal infiltrated 143 143 19.9 (18.2, NE) 14.3 (12.8, 0.68 (0.481, 18.6) 0.968) TCGA: luminal papillary 61 63 22.5 (18.2, 13.4 (10.1, NE) 0.63 (0.370, 26.0) 1.079)

NE, not estimable *Post-chemotherapy.

4521 Poster Session

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

Jonathan E. Rosenberg, Pablo Gajate, Rafael Morales-Barrera, Jae-Lyun Lee, Andrea Necchi, Nicolas Penel, Vittorina Zagonel, Mitchell Robert Sierecki, Weichao Bao, Yinghui Zhou, Peter Ellinghaus, Randy F. Sweis; Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY; Medical Oncology Department, Ramo�n y Cajal University Hospital, Ma- drid, Spain; Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Auto�noma de Barcelona, Barcelona, Spain; Department of Oncology, Asan Medical Center, 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; Bayer HealthCare Pharmaceuticals, Inc., Cambridge, MA; Bayer AG, Berlin, Germany; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL

Background: Rogaratinib (R) is a novel pan-FGFR inhibitor that showed promising efficacy and safety in a Phase I trial in pts with advanced solid tumors, including UC, with FGFR1-3 mRNA overexpression. The Phase Ib/II FORT-2 study (NCT03473756) of R plus atezolizumab (A) in pts with first-line cisplatin-ineligible, FGFR-positive, advanced/metastatic UC previously identified a maximum tolerated dose of R 600 mg twice daily (BID) plus A (1200 mg every 3 weeks). We report updated safety, efficacy, and the recommended Phase II dose (RP2D) for combination therapy from the Phase Ib study. Methods: Pts with cisplatin-ineligible, locally advanced/metastatic UC with FGFR1/3 mRNA overexpression detected by RNA in situ hybridization of archival tissue (RNAscope) received oral R 600 mg BID plus A 1200 mg on day 1 of a 21-day cycle. Archival tissue was examined for programmed cell-death ligand 1 (PD-L1) protein expression levels, FGFR3-activating mutations via a targeted Illumina NGS panel, and FGFR fusions via an Archer fusion plex assay. Primary objectives were safety, tolerability, and determination of the RP2D. Results: 26 pts (enrolled May 25, 2018 to Nov 25, 2020) were treated; 89% were male, median age was 76 years (range 47-85), 58% had an ECOG performance status of 1, and 77% displayed low or absent (negative or non-detectable) PD-L1 expression (combined positive score < 10%). Com- mon treatment-emergent adverse events (TEAEs) included diarrhea (n = 17, 65%; 1 grade [G] 3), hyperphosphatemia (n = 15, 58%; all G1 or 2), and nausea (n = 11, 42%; 1 G3). The most common G3/4 TEAEs were elevated lipase without pancreatitis (n = 5, 19%), elevated amylase (n = 3, 12%), and rash and syncope (n = 2, 8% each). TEAEs led to interruption/reduction/discontinuation of R in 69%/46%/ 19% of pts. R-related unique TEAEs were hyperphosphatemia in 15 pts (58%) and retinal pigment epi- thelium detachment in 1 pt (4%). G5 events occurred in 3 pts (12%), unrelated to treatment. 13 of 24 evaluable pts (54%) had an objective response (OR) per RECIST v1.1. The disease control rate was 83%, including 3 pts (13%) with a complete response (CR), 10 (42%) with a partial response (PR), and 7 (29%) with stable disease. Median duration of response was not reached. OR rate was 56% (2 CRs and 7 PRs) in the 16 pts with tumors having low/negative PD-L1 protein and FGFR3 mRNA overexpression without mutation. The RP2D for R+A was 600 mg BID. Conclusions: First-line treatment with the RP2D of R+A achieved favorable clinical efficacy and tolerability in pts with cisplatin-ineligible, metastatic UC characterized by high FGFR1/3 mRNA expression and generally low/negative PD-L1 expression. Encouraging efficacy was observed regardless of PD-L1 expression or FGFR3 mutation status, warranting future investigation. Clinical trial information: NCT03473756. Research Sponsor: Funding: Bayer AG. Writing support: Complete HealthVizion.

4522 Poster Session

Phase I/II study to evaluate the efficacy of TAS0313, a cancer peptide vaccine, combined with pembrolizumab for locally advanced or metastatic urothelial carcinoma.

Ryuji Matsumoto, Junji Yonese, Takashi Kawahara, Hideaki Miyake, Nobuaki Matsubara, Hiroji Uemura, Masatoshi Eto, Haruhito Azuma, Wataru Obara, Akito Terai, Satoshi Fukasawa, Shigetaka Suekane, Hiroyuki Nishiyama; Department of Renal and Genitourinary Surgery, Hokkaido University, Sapporo, Japan; Department of Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Urology, University of Tsukuba, Tsukuba, Japan; Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan; Division of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan; Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan; Department of Urology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Japan; Department of Urology, Iwate Medical University, Yaha- ba, Japan; Department of Urology, Kurashiki Central Hospital, Kurashiki, Japan; Prostate Center and Di- vision of Urology, Chiba Cancer Center, Chiba, Japan; Department of Urology, Kurume University School of Medicine, Kurume, Japan

Background: TAS0313 is a cancer vaccine cocktail comprising three long peptides with a total of 12 cytotoxic T lymphocyte epitope peptides. We performed a multicenter phase I/II study including patient (pts) with urothelial carcinoma (UC) treated using TAS0313 combined with pembrolizumab. Methods: The enrolled pts with a histologically or cytologically confirmed diagnosis of urothelial carcinoma had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. For cohort C1, eligible pts were those who received platinum-based chemotherapy and were nave to immune checkpoint inhibitors (ICI). For cohort C2, eligible pts were those who progressed onto treatment with pembrolizumab. TAS0313 (9 mg) was subcutaneously administered on days 1, 8, and 15 of cycles 1 and 2 and day 1 of cycle 3 or later in 21-day cycles, while pembrolizumab (200 mg) was intravenously administered on day 1 of cycle 1 or later in 21-day cycles until disease progression or unacceptable toxicity occurred. Tumor response was evaluated using the RECIST v1.1 criteria. The TAS0313 target antigen-specific immunoglobulin G (IgG) was analyzed before and after treatment. The primary objective was to evaluate efficacy, while the secondary objective was to evaluate the safety and tolerability of the combination therapy. Results: As of 10th September 2020, 46 pts with a median age of 71.0 and 65.5 years, in cohort C1 (n = 36) and cohort C2 (n = 10), respectively, have been treated with the combination therapy. For cohorts C1 and C2, the median follow-up duration was 6.47 and 6.95 months, while the median treatment duration was 4.86 and 2.56 months, respectively. In cohort C1, the overall response rate and disease control rate (DCR) were 33.3% (16.7% complete response, 16.7% partial response) and 66.7% (33.3% stable disease), respectively. The median progression-free survival was 5.0 months, median overall survival (OS) was not yet reached, and 1-year OS rate was 74.3%. The best overall response in cohort C2 was stable disease in 5/10 pts, resulting in a DCR of 50.0%. Increase in IgG level was detected after treatment in both the cohorts. The most common adverse drug reactions (ADRs) of TAS0313 and/or pembrolizumab were grade 1–2 injection site reactions and pyrexia. There were no grade 3–5 ADRs with an incidence of $10%. Conclusions: This study confirmed the tolerability, safety, and immune response of TAS0313 combined with pembrolizumab in cohorts C1 and C2. We observed promising efficacy in pts with ICI-nave UC in cohort C1; however, in pts with pembrolizumab-refractory UC in cohort C2, limited efficacy was seen. Therefore, a large-scale randomized study is needed to clarify the benefits of TAS0313 combined with ICI in ICI-nave pts. Clinical trial information: 183824. Research Sponsor: Taiho Pharmaceutical Co., Ltd.

4523 Poster Session

Circulating tumor cell-driven use of neoadjuvant chemotherapy in patients with muscle- invasive bladder cancer.

Nick Beije, Ingeborg Elisabeth de Kruijff, Joep de Jong, Sjoerd O. Klaver, Peter de Vries, Rens Jacobs, Diederik Meindert Somford, Ed te Slaa, Toine van der Heijden, Johannes Alfred Witjes, Laurent Fossion, Egbert Boeve, John van der Hoeven, Harm H.E. van Melick, Carl J Wijburg, John W.M. Martens, Ronald De Wit, Jaco Kraan, Stefan Sleijfer, Joost L. Boormans; Department of Medical Oncol- ogy, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands; Eras- mus MC Cancer Institute, Rotterdam, Netherlands; Maasstad Ziekenhuis, Rotterdam, Netherlands; Zuyderland MC, Heerlen, Netherlands; Canisius-Wilhelmina Ziekenhuis, Nijmegen, Netherlands; Isala Hospital, Zwolle, Netherlands; Radboud University Medical Centre, Nijmegen, Netherlands; Depart- ment of Urology, Radboud University, Nijmegen, Netherlands; Maxima MC, Eindhoven, Netherlands; Franciscus Gasthuis & Vlietland, Rotterdam, Netherlands; Reinier de Graaf Gasthuis, Delft, Nether- lands; Sint Antonius Ziekenhuis, Nieuwegein, Netherlands; Department of Urology, Robotic Surgery, Rijnstate Hospital, Arnhem, Netherlands; Erasmus MC Cancer Institute, Department of Medical Oncol- ogy and Cancer Genomics Netherlands, Rotterdam, Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands; Erasmus University Medical Center, Rotter- dam, Netherlands

Background: International guidelines for the treatment of non-metastatic muscle-invasive bladder cancer (MIBC) recommend neoadjuvant chemotherapy (NAC), which, however, is underutilized in practice. We hypothesized that the absence of circulating tumour cells (CTCs), an established prognostic marker in MIBC, may identify patients with such a favourable prognosis that NAC may be withheld. Methods: The CirGuidance study included adults with clinical stage T2-T4aN0-N1M0 muscle-invasive urothelial carcinoma of the bladder who were fit to undergo radical cystectomy. CTCs were enumerated using the CellSearch system. CTC-negative patients (no CTCs detectable) underwent radical surgery without NAC; CTC-positive patients ($1 detectable CTCs) were advised to receive NAC followed by radical surgery, but NAC could be withheld at the discretion of the treating physician. The primary endpoint was the two-year overall survival (OS) in the CTC-negative group, analysed in the intention-to-treat population. The prespecified criterion for trial success was a two-year OS of minimally 75% (95% confidence interval (CI) ±5%) in the CTC-negative group. Results: Of 315 patients screened for eligibility, 273 were enrolled in the study. The median age was 69 years; the median follow-up was 36 months. The two-year OS in the CTC-negative group was 69.5% (n = 203; 95% CI 62.6%-75.5%); in the CTC-positive group it was 58.2% (n = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality (hazard ratio (HR) 1.61, 95% CI 1.05-2.45, p = 0.03) and disease relapse (HR 1.87, 95% CI 1.28-2.73, p = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC- positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48), with a two-year OS of 74.8% (95%CI 49.5%-88.8%) versus 52.0% (95% CI 37.2%-65.0%), respectively. Conclusions: The two-year OS in the CTC-negative group did not meet the prespecified criterion for trial success. However, given the trial population’s advanced age and high rate of non-cancer related mortality, the benefit of NAC is likely to be limited in CTC-negative MIBC patients. CTC enumer- ation at the moment of diagnosis could aid in the decision to prescribe neoadjuvant chemotherapy for a muscle-invasive bladder cancer patient as a criterion in addition to clinical characteristics. Clinical trial information: NL3954. Research Sponsor: Erasmus MC Grants & Cancer Genomics Netherlands.

4524 Poster Session

Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors: An updated analysis of EV-201 Cohort 2.

Bradley Alexander McGregor, Arjun Vasant Balar, Jonathan E. Rosenberg, Michiel Simon Van Der Heijden, Se Hoon Park, Jae-Lyun Lee, Takahiro Kojima, Michael Roger Harrison, Elisabeth I. Heath, Mark N. Stein, Yohann Loriot, Andrea Necchi, Joyce Leta Steinberg, Shang-Ying Liang, Janet Trowbridge, Daniel P. Petrylak, Evan Y. Yu; Dana-Farber Cancer Institute, Boston, MA; Perlmutter Can- cer Center at NYU Langone Health, New York, NY; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Samsung Medical Center, Seoul, South Korea; Asan Medical Cen- ter and University of Ulsan College of Medicine, Seoul, South Korea; University of Tsukuba, Tsukuba, Japan; Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC; Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, De- troit, MI; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY; Department of Cancer Medicine, Gustave Roussy, Universite� Paris-Saclay, Villejuif, France; Fondazione IRCCS Isti- tuto Nazionale dei Tumori, Milan, Italy; Astellas, Northbrook, IL; Seagen Inc., Bothell, WA; Yale Cancer Center, New Haven, CT; Fred Hutchinson Cancer Research Center and University of Washington, Seat- tle, WA

Background: Cisplatin (cis)-ineligible, platinum-naive patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) who progress on/after anti-PD-1/L1 treatment (tx) have a poor prognosis and few tx options. Enfortumab vedotin (EV), a Nectin-4-directed antibody-drug conjugate, demonstrated overall survival (OS) benefit in pts with la/mUC who previously received anti-PD-1/L1 tx and platinum-containing chemotherapy (EV-301). EV-201 (NCT03219333) is a pivotal, single-arm, 2-cohort (C) study. C2 enrolled cis-ineligible pts with prior anti PD-1/L1 tx and no prior platinum for la/mUC. Re- sults of the C2 primary analysis were previously presented. In this updated analysis, with 3 additional mo of follow-up (f/u), all responders were followed for $6 mo after onset of response. Methods: Pts received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. The primary endpoint was confirmed objective response rate (ORR) per RECIST 1.1 by blinded independent central review (BICR). Second- ary endpoints were duration of response (DOR), progression-free survival (PFS), OS, and safety. Results: 91 pts were enrolled and 89 treated in C2. Median (m) age was 75 y (range: 49-90). Pts were cis-ineligible at baseline, primarily due to CrCl < 60 mL/min (78%). Primary tumor site was upper tract in 43%, and 79% had visceral mets, including 24% with liver mets. As of 04 Dec 2020 (data cut-off), m f/u was 16.0 mo and m tx duration was 6.0 mo (range: 0.3-24.6). Confirmed ORR per BICR was 51% (95% confidence interval [CI] 39.8-61.3), including 22% complete response (CR) among treated pts. mDOR was 13.8 mo (95% CI 6.4-not reached). mPFS and mOS were 6.7 mo (95% CI 5.0-8.3) and 16.1 mo (95% CI 11.3-24.1), respectively. All-grade and grade (G) $3 tx-related adverse events (TRAEs) were reported in 97% and 55% of pts, respectively. Most common all-grade TRAEs were alopecia (51%), peripheral sensory neuropathy (49%), and fatigue (34%). For TRAEs $G3, each preferred term occurred in < 10% pts. TRAEs of interest included skin reactions (61% all grade, 17% $G3), peripheral neuropathy (56% all grade, 8% $G3), and hyperglycemia (10% all grade, 6% $G3). Four deaths were previously reported as tx related by investigators: 3 events #30 d of first EV dose (acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome) and 1 > 30 d of last EV dose (pneumonitis). Conclusions: Efficacy and safety in this updated analysis of EV-201 C2 are consistent with the primary analysis. The majority of platinum-naive, cis-ineligible la/mUC pts who progressed on/ after anti-PD-1/L1 tx responded to EV, with 22% achieving CR and mDOR exceeding a year. PFS and OS continue to be encouraging in this elderly population, with no new safety signals. These data show the potential for EV as a non-platinum option for cis-ineligible pts following anti-PD-1/L1 tx. Clinical trial information: NCT03219333. Research Sponsor: Astellas Pharma Global Development, Inc. and Seagen Inc.

4525 Poster Session

Avelumab first-line (1L) maintenance plus best supportive care (BSC) versus BSC alone for advanced urothelial carcinoma (UC): Analysis of time to end of next-line therapy in JAVELIN Bladder 100.

Petros Grivas, Se Hoon Park, Eric Voog, Evgeny Kopyltsov, Howard Gurney, David Queiroz Borges Muniz, Frederic Rolland, Anne Birgitte Als, Begon~a P. Valderrama, Jing Wang, Nuno Matos Costa, Robert J Laliberte, Alessandra Di Pietro, Thomas Powles, Joaquim Bellmunt; University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA; Sungkyunkwan University Samsung Medical Center, Seoul, South Korea; Centre Jean Bernard Clinique Victor Hugo, Le Mans, France; State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russian Federation; Department of Clinical Medicine, Macquarie University, Sydney, Australia; Fundacao Fac- uldade de Medicina/Instituto do Cancer do Estado de Sa~o Paulo–ICESP, Sao Paulo, Brazil; Institut de Cancerologie de l’Ouest, Nantes, France; Aarhus University Hospital, Aarhus, Denmark; Department of Medical Oncology, Hospital Universitario Virgen del Roc�ıo, Seville, Spain; Pfizer, Cambridge, MA; Pfizer, Porto Salvo, Portugal; Pfizer srl, Milan, Italy; Barts Cancer Institute, Experimental Cancer Medi- cine Centre, Queen Mary University of London, St Bartholomew’s Hospital, London, United Kingdom; Department of Medical Oncology, Beth Israel Deaconess Medical Center; Harvard Medical School, Bos- ton, MA

Background: Avelumab 1L maintenance is approved in various countries for patients (pts) with advanced UC that has not progressed with 1L platinum-based chemotherapy based on significantly prolonged overall survival (OS) seen with avelumab + BSC vs BSC alone in the phase 3 JAVELIN Bladder 100 trial. OS was prolonged despite the more frequent use of subsequent anticancer therapy in the BSC alone arm (42.3% in the avelumab + BSC arm vs 61.7% in the BSC alone arm), most commonly with immune checkpoint inhibitors (6.3% vs 43.7%, respectively). To further characterize the efficacy benefits of avelumab 1L maintenance, we report a post hoc analysis of the time to end of next-line therapy (for any reason) in the randomized trial population. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without disease progression with 4 to 6 cycles of 1L gemcitabine + either cisplatin or carboplatin. The primary endpoint was OS from randomization, assessed in 2 populations: all pts and pts with PD-L1+ tumors (Ventana SP263). In this exploratory analysis, time from randomization until end of next-line treatment received after first progression (due to death or discontinuation) was assessed. Results: A total of 700 pts were randomized 1:1 to avelumab 1L maintenance + BSC or BSC alone. Among all randomized pts, time to end of next-line therapy was prolonged in the avelumab + BSC arm vs the BSC alone arm (Table). Time to end of next-line therapy was also longer in the avelumab + BSC arm vs the BSC alone arm in pts with PD-L1+ tumors (n = 358) or PD-L1À tumors (n = 270). Conclusions: Pts who received avelumab 1L maintenance + BSC had prolonged time to end of next-line treatment compared with those who received BSC alone, irrespective of PD-L1 status. These data provide further evidence of the efficacy of a maintenance approach with avelumab in pts with advanced UC that has not progressed with 1L platinum-based chemotherapy. Clinical trial information: NCT02603432. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

Median time to end of next-line Patients, n therapy (95% CI), months Avelumab + BSC Hazard ratio BSC alone Avelumab + BSC BSC alone (95% CI) All randomized pts 350 350 14.8 (12.0, 9.2 (8.0, 0.67 (0.545, 17.0) 11.5) 0.815) Pts with PD-L1+ tumors 189 169 18.1 (12.5, 9.0 (7.9, 0.61 (0.451, 19.2) 12.5) 0.818) Pts with PD-L12 tumors 139 131 11.9 (9.1, 15.4) 9.3 (7.6, 0.76 (0.560, 12.8) 1.035)

4526 Poster Session

Large cell neuroendocrine carcinoma of the urothelial tract (LNEC): The MSKCC experience.

Brendan John Guercio, Jatin Gandhi, Min Yuen Teo, Michael Lattanzi, Samuel Aaron Funt, David Henry Aggen, Ying-Bei Chen, Samson Fine, Eugene J. Pietzak, Bernard H. Bochner, Guido Dalbagni, Michael F. Berger, David B. Solit, Satish Tickoo, Victor E. Reuter, Dean F. Bajorin, Jonathan E. Rosenberg, Hikmat A. Al-Ahmadie, Gopa Iyer; Memorial Sloan Kettering Cancer Center, New York, NY; Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histo- pathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (

LNEC (includes LNEC with concurrent SNEC) vs SNEC-only cases. Characteristics LNEC (n = 43) SNEC-only (n = 192) Age, median (range) 69 (44-84) 68 (38-94) % Male 74% 81% % M0 at diagnosis 81% 74% NAC (14 LNEC, 62 SNEC-only) Platinum + etoposide (64%) Platinum + etoposide (81%) Platinum + gemcitabine (29%) Platinum + gemcitabine (10%) MVAC (7%) MVAC (5%) Other chemo/unknown (5%) Other treatments (tx) for M0 pts Surgery alone (30%) Surgery alone (32%) (20 LNEC, 72 SNEC-only) Surgery + adjuvant chemo (10%) Surgery + adjuvant chemo (18%) RT ± chemo (35%) RT ± chemo (18%) Chemo only (5%) Chemo only (19%) Other/unknown (20%) Other/unknown (13%) First-line tx for M1 pts (8 LNEC, 46 Platinum + etoposide (50%) Platinum + etoposide (70%) SNEC-only) Platinum + taxane (13%) Platinum + taxane (2%) IO + chemo (13%) MVAC (2%) IO alone (13%) Other chemo (17%) No systemic tx (13%) No systemic tx (9%)

4527 Poster Session

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC) in the JAVELIN Bladder 100 trial: Subgroup analysis by duration of treatment-free interval (TFI) from end of chemotherapy to start of maintenance.

Srikala S. Sridhar, Thomas Powles, Yohann Loriot, Miguel A. Climent Dura�n, Shilpa Gupta, Norihiko Tsuchiya, Aristotelis Bamias, Andrea Ardizzoni, Anders Ulle�n, Bo Huang, Nuno Matos Costa, Robert J Laliberte, Alessandra Di Pietro, Cora N. Sternberg, Petros Grivas; Princess Margaret Cancer Center, Uni- versity Health Network, Toronto, ON, Canada; Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St Bartholomew’s Hospital, London, United Kingdom; Gus- tave Roussy, INSERMU981, Universite� Paris-Saclay, Villejuif, France; Instituto Valenciano de Oncolog�ıa, Valencia, Spain; Department of Hematology and Medical Oncology, Cleveland Clinic, Cleve- land, OH; Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan; Alexan- dra General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi, Bologna, Italy; Department of Pelvic Cancer, Genitourinary Oncology Unit, Karolinska University Hospital, Solna, Sweden; Pfizer, Groton, CT; Pfizer, Porto Salvo, Portugal; Pfizer, Cambridge, MA; Pfizer srl, Milan, Italy; Englander Insti- tute for Precision Medicine, Weill Cornell Medicine, Hematology/Oncology, New York, NY; University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Background: The phase 3 JAVELIN Bladder 100 trial, which enrolled patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy, showed that maintenance therapy with avelumab + best supportive care (BSC) significantly prolonged overall survival (OS) compared with BSC alone (hazard ratio [HR], 0.69 [95% CI: 0.56, 0.86; 1-sided P= 0.0005]). However, the optimal timing for starting avelumab after completing 1L chemotherapy is unknown. In this post hoc analysis, we report efficacy by duration of the TFI from completion of 1L chemotherapy. Methods: In the JAVELIN Bladder 100 trial (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without disease progression following 4 to 6 cycles of 1L platinum-containing chemotherapy. Pts were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350) after a TFI of 4 to 10 weeks from the last dose of chemotherapy. In this exploratory analysis, subgroups with a TFI of 4 to < 6 weeks ( < 42 days), 6 to < 8 weeks (42 to < 56 days), or 8 to 10 weeks ($56 days) were evaluated. Results: In the avelumab + BSC and BSC alone arms, the TFI was 4 to < 6 weeks in 143 and 158 pts, 6 to < 8 weeks in 109 and 80 pts, and 8 to 10 weeks in 98 and 110 pts, respectively. Baseline characteristics in these subgroups were generally well balanced between arms. For both arms combined, however, the TFI 4 to < 6 weeks subgroup vs the other 2 subgroups included more pts with visceral metastases (57.8% vs 54.0% and 50.0%), an objective response with 1L chemotherapy (76.4% vs 69.3% and 68.3%), and an ECOG performance status of 1 (44.5% vs 33.3% and 35.6%). OS was prolonged with avelumab + BSC vs BSC alone in all subgroups; the HR was 0.76 (95% CI: 0.546, 1.059) in the TFI 4 to < 6 weeks subgroup (median OS, 19.9 months [95% CI: 16.3, 25.3] vs 13.5 months [95% CI: 11.7, 17.4]), 0.64 (95% CI: 0.404, 1.021) in the TFI 6 to < 8 weeks subgroup (median OS, 26.1 months [95% CI: 19.9, not estimable] vs 21.0 months [95% CI: 10.7, not estimable]), and 0.70 (95% CI: 0.468, 1.035) in the TFI 8 to 10 weeks subgroup (median OS, 20.1 months [95% CI: 13.8, not estimable] vs 14.1 months [95% CI: 11.7, 19.6]). Conclusions: In patients with advanced UC that had not progressed with 1L platinum-containing chemotherapy, avelumab 1L maintenance prolonged OS irrespective of the TFI assessed in this study (4-10 weeks), supporting this new treatment strategy as a standard of care. Differences in duration of TFI were likely related to individual patient- and disease- specific characteristics or logistics and did not impact the OS benefit observed with avelumab 1L maintenance. Clinical trial information: NCT02603432. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

4528 Poster Session

Study EV-103: Update on durability results and long term outcome of enfortumab vedotin + pembrolizumab in first line locally advanced or metastatic urothelial carcinoma (la/mUC).

Terence W. Friedlander, Matthew I. Milowsky, Mehmet Asim Bilen, Sandy Srinivas, Rana R. McKay, Thomas W. Flaig, Christopher J. Hoimes, Arjun Vasant Balar, Elizabeth Henry, Daniel P. Petrylak, Carolyn Sasse, Ritesh S. Kataria, Yao Yu, Anne-Sophie Carret, Jonathan E. Rosenberg; University of Cal- ifornia San Francisco Medical Center, San Francisco, CA; University of North Carolina, Lineberger Com- prehensive Cancer Center, Chapel Hill, NC; Winship Cancer Institute of Emory University, Atlanta, GA; Stanford University Medical Center, Stanford, CA; University of San Diego San Diego, San Diego, CA; University of Colorado Comprehensive Cancer Center, Aurora, CO; Duke Cancer Institute, Duke Univer- sity, Durham, NC; Perlmutter Cancer Center at NYU Langone Health, New York, NY; Loyola University, Chicago, IL; Yale Cancer Center, New Haven, CT; Astellas Pharma, Inc., Northbrook, IL; Merck, Kenil- worth, NJ; AbbVie, Inc, North Chicago, IL; Seagen Inc., Bothell, WA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY

Background: Significant unmet need remains for people with cisplatin-ineligible (cis-ineligible) locally advanced or metastatic urothelial carcinoma (la/mUC). In the first-line (1L) setting, carboplatin-based regimens have demonstrated poor tolerability, modest objective response rate (ORR) and limited durability. PD-1/PD-L1 inhibitors demonstrate durable responses; however, only a minority of pts achieve a response (ORR 24-29%). Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE) to targeted tumor cells expressing Nec- tin-4. EV has shown an overall survival benefit versus chemotherapy in previously treated la/mUC. Pre- clinical studies show that ADCs utilizing MMAE can induce immunogenic cell death and may enhance antitumor immunity. Clinical data suggests the combination of EV + pembrolizumab (P) may have the potential to induce greater antitumor activity compared to either agent alone. Preliminary data on EV + P was previously presented, and the FDA granted breakthrough therapy designation to EV + P for the treatment of pts with 1L cis-ineligible la/mUC in Feb 2020. Here we report updated data with 24.9 months median follow-up. Methods: This multi-cohort EV-103 study (NCT03288545) evaluates the safety/activity of EV + P (Dose Escalation/Cohort A). This report highlights 1L cis-ineligible pts treated with 3-week cycles of EV 1.25 mg/kg (Days 1, 8) and P (Day 1). Endpoints include safety/tolerability, investigator response per RECIST v1.1, DOR, PFS, and OS. Results: As of 13 Oct 2020, the median follow-up for the 45 1L la/mUC pts (median age 69 yrs [51-90]) was 24.9 months. The median number cycles of EV + P was 9 (range 1-34). The most common treatment-related adverse events were peripheral sensory neuropathy (56%, 4% $G3), fatigue (51%, 11% $G3), and alopecia (49%). There was one death reported as possibly related to study treatment (multiple organ dysfunction syndrome) per investigator assessment. Confirmed ORR is 73.3% (95% CI: 58.1, 85.4) including 17.8% CR and an ORR of 57.1% (8/14) in pts with liver metastasis. The median DOR was 25.6 months (95% CI: 8.3, -). Fifty- three percent of the responders had DOR at 24 months. Additionally, the DCR is 93.3%, the median PFS is 12.3 months (95% CI: 8.0, -), and the median OS is not reached. The OS rate at 24 months is 56.3% (95% CI: 39.8, 69.9). Conclusions: EV + P, a platinum-free option, continues to demonstrate promising activity with a durable response profile in 1L cis-ineligible pts with la/mUC. The safety profile is manageable and stable over time with no new safety signals. Cohort K of EV-103 in cis-ineligible pts with la/mUC is actively randomizing pts to EV monotherapy or EV + P to evaluate the contribution of each agent. Clinical trial information: NCT03288545. Research Sponsor: Astellas and Seagen Inc.

4529 Poster Session

Effect of Bacillus Calmette-Guerin (BCG) exposure on severity of COVID-19 infection: A COVID-19 and Cancer Consortium (CCC19) study.

Andrew Lachlan Schmidt, Ziad Bakouny, Chris Labaki, Babar Bashir, Jessica M. Clement, Natasha Catherine Edwin, Daniel Blake Flora, Jennifer Girard, Shuchi Gulati, Clara Hwang, Chinmay Jani, Gilberto Lopes, Ruben A. Mesa, Gil Redelman-Sidi, Sanjay Mishra, Jeremy Lyle Warner, Toni K. Choueiri; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Dana Farber Cancer Institute - (Individuals), Boston, MA; Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA; University of Connecticut Health Center Carole and Ray Neag Comprehensive Cancer Center, Farmington, CT; Cleveland Clinic, Cleveland, OH; Univ Hosp/Univ of Cincinnati, Cincinnati, OH; University of Michigan Rogel Cancer Center, Michigan, MI; University of Cincinnati Medical Center, Cincinnati, OH; Henry Ford Health System, Detroit, MI; Mount Auburn Hos- pital-Harvard Medical School, Cambridge, MA; University of Miami Miller School of Medicine, Miami, FL; UT Health San Antonio, San Antonio, TX; Memorial Sloan Kettering Cancer Center, New York, NY; Vanderbilt University Medical Center, Nashville; Vanderbilt-Ingram Cancer Center, Nashville, TN; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background: Oncology patients experience more severe disease outcomes from COVID-19 infection than the general population. BCG is a live bovine tuberculosis bacillus with immunotherapeutic effects in urothelial cancers; it is also used as vaccination against Mycobacterium tuberculosis in parts of the world. As BCG vaccination has been associated with broad protection against viral pathogens, BCG exposure through vaccination or intravesical therapy may modulate host immunity and reduce the severity of COVID-19 infection. We report the effect of BCG exposure on COVID-19 severity in oncology patients from the CCC19 registry. Methods: The CCC19 registry (NCT04354701) was used to identify patients with prior BCG exposure. Cohort A received intravesical treatment for bladder carcinoma, and cohort B received prior BCG vaccination. Each cohort was matched 3:1 to non-BCG-exposed controls by age, sex, race, primary cancer type, cancer status, ECOG performance status (PS) and calendar time of COV- ID-19 infection. The primary endpoint was COVID-19 severity reported on an ordinal scale (uncomplicated, hospitalized, admitted to ICU +/- ventilated, died within 30 days) of patients exposed to prior BCG compared to matched non-exposed controls. 2-sided Wilcoxon rank-sum tests were used. Results: As of 6-Feb-2021 we included 124 patients with BCG exposure, 68 patients with bladder carcinoma who had received intravesical BCG (Cohort A), and 64 cancer patients with prior BCG vaccination (Co- hort B). Median age was 76 years, IQR 69-83 (Cohort A) and 67 years, IQR 62-74 (Cohort B). Bladder cancer pts were predominately male (78%) vs 55% for Cohort B. Patients with PS 2+ were uncommon, 18% in Cohort A and 16% in Cohort B. COVID-19 illness severity was no different in patients exposed to prior intravesicular BCG (p=0.87). COVID-19 illness severity was no different in patients exposed to prior intradermal BCG vaccination (p=0.60). Conclusions: Despite this being the largest such cohort reported to date, we failed to demonstrate an association of prior BCG exposure with modulation of severity of COVID-19 illness. Prospective trials evaluating the protective effect of BCG vaccination are ongoing and will add further insight into the effect of BCG on COVID-19 illness. Research Sponsor: P30 CA068485.

COVID-19 severity and relationship to BCG exposure. Uncomplicated Hospitalized ICU +/- Ventilated 30 day mortality COVID-19 severity (n, %) (n, %) (n, %) (n, %) P value

Intravesicular 0.87 Cohort A BCG Exposed(n, %) 25 (37) 20 (29) 8 (12) 14 (21) BCG Non-exposed (n, %) 60 (31) 78 (41) 18 (9) 36 (19) Intradermal 0.60 Cohort B BCG Exposed (n, %) 21 (33) 27 (42) 5 (8) 9 (14) BCG Non-exposed (n, %) 57 (30) 67 (39) 18 (11) 29 (17)

4530 Poster Session

Fibroblast growth factor receptor alteration (FGFRa) status and progression outcomes of patients with advanced or metastatic urothelial cancer (mUC).

Sarah Fleming, Dina Gifkins, Waleed Shalaby, Jianjun Gao, Philip Rosenberg, Christopher Gaj, Albert Crawford, Grace L. Lu-Yao, Vittorio Maio, Arlene O. Siefker-Radtke; Janssen Research & Development, LLC, Raritan, NJ; Janssen Research & Development, Raritan, NJ; Janssen Scientific Affairs, LLC, Hor- sham, PA; The University of Texas MD Anderson Cancer Center, Houston, TX; Research Partnership, Horsham, PA; Jefferson College of Population Health, Philadelphia, PA; Sidney Kimmel Cancer Center at Jefferson Health, Philadelphia, PA

Background: FGFRa appear in approximately 15% of cases of mUC. Data on whether FGFRa in mUC have a prognostic impact or predictive benefit for particular treatments have been limited by small sample sizes. The objective of this study was to evaluate the association between tumor FGFRa and clinical outcomes of patients with advanced UC or mUC regardless of therapy type and status. Methods: A con- venience sample of oncologists and urologists across the United States provided patient level data on 400 patients with stage IIIb or IV UC via a standardized questionnaire over a 1-month period (August 17, 2020 – September 20, 2020). Study design enriched for FGFRa by requiring physicians to provide $1 FGFRa patient record. The questionnaire included physician characteristics, patient demographic information, FGFR status, therapy given, response, and clinical and radiographic measures of progression. Patient records were eligible for inclusion if they were identified and treated during July 1, 2017, to June 30, 2019. Cox proportional hazards models were used to estimate adjusted risk of disease progression by FGFR status. Results: A total of 104 physicians (58.7% medical oncologists, 31.7% hema- tologic oncologists, and 9.6% urologic oncologists) contributed 414 patient records Overall, 73.9% of the patients were male and the average age was 64.5 years (SD ±10.6). Median follow-up was 15 months. Of the 414 patients, 218 (52.7%) had FGFRa and 196 (47.3%) had FGFR wild-type (FGFRwt) mUC. Of the 218 patients with FGFRa, 47.2% were treated with front-line chemo, 27.5% with a programmed death-ligand 1 inhibitor (PD-L1), 11.5% with chemo + PD-L1, and 13.8% with other treatments. Of the 196 FGFRwt patients, 63.2% were treated with front-line chemo, 21.9% with PD-L1, 12.2% with chemo + PD-L1, and 2.6% with other treatments. There was no difference in response or progression status for those receiving front-line chemo (HR, 1.15; 95% CI, 0.86-1.55). Among 97 patients (55 FGFRa and 42 FGFRwt) who received PD-L1 alone as front-line therapy, those who had FGFRa had an adjusted risk of progression 2 times higher than their FGFRwt counterparts (HR, 2.12; 95% CI, 1.13-4.00). Conclusions: Patients with FGFRa mUC progressed earlier than FGFRwt patients treated with front-line PDL-1 inhibitors; however, there was no difference in progression in patients treated with chemo based upon FGFR status. This real-world study using a survey design efficiently gen- erated a relatively large FGFRa dataset, mitigating a core limitation of other studies assessing the patient population with FGFRa. Further work is warranted to validate these results and determine the optimal strategy for treating the patient with FGFRa mUC. Gene expression profiling of FGFRa mUC samples from clinical trials will help determine the potential impact of subtype or other features that may associate with benefit from therapy. Research Sponsor: Janssen Research & Development, LLC.

4531 Poster Session

Safety evaluation of combined PD-1+CTLA4 inhibition concurrently to chemoradiotherapy (CRT) in localized muscle invasive bladder carcinoma (MIBC).

Ben-Max de Ruiter, Jons Wouter van Hattum, Theo Maria De Reijke, Jorg Reinier Oddens, Maarten C.C.M. Hulshof, Adriaan Dirk Bins; Amsterdam UMC, University of Amsterdam, Department of Urology, Cancer Center Amsterdam, Amsterdam, Netherlands; Department of Radiotherapy, Amster- dam University Medical Centers, location VUMC, Amsterdam, Netherlands; Amsterdam UMC, Universi- ty of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Meibergdreef 9, Amsterdam, Netherlands

Background: Neoadjuvant nivolumab (nivo) + ipilimumab (ipi) prior to radical cystectomy showed efficacy in localized MIBC. The safety of PD-1 and PDL-1+CTLA4 inhibition concurrent with CRT in localized MIBC has not been assessed. We present the first clinical trial data on concurrent 3 doses of q4w nivo 480mg (cohort1) and concurrent 4 doses of q3w nivo 3mg/kg + ipi 1kg/mg (nivo3+ipi1, cohort2) in combination with Mitomycin C/Capecitabin (MMC/Cape) CRT. Methods: We report the first 2 cohorts of a phase 1b, EC approved, study with nivo only or nivo3+ipi1 added to MMC/Cape CRT. CRT consists of MMC i.v. on day 1 with Cape 750mg/m2 on days of radiotherapy. Radiotherapy schedule comprises a 20x2Gy whole bladder irradiation with a simultaneous tumorboost of 20x0.75Gy. Patients with MIBC, T2-4N0-1, ECOG performance status <2 were included. A dose escalation scheme, with a staggered enrollment is used. The first 10 patients received nivo 480mg on week 1, 5, 9. Cohort2 of 10 patients received nivo3+ ipi1 at week 1, 4, 7 and 10. Relevant severe Adverse Events (AEs) were registered as Dose Limiting Toxicity (DLT) when they occurred within 6 weeks after start of treatment. Clinical efficacy is evaluated by cystoscopy and CT at week 12 and 24. Results: Both cohorts enrolled 10 patients. Me- dian age was 68 [IQR 61-75] and 70 [IQR 66-75] years in cohort1 and 2, respectively. In cohort1 no patients experienced DLT. No dose reductions were applied. In cohort2, 2 patients experienced DLT, 1 trombocytopenia (grade 4) and 1 asystole (grade 5). 50% of patients did not receive all 4 q3w nivo3+i- pi1 infusions, due to AEs. Table 1 reports an overview of AEs. In cohort2 6 SAE’s occurred in 3 patients. Median follow up is 71 [IQR 59-86] and 30 weeks [IQR 12-45] in cohort1 and 2, respectively. 1year OS and DFS is 100% in cohort1. Conclusions: Concurrent 3 doses nivo 480mg q4w added to MMC/ Cape based CRT is feasible with a favorable toxicity profile and shows promising efficacy in MIBC patients. An escalated regimen with 4 doses nivo 3mg/kg + ipi 1mg/kg q3w concurrent to CRT shows acceptable toxicity. Cohort3 with ipi 3mg/kg and nivo 1mg/kg is enrolling. Clinical trial information: NCT03844256. Research Sponsor: Cure for Cancer Foundation & Dutch Cancer Society.

Nivo only Nivo3 + ipi1 AE All grade, n (%) Grade $3, n (%) All grade, n (%) Grade $3, n (%)

Total patients with AEs 9 (90) 1 (10) 10 (100) 3 (30) GI Diarrhea 7 (70) 1 (10) 6 (60) 1 (10) Duodenal ulcer 2 (20) 1 (10)** Vomiting 2 (20) 1 (10) 1 (10) Nausea 3 (30) 2 (20) Abdominal pain 1 (10)

Renal & urinary UTI 1 (10) 1 (10)** AKI Urgency 1 (10) 1 (10) 2 (20)

Blood Anemia 2 (20) 1 (10) 1 (10) Hyponatremia 1 (10) 1 (10)** Hypercalcemia 1 (10) 1 (10)** Thrombocytopenia 1 (10) 1 (10) Cardiac Asystole 1 (10) 1 (10)*** Auto-immune Colitis 1 (10) 1 (10)** Hepatitis 1 (10) 1 (10) Pancreatitis Endocrine Adrenal insuff. 1 (10) Hypothyroidism 1 (10) 1 (10) hyperthyroidism 1 (10) Skin Pruritus 2 (20) Rash 2 (20) Nervous system Dysgeusia 1 (10) 3 (30) Ataxia 1 (10) General Fatigue 6 (60) 6 (60)

CTCAE scored AE, * = Grade V ** = SAE.

4532 Poster Session

Pembrolizumab (pembro) versus investigator’s choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial.

Joaquim Bellmunt, Andrea Necchi, Ronald De Wit, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang, Miguel A. Climent Dura�n, Daniel P. Petrylak, Toni K. Choueiri, Winald R. Gerritsen, Howard Gurney, David I. Quinn, Stephane Culine, Cora N. Sternberg, Jin Zhi Xu, Blanca Homet Moreno, James Luke Godwin, Dean F. Bajorin, David J. Vaughn, Yves Fradet; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Vita-Salute San Rafaele University and IRCCS San Raf- faele Hospital, Milan, Italy; Erasmus MC Cancer Institute, Rotterdam, Netherlands; Asan Medical Cen- ter and University of Ulsan College of Medicine, Seoul, South Korea; University of California San Francisco, San Francisco, CA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Fundacio�n In- stituto Valenciano de Oncolog�ıa, Valencia, Spain; Smilow Cancer Hospital, Yale New Haven Health, New Haven, CT; Dana-Farber Cancer Institute, Boston, MA; Radboud University Medical Center, Nijme- gen, Netherlands; Westmead Hospital and Macquarie University, Sydney, NSW, Australia; USC Norris Comprehensive Cancer Center, Keck Medicine of USC, Los Angeles, CA; Ho^pital Saint-Louis, Paris, France; Weill Cornell Medicine, New York, NY; Merck & Co., Inc., Kenilworth, NJ; Memorial Sloan Ket- tering Cancer Center, New York, NY; Abramson Cancer Center, Penn Medicine, Philadelphia, PA; CHU de Que�bec-Universite� Laval, Que�bec City, QC, Canada

Background: Pembro was approved for the treatment of locally advanced or metastatic UC that progressed during or after a platinum-containing regimen, based on the phase 3 KEYNOTE-045 (NCT02256436) trial that showed significantly improved OS with use of pembro. Updated results are presented from KEYNOTE-045 after >5 y of follow-up since the last patient (pt) was randomized. Meth- ods: KEYNOTE-045 is a randomized, multisite, open-label, phase 3 trial. Pts with histologically or cytologically confirmed UC, progression after platinum-containing chemo, ECOG PS 0-2, measurable disease per RECIST v1.1, and #2 prior lines of systemic therapy were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Primary end points are PFS (RECIST v1.1, blinded central review) and OS. ORR and duration of response (DOR) were key secondary end points. Results: As of Oct 1, 2020, among 542 enrolled pts, median time from randomization to data cutoff was 62.9 mo (range 58.6-70.9). 9.4% and 0% of pts in the pembro and chemo arms, respectively, completed 2 years of therapy. Median OS was longer for pembro vs chemo (10.1 vs 7.2 mo; HR, 0.71 [95% CI, 0.59-0.86]) overall and in pts with CPS $10 (8.0 vs 4.9 mo; HR, 0.59 [95% CI, 0.40- 0.86]). For pts with CR or PR, median OS was not reached and 16.4 (95% CI, 11.3-25.1) mo in the pembro and chemo arms, respectively (Table). OS rates at 48 mo were 16.7% for pembro and 10.1% for chemo; 60-mo OS rates were 14.9% and 8.7%, respectively. OS benefit with pembro vs chemo continued regardless of age, ECOG PS, prior therapy, liver metastases, baseline hemoglobin, time from last chemo, histology, risk factors, and chemo choice. Median DOR for responders was longer for pembro vs chemo (29.7 mo [1.6+ to 60.5+] vs 4.4 mo [1.4+ to 63.1+]), and a greater proportion of responses lasted $48 mo (40.9% vs 28.3%, Kaplan-Meier) and $60 mo (32.8% vs 28.3%). ORR was higher for pembro vs chemo (21.9% vs 11.0%; difference 10.8% [95% CI, 4.6-17.0]). Fewer pts given pembro vs chemo experienced a treatment-related AE of any grade (62.0% vs 90.6%) or grade $3 (16.9% vs 50.2%). Conclusions: After 5 y, pembro maintained clinically meaningful OS benefit vs chemo in pts with locally advanced or metastatic UC that progressed during or after platinum-based chemo. Pts who responded to pembro experienced a durable response (median >2 y). Clinical trial information: NCT02256436. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

5-y survival and OS by best response. Pembrolizumab Chemo

5-y survival, % (95% CI) 14.9 (10.9-19.6) 8.7 (5.6-12.7) OS by best response, median (95% CI), mo CR or PR n=59 NR n=30 16.4 (11.3-25.1) SD n=47 16.4 (13.7-18.9) n=92 10.5 (8.8-12.6) PD n=129 6.2 (4.9-7.6) n=90 4.7 (3.8-5.5)

4533 Poster Session

Stool microbiota profiling of patients with muscle invasive bladder cancer receiving neoadjuvant pembrolizumab.

Filippo Pederzoli, Irene Locatelli, Michela Riba, Marco Bandini, Daniele Raggi, Laura Marandino, Elisa Alchera, Patrizia Giannatempo, Paolo Provero, Dejan Lazarevic, Roberta Luciano�, Andrea Gallina, Alberto Briganti, Francesco Montorsi, Andrea Salonia, Andrea Necchi, Massimo Alfano; Vita-Salute San Raffaele University, Milan, Italy; IRCCS Ospedale San Raffaele, Urological Research Institute, Milan, Italy; IRCCS Ospedale San Raffaele, Center for Omics Sciences, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Istituto Oncologico della Svizzera Italiana (IOSI), Bellinzona, Swit- zerland; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, IA, Italy; IRCCS Ospedale San Raf- faele, Department of Pathology, Milan, Italy; Ospedale Regionale di Lugano, Lugano, Switzerland

Background: Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic urothelial carcinoma (UC) and promising activity in muscle-invasive and non-muscle invasive UC of the bladder. Recent studies revealed the immunomodulatory effect of the gut microbiota on ICIs efficacy across several malignancies, identifying microbial signatures associated with response to therapy and effective antitu- moral T-cell activity. In our study, we aimed to study the stool microbiota in patients undergoing neoadjuvant immunotherapy (IO) for muscle-invasive UC. Methods: Pre-IO stools were available for analysis from 42 patients enrolled in the PURE-01 trial (NCT02736266), testing 3x200mg flat-dose pembrolizumab every 21 days before radical cystectomy (RC). All samples were collected using Stool Nucleic Acid Collection and Preservation Tubes (Norgen) and extracted using the Stool DNA Isolation Kit (Norgen), according to the manufacturer’s protocol. 16s sequencing was performed using standardized protocols at the internal facility, using mock communities and DNA standards (ZymoBIOMICS) to control for extraction and sequencing contaminations. A QIIME-based bioinformatic pipeline was used for microbiome analyses. Complete response (CR) to neoadjuvant IO was defined as ypT0N0 at pathologic examination on radical cystectomy specimens, while partial response (PR) was defined as < ypT2N0. Concomitant antibiotic therapy (ABT) was defined as any ATB between 30 days prior to the first pembrolizumab dose and the planned RC. Results: In our study sample, 23 patients responded to IO (21 CR + 2 PR). Overall median age was 68.5 years. Among responders, 20 (87%) patients had a smoking history (vs. 15 (79%) in non-responders) and 4 (17%) underwent concomitant ABT (vs. 6 (32%) in non-responders). Alpha-diversity assessed by richness (ACE index) was higher in responders vs. non-responders (p = 0.05), while no significant diversity was found. Beta-diversity did not show clear clustering of responders vs. non-responders. LEfSe identified 16 bacterial taxa with a linear discrimi- nant analysis (LDA) score $2.5 that were differently enriched between responders and non-responders. Among them, we identified the genus Sutterella enriched in responders (p = 0.02), while the species Ruminococcus bromii was enriched in non-responders (p = 0.02). Conclusions: Our analyses showed an association between response to neoadjuvant-IO and microbiome composition in an intention-to-cure population with muscle invasive UC. We found bacterial taxa specifically enriched in responders or non- responders using pre-therapy stool specimens. The identified taxa may be tested in future studies as potential indicators of therapy outcomes, alone or in combination with other IO biomarkers. These results may also inspire new strategies of gut microbiota modulation to promote response in immunotherapy-refractory patients. Research Sponsor: None.

4534 Poster Session

RC48-ADC combined with toripalimab, an anti-PD-1 monoclonal antibody (Ab), in patients with locally advanced or metastatic urothelial carcinoma (UC): Preliminary results of a phase Ib/II study.

Li Zhou, Huayan Xu, Xieqiao Yan, Zhihong Chi, Chuanliang Cui, Lu Si, Bixia Tang, Lili Mao, Bin Lian, Xuan Wang, Siming Li, Xue Bai, Jun Guo, Xinan Sheng; Key Laboratory of Carcinogenesis and Transla- tional Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China; Department of Renal Cancer and Melanoma, Pe- king University Cancer Hospital & Institute, Beijing, China

Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts). Anti-PD-1 Abs have durable antitumor effect for mUC especially in PD-L1 positive patients. The combination may have synergistic antitumor effect. This phase 1b/II study evaluated the safety and activity of RC48-ADC combined with toripalimab in mUC. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/ kg toripalimab with the traditional 3+3 escalation design. In expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS stratified by HER2 and PD-L1 expression. HER2 positivity was determined by IHC and in situ hybridization (ISH). PD-L1 expression was tested with IHC 22C3 pharmDx assay. Re- sults: As of 8 Jan 2021 (data cutoff), 14 mUC pts (9 males, median age 66 y [52-76]) were enrolled. Most pts were systemic treatment nave (57%) in the locally advanced or metastatic setting. The primary site was in upper tract UC in 50%; 50% had visceral metastases (mets), including 36% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 28%, and 43% PD-L1 CPS$10. A total of 36 pts is anticipated to be enrolled by Apr 2021. No dose limiting toxicity was reported and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, 10/14 patients were evaluable for response, with 8 PR, 1 SD (tumor shrinking), and 1 PD. The objective response rate (ORR) was 80%, and disease control rate (DCR) was 90%. All responsive patients have durable efficacy and are still on treatment. Follow-up continues for PFS and OS. Most common treatment-related AEs were grade 1-2, including aminotransferase level increased (7/14, 50%), weight loss (6/14, 43%), alopecia (6/14, 43%), asthenia (4/14, 29%), anemia (3/14, 21%), leukopenia (21%), peripheral sensory neuropathy (21%), hypothyroidism (21%), blood triglycerides increased (21%), and creatine phosphokinase increase (21%). One pt had G3 intestinal obstruction attributed to study drug and went back to treatment after recovery. Conclusions: RC48-ADC in combination with toripalimab had a good tolerance and promising anti-tumor activity in pts with mUC. Further evaluation of safety and efficacy is ongoing. Clinical trial information: NCT04264936. Research Sponsor: Remegen.

4535 Poster Session

Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who receive second-line immunotherapy.

Benjamin Miron, Elizabeth A. Handorf, Kevin Zarrabi, Matthew R. Zibelman, Pooja Ghatalia, Fern Anari, Elizabeth R. Plimack, Daniel M. Geynisman; Fox Chase Cancer Center, Philadelphia, PA; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA

Background: Treatment of advanced urothelial carcinoma (mUC) has improved following approvals of PD-1/PD-L1 inhibitors. Platinum chemotherapy remains the standard-of-care in the first-line (1L). Cis- platin (Cis) regimens are accepted to be superior to carboplatin (Carbo) regimens for patients (pts) who are Cis-eligible. We sought to evaluate if differences in efficacy of 1L Cis vs. Carbo have meaningful impact on overall survival (OS) in the era of second-line (2L) immunotherapy (IO). Methods: We conducted a retrospective, observational cohort study to compare OS for pts treated with 1L Cis or Carbo combined with gemcitabine (Gem) followed by 2L IO using patient-level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Pts included were diagnosed with mUC between 9/1/2015 and 9/15/2020. 2L IO was defined as single-agent atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab. OS was calculated from start of 1L and 2L therapy and compared using Kaplan-Meier curves. Time to 2L IO was calculated from start of 1L to start of IO. Adjusted OS was calculated using multivariable Cox regression models, adjusting for age, gender, race, ECOG performance status, primary site, prior cystectomy, smoking status, and year of diagnosis. Results: A total of 1882 pts were included, 924 (49.1%) received Gem/Cis and 958 (50.9%) received Gem/Carbo in 1L. A similar percentage of pts did not receive any 2L therapy following Gem/Cis (46.4%) or Gem/Carbo (46.0%). Our analysis focused on the 780 pts (41.4%) who received 2L IO—381 after Gem/Cis and 399 after Gem/Carbo. Median follow-up time for the group was 35 months (mo). Pts in the Gem/Cis cohort were younger, had better performance status and lower incidence of upper tract disease (Table). OS from start of 1L therapy was numerically longer in pts who received Gem/Cis compared to Gem/Car- bo on unadjusted (median 18.0 v 16.2 mo, p = 0.06) and adjusted analyses (HR = 0.83, 95% CI 0.69- 1.00, p = 0.055) but neither result was statistically significant. Time to 2L IO was longer for pts receiving Gem/Cis (6.5 mo) vs Gem/Carbo (5.5 mo, p = 0.008). Survival time on 2L IO did not differ significantly by 1L regimen (Gem/Cis 8.0 mo vs Gem/Carbo 8.2 mo p = 0.36). Conclusions: Real world data suggests that in pts with mUC who are able to receive second-line IO, the choice of first-line platinum chemotherapy may not provide a distinguishable OS benefit. Despite methodologic limitations of this data, a greater focus in discussions with patients on toxicity associated with cisplatin vs carboplatin may be warranted. Research Sponsor: None.

Gem/Cis (N = 381) Gem/Carbo (N = 399) p-value Median age at mUC dx [SD] 69 [41-84] 73 [31-85] < 0.001 ECOG PS 0.084 0 145 (48.5%) 132 (41.9%) 1 128 (42.8%) 154 (48.9%) 2 20 (6.7%) 27 (8.6%) Primary Site 0.025 Bladder 292 (76.6%) 274 (68.7%) Renal Pelvis 57 (15.0%) 80 (20.1%) Ureter 28 (7.3%) 44 (11.0%)

4536 Poster Session

Use of neoadjuvant chemotherapy in elderly patients with muscle invasive bladder cancer: A population-based study, 2006 to 2017.

Natasza Posielski, Nathan Jung, Hannah Koenig, On Ho, John Paul Flores, Christopher Porter; Virginia Mason Medical Center, Seattle, WA

Background: Current guidelines recommend neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC). NAC has been shown to confer a survival benefit across all ages. Yet, many elderly patients are not offered NAC due to concern regarding physiologic reserve and postoperative complications. Our objective was to evaluate age-based disparity in treatment and outcomes of MIBC. Methods: Using the National Cancer Database, we identified patients with MIBC from 2006-2017. First, use of different treatments, RC, RC and adjuvant chemotherapy, RC with NAC (optimal treatment), chemo-radiation, and no treatment, was compared between age groups. A second analysis was performed in the cohort of elderly patients, $70, undergoing cystectomy. Propen- sity weighting was used to compare peri-operative and mortality outcomes in those who received NAC vs. no NAC. Results: In 70,911 patients with non-metastatic MIBC, use of RC with NAC was lower in patients $70, 7.2 vs. 20.9%, p<0.001 (Table). Patients receiving RC with NAC were younger, had private insurance, higher high school completion rate and median income, shorter distance to hospital, lower CCI, diagnosis in recent years, and higher stage disease. NAC use was also associated with pelvic lymph node dissection (OR 4.55, p<0.001). In patients $70 undergoing RC, NAC was associated with shorter length of stay (LOS) (8.5 vs 9.6 days, p<0.001), decreased 30-day readmission (8.6 vs 10.6%, p=0.003), lower 30- and 90-day mortality (1.9 vs 3.6%, p=0.01 and 4.9 vs 7.7%, p=0.004, respectively), and better overall survival (OS) (43.8% vs. 37.5%, p<0.001). Multivariate logistic regression found NAC as an independent predictor of shorter LOS, lower 30-and 90-day mortality, and improved OS. Conclusions: Despite increased omission of NAC in patients $70, NAC is not associated with worse peri-operative outcomes or mortality in elderly patients. Advanced age in properly selected patients should not preclude offering NAC prior to radical cystectomy. Research Sponsor: None.

Treatment differences between age groups. Pre-Weights Post-Weights < 70 70+ < 70 70+ Treatment (n=27,228) (n=43,683) p (n=15,143) (n=24,442) p RC, no. (%) 5627 (20.7) 7858 (18.0) <0.001 2959 (19.5) 4483 (18.3) <0.001 RC + AC, no. (%) 3818 (14.) 2316 (5.3) 2250 (14.9) 1401 (5.7) Chemo-Radiation, 1830 (6.7) 5620 (12.9) 857 (5.7) 2785 (11.4) no. (%) NAC + RC, no. (%) 4872 (17.9) 2643 (6.1) 3163 (20.9) 1760 (7.2) No Treatment, no. (%) 197 (0.7) 593 (1.4) 0 (0) 0 (0) Missing, no. (%) 10884 (40.0) 24653 5914 (39.1) 14013 (56.4) (57.3) *Propensity score weighted adjustment for age, race, year of diagnosis, insurance status, percentage of non- high school completion, area of residence, proximity to hospital, Charlson score, histology, clinical T stage, LN dissection, and surgery type.

4537 Poster Session

Response and outcomes to immune checkpoint inhibitors (ICI) in advanced urothelial cancer (aUC) based on prior intravesical BCG.

Rafee Talukder, Dimitrios Makrakis, Daniel Castellano, Vadim S Koshkin, Ajjai Shivaram Alva, Tyler F. Stewart, Victor Sacristan Santos, Jayanshu Jain, Rafael Morales-Barrera, Michael Grant, Ariel Ann Nelson, Evan Shreck, Alexander Sankin, Roubini Zakopoulou, Alejo Rodriguez-Vida, Sandy Liu, Ana Fro€be, Giuseppe Di Lorenzo, Petros Grivas, Ali Raza Khaki; University of Washington, Seattle, WA; The University of Washington School of Medicine, Seattle, WA; Hospital Universitario 12 de Octubre, Ma- drid, Spain; University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Michigan Rogel Cancer Center, Ann Arbor, MI; University of California, San Diego, La Jolla, CA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Department of Medicine, University of Iowa Health Care, Iowa City, IA; Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Auto�noma de Barcelona, Barcelona, Spain; Barts Health NHS Trust, London, United Kingdom; Medical College of Wisconsin, Milwaukee, WI; Montefiore Medi- cal Center, Bronx, NY; Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; Hel- lenic Cooperative Oncology Group (HeCOG), Athens, Greece; Medical Oncology Department, Hospital del Mar Research Institute, Barcelona, Spain; Department of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, CA; Department of Oncology University Hos- pital Center Sisters of Mercy University of Zagreb Medical School, Zagreb, Croatia; Oncology Unit, An- drea Tortora Hospital, ASL Salerno, Pagani, Italy; University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Background: Little is known regarding response and outcomes to ICI for patients (pts) with aUC who were previously treated with BCG for non-muscle invasive bladder cancer. We hypothesized that prior intravesical BCG would not be associated with changes in objective response or survival in pts with aUC treated with ICI. Methods: We performed a retrospective cohort study across 25 institutions. Demographic, intravesical BCG history, treatment and outcomes data were collected for pts with aUC who received ICI. Pts with aUC treated with ICIs were included, pts with pure non-UC, those treated with combination or on clinical trials, pts with multiple ICI treatment lines and those with upper tract UC were excluded. Pts were stratified to prior exposure versus no exposure to BCG. We compared overall response rate (ORR) using logistic regression; and progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox proportional hazards. All analyses were performed in the overall population and further stratified by treatment line (first-line [1L] vs salvage [2+L]) and multivariable models. The stratified analysis was also adjusted for an internally developed risk score for 1L and Bellmunt risk score for 2+L; p<0.05 was significant. Results: 1026 aUC pts treated with ICI were identified; 614 pts, 617 pts, and 641 pts were included in ORR, OS and PFS analyses, respectively. Overall, mean age at CPI initiation was 70, 76% were men, 70% were current or former smokers, 75% White, 29% with mixed histology, and 24% had prior exposure to BCG. ORR to ICI in pts with or without prior exposure to BCG was similar, 27% and 28% respectively (OR=0.93 [95% CI 0.61-1.42], p=0.73). Median OS (mOS) for pts with vs without prior BCG exposure was 9 vs 10 mo (HR=1.13 [95% CI 0.88-1.44], p=0.35). Median PFS (mPFS) was 4 months (mo) in both groups (HR=1.02 [95% CI 0.82-1.27], p=0.83). ORR, PFS and OS analyses stratified by ICI treatment line (1L vs 2+L) are listed in the table. Conclusions: In this multi-institutional retrospective analysis, prior intravesical BCG was not associated with objective response or survival in pts with aUC treated with ICI. Limitations of this study include retrospective nature, lack of randomization and possible confounding, but it does provide important preliminary data that selection for ICI treatment should not be impacted by prior exposure to BCG. Further clinical and molecular biomarker exploration is needed to refine patient selection for ICI in aUC. Re- search Sponsor: None.

mOS, mPFS, ORR % OR months HR months HR N (95% Cl) (95% CI) p N (95% CI) (95% CI) p N (95% CI) (95% CI) p

First Line No BCG 273 31 (26-37) Ref 0.08 279 11 (8-14) Ref 0.79 286 4 (4-6) Ref 0.55 Hx of BCG 71 23 (14-34) 0.55 (0.28-1.06) 74 11 (6-15) 1.05 (0.71-1.56) 77 3 (2-7) 1.12 (0.77-1.62) 2+ Line No BCG 198 24 (18-30) Ref 0.12 191 10 (8-12) Ref 0.49 203 4 (3-4) Ref 0.39 Hx of BCG 72 31 (21-42) 1.65 (0.88-3.10) 73 7 (5-12) 1.13 (0.79-1.63) 72 4 (3-7) 0.87 (0.63-1.19)

4538 Poster Session

Real-world treatment patterns and clinical outcomes among patients with metastatic urothelial carcinoma.

Daniel M. Geynisman, Edward Broughton, Hasan Alhasani, Yi Hao, Ying Zhang, Brian Stwalley, Trong Kim Le, Stephen Huo; Fox Chase Cancer Center, Department of Hematology and Oncology, Phila- delphia, PA; Bristol Myers Squibb, Princeton, NJ

Background: Knowledge of large-scale real-world treatment patterns and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC) is limited. We conducted this study to address the lack of knowledge and identify unmet needs in pts with mUC in real-world clinical practice. Methods: The US nationwide Flatiron Health electronic health records–derived, de-identified database, com- prised of 280 oncology practices across the US, was utilized to conduct a retrospective cohort analysis of pts diagnosed with mUC between Jan 1, 2011, and Aug 31, 2020. Baseline pt characteristics were assessed descriptively, and treatment patterns were classified by cisplatin (CIS) eligibility. Kaplan–Mei- er methods were used to evaluate overall survival (OS) and progression-free survival (PFS). In a subgroup analysis of cisplatin-ineligible (CIS-inelig) pts, a multivariable model adjusting for baseline covariates was used to assess survival outcomes. Results: Of 8183 pts with mUC, median age was 73.0 years at diagnosis. Primary tumor sites were bladder (78.5%), upper tract (20.6%), and urethra (0.9%). Median (range) follow-up from mUC diagnosis was 9.7 (0.2-116.6) months. Of 5855 (71.6%) pts who received first-line (1L) systemic therapy, 1764 (30.1%) were CIS eligible (CIS-elig), 2293 (39.2%) were CIS-inelig, and 616 (10.5%) did not receive CIS despite qualifying ECOG PS (0–1) and renal function; CIS eligibility was unknown in 1182 (20.2%). Among all 1L pts, 4380 (74.8%) received chemotherapy and 1410 (24.1%) received immunotherapy (IO); of the IO users, 1345 (95.4%) received monotherapy. Among CIS-elig pts, CIS plus gemcitabine (GC) and methotrexate, vinblastine, doxorubicin, CIS (MVAC) accounted for 1562 (88.5%) of 1L therapy. Among CIS-inelig pts, carboplatin plus gemcitabine (GCa; 36.1%), pembrolizumab (pembro) monotherapy (18.5%), and atezolizumab (atezo) monotherapy (15.1%) were the most common 1L therapies. Across CIS eligibility groups, the most common second-line therapies included pembro, atezo, and GCa; the most common third-line therapies included atezo, pemetrexed, paclitaxel, and GCa. Median OS (95% CI) was longer in pts who received $ 1 line of systemic therapy (14.5 [14.0–15.2] months) than in those who did not receive therapy (6.8 [6.2–7.3] months). Median (95% CI) OS and PFS were also longer in CIS-elig pts (OS, 19.7 [18.2–21.4] months; PFS, 11.5 [10.8–12.1] months) than in CIS-inelig pts (OS, 11.4 [10.8–12.0] months; PFS, 7.0 [6.7–7.4] months), irrespective of receiving treatment. In a subgroup analysis of CIS-inelig pts, 1L IO monotherapy was associated with worse OS than 1L chemotherapy (HR, 1.26; 95% CI, 1.13–1.40, P < 0.0001). Conclusions: This study of > 8000 mUC pts, of whom almost 30% never received systemic therapy, demonstrates real-world treatment patterns in mUC and highlights the substantial unmet need in this population, in particular for CIS-inelig pts. Research Sponsor: None.

4539 Poster Session

Quality of life, functioning, and symptoms in patients with previously treated locally advanced or metastatic urothelial carcinoma from EV-301: A randomized phase 3 trial of enfortumab vedotin versus chemotherapy.

Ronac Mamtani, Jonathan E. Rosenberg, Thomas Powles, Guru P. Sonpavde, Yohann Loriot, Ignacio Duran, Jae-Lyun Lee, Nobuaki Matsubara, Christof Vulsteke, Daniel Castellano, Srikala S. Sridhar, Helle Pappot, Begon~a P. Valderrama, Howard Gurney, Jens Bedke, Michiel Simon Van Der Heijden, Chunzhang Wu, Zsolt Hepp, Caroline McKay, Daniel P. Petrylak; University of Pennsylvania, Philadel- phia, PA; Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY; Barts Cancer Institute, Cancer Research UK Experimental Can- cer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, Lon- don, United Kingdom; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Cancer Medicine, Gustave Roussy, Universite� Paris-Saclay, Villejuif, France; Hospital Universitario Marque�s de Valdecilla, IDIVAL, Cantabria, Spain; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Division of Breast and Medical Oncology, National Cancer Center Hos- pital East, Chiba, Japan; Center for Oncological Research (CORE), University of Antwerp, Integrated Cancer Center Ghent, Ghent, Belgium; Hospital Universitario 12 de Octubre, Madrid, Spain; Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, ON, Canada; Rigshospitalet, Univer- sity Hospital of Copenhagen, Copenhagen, Denmark; Department of Medical Oncology, Hospital Univer- sitario Virgen del Roc�ıo, Seville, Spain; Macquarie University Hospital, Sydney, NSW, Australia; Department of Urology, University of Tubingen, Tuebingen, Germany; Netherlands Cancer Institute, Amsterdam, Netherlands; Astellas Pharma, Inc., Northbrook, IL; Seagen Inc., Bothell, WA; Astellas Pharma Inc, Northbrook, IL; Yale School of Medicine, New Haven, CT

Background: In EV-301, a randomized, open-label phase 3 study (NCT03474107), enfortumab vedotin (EV), a Nectin-4–directed therapy, significantly prolonged median overall survival by ~3.9 months and reduced the risk of death by 30% compared with standard chemotherapy (SC; docetaxel, paclitaxel, or vinflunine) in patients with previously treated locally advanced/metastatic urothelial carcinoma. Under- standing patient perspectives and experiences is important to further contextualize the benefits/risks of EV. Here, we report key prespecified quality-of-life (QoL) endpoints, a secondary objective of EV-301. Methods: Patients completed the validated European Organization for Research and Treatment of Can- cer Core Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, on Day 1 of each week for the first 12 weeks, and then every 12 weeks until discontinuation. The QLQ-C30 assessed functional domains, symptom scales/items, financial impact, and overall health/QoL. Descriptive statistics were used to summarize instrument compliance rates and scores; mixed model repeated measures were used to evaluate changes from baseline over time. Logistic regressions were conducted to assess confirmed improvement rates, defined as clinically meaningful improvement (predefined per domain) over two subsequent visits. Results: Of the 608 randomized patients (EV, n = 301; SC, n = 307), 77.3% were male, median age was 68 (range: 30-88), and 30.9% had liver metastasis. Questionnaire compliance rates at baseline were ~90% in both groups; during the study, average rates were 70.2% (EV) and 66.9% (SC). Baseline QLQ-C30 scores were similar between groups. At Week 12, scores on the global health status (GHS) scale were similar between groups (EV: -2.8, SC: -5.0; P=.2429), but SC was associated with numerically greater deterioration and more variability in QoL over the first 12 weeks. Pa- tients receiving EV had significant reduction in pain symptoms (EV: -5.62, SC: +0.11; adjusted difference: -5.73, P<.05), but significant worsening of appetite loss (EV: +8.55, SC: +1.26; adjusted difference: 7.29, P<.05) compared with SC. Other symptom scores were not significantly different between groups. Higher proportions of patients on EV vs SC had significant confirmed improvements across all functioning domains (role, physical, emotional, social, cognitive), GHS, and several symptom scales (pain, fatigue, dyspnea, constipation). The greatest difference in improvement was reported for pain (EV: 51.6%, SC: 28.8%; OR = 2.76[1.81, 4.22]). Conclusions: Compared with SC, patients receiving EV had numerically less deterioration and variability in QoL during the first 12 weeks of treatment. More patients in the EV group had improvements over SC in 10 of 15 QLQ-C30 domains; improvement in pain showed the largest benefit. Clinical trial information: NCT03474107. Research Sponsor: Astellas Pharma, Inc, Pharmaceutical/Biotech Company.

4540 Poster Session

Impact of recurrence on health-related quality of life in patients at high risk of recurrence after radical surgery for muscle-invasive urothelial carcinoma (MIUC): Results from the phase 3 CheckMate 274 trial.

Matt D. Galsky, Johannes Alfred Witjes, Ju€rgen Gschwend, Julia Braverman, Edward Broughton, Federico Nasroulah, Hasan Alhasani, Mario Maira-Arce, Xiaomei Ye, Ling Shi, Melissa Hamilton, Dean F. Bajorin; Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Urology, Radboud University, Nijmegen, Neth- erlands; Department of Urology, Technical University of Munich, Munich, Germany; Bristol Myers Squibb, Princeton, NJ; Bristol-Myers Squibb, Princeton, NJ; Evidera, Waltham, MA; Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

Background: Patients (pts) undergoing radical surgery for MIUC face a high risk of disease recurrence. Recurrence is associated with worse survival, but its effect on health-related quality of life (HRQoL) is unclear. This post hoc analysis assessed the impact of recurrence on HRQoL using data from the phase 3 CheckMate 274 trial. Methods: Pts who had undergone radical surgery for high-risk MIUC (# 120 days previously) were randomized 1:1 to nivolumab 240 mg Q2W or placebo for # 1 year. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D-3L every 4–6 weeks during treatment; 35 and 115 days after the last dose; and every 3 months after that until the end of the study (EQ-5D-3L only). The analysis included pts with a valid HRQoL assessment at baseline and at $1 post-baseline visits. Con- firmed deterioration in HRQoL was defined as worsening exceeding an a priori points threshold (± 10 for the EORTC QLQ-C30 domains, –7 for the EQ-5D visual analogue scale [VAS]) at $ 2 consecutive visits. Recurrence was classified as local only or distant (with or without local recurrence). The effect of recurrence on HRQoL deterioration was assessed by Cox proportional hazards regression with recurrence as a time-dependent covariate. The models controlled for treatment arm and baseline HRQoL score, and were stratified by PD-L1 expression, pathologic nodal status, and use of neoadjuvant cisplatin-based chemotherapy. Results: The analysis included 645 pts for EORTC QLQ-C30, of whom 71 (11%) had local recurrence only and 136 (21%) had distant recurrence during the HRQoL assessment period; and 648 pts for EQ-5D-3L. with recurrence had a significantly higher risk of confirmed deterioration in all HRQoL domains than those without recurrence (see table). However, hazard ratios were consistently greater for distant recurrence than for local recurrence across all HRQoL domains. For local recurrence only, a higher risk of confirmed deterioration in HRQoL compared to no recurrence was observed only for global health status/QoL. Conclusions: Recurrence, particularly distant recurrence, had a significant, negative impact on HRQoL. This suggests that treatment delaying recurrence after radical surgery for high-risk MIUC may prevent or delay HRQoL deterioration in these pts. Clinical trial information: NCT02632409. Research Sponsor: Bristol Myers Squibb.

Adjusted hazard ratios (95% confidence interval) for recurrence vs. no recurrence. Any Recurrence Local Recurrence Only Distant Recurrence

EORTC QLQ-C30 (N = 645) n = 207 (32%) n = 71 (11%) n = 136 (21%) Global health status/QoL 3.5 (2.3–5.3) 3.0 (1.6–5.7) 3.8 (2.4–6.2) Physical functioning 4.2 (2.8–6.3) 1.2 (0.4–3.2) 6.6 (4.2–10.2) Role functioning 3.1 (2.1–4.5) 1.5 (0.7–3.1) 4.3 (2.8–6.6) Fatigue 1.7 (1.1–2.6) 0.9 (0.4–2.0) 2.3 (1.4–3.7) EQ-5D-3L (N = 648) n = 209 (32%) n = 72 (11%) n = 137 (21%) VAS 1.8 (1.2–2.8) 1.1 (0.5–2.5) 2.3 (1.4–3.9)

Bold values denote P < 0.05.

4541 Poster Session

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, Wassim Kassouf, Sima P. Porten, Rick Bangs, Melissa Plets, Seth P. Lerner, Ian Murchie Thompson; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; Fred Hutchinson Cancer Research Cen- ter, Seattle, WA; Mayo Clinic, Phoenix, AZ; Johns Hopkins Greenberg Bladder Cancer Institute, Balti- more, MD; University of Colorado, Denver, CO; University of Utah Hunstman Cancer Institute, Salt Lake City, UT; Division of Hematology/Oncology, Department of Medicine, University of California San Fran- cisco, San Francisco, CA; University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK; Johns Hopkins Hospital, Baltimore, MD; McGill University Health Centre, Mon- tre�al, QC, Canada; University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; BCAN, Bethesda, MD; SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; Baylor College of Medicine, Houston, TX; Christus Santa Rosa Medical Center Hospital, Houson, 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. 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 the 18 month results for all eligible patients who received at least one protocol treatment. The co-primary endpoints were pathological complete response (CR) rate at 6 months in patients with CIS (reported at ASCO 2020), and event-free survival (EFS) in all patients at 18 months using Kaplan-Meier methods (KM), conditional on a positive CIS response rate. A sample size of 135 evaluable patients provided 93% statistical power for detecting a 30% 18-month EFS rate versus 20% using a one-sided alpha = 0.05. EFS in the subset with Ta/T1 disease and duration of response in CIS patients were secondary endpoints. Results: 172 patients were enrolled, 166 received at least one dose of atezolizumab and are included in the safety analysis, and, of those, 128 were eligible and included in the efficacy analysis. As previously reported, 20 (27%) out of 74 patients with CIS attained a pathologic CR at 6 months. The KM estimate of 12 month (actual 11.9 mo) duration of response after 6 month CR for CIS patients was 54% (95% CI 30%, 78%) and the median duration of response was 16.5 months. The KM EFS rate at 18 months in 74 patients with CIS was 17% (90% CI 9%, 25%). The 18 month KM EFS rate in the overall population of 128 patients with Ta, T1 and CIS was 29% (90% CI 22%, 36%). The 18 month actuarial EFS rate in 54 patients with Ta/T1 disease was 45% (90% CI 34, 57%). Any possibly or probably treatment-related adverse event (TRAE) was observed in 142 out of 166 (86%) patients who received any atezolizumab regardless of eligibilty. The most frequent TRAEs were fatigue 72 (43%), diarrhea 34 (20%), and anemia 38 (23%). Grade 3-5 TRAEs occurred in 28 (17%) patients, including rash in 4 (2%), hyponatremia in 4 (2%), hypertension in 3 (2%) and elevated liver function tests in 3 (2%). There were two treatment-related deaths (sepsis and respiratory failure due to myasthe- nia gravis). Conclusions: The observed response of atezolizumab at 6 and 18 months in patients with BCG-unresponsive CIS suggests that this could be a valuable treatment to address a critical unmet need in this patient population. The 18 month EFS in patients with Ta/T1 disease suggests activity in this patient subset. This trial provided no new safety concerns. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, CA180863 and in part by Genentech. Clinical trial information: NCT02844816. Research Sponsor: U.S. National Institutes of Health, Pharmaceutical/Biotech Company.

4542 Poster Session

Genomic predictors of response to PD-1 axis inhibitors in metastatic urothelial cancer (mUC) patients using machine learning analysis of tissue comprehensive genomic profiling (CGP).

Raquel Reisinger, Victor Sacristan Santos, Roberto Nussenzveig, Sergiusz Wesolowski, Edgar Javier Hernandez, Alexander Ryan Henrie, Benjamin L. Maughan, Umang Swami, Mark Yandell, Petros Grivas, Neeraj Agarwal; University of Utah School of Medicine, Salt Lake City, UT; Complejo Hospitalar- io Universitario, A Corun~a, UT, Spain; University of Utah Huntsman Cancer Institute, Salt Lake City, UT; University of Utah, Salt Lake City, UT; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; University of Wash- ington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA

Background: Immune check point inhibitors (ICI), specifically PD-1 axis inhibitors, are an established treatment for mUC patients (pts), though molecular markers of response are not well-established. Prob- abilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that machine learning analysis can reveal biomarkers of response to ICI beyond Tumor Mutational Burden (TMB) and PD-L1 expression. Methods: Pts with mUC receiving systemic therapy and available tumor CGP were included in the analysis. CGP was performed by a CLIA validated NGS panel (Foundation Medicine). 17 clinically relevant variables were included in the analyses. Multilevel molecular and clinical interdependencies between ICI response were assessed using a Bayesian network (BN) machine learning approach. To account for high computational cost of the BN dependence structure discovery, variables were selected based on primary and secondary dependencies to ICI Objec- tive Response Rate (ORR) via Hill Climbing Algorithm. Genes selected for analysis included those present in > 5% of the cohort. All variants of unknown significance were removed. Kaplan-Meyer (KM) survival analysis was also performed. Results: 174 pts were eligible and included: median age was 67 (33 – 86), 54.6% were smokers, 27.6% male, 14.4% had upper tract disease at diagnosis and 77 pts were treated with an approved ICI. Results from BN analysis revealed strong positive interdependencies between ICI ORR and TMB $ 10 or mutated PIK3CA gene. KM analysis was in agreement with BN results, a low TMB ( < 10 muts/MB) and wild-type PIK3CA were predictive of poor PFS (Table). PGMs will be presented at the meeting. Conclusions: BN and KM survival analysis supported TMB $ 10 as a biomarker of improved outcomes to ICI. Moreover, these results reveal mutated PIK3CA as a novel biomarker of improved outcomes to ICI. Study has limitations as expected in a retrospective analysis. These hypothesis-generating data require external validation. Research Sponsor: U.S. National Insti- tutes of Health.

RR of ICI ORR1 Biomarker (± Std Dev) High TMB ($10 Muts/MB) 1.31 (0.22) PIK3CA (mutant) 1.61 (0.25) PFS HR (95% CI), p-value

TMB ( < 10 vs $10 Muts/MB) 2.411 (1.244 - 4.672), p < 0.01 PIK3CA (wild-type vs mutant) 2.223 (1.160 - 4.260), p < 0.02

1Relative risk of codependency of biomarker and ICI ORR compared to biomarker alone.

4543 Poster Session

Survival outcomes in patients receiving immune checkpoint inhibitor (ICI) for metastatic small cell urothelial cancer (SCUC).

Omar Alhalabi, Nathaniel Wilson, Neema Navai, Matthew T Campbell, Amishi Yogesh Shah, Jianjun Gao, Paul G. Corn, Ana Aparicio, Bogdan Czerniak, Charles Guo, Christopher Logothetis, Nizar M. Tannir, Seungtaek Choi, Arlene O. Siefker-Radtke; Beaumont Health, Royal Oak, TX; University of Texas Health Science Center at Houston, Houston, TX; The University of Texas MD Anderson Cancer Center, 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 Tex- as MD Anderson Cancer Center, Houston, TX; The University of Texas M. D. Anderson Cancer Center, Houston, TX

Background: The prognosis in patients with metastatic SCUC (mSCUC) remains poor with median survival around 1 year with systemic chemotherapy. We aimed to investigate the impact of ICI on survival of patients with mSCUC. Methods: Patients who received systemic therapy at MD Anderson Cancer Cen- ter (MDACC) for de novo or metachronous mSCUC after completing local management. within 12 months of neoadjuvant or adjuvant chemotherapy were included in this cohort, with overall survival (OS) calculated from the time of receipt of initial chemotherapy. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using logrank test. Results: 102 patients with mSCUC received systemic therapy at MDACC between April 2006 and June 2020. Median age was 66 (range 24 – 86 years), male to female ratio was 5. Bladder was the primary site in 85 (83%), 45 (44%) had prior cystectomy and 9 (9%) had prior nephroureterectomy. Histologies included 51 (50%) with predominant small cell (SC) features, 28 (27%) with focal SC features, 20 (20%) with pure SC, and 3 (3%) mixed with large cell component. Thirty-nine (38%) received ICI during their disease course: 29 (28%) following front-line chemotherapy (15 of whom within 12 months of neoadjuvant/adjuvant platinum therapy), 5 (5%) combined with front-line chemotherapy, and 5 (5%) received ICI front-line (two of whom were able to receive second-line chemotherapy). ICI agents used included anti-PD-1 (n=19), anti-PD-L1 (n=12), anti-PD-1/anti-CTLA-4 (n=5), anti-PD-1/anti-TIM3 (n=1), anti-PD-1/anti-STAT3 (n=1), anti-PD-L1/PARPi (n=1). Those who received ICI at any time had an improved median OS compared to those treated with chemotherapy alone (20.1 vs 12 months), [HR=0.45, 95% CI 0.27-0.72, p=0.003]. When we limited the analysis to those with de novo mSCUC (n=36), those who received ICI at any time (n=13) had an improved median OS compared to those treated with chemotherapy alone (n=23) (not reached vs 9.41 months), [HR=0.28, 95% CI 0.12-0.68, p=0.03]. Among patients who received ICI (n=39), median OS in those with liver metastases (n=11) was numerically shorter than those without (n=28) (13.1 vs 21.6 months), [HR=1.83, 0.59-5.7, p=0.21]. Conclusions: ICI improves OS for patients with mSCUC. Although clinical trials remain difficult in these rare variants, further prospective studies are indicated to confirm this finding. Research Sponsor: None.

4544 Poster Session

Phase I/II trial of pembrolizumab and cabozantinib in the treatment of metastatic renal cell carcinoma (mRCC).

Elizabeth R Kessler, Junxiao Hu, Geetika Srivastava, Douglas Jerome Kemme, Praveena Iruku, Vishal Rana, Steven Robert Schuster, Mali Amirault, Eryn Callihan, Thomas W. Flaig, Elaine Tat Lam; Univer- sity of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO; University of Colorado Cancer Center, Aurora, CO; UCHealth Cancer Care and Hematology Clinic, Memorial Hospital, Colorado Springs, CO; UCHealth Cancer Center Harmony Campus, Fort Collins, CO

Background: Checkpoint inhibitors (CPI) and vascular endothelial growth factor receptor inhibitors (VEGFi) are standard treatments for patients (pts) with mRCC. This phase I/II study evaluated the safety and efficacy of the novel combination of pembrolizumab (pembro) and cabozantinib (cabo). The phase I dose escalation data was presented at ASCO GU 2019. We now report the objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity of patients in the phase II dose expansion. Methods: Eligible pts had metastatic clear cell (ccRCC) or non-clear cell (nccRCC) histology, normal organ function, ECOG 0-1, and no prior exposure to pembro or cabo. Pts could be treatment- nave or have received prior CPI and/or VEGFi. Pts were dosed at the recommended phase 2 dose of pembro 200 mg IV Q3W in combination with cabo 60 mg PO QD. Scans were obtained every 9 weeks. Treat- ment beyond progression, in the setting of continued clinical benefit, was allowed. The primary endpoint was ORR. Simon’s two-stage design was implemented to test the null hypothesis that ORR # 0.20 versus the alternative that ORR $ 0.50. Results: Forty pts were enrolled, of which 34 pts (85%) had ccRCC and 6 pts (15%) had nccRCC. This was first-line treatment for 15 pts (38%) and second- and subsequent-line therapy for 25 pts (62%). IDMC risk category was favorable in 15%, intermediate in 72.5%, and poor in 12.5% of pts. Prior therapies included VEGFi in 17 pts (43%), CPI in 17 pts (43%), and 9 pts (23%) had both prior VEGFi and CPI in combination or sequentially. At a median follow up of 17.8 months (mo), the ORR was 60% (95% CI 0.458-1.00), clinical benefit rate (CBR) was 92.5% (95% CI 0.817-1.00), median time to response was 4.2 mo; median duration of response was 8.4 mo. Three of six nccRCC pts achieved partial response. Median PFS was 10.4 mo (95% CI 6.3 mo- NR). Median OS was not reached. Twelve patients remain on treatment. The most common grade 1 and 2 (G1/2) treatment-related AEs were diarrhea (53%), fatigue (49%), weight loss (47%), nausea (43%), and dysgeusia (43%). Twenty-five patients (47%) experienced a treatment-related G3 AE and there were no G4 related AEs. Thirteen pts experienced serious adverse events, 8 of which were related to treatment: G3 transaminitis and hypoglycemia were attributed to the combination; G3 pancreatitis, ne- phritis, and pneumonitis attributed to pembro; G3 pulmonary embolus, confusion due to reversible pos- terior leukoencephalopathy (RPLS), and stroke attributed to cabo. There was one treatment-related death in the pt with RPLS, possibly related to cabo. Conclusions: This study of the combination of pembrolizumab 200mg and cabozantinib 60mg met the primary endpoint of ORR. Benefit was seen in first- and subsequent-line therapy. The safety profile was manageable. This combination warrants further confirmation in a randomized controlled trial. Clinical trial information: NCT03149822. Research Sponsor: Merck.

4545 Poster Session

Health care disparities and barriers to palliative care among metastatic renal cell carcinoma patients: An NCDB analysis.

Janvi Wadiwala, Mausam Patel, Chenghui Li, Sanjay Maraboyina, Ahmed Safar, Thomas Kim; Houston Healthcare, Perry, GA; University of Arkansas for Medical Sciences, Little Rock, AR; Rush University, Chicago, IL

Background: Palliative care improves quality of life for both patients and caregivers but may be underutilized due to socioeconomic barriers to access. An NCDB analysis was performed to analyze the effect of socioeconomics on palliative care receipt among patients with metastatic renal cell carcinoma. Meth- ods: A retrospective hospital-based analysis was performed using the National Cancer Database to identify variables that significantly affect receipt of palliative care among patients diagnosed with metastatic renal cell carcinoma diagnosed between 2004 and 2016. Sub-cohort analysis was also performed among patients with the most severe disease. Multivariate binominal logistic regression was performed to determine the association of underlying socioeconomics with receipt of palliative care. The odds of receiving palliative care based on socioeconomic factors was reported as odds ratios (OR) with 95% CI. Results: There were 50405 patients meeting inclusion criteria with 40448 (80.2%) undergoing no palliation and 9957 (19.8%) undergoing palliative care. Both Black and Spanish/Hispanic patients had decreased odds of receiving palliative care (OR, 0.816, 95% CI, 0.753 to 0.885 and OR, 0.599, 95% CI, 0.540 to 0.665, respectively). Increasing age, papillary histology, increasing income, and increasing distance were also significantly associated with decreased odds of receiving palliation while treatment at an integrated network cancer program or comprehensive community cancer program and higher educational attainment were associated with increased odds of receiving palliative care. Similar findings were demonstrated among patients with the most severe disease. Limitations include the retrospective design and potential underlying selection biases of this study. Conclusions: Significant associations between receipt of palliative care and socioeconomic factors exist among patients with metastatic renal cell carcinoma. In this study among patients with metastatic renal cancer, we found associations between socioeconomics and palliative care access including age, race, Spanish/Hispanic or- igin, income, education, and other factors. Research Sponsor: None.

4546 Poster Session

TIVO-3: Durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC).

Elena Verzoni, Bernard Escudier, Thomas E. Hutson, David F. McDermott, Sumanta K. Pal, Camillo Porta, Brian I. Rini, Michael N. Needle, Michael B. Atkins; Fondazione IRCCS Istituto Nazionale Tu- mori, Milan, Italy; Gustave Roussy, Villejuif, France; Texas A&M College of Medicine, Bryan, TX; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA; University of Bari ’A. Moro’ and Policlinico Consorziale di Bari, Bari, Italy; Vanderbilt-Ingram Cancer Center, Nash- ville, TN; Aveo Oncology, Boston, MA; Georgetown Lombardi Comprehensive Cancer Center, Washing- ton, DC

Background: Tivozanib is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for mRCC. Methods: The TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized 1:1 to T or sorafenib. Tivozanib demonstrated PFS and ORR advantages over sorafenib. Here we report long term durability of response based on investigator assessment and updated overall survival. Results: There were 41 responders (23%) to tivozanib and 20 responders (11%) to sorafenib. The median duration of response (mDoR) was 20.3 months (95% CI: 9.8, 29.9) and 9.0 months (95% CI: 3.7, 16.6) for tivozanib and sorafenib, respectively. With prolonged follow up there were 270 deaths; the HR for overall survival favored tivozanib at 0.91 (95% CI: 0.716, 1.165). Clinical trial information: NCT02627963. Conclu- sions: Tivozanib treatment in third and fourth line mRCC results in longer PFS, higher objective response rate and more durable responses compared to sorafenib. There is no difference in overall survival. Research Sponsor: AVEO Oncology.

Treatment N Objective Response Ongoing Response mDoR in Months (95% CI) HR (95% CI)

Sorafenib 175 20 (11%) 3 9.0 (3.7, 16.6) 0.55 Tivozanib 175 41 (23%) 13 20.3 (9.8, 29.9) (0.30, 1.00)

4547 Poster Session

Integrating peripheral biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A + Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).

Toni K. Choueiri, Amber C Donahue, Brian I. Rini, Thomas Powles, John B. A. G. Haanen, James Larkin, Xinmeng Jasmine Mu, Jie Pu, Despina Thomaidou, Alessandra Di Pietro, Paul B. Robbins, Robert J. Motzer; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA; Pfizer, La Jolla, CA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Barts Cancer Institute, Can- cer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom; Netherlands Cancer Institute, Amsterdam, Netherlands; Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom; Pfizer Inc., San Diego, CA; Pfizer Hellas, Athens, Greece; Pfizer srl, Milan, Italy; Memorial Sloan Kettering Cancer Center, New York, NY

Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), treatment-naive patients (pts) with aRCC demonstrated prolonged progression-free survival (PFS) and a higher objective response rate with A + Ax vs S. We report the association of blood-based biomarkers with differential responses to treatment. Methods: Biomarkers in pretreatment (pre-tx) and on-treatment (on-tx) blood samples from 886 enrolled pts were correlated with clinical outcomes and molecular profiling data from corresponding tumor samples. Analyses include blood counts of unique populations, T-cell receptor sequencing, circulating cytokines, and serum proteomics by mass spectrometry MALDI-TOF. Results: At baseline, higher pre-tx monocyte counts were associated with shorter PFS in the A + Ax arm (Table). In the S arm, higher pre-tx levels of multiple T-cell–related metrics, including the percent of productively rearranged peripheral T cells, were associated with longer PFS but had no association in the A + Ax arm (Table). Higher pre-tx neutrophil counts were associated with shorter PFS in both arms, but neutrophil-to-lymphocyte ratio (NLR) was only associated with PFS for the S arm (Table). On-therapy biomarkers showed differential post-tx changes in T-cell numbers and clones at C2D1. Tx-specific differences were also seen in non–T-cell populations such as monocytes and neutrophils at multiple time points through C3D1. Serum levels of pre- and on-tx VEGF, CRP, and several interleukins showed differential associations with PFS (eg, higher pre-tx VEGF was associated with shorter PFS in only the S arm) (Table). Spe- cific genomic alterations in tumor tissues were associated with differences in several pre- and on-tx angiokines & cytokines. Conclusions: Response to treatment with first-line A + Ax or S was associated with immune fitness and tx-specific immunomodulation. We identified peripheral biomarkers in pts with aRCC associated with the presence of impactful genomic alterations and differential clinical outcomes. Clinical trial information: NCT02684006. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

Pre-Tx Biomarker ($ < med) A + Ax (N = 442) S (N = 444)

Monocyte counts (n) 200 vs 183 195 vs 201 mPFS, (95% CI), mo 11.07 (8.54-12.55) vs 16.62 (12.45-23.49) 8.54 (7.16-9.96) vs 9.23 (7.00-10.84) HR* (95% CI) 1.50 (1.14-1.97) 1.09 (0.85-1.39) T-cells % (n) 177 vs 198 193 vs 171 mPFS, (95% CI), mo 15.08 (11.11-20.73) vs 12.45 (9.79-17.77) 9.82 (8.31-12.45) vs 8.35 (6.24-9.69) HR* (95% CI) 0.86 (0.66-1.14) 0.73 (0.57-0.94) NLR (n) 220 vs 214 217 vs 222 mPFS, (95% CI), mo 12.45 (9.89-17.77) vs 15.08 (11.11-18.20) 7.16 (5.75-9.04) vs 11.07 (8.38-12.49) HR* (95% CI) 1.10 (0.85-1.42) 1.58 (1.25-2.00) VEGF (n) 189 vs 193 192 vs 183 mPFS, (95% CI), mo 13.77 (11.11-17.97) vs 12.22 (9.79-16.59) 8.21 (5.68-8.54) vs 11.07 (9.69-12.49) HR* (95% CI) 0.92 (0.70-1.20) 1.49 (1.16-1.92)

HR, hazard ratio; med, global median *Unstratified.

4548 Poster Session

Association of C-reactive protein (CRP) with efficacy of avelumab + axitinib (A + Ax) in advanced renal cell carcinoma (aRCC): Long-term follow-up results from JAVELIN Renal 101.

Yoshihiko Tomita, James Larkin, Balaji Venugopal, John B. A. G. Haanen, Hiro-Omi Kanayama, Masatoshi Eto, Marc-Oliver Grimm, Yosuke Fujii, Yoshiko Umeyama, Mariangela Mariani, Alessandra Di Pietro, Toni K. Choueiri; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom; University of Glas- gow, Glasgow, United Kingdom; Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Urology, Graduate School, The University of Tokushima, Tokushima, Japan; Department of Urology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Department of Urology, Uni- versitaetsklinikum Jena, Jena, Germany; Pfizer R&D Japan, Tokyo, Japan; Pfizer srl, Milan, Italy; Dana- Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background: CRP is an important prognostic and predictive factor in patients with aRCC receiving various therapies, such as cytokines and tyrosine kinase inhibitors. In this extended follow-up to the phase 3 JAVELIN Renal 101 trial (NCT02684006), we report the association of CRP levels at baseline (BL) and early after treatment with the efficacy of A + Ax or sunitinib (S). Methods: CRP levels were assessed at screening and day 1 of each 6-week cycle. Patients were categorized into CRP normal (BL CRP < 10 mg/L), normalized (BL CRP $10 mg/L and $1 CRP value decreased to < 10 mg/L during 6 weeks of treatment), and non-normalized (CRP $10 mg/L at BL and during 6 weeks of treatment) groups. Multi- variate analysis of BL characteristics, including CRP for efficacy, was also conducted. Progression-free survival (PFS) and best overall response per independent central review (RECIST 1.1) from the second interim analysis (IA2) of overall survival (OS) and OS from the third interim analysis (IA3) were assessed. Results: Minimum duration of follow-up for IA2 and IA3 were 13 and 28 months, respectively. The table shows objective response rate (ORR), PFS, and OS by CRP group. Efficacy outcomes in the normal and normalized groups were favorable compared with the non-normalized group with both A + Ax and S. In the A + Ax arm, the complete response rate was 11.8% (normalized group), 3.8% (normal group), and 0.9% (non-normalized group). With A + Ax, the PFS in the normalized group was longer than in the normal group, but this was not observed with S. In each CRP group, all efficacy outcomes were favorable with A + Ax vs S. In the multivariate analysis, normalized or non-normalized CRP was an independent predictive factor of ORR or OS with A + Ax. Conclusions: Normal and normalized CRP levels were associated with improved A + Ax efficacy. A + Ax demonstrated favorable efficacy across CRP groups. OS in this study was immature; follow-up for the final analysis is ongoing. Further research in defining predictive value of CRP is warranted. Clinical trial information: NCT02684006. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

A + Ax A + Ax A + Ax S S S Normal Normalized Non-normalized Normal Normalized Non-normalized CRP group n = 234 n = 51 n = 108 n = 232 n = 36 n = 128

ORR (95% CI), % 56.0 66.7 45.4 30.6 41.7 19.5 Odds ratio (95% CI)* (49.4-62.4) (52.1-79.2) (35.8-55.2) (24.7-37.0) (25.5-59.2) (13.1-27.5) Ref 1.572 0.653 Ref 1.620 0.550 (0.832-2.973) (0.413-1.033) (0.789-3.324) (0.328-0.924) mPFS (95% CI), mo 15.2 NE 7.0 11.2 11.2 4.2 HR (95% CI)* (12.5-21.0) (11.1-NE) (5.6-9.9) (8.4-13.9) (6.7-13.8) (2.8-5.6) Ref 0.724 1.923 Ref 1.099 2.090 (0.453-1.156) (1.428-2.590) (0.689-1.753) (1.585-2.757) mOS (95% CI), mo NE NE 23.0 NE 39.8 19.1 HR (95% CI)* (42.2-NE) (30.4-NE) (18.4-33.1) (39.0-NE) (21.7-NE) (16.3-25.3) Ref 1.218 2.428 Ref 1.343 2.494 (0.734-2.022) (1.722-3.423) (0.774-2.331) (1.823-3.412) HR, hazard ratio; m, median; NE, not estimable; Ref, reference. *Unstratified.

4549 Poster Session

Association between neutrophil-to-eosinophil ratio (NER) and efficacy outcomes in the JAVELIN Renal 101 study.

Matthew D. Tucker, Martin H Voss, Toni K. Choueiri, Mehmet Asim Bilen, Marc-Oliver Grimm, Paul D. Nathan, Christian K. Kollmannsberger, Yoshihiko Tomita, Bo Huang, Despina Thomaidou, Mariangela Mariani, Alessandra Di Pietro, Brian I. Rini; Vanderbilt University Medical Center, Nashville, TN; Memo- rial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA; Department of Hematology and Medical Oncology, Emory Univer- sity School of Medicine, Atlanta, GA; Department of Urology, Universitaetsklinikum Jena, Jena, Germa- ny; Mount Vernon Cancer Centre, Northwood, United Kingdom; Division of Medical Oncology, University of British Columbia, Vancouver, BC, Canada; Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Pfizer, Groton, CT; Pfizer Hellas, Athens, Greece; Pfizer srl, Milan, Italy; Vanderbilt-Ingram Cancer Center, Nashville, TN

Background: Baseline NER has been reported to be associated with outcomes of immuno-oncology based combination treatment in advanced renal cell carcinoma (aRCC). We report outcomes by baseline NER of patients with aRCC in the JAVELIN Renal 101 trial who received avelumab + axitinib (A + Ax) or sunitinib (S). Methods: We calculated the median NER (mNER) for patients in the A + Ax and the S arms at the data cutoff (April 20, 2020) for the 3rd interim analysis (IA3). Progression-free survival (PFS), overall survival (OS), and objective response (OR) by NER are reported. Multivariate Cox regression analyses of PFS and OS were also conducted. Results: At the IA3 cutoff date, the mNERs for the A + Ax arm (n = 383) and S arm (n = 396) were 29.2 and 27.0, respectively. OR, PFS and OS for both arms are summarized in the table below. Better observed treatment outcomes in OR (63.9% vs 55.2%) and median PFS (15.5 vs, 11.1 months) were observed for patients with a NER < median vs. NER $ median in the A + Ax arm, while there were not major differences in outcome based on NER in the S arm. The stratified hazard ratio (HR) for PFS in patients with a NER < median compared with those with a NER $ median in the A + Ax arm was 0.81 (95% CI, 0.630-1.035) and 0.93 (95% CI, 0.728- 1.181) in the S arm. Patients with a NER < median had improved OS compared with those with a NER $ median in the A + Ax arm (stratified HR, 0.67; 95% CI, 0.481-0.940) and the S arm (stratified HR, 0.57; 95% CI, 0.424-0.779). Multivariate analysis showed that a low NER was associated with longer PFS and OS by treating baseline NER as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Baseline NER may be predictive of OR and PFS in aRCC patients treated with A + Ax, and prognostic for overall survival regardless of therapy. Clinical trial information: NCT02684006. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

A + Ax A + Ax S S NER < mNER NER $ mNER NER < mNER NER $ mNER (n = 191) (n = 192) (n = 195) (n = 201)

OR, % 63.9 55.2 32.8 30.8 mPFS, mo 15.5 11.1 9.7 8.3 18-mo PFS, % 45.6 37.6 29.6 25.0 36-mo PFS, % 23.7 18.5 10.6 10.6 mOS, mo NE NE NE 28.1 18-mo OS, % 81.4 73.5 79.3 64.4 36-mo OS, % 66.0 52.2 62.6 41.7

4550 Poster Session

Camrelizumab plus famitinib for advanced renal cell carcinoma or unresectable urothelial carcinoma: Updated results from a phase II trial.

Yuan-Yuan Qu, Qing Zou, Hongqian Guo, Nianzeng Xing, Zhongquan Sun, Weiqing Han, Hong Luo, Shujie Xia, Xuepei Zhang, Chaohong He, Hailiang Zhang, Jinling Cai, Xiao Zhang, Quanren Wang, Dingwei Ye; Department of Urology Surgery, Fudan University Shanghai Cancer Center, Shanghai, Chi- na; Department of Urology Surgery, Jiangsu Cancer Hospital, Nanjing, China; Urinary Surgery Center, Nanjing Drum Tower Hospital, Nanjing, China; Urinary Surgery Center, Cancer Hospital Chinese Acade- my of Medical Sciences, Beijing, China; Department of Urology Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China; Urinary Surgery Center, Hunan Cancer Hospital, Changsha, China; Department of Urology Surgery, Chongqing Cancer hospital, Chongqing, China; Urology Center, Shang- hai General Hospital, Shanghai, China; Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Department of Urology Surgery, Henan Cancer Hospital, Zhengzhou, China; Clinical Research & Development, Jiangsu Hengrui Medicine Co., Ltd, Shanghai, China; Jiangsu Hengrui Medicine Co., Ltd, Shanghai, China; Fudan University Shanghai Cancer Center, Shanghai, China

Background: Considering the synergistic/additive effect of PD-1 blockade and angiogenesis inhibition, we conducted an open-label, multi-center phase II study of camrelizumab (an anti-PD-1 antibody) plus famitinib (a TKI against VEGFR-2, PDGFR, c-kit, and FGFR) in pts with heavily treated advanced renal cell carcinoma (RCC) and unresectable urothelial carcinoma (UC). Methods: Based on an adaptive two- stage design, 22 pts were enrolled in the RCC and UC cohort, respectively, at stage 1; if there were $7 responders of the 22 pts, enrollment would be extend to 33 at stage 2. Pts received famitinib 20 mg orally QD plus camrelizumab 200 mg IV Q3W. Primary endpoint was ORR per RECIST v1.1. Preliminary data at stage 1 were reported at ASCO 2020 annual meeting (#5085). More than 7 pts in each cohort had CR/PR during stage 1; enrollment of stage 2 had been completed, and the data are firstly reported here. Results: 74 pts (38 advanced RCC and 36 unresectable UC) were enrolled from Jan 23, 2019 to Dec 14, 2020. In RCC cohort, 65.8% of pts had received $1 prior VEGFR inhibitors. In UC cohort, all pts had progressed on or relapsed after a platinum-containing chemotherapy. As of Jan 10, 2021, median time from enrollment to data cutoff was 18.8 mos (range, 8.5-22.7) for RCC cohort and 7.0 mos (range, 0.9-23.6) for UC cohort. In RCC cohort, ORR was 63.2% (95% CI, 46.0-78.2; 24 PRs), DCR was 89.5% (95% CI, 75.9-95.8), median DOR was not reached (range 2-19+ mos), mPFS was not reached, and 12-mo OS rate was 88.0%. Most pts (92.1%) had reduction in target lesions, and median reduction was 47% from baseline. ORR was 84.6% (95% CI, 57.8-97.3; 11/13) for untreated RCC pts and 52.0% (95% CI, 31.3-72.2; 13/25) for pre-treated pts; DCR was 100% (95% CI, 77.2-100.0) and 84.0% (95% CI, 65.3-93.6), mPFS was not reached and 13.4 mos (95% CI: 4.1-21.0), respectively. In UC cohort, of the 33 pts with post-baseline efficacy evaluation, ORR was 33.3% (95% CI, 19.8-50.4; 1 CR, 10 PRs), DCR was 60.6% (95% CI, 43.7-75.3), median DOR was not reached (range 1.0+-16.7+ mos), mPFS was 6.4 mos (95% CI, 2.1-11.8), and mOS was not reached. ORR trended to be higher for bladder cancer (43.8%, 7/16) than upper tract urothelial carcinoma (25.0%, 4/16). Treatment-related AEs (TRAEs) occurred in 97.3% of 74 pts. Grade 3 or 4 TRAEs occurred in 63.5% of pts, mainly hypertension (23.4%), decreased platelet count (21.3%), proteinuria (17.0%), anemia (14.9%), and palmar-plantar erythrodysesthesia syndrome (14.9%). 1 pt died of TRAE (multiple organ dysfunction syndrome). Conclusions: Camrelizumab plus famitinib showed potent anti-tumor activity in pts with advanced RCC and UC with no new safety concerns. Additionally, promising ORR and durable DOR were observed in pts with heavily-treated RCC. These results support further investigation in these settings. Clinical trial information: NCT03827837. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd.

4551 Poster Session

Real-world outcomes in patients with metastatic clear cell renal cell carcinoma receiving front-line axitinib plus pembrolizumab versus ipilimumab plus nivolumab.

Kevin Zarrabi, Elizabeth A. Handorf, Benjamin Miron, Matthew R. Zibelman, Fern Anari, Pooja Ghatalia, Elizabeth R. Plimack, Daniel M. Geynisman; Fox Chase Cancer Center, Philadelphia, PA; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA

Background: Front-line treatment for patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) has undergone rapid advances in the last five years. This evolution has led to uncertainty about the optimal first line combination regimen. Herein, we compare real-world outcomes in pts treated with either axitinib/pembrolizumab (A/P) or ipilimumab/nivolumab (I/N) reported by International Metastatic RCC Database Consortium (IMDC) score. Methods: The nationwide Flatiron Health electronic health records-derived database was used to select pts diagnosed with mRCC and treated with front-line A/P or I/ N from 2018-2020. The primary endpoints were overall-survival (OS) and real-world progression free survival (rwPFS). The survival analyses were adjusted using propensity score-based Inverse Probability of Treatment weighting, providing balance on age, gender, insurance, race, IMDC, practice type, and nephrectomy. Survival was assessed from beginning of therapy, and survival by treatment groups was compared using weighted and unweighted Kaplan-Meier curves with log-rank tests and weighted Cox proportional hazards regressions. Disease characteristics between the treatment groups were compared using chi-square and T-tests. Results: 821 pts received frontline A/P (n=259) or I/N (n= 562). Demo- graphics and clinical parameters were similar between the two cohorts. Median age was 66 years, 73% were male, and 54.9% had a nephrectomy. 459 pts had all IMDC criteria factors available, 242 pts had missing factors but enough to define as intermediate/poor risk, 120 pts had unknown IMDC risk. Adjust- ed median OS was not statistically different: mOS for A/P was not reached (NR) while I/N was 22 mo (95% CI, 19.8-NR; p=0.40). Twelve-month survival was 68.5% for A/P treated pts and 65.8% for I/N treated pts (P=0.41). Twelve-month rwPFS was 41.4% for A/P treated pts and 39.7% for I/N treated pts (P=0.14). No statistical difference in survival was seen within IMDC risk strata (see table). Conclu- sions: In this retrospective, real-world study of pts treated with front-line A/P or I/N, 12-month survival was not statistically different irrespective of IMDC risk. Longer follow-up will be necessary to discern any significant differences. Research Sponsor: None.

Adjusted 12-month survival. A/P I/N IMDC Score n=259 n=562 p-value

Favorable (n=69) 93.2% 72.5% 0.31 Intermediate/Poor (n=632) 64.6% 56.1% 0.61 Int. 73.9% 65.9% 0.29 Poor 52.1% 51.9% 0.80 Unknown (n=120) 76.4% 76.7% 0.61 Full cohort (n=821) 68.5% 65.8% 0.41

4552 Poster Session

The impact of antibiotic (Ab) exposure on clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or VEGF targeted therapy (VEGF-TT).

Matthew Scott Ernst, Sarah Abou Alaiwi, Nazli Dizman, Chris Labaki, Pier Vitale Nuzzo, Elio Adib, Andrew Lachlan Schmidt, Luis A Meza, Chun Loo Gan, J Connor Wells, Ziad Bakouny, Sumanta K. Pal, Toni K. Choueiri, Daniel Yick Chin Heng, Shaan Dudani; Tom Baker Cancer Center, University of Calga- ry, Calgary, AB, Canada; The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA; City of Hope Comprehensive Cancer Center, Duarte, CA; Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada; Division of Oncology and Hema- tology, William Osler Health System, Brampton, ON, Canada

Background: Retrospective studies have shown an association between Ab exposure and inferior clinical outcomes in patients receiving ICI across various tumor types, including mRCC. However, it is unclear whether Ab exposure has a unique interaction with ICI or is an independent prognostic marker, regardless of treatment. We sought to examine Ab exposure and its association with clinical outcomes in patients with mRCC treated with ICI compared to VEGF-TT. Methods: We identified patients treated with ICI (anti-PD-L1 alone or in combination with VEGF or CTLA4 inhibitor) or VEGF-TT alone in first to fourth line settings from 2009-2020 across 3 academic centers in North America. Ab exposure was defined as administration of Ab within 60 days prior to initiation of systemic therapy. Outcomes of interest were response rate (RR), time to treatment failure (TTF) and overall survival (OS). Multivariable Cox regression was performed to control for imbalances in International mRCC Database Consortium (IMDC) risk factors, histology, and treatment line. Results: We identified 748 patients. Among the ICI (n=427) and VEGF-TT (n=321) cohorts, 13% vs 15% (p=0.47) had Ab exposure and 57% vs 48% (p=0.046) were treated in the first line setting. The proportion of favorable, intermediate, and poor risk disease by IMDC criteria differed between Ab exposed and unexposed patients in the ICI (14% vs 18%, 47% vs 62%, 39% vs 21% p=0.03) and VEGF-TT (7% vs 13%, 43% vs 60%, 50% vs 27%, p=0.01) cohorts. RR, TTF and OS results are displayed in Table 1. Multivariable analysis did not show a significant independent association between Ab exposure and OS in both the ICI (HR 1.13, p=0.62) and VEGF-TT (HR 1.32, p=0.16) cohorts. Treatment modality (ICI vs VEGF-TT) did not modify the effect of Ab exposure on OS (p=0.84). Conclusions: Ab exposure was associated with higher IMDC risk scores in both the ICI and VEGF-TT cohorts as well as inferior OS on univariable analysis. After adjusting for IMDC risk factors, histology and treatment line, we were unable to find an independent association between Ab exposure and OS in multivariable analysis for either cohort. Research Sponsor: None.

ICI Cohort VEGF-TT Cohort Ab No Ab P-value Ab No Ab P-value

RR (%) 36 38 0.81 21 24 0.66 Median TTF, mo (95% CI) 6.2 (4.7-10.7) 8.1 (6.4-10.3) 0.23 5.5 (4.3-7.6) 6.3 (3.6-8.6) 0.14 Median OS, mo (95% CI) 22.5 (11.5-79.6) 36.8 (30.1-47.1) 0.02 13.5 (6.0-21.1) 21.6 (17.2-25.6) <0.01

4553 Poster Session

Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial.

Andrea B. Apolo, Thomas Powles, Mauricio Burotto, Maria Teresa Bourlon, James J Hsieh, Umberto Basso, Amishi Yogesh Shah, Cristina Suarez, Camillo Porta, Carlos H. Barrios, Howard Gurney, Elizabeth R Kessler, Margitta Retz, Saby George, Bernard Escudier, Joshua Zhang, Burcin Simsek, Christian Scheffold, Robert J. Motzer, Toni K. Choueiri; National Cancer Institute, National Institutes of Health, Bethesda, MD; Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom; Bradford Hill Clinical Research Center, Santiago, Chile; Urologic Oncology Clinic, Instituto Nacional de Ciencias Me�dicas y Nutricio�n Salvador Zubira�n, Mexico City, DF, Mexico; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO; Istituto Oncologico Veneto IOV IRCCS, Padua, Italy; MD Anderson Cancer Center, Houston, TX; Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d�Hebron, Vall d�Hebron Barcelona Hospital Campus, Barcelona, Spain; University of Pavia, Pavia, Italy; Hospital Sa~o Lucas, PUCRS, Porto Alegre, Brazil; Westmead Hospital and Macquarie University, Sydney, NSW, Australia; University of Colorado School of Medicine, Aurora, CO; Rechts der Isar Medical Center, Technical University Munich, Munich, Germany; Roswell Park Comprehensive Cancer Center, Buffalo, NY; Gustave Roussy, Villejuif, France; Bristol Myers Squibb, Princeton, NJ; Exelixis, Inc., Alameda, CA; Memorial Sloan Kettering Cancer Center, New York, NY; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hos- pital, and Harvard Medical School, Boston, MA

Background: First-line N+C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in aRCC patients (pts) in the phase 3 CheckMate 9ER trial, lead- ing to FDA approval of N+C in this setting. A deeper understanding of how baseline disease characteristics may impact clinical outcomes with N+C vs S may inform clinical decision making. Methods: Pts with clear cell aRCC were randomized to N 240 mg IV Q2W + C 40 mg PO QD vs S 50 mg PO QD (4 weeks of 6-week cycles). In this post hoc exploratory analysis, PFS, OS, and ORR were evaluated across pt subgroups defined by baseline IMDC risk status, organ sites of metastases (mets), number of organs with any lesions, or target lesion size. Consistent with primary/secondary efficacy endpoints in ITT pts, PFS and ORR were evaluated per RECIST v1.1 by blinded independent central review in subgroups. Re- sults: Median follow-up in ITT pts was 23.5 months. PFS, OS, and ORR (including complete response [CR]) outcomes are summarized in the table across subgroups: IMDC risk (favorable [FAV], intermediate [I], poor [P]); number of organs with $ 1 target/nontarget lesion (T/NT; 1 and $ 2); sum of diameters of target lesions (sDTL; < and $ median [72.1 mm]), and in pts with liver, bone, or lung mets. The PFS HR favored N+C vs S and median (m) PFS was longer with N+C vs S across all subgroups. The OS HR also favored N+C vs S across most subgroups. ORR ranged from 38%–66% (N+C) vs 10%–44% (S) across subgroups, and CR benefits were seen with N+C in most subgroups. Additional outcomes including landmark OS and response details in subgroups will be reported. Conclusions: Consistent with outcomes in ITT pts, efficacy benefits with N+C vs S were observed regardless of IMDC risk status, organ site of mets, or extent of tumor burden at baseline. These results support N+C as a new first-line treatment option for pts with aRCC. Clinical trial information: NCT03141177. Research Sponsor: Bristol Myers Squibb.

1 organ site $ 2 organ sites sDTL sDTL Pts w/ lung Pts w/ bone Pts w/ liver Subgroup FAV risk I risk P risk with T/NT with T/NT < 72.1 mm $ 72.1 mm mets mets mets (N+C v S, n) (74 v 72) (188 v 188) (61 v 68) (61 v 68) (261 v 258) (160 v 167) (163 v 161) (240 v 251) (79 v 72) (73 v 54)

PFS, HR (95%) 0.58 0.58 0.36 0.53 0.53 0.52 0.53 0.51 0.38 0.51 (0.36–0.93) (0.45–0.76) (0.23–0.56) (0.32–0.88) (0.43–0.67) (0.39–0.71) (0.40–0.70) (0.40–0.64) (0.25–0.59) (0.33–0.79) mPFS, mo 25 v 13 17 v 9 10 v 4 25 v 13 15 v 7 20 v 10 11 v 6 17 v 8 18 v 4 11 v 6 OS, HR (95%) 0.94 0.74 0.45 0.79 0.63 0.64 0.64 0.63 0.64 0.47 (0.46–1.92) (0.50–1.08) (0.27–0.76) (0.33–1.90) (0.47–0.84) (0.38–1.06) (0.46–0.89) (0.46–0.86) (0.39–1.06) (0.27–0.82) ORR per 66 (54–77) 56 (48–63) 38 (26–51) 62 (49–74) 53 (47–59) 62 (54–69) 48 (40–56) 56 (49–62) 48 (37–60) 49 (37–61) RECIST v1.1 v v v v v v v v v v (95% CI), % 44 (33–57) 29 (22–36) 10 (4–20) 35 (24–48) 27 (21–33) 36 (29–44) 20 (15–28) 29 (24–36) 11 (5–21) 20 (11–34) CR, % 9 v 10 11 v 3 5 v 1 20 v 4 7 v 4 16 v 8 2 v 0 8 v 4 6 v 0 1 v 2

4554 Poster Session

Outcomes of first-line (1L) ipilimumab and nivolumab (IPI-NIVO) and subsequent therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).

Chun Loo Gan, J Connor Wells, Andrew Lachlan Schmidt, Thomas Powles, Ben Tran, Luis A Meza, Chris Labaki, Jae-Lyun Lee, Lori Wood, Julia Shapiro, D. Scott Ernst, Anil Kapoor, Christina M. Canil, Takeshi Yuasa, Rana R. McKay, Benoit Beuselinck, Frede Donskov, Shaan Dudani, Toni K. Choueiri, Daniel Yick Chin Heng; Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Universi- ty of Calgary, Calgary, AB, Canada; Liz Plummer Cancer Centre, Cairns and Hinterland Hospital and Health Service, Cairns, QLD, Australia; Barts Cancer Institute, Cancer Research UK Experimental Can- cer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, Lon- don, United Kingdom; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; City of Hope Comprehensive Cancer Center, Duarte, CA; Dana Farber Cancer Institute - (Individuals), Boston, MA; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Dalhousie Uni- versity, Halifax, NS, Canada; Cabrini Health, Melbourne, Australia; Division of Medical Oncology, De- partment of Oncology, London Regional Cancer Program, London Health Sciences Centre and University of Western Ontario, London, ON, Canada; McMaster Institute of Urology, St Joseph’s Health- care, Hamilton, ON, Canada; Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; Cancer Insti- tute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; University of California San Diego, Moores Cancer Center, La Jolla, CA; Leuven Cancer Institute, Universitaire Ziekenhuizen, Leu- ven, Belgium; Aarhus University Hospital, Aarhus, Denmark; Ottawa Hospital Cancer Center, University of Ottawa, Ottawa, ON, Canada; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncol- ogy, Boston, MA

Background: IPI NIVO is approved for 1L treatment of IMDC intermediate/poor risk mRCC based on the CHECKMATE 214 trial. Herein, we report the clinical effectiveness of 1L IPI NIVO and second line (2L) therapy in the real-world setting. Methods: Using the IMDC dataset, patients (pts) treated with 1L IPI NIVO were identified. The outcomes of interest were 1L and 2L overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). Results: 706 pts were included: 9% (57/614), 58% (354/614), and 33% (203/614) were IMDC favorable (fav), intermediate (int), and poor risk, respectively. Median age was 61 years. The majority of pts were males (71%), had clear cell histology (85%), and underwent nephrectomy (61%). 36%, 19%, and 8% of patients had bone, liver, and brain metastases, respectively. The 12-month OS for pts with IMDC fav, int, and poor risk disease was 92%, 79%, and 56%, respectively (p<0.01). The corresponding estimates for 24 months were 80%, 69%, and 38% (p<0.01). Pts who responded (39%) were more likely to have better IMDC risk category (p=0.02), received nephrectomy (p=0.04), normal neutrophil count (p<0.01), and clear cell histology (p=0.01). Pts with progressive disease as best response (27%) were more likely to have not received nephrectomy (p<0.01), worse IMDC risk category (p=0.02), bone metastases (p=0.01), liver metastases (p=0.04), and non-clear cell histology (p=0.01). Of the 66% (466/706) of pts who discontinued 1L IPI NIVO, 51% (236/466) received 2L therapy: sunitinib (40%), cabozantinib (25%), pazopanib (18%), axitinib (8%), and others (9%). The ORR, median TD, and median OS for those who received either sunitinib, cabozantinib, pazopanib or axitinib was 16%, 4.5 months (mo) (95% CI 3.7- 5.6), and 14.5 mo (95% CI 10.9-25.9), respectively. 33% (129/386) of pts discontinued IPI NIVO due to irAEs. Conclusions: Our study benchmarks the real-world experience of 1L IPI NIVO in mRCC. IMDC criteria is prognostic for clinical outcome. Tyrosine kinase inhibitors have clinical activity post IPI NIVO. Research Sponsor: None.

All IMDC risk category IMDC Int/Poor 1L IPI NIVO Clear Cell Non clear Clinical Outcome Overall Fav* Int Poor All histology cell

ORR %, (n/n) 39% 45% 43% (129/303) 30% 38% (170/467) 43% (151/352) 30% (201/518) (23/51) (49/164) (14/46) P=0.02 Median TD (mo) 5.0 6.9 6.4 3.0 5.0 6.2 4.2 (95% CI) (4.0-6.4) (4.3-13.6) (4.3-7.9) (2.5-5.4) (3.9-6.6) (4.6-7.9) (2.6-8.5) P=0.03 Median TTNT (mo) 11.3 24.0 12.9 7.5 10.5 11.3 9.3 (95% CI) (9.6-13.9) (10.9-NR) (9.9-17.9) (5.4-9.8) (9.1-12.6) (9.4-15.4) (4.1-NR) P<0.01 Median OS (mo) 41.4 47.8 48.0 14.0 40.2 48.1 17.6 (95% CI) (27.6-53.4) (40.8-NR) (35.1-NR) (11.2-22.1) (25.7-NR) (35.1-NR) (7.9-NR) P<0.01

*Interpret with caution as the use of IPI NIVO in IMDC fav was highly selected in the real-world. NR= not reached. .

4555 Poster Session

Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2a (HIF-2a) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC).

Ramaprasad Srinivasan, Frede Donskov, Othon Iliopoulos, Wendy Kimryn Rathmell, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Sarah Joanne Welsh, Ananya Roy, Yanfang Liu, Rodolfo F. Perini, W. Marston Linehan, Eric Jonasch; Center for Cancer Research, National Cancer Institute, Bethesda, MD; Aarhus University Hospital, Aarhus, Denmark; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Pennsylvania, Philadelphia, PA; University of Utah, Salt Lake City, UT; Ho^pital Europe�en Georges Pompidou, Paris, France; University of Michigan, Ann Arbor, MI; Univer- sity of Pittsburgh, Pittsburgh, PA; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Merck & Co., Inc., Kenilworth, NJ; The University of Texas MD Anderson Cancer Cen- ter, Houston, TX

Background: Inactivation of VHL leads to aberrant stabilization and accumulation of HIF-2a, which drives tumor growth. Patients (pts) with VHL disease are at risk for ccRCC, pancreatic neuroendocrine tumors (pNETs), and hemangioblastomas. Repeated surgeries are often needed to control ccRCC and other VHL disease manifestations. Prior results of this ongoing open-label phase 2 study (NCT03401788) showed activity with belzutifan in VHL disease. Updated results are presented. Meth- ods: Adults with germline VHL alterations, measurable and localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS 0 or 1 received belzutifan 120 mg once daily until progression, intolerable toxicity, or decision to withdraw. The primary end point is ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent review committee (IRC). Secondary end points include DOR, time to response (TTR), PFS, and safety. Results: As of June 1, 2020, 61 pts enrolled. Most pts (82%) had ECOG PS 0, and the median number of prior tumor reduction procedures (eg, partial nephrectomy, craniotomy, radiation therapy) per pt was 5 (range, 0-15). Lesions outside the kidney (non-RCC tumors) evaluable by IRC included pNETs (33%) and CNS hemangioblastomas (82%). Median follow-up was 69 wk (range, 18-105), median duration of treatment was 68 wk (range, 8-105), and 56 pts (92%) remain on therapy. There were 22 confirmed responses (ORR, 36% [95% CI, 24-49]) and 7 (11%) un- confirmed responses (documented at 1 time point, to be confirmed at subsequent time point); all were PRs. In pts with confirmed PR, median DOR was not reached (range, 12+ to 62+ wk), median TTR was 31 wk (range, 12-61), and 56 pts (92%) had some reduction in the sum of all target lesion diameters. PFS rate at 52 wk was 98% (95% CI, 89-100). For non-RCC tumors, ORR was 80% (16/20; 1 CR) in pNETs and 32% (16/50; 1 CR) in CNS hemangioblastomas. Of 16 pts with evaluable retinal hemangioblastomas at baseline, 11 (69%) showed improvement per IRC. In those 16 pts, 29 eyes were monitored for retinal hemangioblastomas: 16 eyes (55%) showed improvement, 12 (41%) were stable, and no evaluation was available for 1 eye (3%). All 61 pts (100%) had at least one AE. The most common all-cause AE was anemia (90%), which is considered an on-target toxicity. Treatment-related AEs (TRAE) were reported by 60 pts (98%), and 8 pts (13%) had a grade 3 TRAE. No pts had grade 4/5 TRAEs. One pt discontinued treatment because of a TRAE (grade 1 dizziness). Conclusions: Belzutifan demonstrates clinical benefit and has a favorable safety profile in patients with VHL disease–associated ccRCC, pNETs, and hemangioblastomas. Clinical trial information: NCT03401788. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

4556 Poster Session

Randomized phase Ib study to evaluate safety, pharmacokinetics and therapeutic activity of simlukafusp a in combination with atezolizumab ± bevacizumab in patients with unresectable advanced/ metastatic renal cell carcinoma (RCC) (NCT03063762).

Jose Luis Perez-Gracia, Aaron Richard Hansen, Rikke Helene Loevendahl Eefsen, Carlos A. Gomez- Roca, Sylvie Negrier, Paolo Pedrazzoli, Jae-Lyun Lee, Teresa Alonso Gordoa, Cristina Suarez Rodriguez, Begona Mellado, Victor Moreno, Alejo Rodriguez-Vida, Arif Hussain, Nicole Getzmann, David Dejardin, Christophe Boetsch, Anton Kraxner, Taner Vardar, Volker Teichgra€ber, Thomas Powles; Department of Medical Oncology, Clinica Universidad de Navarra, Pamplona, Spain; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Herlev Hospital, Herlev, Denmark; Institut Claudius Regaud/IUCT-Oncopole, Toulouse, France; Departement of Medical Oncology, Centre Le�on Be�rard, Lyon, France; Fondazione IRCCS Policlinico San Matteo, Pa- via, Italy; Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea; Hospi- tal Universitario Ramo�n y Cajal, Madrid, Spain; Medical Oncology, Vall d�Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d�Hebron, Vall d�Hebron Barcelona Hospital Campus, Barcelona, Spain; Hospital Cl�ınic, Provincial de Barcelona, Barcelona, Spain; START Madrid-FJD, Fundacio�n Jime�nez D�ıaz Hospital, Madrid, Spain; Medical Oncology Department, Hospital del Mar Research Insti- tute, Barcelona, Spain; University of Maryland Cancer Center, Baltimore, MD; Roche, Basel, Switzer- land; Roche, Biostatistics Oncology pRED, Basel, Switzerland; Roche Innovation Center, Basel, Switzerland; Roche/Genentech, Basel, Switzerland; F. Hoffmann-La Roche AG, Basel, Switzerland; Hoffmann-La Roche, Basel, Switzerland; Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom

Background: Simlukafusp a ([SIM], FAP-IL2v) is a novel IL-2v immunocytokine engineered to preferen- tially activate effector CD8 T and NK cells, but not regulatory T cells (Tregs), due to abolished binding to Interleukin-2 receptor a (IL-2Ra) and retained affinity to IL-2Rbc. High affinity binding of SIM to fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, mediates its accumulation in malignant lesions. Methods: The Dose-Escalation (DE) consisted of: Arm A: SIM 5-25 mg weekly for 4 weeks, and every 2 weeks (Q2W) thereafter in combination with atezolizumab [ATZ] 840mg Q2W; and Arm B: same as Arm A + bevacizumab [BEV] 10 mg/kg Q2W. Patients (pts) not previously treated were evaluated in the Extension Part: Arm C (n=3): SIM + ATZ every 3 weeks (Q3W); or Arm D (n=25): SIM + ATZ + BEV (triplet) Q3W. Primary objectives were: finding the recommended dose of SIM and assessment of objective response rate (ORR) by RECIST v1.1. Results: We enrolled 69 pts with unresectable advanced/ metastatic clear-cell and/or sarcomatoid RCC. Median age of patients was 57 years (range: 35-78). The recommended dose for extension of SIM was 10 mg. Median treatment duration in days in each arm were: A: 106 (range: 1-877); B: 324 (8-940); C: 659 (71-768); D: 437 (1-682). Twenty-five pts are evaluable for therapeutic activity in Arm A [ORR: 24% (6 PR; 90% CI 12.95, 40.12)]; 15 in Arm B [46.7% (1 CR, 6PR; 90% CI 27.67, 66.68)]; 3 in Arm C [33.3% (1PR; 90% CI 7.83, 74.65)]; and 23 in Arm D [47.8% (2 CR, 9 PR; 90% CI 35.74, 68.15)]. Twelve patients are ongoing on study treatment. Treatment related grade 3 and 4 adverse events (AE) occurred respectively in 69.7% and 9.1% patients. The most common serious AEs were pyrexia (10.6 %) and infusion-related reactions (9.1%). 65.2% Of the patients reported at least one AE of elevations in liver transaminases/ GGT/ alkaline phosphatase/bilirubin. Drug-related AEs led to dose modification/interruption in 37.9 % of the pts, and treatment discontinuation in 3% of the patients. SIM led to preferential expansion and activation of NK and CD8 T cells (but not Tregs) in peripheral blood and augmented tumor infiltration and tumor inflammation. Intriguingly responses were observed not only in pts with PD-L1 positive or in- flamed tumors, but also in pts with PD-L1 negative tumors (n=13) or poorly infiltrated tumors classified as immune deserts (n=2). Conclusions: The combination of SIM with ATZ ± BEV was feasible with an acceptable safety profile. Clinical activity was more favorable for the triplet among the study Arms, but comparable to the ATZ + BEV combination in the IMmotion151 (Rini B, et al 2019). Observed pharma- codynamic findings were consistent with the expected effects. Clinical trial information: NCT03063762. Research Sponsor: Roche.

4557 Poster Session

Treatment outcomes in renal cell carcinoma patients with metastases to the pancreas and other sites.

Cassandra Duarte, Benoit Beuselinck, Nicole Weise, Nazli Dizman, Katharine Collier, Haoran Li, Nieves Martinez Chanza, Roy Elias, Tracy L Rose, James Brugarolas, Neeraj Agarwal, Amir Mortazavi, Sumanta K. Pal, Rana R. McKay, Junxiao Hu, Elaine Tat Lam; University of Colorado Denver, Denver, CO; Leuven Cancer Institute, Universitaire Ziekenhuizen, Leuven, Belgium; UC San Diego Moores Can- cer Center, La Jolla, CA; City of Hope Comprehensive Cancer Center, Duarte, CA; Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH; Tom Baker Cancer Centre, Toronto, ON, Canada; Consorcio Hospital General Universitario de Valencia, Valencia, Spain; University of Texas Southwestern Medical Center, Dallas, TX; 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 Texas Southwestern Medical Center, Dallas, TX; Huntsman Cancer Institute, Universi- ty of Utah, Salt Lake City, UT; Arthur G. James Cancer Hospital, Ohio State University Wexner Medical Center, Columbus, OH; Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA; University of California San Diego, Moores Cancer Center, La Jolla, CA; Uni- versity of Colorado Cancer Center, Aurora, CO; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO

Background: Metastatic RCC (mRCC) involving the pancreas is distinct from RCC involving other metastatic sites and is characterized by an indolent clinical course, heightened angiogenesis, and an in- flamed stroma (PMID: 32271170). We previously reported on outcomes of RCC patients (pts) with pancreatic oligometastasis (ASCO GU 2020). We now report on outcomes in pts with mRCC involving the pancreas in conjunction with other metastases (mets). Methods: We conducted a retrospective, multi-institutional study of mRCC pts with mets to the pancreas and other sites. Data on pt demographics, tumor characteristics, systemic therapy, and outcomes were collected. Pts were classified based on treatment category: immunotherapy (IO) or vascular endothelial growth factor/receptor inhibitors (VEG- FI). Outcomes measured included objective response rates (ORR), time-on-treatment (TOT), and overall survival (OS). Results: The analysis included 229 pts from 9 institutions, diagnosed between 1985- 2020. Of these, 211 (92%) had clear-cell histology; 131 (57%) had nephrectomy; 41 (18%) had local pancreas-directed therapy; 111 (48%) had synchronous presentation of disease in the pancreas and other sites at time of mets. IMDC risk was favorable in 33%, intermediate in 41%, poor in 11%, and unknown in 15% pts. Median lines of therapy was 2 (range 0-9). Of 219 pts who received first-line (1L) therapy, 151 (69%) had VEGFI therapy, 41 (19%) had IO, and 18 (8%) had VEGFI/IO combination (Ta- ble). The IO group included 21 pts on checkpoint inhibitor (CPI), 16 pts on HD-IL2, 4 pts on other IO. 1L ORR was 39.7% for VEGFI (95% CI 31.8-48.0) and 31.7% for IO (95% CI 18.1-48.1) and was not statistically significant (NS, OR 1.4, 95% CI 0.65-3.23, p = 0.371). Median TOT for 1L therapy was 11.6m for VEGFI and 6.5m for IO (p = 0.0106). With a median follow-up of 51.5m, the median OS (mOS) for all pts from time of metastatic disease was 7.7 years (y) (95% CI 6.3-10.3). The mOS for pts who received 1L VEGFI was 7.6y (95% CI 5.5-9.5) and was not reached (NR) for those who got 1L IO (95%CI 6.5-NR); this difference was significant with an unadjusted p-value of 0.029. The pair-wise comparison between mOS of the 1L CPI subgroup compared to that of the 1L VEGFI group was significant (p = 0.0148). Conclusions: Consistent with the literature, mRCC pts with involvement of the pancreas in this study have prolonged OS compared to historical OS for the standard mRCC population. Additionally, our findings suggest that the choice of first-line therapy may impact outcomes. Additional analyses will be presented. Research Sponsor: None.

First-Line therapy. N=219 ORR % Median TOT, months [IQR] Median OS, years (95% CI) VEGFI 151 39.7 11.6 [4.0-28.1] 7.6 (5.5, 9.5) Immunotherapy 41 31.7 6.5 [3.0-10.0] NR (6.5, NR) CPI 21 38 4.3 [2.0-11.6] NR (NR, NR) HD-IL2 16 25 7.5 [4.0-9.0] 7.4 (6.5, NR) Other Immuno 4 25 9.5 [2.0-33.0] 6.0 (5.8, NR) VEGFR + CPI 18 44 15.0 [5.7-21.3] 6.2 (2.8, NR) Other 9 11 19.6 [8.6-34.0] 3.3 (2.1, NR)

4558 Poster Session

Programmed death ligand-1 (PD-L1) expression in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in NIVES study.

Cristina Masini, Gabriele Carlinfante, Cinzia Iotti, Ugo De Giorgi, Roberto Salvatore Bellia, Sebastiano Buti, Francesco Salaroli, Ilaria Zampiva, Renzo Mazzarotto, Claudia Mucciarini, Maria Giuseppa Vitale, Alessio Bruni, Giuseppe Procopio, Stefania Kinspergher, Valentina Vanoni, Franco Nole, Franco Morelli, Susanne Baier, Consuelo Buttigliero, Carmine Pinto; Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy; Pathology Unit, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy; Oncological Radiotherapy Unit, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Radiotherapy Unit, Azienda Universitario- Ospedaliera di Parma, Parma, Italy; University of Verona, Verona, Italy; Radiotherapy Unit, Azienda Ospedaliero Universitaria Integrata Verona, Verona, Italy; Medical Oncology Unit, Ramazzini Hospital, Carpi, Italy; Oncology Unit, Azienda Policlinico-Universitaria di Modena, Modena, Italy; Radiotherapy Unit, Azienda Policlinico Universitaria di Modena, Modena, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Santa Chiara Hospital, Trento, Italy; Medical Oncology Division of Urogenital and Head and Neck Tumors, European Institute of Oncology, Milan, Italy; IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Medical Oncology Unit, Azienda Sanitaria dell’Alto Adige, Bolzano, Italy; Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy; Medical Oncology Unit, Clinical Cancer Center, AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy

Background: The NIVES study represents the first prospective trial with NIVO in combination with SBRT in pre-treated mRCC patients. This study did not meet the primary endpoint in terms of objective response rate (ORR) as previously reported. However this combination showed a faster time to treatment response, a long progression free survival and median duration of response without increasing toxicities. Here we have tested with an exploratory analysis the correlation between PD-L1 expression and clinical outcomes in pts treated with NIVO plus SBRT. Methods: PD-L1 expression was assessed in archival collected tumour samples in our central laboratory using 4 commercial kits for immunoistochemical (ICH) analysis (clone 22C3 pharm DX Dako Agilent, 28.8 Abcam and SP142 and SP263 Ventana Medical System). A tumor cell was considered positive if any membranous staining was found regardless of the intensity. In particular the immunostaining was scored 0 when all tumor cells were unstained (PD-L1- negative), 1+ when < 1% positive tumor cells were counted, 2+ when the percentage was between 1% and 50%,3+ when the number of stained cells was more than 50%. ORR and overall survival (OS) were correlated with PD-L1 staining. Results: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 44 of 69 pts enrolled in the NIVES study. Twenty-two pts of 44 (50%) were considered PD- L1-negative using all the 4 commercial kits for ICH analysis, while 14 of 44 pts (31,8%) were defined PD-L1 weakly positive (positive tumor cells < 1% at least in one kit for ICH). Eight of 44 pts (18.1%) were defined PD-L1 strong positive when at least one kit for ICH scored 2+ or 3+. About the correlation between ORR and PDL1 staining in the 42 pts (2/44 pts are not evaluable for ORR), ORR was 18.2% (95% CI, 5.2% to 40.3%) in the PD-L1-negative group vs 20% (95% CI, 5.7% to 43.7%) in weakly/ strongly PD-L1 positive (p = 1.00). Among the 44 pts in the intention-to-treat population with available PD-L1 status, median OS was not significantly different between pts with PD-L1 negative (20.56 months, 95% CI, 7.16 to NR) and PD-L1 positive (18.33 months, 95% CI, 6.83 to NR) (p = 0.56). Conclusions: For the first time four commercial kits for ICH analysis were used to test PD-L1 expression in pretreated mRCC pts. Data from these small sample size seem to confirm that PD-L1 in pre-treated mRCC cancer is not a predictive biomarker for selecting pts to receive NIVO-based treatment. Clinical trial information: NCT03469713. Research Sponsor: GOIRC, Pharmaceutical/Biotech Company.

4559 Poster Session

An FDA-pooled analysis of frontline combination treatment benefits by risk groups in metastatic renal cell carcinoma (mRCC).

Daniel Lee, Haley Gittleman, Chana Weinstock, Daniel L. Suzman, Erik Bloomquist, Sundeep Agrawal, Michael Holman Brave, Jamie Renee Brewer, Harpreet Singh, Shenghui Tang, Richard Pazdur, Julia A. Beaver, Amna Ibrahim, Laleh Amiri-Kordestani; Natl Cancer Inst, Germantown, MD; U.S. Food and Drug Administration, Silver Spring, MD; Johns Hopkins University, Baltimore, MD; Medstar Washington Hosp Ctr, Washington, DC; University of Chicago, Chicago, IL

Background: The International Metastatic RCC Database Consortium (IMDC) risk model was developed for prognosis of patients with mRCC treated with vascular endothelial growth factor (VEGF)-targeted monotherapy in the first-line setting. Efficacy in trials of anti-VEGF therapy has been generally consistent across risk groups, including for overall survival (OS). For trials of immunotherapy combinations, the small numbers of OS events for the favorable risk group in each trial limited reliable conclusions; however, there was a suggestion of possible differential effects on OS between favorable risk and other risk groups. Methods: We pooled individual patient data (n=3447) from four phase III randomized trials of combinations of immunotherapy + immunotherapy (n=1) or immunotherapy + anti-VEGF therapy (n=3) submitted to the US Food and Drug Administration in support of marketing applications. All trials calculated IMDC risk group for each patient and used a control arm of sunitinib. We combined intermediate and poor prognostic groups (intermediate/poor) and compared their OS to that of the favorable risk group using Kaplan-Meier and Cox Proportional Hazards methods. Results: In this pooled analysis, treatment with combination immune checkpoint therapy did not demonstrate an improvement in OS compared to sunitinib in the favorable risk group (HR 0.953; 95% CI: 0.72, 1.27). An improvement in OS was observed in the intermediate/poor risk group (HR 0.696; 95% CI: 0.62, 0.78). Conclusions: Our analysis of OS in patients treated with immunotherapy combinations compared to sunitinib suggests possible differential benefit in the favorable risk compared to the intermediate/poor risk group. These results are not conclusive and considered exploratory due to the relative immaturity of OS in the favorable risk group. Follow-up for survival continues in each study to allow for more definitive results. Research Sponsor: FDA.

Overall survival by risk status. Favorable Risk Arm N Deaths (%) Median (95% CI)* HR (95% CI) Combination 422 93 (22.0) NR (NR, NR) 0.953 (0.72, 1.27) Sunitinib 404 93 (23.0) NR (NR, NR) Intermediate/Poor Arm N Deaths (%) Median OS (95% CI) HR (95% CI)

Combination 1,308 534 (40.8) 46.8 (39.9, NR) 0.696 (0.62, 0.78) Sunitinib 1,313 668 (50.9) 29.3 (26.0, 32.9)

*Months.

4560 Poster Session

Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): Depth of response and efficacy for selected subgroups in the lenvatinib (LEN) + pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms.

Viktor Gru€nwald, Thomas Powles, Evgeny Kopyltsov, Vadim Kozlov, Teresa Alonso Gordoa, Masatoshi Eto, Thomas E. Hutson, Robert J. Motzer, Eric Winquist, Pablo Maroto-Rey, Bhumsuk Keam, Giuseppe Procopio, Shirley Wong, Bohuslav Melichar, Frederic Rolland, Mototsugu Oya, Karla Rodriguez-Lopez, Kenichi Saito, Alan D. Smith, Camillo Porta; University Hospital Essen, Essen, Germany; The Royal Free NHS Trust, London, United Kingdom; State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russian Federation; State Budgetary Health Care Institution Novosibirsk Regional Clinical Oncology Dispensary, Novosibirsk, Russian Federation; Hospital Universitario Ramo�n y Cajal, Madrid, Spain; Kyushu University, Fukuoka, Japan; Texas Oncology, Dallas, TX; Memorial Sloan Ketter- ing Cancer Center, New York, NY; Western University, London, ON, Canada; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Seoul National University Hospital, Seoul, South Korea; Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Western Health, Vic, Australia; Palacky� University Medical School and Teaching Hospital, Olomouc, Czech Republic; Centre Rene� Gauducheau Centre de Lutte Contre Le Cancer Nantes, Saint-Herblain, France; Keio University School of Medicine, Tokyo, Japan; Merck & Co., Inc., Kenilworth, NJ; Eisai Inc., Woodcliff Lake, NJ; Eisai Ltd., Hatfield, United Kingdom; San Matteo University Hospital Foundation, Pavia, Italy

Background: In the multicenter, open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS and OS benefits, and improved ORR vs SUN in first-line advanced RCC. Herein, we explore efficacy according to selected subgroups and the association between pts’ depth of response and OS. Methods: Pts in the CLEAR study were randomly assigned 1:1:1 to 1 of 3 treatment arms: LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + everolimus 5 mg orally QD; or SUN 50 mg orally QD (4 weeks on/2 weeks off). We report PFS, OS, and ORR based on IMDC risk group (favorable and intermediate/poor) and presence of a target kidney lesion at baseline (post hoc analysis). Post hoc 6- month landmark analyses assessed the association between tumor shrinkage and OS. Pts who were alive at 6 months were grouped based on maximum tumor shrinkage from baseline or confirmed complete response (CR) up to 6 months. Tumor assessments were performed by independent review committee per RECIST v1.1. Odds ratios were calculated using the Cochran-Mantel-Haenszel method; HRs were based on stratified Cox proportional hazards model. Results: Among 1069 pts randomized in the CLEAR study, 355 were assigned to LEN + PEMBRO and 357 to SUN. Median follow-up was 27 months for the LEN + PEMBRO group and 26 months for the SUN group. PFS favored LEN + PEMBRO (median 22.1 months, n=243) vs SUN (median 5.9 months, n=229) in the IMDC-intermediate/poor subgroup (HR 0.36 [95% CI 0.28-0.47]); and in the IMDC-favorable subgroup (median 28.1 months, n=110 vs median 12.9 months, n=124; HR 0.41 [95% CI 0.28-0.62]). OS favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (HR 0.58 [95% CI 0.42-0.80]); few events were observed in the IMDC-favorable subgroup thus, it was inadequate to evaluate OS. ORR favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (72.4% vs 28.8%; odds ratio 6.60 [95% CI 4.39-9.90]) and the IMDC-favorable subgroup (68.2% vs 50.8%; odds ratio 2.00 [95% CI 1.17- 3.42]). In pts with target kidney lesions, PFS, OS, and ORR were improved with LEN+PEMBRO vs SUN (table). The 6-month landmark analysis in the LEN + PEMBRO group showed that the OS rate at 24 months was 100% (95% CI not estimable [NE]-NE) for pts with confirmed CR per RECIST v1.1 and 91.7% (95% CI 53.9-98.8) both for pts with >75% to <100% target-lesion reduction and pts with 100% target-lesion reduction. Conclusions: In pts with target kidney lesions, LEN + PEMBRO conferred survival benefits vs SUN similar to benefits observed in the overall population. Overall, pts treated with LEN + PEMBRO who had greater than 75% reduction in target lesions had similar OS rates to pts with CR. Clinical trial information: NCT02811861. Research Sponsor: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

LEN + PEMBRO SUN (n=78) (n=74) mPFS (mos) 22.1 7.5 HR (95% CI) 0.40(0.25-0.65) mOS (mos) Not reached 30.7 HR (95% CI) 0.44 (0.26-0.77) ORR (%) 71.8 27.0 Odds ratio (95% CI) 10.55 (4.54-24.52) m, median.

4561 Poster Session

Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).

Amishi Yogesh Shah, Robert J. Motzer, Andrea B. Apolo, Thomas Powles, Bernard Escudier, Joshua Zhang, Christian Scheffold, Sravan Karumanchi, Linh Thuy Nguyen, Toni K. Choueiri; The University of Texas MD Anderson Cancer Center, Houston, TX; Memorial Sloan Kettering Cancer Center, New York, NY; National Cancer Institute, National Institutes of Health, Bethesda, MD; Barts Cancer Institute, Can- cer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom; Gustave Roussy, Villejuif, France; Bristol My- ers Squibb, Princeton, NJ; Exelixis, Inc., Alameda, CA; Ann Arbor Pharmacometrics Group, Ann Arbor, MI; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression- free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Meth- ods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time- to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr $1], diarrhea [Gr $3], hypertension [Gr $3], fatigue/asthenia [Gr $3], and ALT/AST elevation [Gr $3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177. Research Sponsor: BMS/Exelixis.

4562 Poster Session

Post hoc analysis of the CLEAR study in advanced renal cell carcinoma (RCC): Effect of subsequent therapy on survival outcomes in the lenvatinib (LEN) + everolimus (EVE) versus sunitinib (SUN) treatment arms.

Thomas E. Hutson, Toni K. Choueiri, Robert J. Motzer, Sun Young Rha, Anna Alyasova, Jaime R. Merchan, Howard Gurney, Avivit Peer, Toshio Takagi, Camillo Porta, Thomas Powles, Viktor Gru€nwald, Ugo De Giorgi, Ulka N. Vaishampayan, Manuela Schmidinger, Hilary Glen, Karla Rodriguez-Lopez, Dongyuan Xing, Lea Dutta, Masatoshi Eto; Texas Oncology, Dallas, TX; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Yonsei Cancer Center, Yonsei Uni- versity Health System, Seoul, South Korea; Prevoljskiy Region Medical Centre, Novgorod, Russian Fed- eration; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; Macquarie University Hospital, Sydney, NSW, Australia; Rambam Health Care Campus, Haifa, Israel; Tokyo Women’s Medi- cal University, Tokyo, Japan; San Matteo University Hospital Foundation, Pavia, Italy; The Royal Free NHS Trust, London, United Kingdom; University Hospital Essen, Essen, Germany; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; University of Michigan, Ann Arbor, MI; Medical University of Vienna, Vienna, Austria; Beatson West of Scotland Cancer Center, Glasgow, United Kingdom; Merck & Co., Inc., Kenilworth, NJ; Eisai Inc., Woodcliff Lake, NJ; Kyushu University, Fukuoka, Japan

Background: The multicenter, open-label, randomized, phase 3 CLEAR study showed that LEN + EVE had a significant PFS benefit (HR 0.65, 95% CI 0.53-0.80, P<0.001) and improved objective response rate (relative risk 1.48, 95% CI 1.26-1.74) vs SUN in the first-line treatment of patients (pts) with advanced RCC. The difference in overall survival (OS) for LEN + EVE vs SUN was not statistically significant (HR 1.15, 95% CI 0.88-1.50) (Motzer R et al. NEJM. 2021). Post hoc subgroup analyses were performed to assess the impact of subsequent therapy on OS. Methods: Pts in the CLEAR study were randomly assigned (1:1:1) to 1 of 3 treatment arms, including LEN 18 mg + EVE 5 mg once daily (QD) and SUN 50 mg QD (4 weeks on then 2 weeks off). These post hoc analyses examined OS by subsequent systemic anticancer medication in the LEN + EVE and SUN arms. Hazard ratios (HR; LEN + EVE vs SUN) were based on stratified (geographic region and MSKCC prognostic risk groups) Cox proportional hazards model. Results: Among 1069 pts with advanced RCC randomized in the CLEAR study, 714 pts were randomly assigned to the LEN + EVE and SUN arms (N=357/each). The median duration of survival follow-up was 27 months in the LEN + EVE arm and 26 months in the SUN arm. Given the shorter median duration of study treatment with SUN (7.8 months) vs LEN + EVE (11.0 months), more pts in the SUN arm received subsequent anticancer therapy during survival follow-up (LEN + EVE, n=167; SUN, n=206). Among pts who received subsequent therapy, pts in the LEN + EVE arm had a longer median time from randomization to initiation of subsequent therapy vs those in the SUN arm (8.0 vs 6.6 months, respectively). OS for the overall population, for pts with no subsequent anticancer therapy, and for pts with no subsequent immunotherapy is shown in the table. In the US population subgroup (LEN + EVE, n=62; SUN, n=61) of the CLEAR study, in which a similar number of pts received subsequent systemic anticancer therapies in the LEN + EVE vs SUN arms (62.9% vs 65.6%, respectively), OS was comparable among the 2 arms (HR 0.95, 95% CI 0.51-1.76). Overall, the safety profile was consistent with the known safety profiles of LEN + EVE and SUN. In both arms, most treatment-emergent deaths were due to progressive disease; there were few treatment-related deaths (<1%, per arm) and no clustering of events. Conclusions: In the CLEAR study, LEN + EVE met the primary endpoint of a significant benefit in PFS vs SUN. The results of these exploratory analyses suggest that subsequent systemic anticancer therapy affected the OS outcome results for LEN + EVE vs SUN in the CLEAR study. Clinical trial information: NCT02811861. Research Sponsor: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

LEN + EVE SUN

Overall, n 357 357 Median OS Not reached (NR) NR HR (95% CI) 1.15 (0.88-1.50) No subsequent anticancer therapy, n 190 151 Median OS NR NR HR (95% CI) 0.91 (0.58-1.44) No subsequent immunotherapy, n 231 203 Median OS NR NR HR (95% CI) 1.09 (0.75-1.57)

4563 Poster Session

Association of baseline neutrophil-to-eosinophil ratio (NER) and neutrophil-to-lymphocyte ratio (NLR) with response to combination immunotherapy (IO) with ipilimumab plus nivolumab (ipi/nivo) in patients with metastatic renal cell carcinoma (mRCC).

Matthew D. Tucker, Landon Carter Brown, Chester Kao, Nathan Hirshman, Emily Noelle Kinsey, Yu-Wei Chen, Kristin Kathleen Ancell, Katy Beckermann, Nancy B. Davis, Renee McAlister, Kerry Schaffer, Andrew J. Armstrong, Michael Roger Harrison, Daniel J. George, Wendy Kimryn Rathmell, Brian I. Rini, Tian Zhang; Vanderbilt University Medical Center, Nashville, TN; Duke University Medical Center, Dur- ham, NC; Vanderbilt-Ingram Cancer Center, Nashville, TN; Duke Cancer Institute Center for Prostate & Urologic Cancers, Duke University, Durham, NC; Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC

Background: Previous reports have shown that the baseline neutrophil-to-lymphocyte ratio (NLR) is associated with prognosis in patients with mRCC. However, NLR has not been shown to reliably predict for response to IO. Retrospective analyses in metastatic melanoma and mRCC have shown an association of eosinophilia with improved outcomes to single agent immunotherapy. We sought to evaluate and compare the baseline NLR and NER with response to ipi/nivo in patients with mRCC. Methods: A retrospective review of patients with mRCC treated at the Vanderbilt-Ingram Cancer Center or Duke Cancer Institute with ipi/nivo was performed. Patients with clear cell histology and a baseline complete blood count with differential were included. Patients previously treated with IO were excluded. Patients were separated into groups (above and below the median) based on baseline median NER and baseline median NLR. Analyses of progression free survival (PFS) and overall survival (OS) were conducted using the log rank test. The odds ratio (OR) for objective response rate (ORR) was analyzed using Fisher’s exact test. Results: 111 patients met inclusion criteria. The median age was 60, 77% of patients were male, 68% had prior nephrectomy, 74% were nave to systemic therapy, and 84% were IMDC intermediate/ poor risk. The median NER was 25.0 and median NLR was 3.4. Patients with < median baseline NER had significant improvement in PFS, OS, and ORR (see table). Patients with < median baseline NLR had significant improvement in OS but not in PFS or ORR. Conclusions: Baseline NER was associated with improved outcomes with ipi/nivo. While both NER and NLR were associated with improved OS, only NER was additionally associated with both improved PFS and ORR. With multiple first-line treatment options for mRCC, baseline NER may serve as an early non-invasive predictor for response to ipi/ nivo. Research Sponsor: None.

median median median median NER NER NLR NLR (n = 56) (n = 55) (n = 56) (n = 55) mPFS (mo) 8.3 2.9 HR 0.49, p < 0.01 5.6 5.1 HR 1.06, p = 0.81 mOS (mo) NR 27.3 HR 0.32, P < 0.01 NR 27.3 HR 0.31, p < 0.01 ORR (%) 39.3% 20.0% OR 2.59, p = 0.04 28.6% 30.9% OR 0.89, p = 0.84

4564 Poster Session

Phase II trial of stereotactic ablative radiation (SAbR) for oligoprogressive kidney cancer.

Raquibul Hannan, Michael Christensen, Aurelie Garant, Hans J. Hammers, Waddah Arafat, Kevin Dale Courtney, Isaac Alex Bowman, Suzanne Cole, David Sher, Chul Ahn, Robert D. Timmerman, James Brugarolas; University of Texas Southwestern Medical Center, Dallas, TX; Laval University, Montreal, QC, Canada; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dal- las, TX; University of Wisconsin, Madison, WI; UT Southwestern Medical Center, Dallas, TX; University of Texas Southwestern, Dallas, TX; The University of Texas Southwestern Medical Center, Dallas, TX

Background: Metastatic renal cell carcinoma (mRCC) patients on systemic therapy may experience oligoprogression. SAbR has been demonstrated to be safe and is associated with high local control rates in mRCC. In this prospective phase II single arm trial, we investigated SAbR to control oligoprogressive mRCC. Methods: Patients with mRCC who demonstrated response to systemic therapy with subsequent radiographic evidence of three or fewer sites of progression were treated with SAbR to all progressive sites. Systemic therapy was held during SAbR at the discretion of the treating oncologist. Follow-up included radiographic imaging at three-month intervals. Sequential SAbR for continued oligoprogression was allowed. The primary objective was extension of ongoing systemic therapy by >6 months in 40% of the patients. Progression was defined by any of these 3 criteria: (1) local failure at a radiated site; (2) progression ineligible for additional SAbR (>3 sites) or involving >30% of metastasis; or (3) progression as clinically determined by treating physicians. An exact binomial test was used to test the probability of postponing systemic therapy. Secondary endpoints focused on overall survival (OS), local control (LC) rates, toxicity, and health-related quality of life (QOL). Results: The trial completed accrual with enrollment of 20 patients who received SAbR to a total of 36 sites. At enrollment four, twelve, three, and one patients were on first, second, third, and fourth line of systemic therapy, respectively. Eleven were on immunotherapy and nine on a tyrosine-kinase inhibitor. Three patients required repeat SAbR to a new site for sequential disease control. At a median follow-up of 8.3 months (interquartile range 3.9 – 15.1), SAbR extended the duration of the ongoing systemic therapy by >6 months in 12 out of 17 patients (70.6%, 95% CI: 48.9%-92.3%). Thirteen out of 20 patients progressed with a median PFS of 8.7 months (95% CI: 3.2-12.4). Five patients died and the OS did not reach the median. LC was 36/36 (100%). Treatment related grade 1 and grade 2 toxicity was experienced by three and one patient, respectively; no grade 3 toxicities were reported. When compared to baseline, no significant decline in QOL was detected. Conclusions: SAbR extended PFS of ongoing systemic by >6 months in oligoprogressive patients with mRCC. SAbR was safe and did not adversely affect QOL. These data support further evaluation of SAbR for oligoproressive mRCC in a prospective randomized setting. Clinical trial information: NCT03696277. Research Sponsor: UT Southwestern Medical Center Department of Radiation Oncology.

4565 Poster Session

Ipilimumab + nivolumab in people with rare variant renal cell carcinoma refractory to nivolumab alone: Part 2 of UNISON (ANZUP 1602) nivolumab then ipilimumab + nivolumab in advanced non-clear cell renal cell carcinoma.

Craig Gedye, David William Pook, Laurence Eliot Miles Krieger, Carole A. Harris, Jeffrey C. Goh, Ganessan Kichenadasse, Howard Gurney, Craig Underhill, Francis Parnis, Anthony M. Joshua, Tom Ferguson, Felicia Roncolato, Michelle L. Harrison, Stephen Begbie, Michelle Frances Morris, Elizabeth J. Hovey, Mathew George, Prashanth Prithviraj, Emma Link, Ian D. Davis, Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP); Calvary Mater Newcastle, Waratah, NSW, Australia; Monash University, Melbourne, VIC, Australia; Royal North Shore Hospital, Northern Cancer Institute, St. Leonards, NSW, Australia; St. George Hospital Cancer Care Center, Kingsford, NSW, Australia; Royal Brisbane and Women’s Hospital, Herston and University of Queensland, St. Lu- cia, QLD, Australia; Southern Oncology Clinical Research Unit, Bedford Park, SA, Australia; Depart- ment of Clinical Medicine, Macquarie University, Sydney, NSW, Australia; UNSW Rural Medical School, Albury Campus, Albury-Wodonga, Australia; Ashford Cancer Center, Adelaide, Australia; St Vin- cent’s Hospital, Sydney, Australia; Royal Perth Hospital, Perth, Australia; Macarthur Cancer Therapy Center, Sydney, Australia; Royal Prince Alfred Hospital, Hunters Hill, NSW, Australia; Port Macquarie Base Hospital, Port Macquarie, Australia; Sunshine Coast Cancer Services, Nambour, Australia; Prince of Wales Hospital, Sydney, Australia; Northwest Cancer Center, North Tamworth, Australia; Ballarat On- cology and Haematology Services, Ballarat, Australia; Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia; Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia

Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Sta- ble disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239. Research Sponsor: Bristol Myers Squibb, Other Gov- ernment Agency, Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).

4566 Poster Session

Survival trends of men and women with metastatic clear cell renal cell carcinoma.

Claud Grigg, Sally Trufan, Peter E Clark, Stephen Boyd Riggs, Jason Zhu, Justin T. Matulay, Derek Raghavan, Earle F Burgess; Levine Cancer Institute, Atrium Health, Charlotte, NC

Background: Clear cell renal cell carcinoma (ccRCC) is nearly twice as common in men as in women, and women with non-metastatic RCC have a better prognosis than men. The etiology for these disparities is not known, though sex-specific differences in risk factor prevalence and tumor biology have been reported. The differential impact of systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), on prognosis in women and men with metastatic ccRCC is not defined. Methods: Clinicopathologic features and survival of patients with clinical stage IV ccRCC were obtained from the National Cancer Database (NCDB). Patients were grouped by date of metastatic diagnosis into three eras that correspond to major advances in systemic therapy: 2004-2005 (pre-TKI), 2006-2014 (TKI), and 2015-2016 (ICI). Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: 15,025 male and 7,100 female patients with metastatic ccRCC were identified. Demo- graphic features were similar between cohorts though females were slightly older (median 64.8 vs 62.7 mo, p < 0.0001), more likely to be black (6.5% vs 6.0%, p = 0.0119) or receiving Medicare benefits (46.4% vs 39.9%, p < 0.0001). In the combined cohort, median overall survival (OS) was higher in patients diagnosed in the ICI vs TKI (23.0 vs 16.5 mo) and pre-TKI eras (14.4 mo, log-rank p < 0.0001). Compared with men of the same age groups, OS was inferior for women age 50-64 yr (median 18.4 vs 21.1mo, p = 0.0084) and > 64 yr (15.3 vs 12.6mo, p = 0.0001), but not < 50 yr (20.3 vs 21.7mo, p = 0.6290). In the ICI era, median OS improved by a lesser absolute but similar relative amount for women compared to men (+5.6mo [+39%] and +7.2mo [+41%]), respectively). After controlling for age, race, Charlson-Deyo score, initial treatment modality, and insurance and socioeconomic status, women remained at increased risk of death in both the ICI era (HR 1.12 [95% CI 1.04-1.22], p = 0.004) and the TKI era (HR 1.08 [1.04-1.12], p < 0.001). Conclusions: Women with metastatic ccRCC have a worse prognosis than men which is not explained by demographic differences. This disparity is observed in both the TKI and ICI eras. This finding contrasts with previous studies suggesting women with localized RCC have a favorable prognosis compared with men. Further investigation into the sex-specific biology of metastatic ccRCC is warranted. Research Sponsor: None.

4567 Poster Session

Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.

Sumanta K. Pal, David F. McDermott, Bernard Escudier, Thomas E. Hutson, Camillo Porta, Elena Verzoni, Michael B. Atkins, Michael N. Needle, Brian I. Rini; Department of Medical Oncology & Thera- peutics, City of Hope Comprehensive Cancer Center, Duarte, CA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Gustave Roussy, Villejuif, France; Texas A&M College of Medicine, Bryan, TX; University of Bari ’A. Moro’ and Policlinico Consorziale di Bari, Bari, Italy; Fon- dazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Aveo Oncology, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN

Background: The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience. Methods: Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm. Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR. Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR. Clinical trial information: NCT02627963. Research Sponsor: AVEO Oncology.

Time to onset TEAE Duration TEAE Dose Days Days modification Any grade (%) Grade >3 (%) (IQ range) (IQ range) rate (%)* TIVO SOR TIVO SOR TEAE (n = 173) (n = 170) (n = 173) (n = 170) TIVO SOR TIVO SOR TIVO SOR

HTN 43% 29% 24% 15% 17 15 29 50 20% 26% (11-35) (6-29) (7-66) (10-–) Diarrhea 43% 54% 2% 11% 58 43 15 31 18% 34% (27-127) (15-85) (3-57) (4-102) Asthenia/Fatigue 66% 48% 13% 12% 29 17 90 84 24% 37% (11-74) (7-68) (28-–) 28-–) Nausea/Vomiting 34% 26% 1% 5% 54 38 15 14 25% 58% (14-107) (6-85) (3-71) (4-42) Rash 13% 34% < 1% 15% 110 12 51 15 18% 55% (39-294) (10-15) (14-–) (7-32) PPE 16% 41% 1% 10% 40 15 62 23 14% 46% (29-71) (10-22) (26-–) (10-94)

*Proportion of patients with TEAE that resulted in study drug dose interruption, reduction, or discontinuation.

4568 Poster Session

Immune checkpoint inhibitors (ICI) in advanced sarcomatoid renal cell carcinoma (sRCC): A multicenter study.

Dharmesh Gopalakrishnan, Katharine Collier, Joseph J Park, Jacob P Zaemes, Elaine Tat Lam, Sabah Alaklabi, Ellen Jaeger, Rahul Atul Parikh, Pedro C. Barata, Eric Kauffman, Michael B. Atkins, Ajjai Shivaram Alva, Yuanquan Yang, Saby George; Roswell Park Comprehensive Cancer Center, Buffa- lo, NY; Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH; Division of Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI; Georgetown Lom- bardi Comprehensive Cancer Center, Washington, DC; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO; Tulane University, New Orleans, LA; University of Kansas Medical Center, Westwood, KS; Tulane Cancer Center, New Orleans, LA; Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; University of Michigan Rogel Cancer Center, Ann Arbor, MI; The Ohio State Univer- sity James Comprehensive Cancer Center, Columbus, OH

Background: Advanced sRCC is an aggressive disease with limited responsiveness to chemotherapy and VEGF-targeted therapies. Subgroup analyses from randomized trials showed improved outcomes with ICI, though sample sizes were relatively small. Methods: We conducted a multi-institutional retrospective analysis of consecutive patients (pts) who had RCC with any sarcomatoid component and received systemic therapy for advanced disease. The pts were classified into ICI+ and ICI- groups (gp) based on whether they had received ICI in any treatment line. Overall survival (OS) was measured from the initiation of first systemic therapy. Time to ICI failure (TIF) was defined as the interval from initiation of ICI to subsequent therapy or death. Survival distributions were estimated using the Kaplan-Meier method. As- sociation between covariates and survival was analyzed using multivariate Cox regression. Two-tailed P < 0.05 was considered statistically significant. Results: 203 pts from 6 US academic cancer centers met the inclusion criteria – 155 in ICI+ gp and 48 in ICI- gp. Overall, 137 (67%) pts were male and 181 (89%) were white; median age at mRCC diagnosis was 59.7 (IQR 52.4-67.7) years; 129 (63%) pts presented de novo with distant metastases, 154 (76%) had clear cell (CC) histology, and 182 (90%) had intermediate/poor risk by IMDC criteria. ICI+ had a higher proportion of purely CC tumors (81% vs 64%, P =.02); other demographic and clinical features were similar between the two gps. After a median follow-up of 48.1 (95% CI 40.7-55.5) months (mos), median OS and response rates were significantly higher in the ICI+ gp (Table). OS benefit, compared to ICI-, was maintained in pts who received ICI in $ second line (39.6 vs 7.6 mos, HR 0.33, 95% CI 0.22-0.51, log-rank P <.001). TIF was comparable between pts treated with ICI upfront vs in $ second line (6.0 vs 5.3 mos, HR 1.27, 95% CI 0.87-1.85, P =.21). On multivariate analysis, ICI- (HR 2.50, 95% CI 1.61-3.88, P <.001), non-CC histology (HR 3.14, 95% CI 1.98-5.00, P <.001) and sarcomatoid component $20% (HR 1.92, 95% CI 1.28- 2.90, P =.002) were predictive of all-cause mortality. Among pts with non-CC or mixed histology (n=45), ICI+ had higher OS (18.0 vs 5.5 mos, HR 0.20, 95% CI 0.09-0.44, P <.001) and ORR (44% vs 12%, P =.03), compared to ICI-. Conclusions: Treatment with ICI led to markedly higher survival and response rates in advanced sRCC. OS benefit was maintained with ICI in the second line and beyond. Significant benefit was also noted among pts with non-CC or mixed histology sRCC. Research Sponsor: None.

ICI+ (n = 155) ICI- (n = 48) P value/ HR (95% CI)

Median OS, mos (95% CI) 31.0 (21.5-40.5) 7.6 (5.5-9.7) HR 0.40 (0.27-0.58), P <.001 Median RCC-specific survival, 37.8 (25.0-50.6) 7.6 (5.5-9.7) HR 0.38 (0.25-0.58), P <.001 mos (95% CI) Complete response, % 12.0* 4.3¶ .009 Overall response rate (ORR), % 43.0* 19.6¶ .004 Disease control rate, % 66.2* 39.1¶ .001

*Best response to ICI, ¶best response to non-ICI in any line.

4569 Poster Session

A phase 2 single-arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pretreated with one immune checkpoint inhibitor: The BREAKPOINT trial (MeetUro trial 03-NCT03463681).

Giuseppe Procopio, Melanie Claps, Chiara Pircher, Luca Porcu, Pierangela Sepe, Valentina Guadalupi, Ugo De Giorgi, Cristian Lolli, Marco Maruzzo, Franco Nole, Roberto Iacovelli, Cristina Masini, Cinzia Baldessari, Laura Doni, Antonio Cusmai, Angela Gernone, Sarah Scagliarini, Sandro Pignata, Filippo G. De Braud, Elena Verzoni; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; IRCCS Mario Negri Institute for Pharmacological Research, Milan, Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; Istituto Scienti- fico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy; Medical Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IOV IRCCS, Padua, Italy; Medical Oncology Divi- sion of Urogenital and Head and Neck Tumors, European Institute of Oncology, Milan, Italy; Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy; AUSL/IRCCS di Reggio Emilia, Reggio Emilia, Italy; Oncology Unit, Azienda Ospedaliero Universitaria Policlinico di Mondea, Modena, Italy; Clinical Oncol- ogy Unit, Careggi Hospital, University of Florence, Florence, Italy; Department of Oncology Don Tonino Bello, IRCCS Giovanni Paolo II, Bari, Italy; Medical Oncology Unit, Policlinico Hospital Bari, Bari, Italy; Department of Oncology, Cardarelli Hospital, Naples, Italy; Istituto Nazionale Tumori IRCCS-Fonda- zione G. Pascale, Naples, Italy; Medical Oncology Department, ENETS Center of Excellence, Fonda- zione IRCCS Istituto Nazionale dei Tumori and Oncology and Hemato-oncology Department, University of Milan, Milan, Italy

Background: For many years, vascular endothelial growth factor (VEGF)-targeted therapy (tp) has been a milestone for metastatic renal cell carcinoma (mRCC). Recently, first line tp based on anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICIs) plus tyrosine-kinase-inhibitors (IO-TKI) and anti-PD-1 plus anti- CTLA-4 combos (IO-IO) significantly improved survival of mRCC patients (pts). Prospective data are lacking to determine the efficacy of anti-VEGF tp after IO-IO or IO-TKI. Cabozantinib (Cabo) showed to prolong survival in mRCC pts pre-treated with TKIs and to target kinases involved in immune-escape. So, it may represent an ideal agent to be used sequentially after ICIs. Methods: This is an open label, single arm, multicenter, phase II study evaluating efficacy and safety of Cabo in mRCC pts who received an anti-PD-1/PD-L1-based adjuvant (adj) or first line tp. Cabo 60 mg/daily was administered until progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression free survival (PFS) by Brookmeyer-Crowley test, secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Exploratory endopoints were to investigate tissue PD-L1 expression, to assess the modulat- ing activity of Cabo on local and systemic tumor immunity and to explore bone formation and reabsorp- tion markers. Results: From July 2018, 49 pts were enrolled and 48 were included in the analysis. Median age was 62.5 years (range: 30-78), 63% of pts were male. At baseline, 26% of pts had a good Heng risk score, 47% intermediate and 28% a poor risk, while in 2% of pts the class of risk was unde- termined. 74% of pts received an IO-IO combo as first line tp, 17% IO-TKI, 9% pts an adj IO monotherapy. Pts received a median of 10 cycles of Cabo (range 5-17 cycles). 25 pts (53%) are still on tp, 1 patient discontinued Cabo for AEs, 13 pts for radiological PD, 6 pts discontinued for clinical PD or death, while 2 pts for reasons other than AEs or PD. Among evaluable cases, 17 pts (43%) achieved a partial response and 15 pts (37%) stable disease. Complete responses were not observed. At a median (m) follow-up of 8.0 months (mo) (4.4-13.5 mo), 71% of pts were alive and mPFS was 9.3 mo (95% CI 7.1-29.0 mo). Grade (G) 3-4 adverse events (AEs) occurred in 34% of pts, including more frequently serum bilirubin increase, hypertension, calcium and sodium serum levels alterations and oral mucositis. G1-2 were observed in 61% of pts, including in most of cases diarrhoea, nausea, oral mucositis, dis- geusia, hand-foot syndrome, fatigue and hypothyroidism. Due to AEs, transitory withholding of Cabo was observed in 53.5% of pts and for 23 pts (48%) dose reductions were needed. Conclusions: So far, Cabo tp after IO-IO or IO-TKI showed promising results and was well tolerated. Longer follow-up is needed for final OS and exploratory endpoints results. Clinical trial information: NCT03463681. Research Sponsor: Ipsen.

4570 Poster Session

Plasma exosome microRNA-155 expression in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors: A potential biomarker of response to systemic therapy.

Maryam Soleimani, Marisa Thi, Neetu Saxena, Bernhard J. Eigl, Daniel Joseph Khalaf, Kim N. Chi, Christian K. Kollmannsberger, Lucia Nappi; BC Cancer, Vancouver, BC, Canada; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Medical Oncology, BC Cancer-Vancouver Centre, Vancouver, BC, Canada; BC Cancer-Vancouver Centre, Vancouver, BC, Canada; Division of Medical Oncology, University of Brit- ish Columbia, Vancouver, BC, Canada

Background: The search for a reliable predictive biomarker of response to immune checkpoint-based therapy (ICBT) remains a critically unmet need in the management of metastatic renal cell carcinoma (mRCC). We sought to evaluate the biomarker potential of plasma exosome microRNAs (miRNAs) implicated in RCC and in augmentation of the tumour microenvironment (TME) for such a role. Methods: Eleven miRNAs that are over-expressed in RCC and/or immune-associated were evaluated in 40 patients with mRCC (prior to initiating ICBT) and in 30 healthy volunteers. Exosomes were extracted from 500 uL of plasma and were used for miRNAs extraction. MiRNAs expression was evaluated by RT-PCR. Cycle threshold values were normalized to miR-30-3b, and the relative quantity of the expression (RQ) was compared to those of healthy volunteers and calculated using the 2DDCt method. Mann-Whitney U test was used to evaluate the expression of miRNAs between mRCC pts and healthy volunteers according to best response to first line ICBT between responders (n = 27) v non-responders (n = 13). The cutoff value of significant expression was established by Youden’s index. Responders were defined as those patients experiencing complete response, partial response or stable disease and non-responders were those who experienced progressive disease. Results: The most common first line ICBT was nivolumab + ipilimumab (n = 32), followed by pembrolizumab + axitinib (n = 5), and avelumab + axitinib (n = 3). A significantly higher expression of miRNA-1233 (median 1.85 v 0.81 p = 0.008) and miRNA-155 [miR-155] (3.69 v 0.21 p = 0.006) were found in patients compared to healthy volunteers. Higher miR-155 expression was associated with higher Fuhrman grade (p = 0.002). There was no association with other clinical prognostic factors. MiR-155 was expressed at a significantly lower level in responders than in non-responders (median 0.61 v 35.29, p = 0.042). Response rate amongst patients with low and high expression of miR-155 (RQ # 2.5) was statistically different (p = 0.042) and 84.2% of the pts with low miR-155 expression responded to the treatment. Conclusions: Lower expression of miR- 155 was associated with response to ICBT in patients with mRCC. Functionally, miR-155 is involved in regulation and modulation of the TME. These results underscore the need for further work in this area to elucidate the role of this and other miRNAs as biomarkers of response in mRCC. Research Sponsor: GU- MOC Bayer Research Grant Program jointly established by the Genitourinary Medical Oncologists of Canada (GUMOC) and Bayer Canada.

4571 Poster Session

A phase 2 prospective trial of cabozantinib as first-line treatment for metastatic collecting ducts renal cell carcinoma: The BONSAI trial (Meeturo 2) clinical trial information— NCT03354884.

Giuseppe Procopio, Pierangela Sepe, Sebastiano Buti, Melanie Claps, Maurizio Colecchia, Loris De Cecco, Devecchi Andrea, Matteo Dugo, Chiara Gargiuli, Patrizia Giannatempo, Valentina Guadalupi, Luigi Mariani, Arianna Ottini, Marialuisa Sensi, Filippo G. De Braud, Elena Verzoni; Fondazione Istituto Nazionale Tumori Oncologia Medica Genitourinaria, Milan, Italy; Department of Medical Oncology, Fon- dazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy; Department of Experimental Oncology and Molecular Medi- cine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Experimental Oncol- ogy and Molecular Medicine, Functional Genomics and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Medical Oncology Department, Fondazione IRCCS Is- tituto Nazionale dei Tumori, Milan, Italy; Medical Oncology Department, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori and Oncology and Hemato-oncology Department, Uni- versity of Milan, Milan, Italy

Background: Metastatic collecting ducts carcinoma (mCDC) is a rare disease with bad prognosis and no standard treatments. Due to its rarity, mCDC is biologically poorly characterized and under-represented in prospective randomized trials. We recently identified two different molecular subtypes of mCDC based on relative expression levels of angiogenesis, metabolic and immune-related genes. Methods: : This prospective, monocentric, phase II trial evaluated cabozantinib (cabo) 60 mg orally once daily until progression or unacceptable toxicity in untreated mCDC patients (pts). Primary endpoint was objective response rate (ORR) as the proportion of pts with best overall response of confirmed complete (CR) or partial responses (PR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), overall survival and safety profile. Exploratory objectives were: to identify somatic mutations by targeted NGS-based sequencing; to define molecular subtypes, signatures and transcript fusions genes by RNA sequencing; to monitor circulating immune cells and study the immunological context of tumor cells. A central pathological review was mandatory. The study was based on a Simon’s two stage optimal design: at least 2 responses in 9 pts in the first stage were needed to proceed to the second stage where at least 6 responses in 14 additional pts were needed to prove activity of cabo. Results: From January 2018 to November 2020, 25 pts were enrolled, of whom 23 started treatment. Median age was 66 years, 19 pts were male. 19 (83%) pts received a previous nephrectomy. 9 pts presented with only one metastatic site, 8 pts with two, while the remaining part with multiple sites. The most common metastatic sites were lymphnodes and bone (15 and 13 pts respectively), followed by lung and liver (10 and 4 pts respectively). Median follow up was 8 months. As best overall response, 6 pts presented a stable disease (26%),1 pt achieved a confimed CR and 7 a PR for an ORR of 35%. Median PFS was 6 months. Treat- ment was feasible and well tolerated. All pts reported at least one grade (G) 1-2 adverse event (AE): the most common were fatigue (43%), hypotiroidism (28%), stomatitis (28%), anorexia (26%), Hand-Foot Syndrome (13%), hypertension (17%), and diarrhea (13%). 5 pts reported G3 AEs (2 thromboembolic events, 2 arterial hypertension, 1 fatigue), while no G4-5 AEs were reported. 17% of pts required dose reduction. DNA sequencing on CDC showed to be feasible, finding 256 mutations in 119 genes (mis- sens mutations the majority). Altered genes, molecular subtypes and signatures will be associated to different outcomes and responses to cabo. Conclusions: The study met its primary endpoint showing promising efficacy and acceptable tolerability of cabo in mCDC pts. Mature results according to mutational profiles and gene signatures will be presented. Clinical trial information: NCT03354884. Re- search Sponsor: IPSEN PHARMA.

4572 Poster Session

Characterization of the tumor immune microenvironment in clear cell renal cell carcinoma (ccRCC): Prognostic value and therapeutic implications of an M0-macrophage enriched subtype.

Mark Farha, Randy Vince, Srinivas Nallandhighal, Judith Stangl-Kremser, Steven Goldenthal, Daniel Triner, Todd Matthew Morgan, Ganesh S. Palapattu, Aaron M. Udager, Simpa Samuel Salami; Universi- ty of Michigan Medical School, Ann Arbor, MI; University of Michigan Cancer Center, Ann Arbor, MI; University of Michigan, Ann Arbor, MI; Department of Urology, Michigan Medicine, Ann Arbor, MI

Background: Metastatic clear cell renal cell carcinoma (ccRCC) has a 5-year survival of 12%, but the number of approved immune checkpoint blockade (ICB) agents is growing, necessitating the need to better identify responders. The composition and role of the tumor immune microenvironment (TIME) has yet to be comprehensively characterized in ccRCC. Here, we leveraged a genomic data driven approach to characterize TIME subtypes in ccRCC. Methods: Whole transcriptome data from patients with local and metastatic disease in the Cancer Genome Atlas KIRC (TCGA-KIRC) project was utilized (n = 537). CIBERSORT was used for immune cell deconvolution, and unsupervised hierarchical clustering divided the cohort based on similar immune profiles. Progression free (PFS) and overall (OS) survival of each cluster was analyzed, and Gene Set Enrichment analysis was performed among clusters. The tumor immune dysfunction and exclusion (TIDE) tool, which uses a genomic signature validated on immunotherapy treated melanoma patients to model tumor immune evasion, was then used to predict response to ICB in the TCGA-KIRC clusters. Results: There was a distinct M0hi cluster identified which demonstrated a higher proportion of patients with stage III/IV disease, decreased PFS and OS (Table). Additionally, the M0hi cluster was characterized by lower PD-L1 expression (ANOVA, p = 0.0045) and an enrichment of epithelial to mesenchymal transition (EMT) hallmark genes [Enrichment Score = 0.64, p = 0.001]. The M0hi cluster also showed a higher degree of T-Cell Exclusion (ANOVA, p = 2.2x10-16), predominance of Cancer Associated Fibroblasts (CAFs; ANOVA, p = 2.2x10-16) and Mye- loid Derived Suppressor Cells (MDSCs; ANOVA, p = 4.1x10-10). The M0hi cluster had the lowest predicted response to immunotherapy using the TIDE tool (Table). Conclusions: Comprehensive characterization of the TCGA-KIRC cohort led to identification of a distinct cluster of ccRCC defined molecularly by decreased PD-L1 and increased EMT gene expression and cellularly by enrichment of M0 macrophages, CAFs, MDSCs, and an exclusion of T Cells. Pa- tients within this cluster exhibited aggressive disease and poor predicted response to ICB. These findings warrant further validation to identify appropriate therapeutic approaches for this ccRCC subgroup. Research Sponsor: None.

CL1 CL4 CL5 (M2hi) CL2 CL3 (M0hi) (CD8hi) N = 132 N = 130 N = 124 N = 28 N = 86 Median OS (mo., 95% CI, one-sided) NR 123.8 NR 45.9 78.4 (91.4 – ) (73 – ) (89.9 – ) (22.6 – ) (57.7 – ) Median PFS (mo., 95% CI, one-sided) 86.7 71.5 92.1 26.1 74.2 (65.5 – ) (57.1 – ) (91.7 – ) (13.0 – ) (52.2 – ) Stage III/IV (%) 27.3 45.0 33.9 71.4 52.9 PD-L1** -0.04 -0.04 -0.06 -0.60 0.23 T-Cell Exclusion** 0.28 0.20 0.32 0.79 -0.19 Predicted ICB Response (%) 32 31 19 4 32 CAF** 0.05 0.03 0.04 0.09 -0.04 MDSC** 0.02 0.02 0.03 0.06 0.01

NR: not reached. **Signatures from TIDE tool, Z scores.

4573 Poster Session

Dynamic changes of the immune infiltrate after neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).

Axel Bex, Yasmin Abu-Ghanem, Johannes V. Van Thienen, Niels Graafland, Brunolf Lagerveld, Patricia Zondervan, Harrie Beerlage, Jeroen van Moorselaar, Mark Kockx, Pieter-Jan Van Dam, Bernadett Szabados, Christian U. Blank, Thomas Powles, John B. A. G. Haanen; The Netherlands Cancer Insti- tute, Amsterdam, Netherlands; Sheba Medical Center, Ramat Gan, Israel; Netherlands Cancer Insti- tute, Amsterdam, Netherlands; Netherlands Cancer Insitute, Amsterdam, Netherlands; Onze Lieve. Vrouwe Gasthuis, Amsterdam, Netherlands; Amsterdam University Medical Center, Amsterdam, Neth- erlands; CellCarta, Wilrijk, Belgium; Barts Cancer Institute, London, United Kingdom; Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands; Barts Cancer Institute, Can- cer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London, United Kingdom

Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a front-line standard of care for metastatic RCC. Neoadjuvant use of these combinations is associated with tumor downsizing, but dynamic effects on key immune biomarkers are uncertain. We report early dynamic changes in the tumour immune environment after neoadjuvant treatment with avelumab/axitinib. Methods: Neoavax is an open label, single arm, phase II trial, investigating 12 weeks of neoadjuvant avelumab/axitinib prior to nephrectomy in patients with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4N0-1M0). Partial primary tumour response (RECIST 1.1) occurring in $25% is the primary endpoint. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD- L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and major histocom- patibility complex class I (MHC-I) were compared on paired samples (pre-treatment biopsy and nephrectomy) (NCT03341845). Results: Paired, sequential tissue from the first 24 patients was analysed for immune biomarker expression. Of these patients, 70% were $pT3a, 30% pN1, 58% had ISUP/ WHO grade $3 with 8% sarcomatoid features. Compared to pre-treatment biopsy there was a significant increase in PD-L1 (p = 0.0002) and CD8+ expression (p = 0.0003) after therapy, whereas changes in CD8/GZMB+, MHC-I and CD8/CD39+ were not significant. Furthermore, neoadjuvant avelumab/axitinib therapy was associated with a significant decrease in Foxp3+ cells (p = 0.009). Conclusions: 12 weeks of neoadjuvant axitinib/avelumab treatment in ccRCC leads to significant dynamic changes in the tumour microenvironment for CD8+, PD-L1 and Foxp3+ expression. High baseline Foxp3+ infiltration is associated with an unfavorable outcome in the majority of solid tumours. The significant on-treatment decrease in Foxp3+ may account for the positive interaction seen between VEGF targeted therapy and immune checkpoint inhibitors in mRCC. If these cells represent regulatory T cells (Tregs), activated CD4 T cells or fragile Tregs remains to be determined. Clinical trial information: NCT03341845. Re- search Sponsor: Pfizer.

4574 Poster Session

Efficacy of avelumab + axitinib (A + Ax) versus sunitinib (S) by IMDC risk group in advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.

John B. A. G. Haanen, James Larkin, Toni K. Choueiri, Laurence Albiges, Brian I. Rini, Michael B. Atkins, Manuela Schmidinger, Konstantin Penkov, Despina Thomaidou, Jing Wang, Mariangela Mariani, Alessandra Di Pietro, Robert J. Motzer; Netherlands Cancer Institute, Amsterdam, Nether- lands; Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA; Department of Cancer Medicine, Gustave Roussy Cancer Campus, University of Paris Sud, Boston, MA; Vanderbilt-Ingram Cancer Cen- ter, Nashville, TN; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Medical Uni- versity of Vienna, Vienna, Austria; Private Medical Institution Euromedservice, Saint-Petersburg, Russian Federation; Pfizer Hellas, Athens, Greece; Pfizer, Cambridge, MA; Pfizer srl, Milan, Italy; Me- morial Sloan Kettering Cancer Center, New York, NY

Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), treatment-naive patients with aRCC receiving A + Ax showed improved progression-free survival (PFS) and objective response rate (ORR) across International Metastatic RCC Database Consortium (IMDC) risk groups (favorable [F], intermediate [I], and poor [P]) compared with patients receiving S. Here we report updated efficacy results for A + Ax vs S by IMDC risk groups from the third interim analysis. Methods: Patients were randomized 1:1 to receive either A (10 mg/kg intravenously every 2 weeks) plus Ax (5 mg orally twice daily) or S (50 mg orally once daily) for 4 weeks (6-week cycle). Patients were categorized per IMDC risk group into F, I, and P subgroups, and outcomes were assessed for F, I, P, and I + P. Overall survival (OS) and PFS, ORR, complete response (CR), and duration of response (DoR) per investigator assessment (RECIST v1.1) were assessed. Results: The study enrolled 886 patients with aRCC. At data cutoff (Apr 2020), median (95% CI) follow-up for OS in the A + Ax was NR (42.2-NE) vs 37.8 (31.4-NE) months with S. The Table shows OS, PFS, ORR, CR, and DOR by IMDC risk group. A + Ax generally showed improved efficacy compared with S across IMDC groups. Conclusions: Consistent with previously reported results from prior interim analyses, extended follow-up confirms the efficacy benefits of A + Ax vs S across IMDC risk groups in patients with aRCC. Patients continue to be followed up for the final OS analysis. Clinical trial information: NCT02684006. Research Sponsor: Funded by Pfizer as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer.

Poor Intermediate + Intermediate + Favorable Favorable Intermediate Intermediate Poor S Poor Poor IMDC risk A + Ax (N = S A + Ax S A + Ax (N = A + Ax S group 442) (N = 444) (N = 442) (N = 444) (N = 442) 444) (N = 442) (N = 444) n 94 96 270 276 73 71 343 347 mOS NE NE 42.2 37.8 21.3 11.0 40.0 29.5 (95% CI), (NE-NE) (39.8- (33.1-NE) (29.6-NE) (14.7- (7.8- (30.5-NE) (24.8-38.0) mo 0.66 NE) 0.84 Ref 33.1) 16.5) 0.79 Ref HR* (0.356-1.22) Ref (0.649- 0.60 Ref (0.636-0.98) (95% CI) 1.08) (0.399- 0.912) mPFS 20.7 13.8 12.9 8.4 8.7 4.2 11.1 8.2 (95% CI), (16.6-26.3) (11.1- (11.1- (7.9-10.1) (5.6-11.1) (2.8- (9.8-14.6) (6.9-8.4) mo 0.71 23.5) 16.6) Ref 0.45 5.5) 0.66 Ref HR* (0.490-1.02) Ref 0.71 (0.304- Ref (0.550-0.787) (95% CI) (0.578- 0.678) 0.866) ORR 75.5 45.8 59.6 31.2 38.4 15.5 55.1 28 (95% CI), (65.6-83.8) (35.6- (53.5- (25.7- (27.2- (8.0- (49.7-60.4) (23.3-33.0) % 56.3) 65.5) 37.0) 50.5) 26.0) CR, n (%) 9 (9.6) 5 (5.2) 11 (4.1) 8 (2.9) 1 (1.4) 1(1.4) 12 (3.5) 9 (2.6) DoR 22.6 20.8 19.3 12.5 18.2 5.6 19.3 9.8 (95% CI), (15.2-31.7) (14.5- (13.9- (7.1-16.6) (6.8-NE) (2.5- (13.9-22.1) (7.0-15.3) mo (n = 71) 24.9) 22.1) (n = 86) (n = 28) 8.3) (n = 189) (n = 97) (n = 44) (n = 161) (n = 11) m, median; mo, months; NE, not estimable; HR, hazard ratio; Ref, reference. * Unstratified.

4575 Poster Session

Association with immune checkpoint inhibitor efficacy of a 27-gene classifier in renal cell cancer.

Robert Seitz, Tyler J Nielsen, Brock Lloyd Schweitzer, David R. Gandara, Mamta Parikh, Douglas Teller Ross; Oncocyte Inc, Nashville, TN; Oncocyte, Irvine, CA; University of California Davis Comprehensive Cancer Center, Sacramento, CA; UC Davis Comprehensive Cancer Center, Sacramento, CA

Background: The 27-gene immuno-oncology (IO) signature that incorporates expression from activated inflammatory cells, cancer associated fibroblasts, and tumor cells to produce a binary classifier has been shown to be associated with efficacy to immune checkpoint inhibitors (ICIs) in breast, lung, and bladder cancers. Here we created clustered heat maps using data from The Cancer Genome Atlas (TCGA) to confirm the classifier function and diagnostic threshold in renal cell carcinoma (RCC), then applied the predefined algorithm to RNAseq data from a community RCC cohort treated with ICI therapy. Methods: Previously, we described the selection of 939 genes from the TCGA breast and lung datasets that comprise mesenchymal (M), mesenchymal stem-like (MSL), and immunodulatory (IM) gene expression patterns centered upon the twenty-seven genes selected for the IO score (AACR, 2021). We created an expression dataset using these genes in clear cell (n = 403) and papillary (n = 203) RCC and used k-means clustering to organize the genes and cases (k=3). We assessed the 27-gene classification of cases by utilizing area under the curve for phenotypic classification and determining the sensitivity and specificity of the previously established threshold compared to optimal accuracy for quantitating the fraction of cases enriched into the IM+ cluster (likely sensitive to ICIs) as opposed to the M or MSL clusters (likely insensitive). Finally, the IO score was evaluated in a small multi-institutional RNAseq dataset of forty-three RCC patients treated with an ICI for which there was definitive one-year progression free survival (PFS) data. Results: The 27-gene IO signature applied to the TCGA sample data had an AUC of 90.3 for stratification of cases into IM+ as opposed to M and MSL clusters while the established threshold for likely sensitive enriched 90% of cases into the appropriate IM cluster as opposed 28% into the M and MSL. Efficacy was defined by PFS. Given this result, the 27-gene IO signature was applied with the predefined threshold to the forty-three ICI treated patients. Patients who had a IO+ score by the 27-gene signature had significantly better one-year PFS compared to patients with a negative IO score (hazard ratio = 0.235, 95% CI = 0.069 - 0.803, p < 0.01). Median PFS was 5.2 months for patients classified as IO score negative versus 8.6 months for those classified as IO score+. Conclu- sions: The 27-gene IO signature has been validated across multiple tumor types and here in RCC to clas- sify the tumor immune microenvironment without changing the algorithm or threshold. Results demonstrate that the 27-gene classifier has a strong correlation with efficacy of ICI therapy in RCC. This is the fourth tumor type in which the same algorithm has been validated as a predictor of ICI efficacy. These data support this assay as a strong pan-cancer immune system classifier worthy of further prospective study for ICI therapy. Research Sponsor: Oncocyte Inc.

4576 Poster Session

Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC).

Marc-Oliver Grimm, Emilio Esteban, Philippe Barthe�le�my, Manuela Schmidinger, Jonas Busch, Begon~a P. Valderrama, Marc Schmitz, Ulrike Schumacher, Gustavo Bruno Baretton, Ignacio Duran, Guillermo de Velasco, Frank Priou, Pablo Maroto-Rey, Giovanni Schinzari, Laurence Albiges; Depart- ment of Urology, Universitaetsklinikum Jena, Jena, Germany; Department of Medical Oncology, Hospi- tal Universitario Central de Asturias, Oviedo, Spain; Institut de Cance�rologie Strasbourg Europe, Strasbourg, France; Department of Internal Medicine I, Vienna General Hospital (AKH), Medizinische Universita€t Wien, Vienna, Austria; Department of Urology, University Hospital Charite� Berlin, Berlin, Germany; Department of Medical Oncology, Hospital Universitario Virgen del Roc�ıo, Seville, Spain; In- stitute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany; Center for Clinical Studies, Universitaetsklinikum Jena, Jena, Germany; Institute of Pathology, Universitaets- klinik Carl Gustav Carus, TU Dresden, Dresden, Germany; Hospital Universitario Marque�s de Valdecilla, IDIVAL, Cantabria, Spain; Department of Oncology, Hospital 12 de Octubre, Madrid, Spain; CHD Vend- ee-Hopital Les Oudairies, La Roche-sur-Yon, France; Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; Policlinico Universitario A. Gemelli, Universita� Cattolica del Sacro Cuore, Rome, Italy; Department of Cancer Medicine, Gustave Roussy Cancer Campus, University of Paris Sud, Villejuif, France

Background: TITAN-RCC uses a tailored immunotherapy approach in renal cell carcinoma (RCC), starting with nivolumab (nivo) induction followed by nivo + ipilimumab (ipi) as immunotherapeutic boost in non-responders. Patients with initial partial or complete response (PR/CR) continued with nivo maintenance but received later boosts for progressive disease (PD). Here we report updated results focusing on the efficacy of nivo+ipi in patients with initial PD vs. initial responders with later PD. Methods: Patients with IMDC intermediate and poor risk advanced clear cell RCC were recruited between OCT 2016 and DEC 2018. Patients started with nivo 240 mg Q2W induction. Patients with early significant PD (week 8) or non-responders at week 16 received 2-4 nivo+ipi boost cycles. Responders (PR/CR) to nivo monotherapy continued with maintenance but could receive nivo+ipi for later PD. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST in first line (1L) and second line (2L). Secondary endpoints included activity of nivo monotherapy, remission rate with nivo+ipi boost, safety and overall survival (OS). Results: 109 1L and 98 2L (after TKI) patients were analyzed for efficacy. Median age was 65 years (range 20-87). 71 % were intermediate and 25 % poor risk. Con- firmed ORR with nivo monotherapy was 28 % for 1L and 17 % for 2L. After a median follow-up of 12.8 months best overall response after nivo induction ± nivo+ipi was 36 % in 1L and 30 % in 2L. Of all patients, 38 received nivo+ipi for stable disease (SD) up to week 16, with 1 (3 %), 4 (11 %) and 26 (68 %) achieving CR, PR and SD, respectively. 28 patients in 1L and 43 in 2L were boosted with nivo+ipi for initial PD. Of these, 3 (11 %) and 8 (29 %) achieved PR and SD, respectively, in 1L, whereas 3 (7.0 %) achieved CR, 6 (14 %) PR and 13 (30 %) SD in 2L. 16 and 10 patients received boosts later than week 16 for PD during nivo maintenance in 1L and 2L, respectively. Thereof, 3 (19 %) achieved PR and 5 (31 %) SD in 1L, whereas 2 (20 %) achieved PR and 3 (30 %) SD in 2L. Progression-free survival was 6.3 months (95 % CI 3.7 – 10.1) and 3.7 months (95 % CI 2.0 - 4.5) in 1L and 2L, respectively. OS was 27.2 months (95 % CI 19.9 – not estimable (NE)) in 1L and 20.2 months (95 % CI 15.6 – NE) in 2L. Treatment-related adverse events will be presented. Conclusions: Our tailored approach with nivo+ipi boosts results in improved response rates compared to nivo monotherapy. Our updated analysis suggests that almost half of the patients receiving boosts for PD improve to either PR/CR (18 %) or SD (30 %), irrespective of initial or later progression with nivo. Clinical trial information: NCT02917772. Research Sponsor: Bristol-Myers Squibb.

1L 2L Initial PDn=28 Late PDn=16 Initial PDn=43 Late PDn=10

CR - - 3 (7.0) - PR 3 (11) 3 (19) 6 (14) 2 (20) SD 8 (29) 5 (31) 13 (30) 3 (30) PD 17 (61) 7 (44) 18 (42) 4 (40) Not evaluable - 1 (6.3) 3 (7.0) 1 (10)

4577 Poster Session

Retrospective study for the characterization of COVID-19 in renal cancer (COVID-REN) patients treated with antiangiogenics or immunotherapy and outcome comparison with non-infected cases.

Jesus Garcia Donas, Guillermo de Velasco, Teresa Alonso Gordoa, Jesu�s Chamorro, Diana Rosero, Olatz Etxaniz, Jose Luis Perez-Gracia, Alvaro Pinto, Ignacio Duran, Diego Cacho, Mar�ıa Barba, Monica Yagu€e, Pablo Borrega, Mart�ın La�zaro, Laura Rodriguez, Maria Laura L. Villalobos Leon, Lourdes Garcia Sanchez, M. Andres Cuellar, Juan Francisco Rodriguez-Moreno; Hospital Universitario Madrid Sanchi- narro, Madrid, Spain; Department of Oncology, Hospital 12 de Octubre, Madrid, Spain; Hospital Uni- versitario Ramo�n y Cajal, Madrid, Spain; Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medical Oncology, Clinica Universidad de Navarra, Pamplona, Spain; Department of Medical Oncology, La Paz University Hospital, Madrid, Spain; Hospital Universitario Marque�s de Valde- cilla, IDIVAL, Cantabria, Spain; Hospital Universitario Marque�s de Valdecilla, Santander, Spain; HM Sanchinarro Centro Integral Oncologico Clara Campal (CIOCC), Madrid, Spain; HM Hospitales-Centro Integral Oncolo�gico Clara Campal, Madrid, Spain; Hospital San Pedro de Alca�ntara, Ca�ceres, Spain; Hospital A�lvaro Cunqueiro, Vigo, Spain; Hospital Universitario Fuenlabrada, Fuenlabrada, Spain; Hos- pital Universitario Principe de Asturias, Madrid, Spain; Hosp General De Segovia, Segovia, Spain; Medi- cal Oncology. Institut Catala� d’Oncologia (ICO) L’Hospitalet del Llobregat, Barcelona, Spain

Background: Cancer is recognized as a major risk factor for severe COVID19. However little is known about the impact of oncologic treatments in the evolution of the disease. On the other hand, the influence of SARS-CoV2 in cancer response remains to be established. We aim to determine both aspects in renal cancer patients receiving different therapeutic options. Methods: We designed a retrospective case-control study to compare the outcome of patients with advanced renal cancer who developed COV- ID19 under antiangiogenic treatment (cohort A [ChA]) vs immunotherapy (alone or in combination: cohort B [ChB]) vs matched controls (cohort C [ChC]). Controls were renal cancer patients who were not infected during the period of study. One control per case was selected regarding age, gender, kidney cancer histology and type of treatment. Results: From May 20 to Feb 21, 80 patients were recruited. We present the first 55 patients included (15 ChA, 16 ChB and 20 ChC, 4 patients were screening failure) from 13 centers in Spain. Median age was 62 (range 25 to 88) overall and 62 (range 44 to 88) in Ch A, 64,5 (range 42 to 83) in ChB and 61 (range 41 to 77) in ChC. 38 patients were male and 13 were female. Overall 45 cases were clear cell carcinoma (13 ChA, 14 ChB and 18 ChC), 4 papillary (1 ChA, 2 ChB and 1 ChC), 1 chromophobe (ChA) and 1 unclassified (ChC). Median number of prior lines of treatment was 2 (range 1 to 6) overall, (1 [range 1 to 4] in ChA, 2 [range 1 to 4] in ChB and 2 [range 1 to 6] in ChC). 25 patients required treatment interruptions (8 in ChA [32%], 14 in ChB [56%] and 3 [12%] in ChC). 9 patients were hospitalized (4 in Ch A, 5 in ChB and none in ChC) for a median of 10 days (range 4 to 16) overall (7 [range 4 to 14] in ChA and 12 [range 5 to 16] in ChB). No patient required ICU admission. Best tumor response was complete or partial (CR+PR) in 25 patients (5 [20%] in ChA, 9 [36%] in ChB and 11 [44%] in ChC). Clinical benefit (CR+PR+stable disease) was observed in 38 patients (11 [28,9%] in ChA, 10 [26,3%] in ChB and 17 [44,7%] in ChC). One patient in ChB died (due to COVID19). Updated results will be presented. Conclusions: Patients with renal cancer who developed COVID19 held treatment more frequently and presented lower clinical benefit rates than non infected cases. Patients receiving immunotherapy required more frequent dose interruptions and longer hospi- talizations than cases on antiangiogenics. These results point to an impact of SARS-CoV2 in renal cancer outcome. Therapies administered to treat renal cancer, could play a role in the evolution of COVID19. Research Sponsor: unrestricted grant from Pfizer.

4578 Poster Session

Efficacy outcomes of nivolumab + cabozantinib versus pembrolizumab + axitinib in patients with advanced renal cell carcinoma (aRCC): Matching-adjusted indirect comparison (MAIC).

Bradley Alexander McGregor, Daniel M. Geynisman, Mauricio Burotto, Camillo Porta, Cristina Suarez Rodriguez, Maria Teresa Bourlon, Pedro C. Barata, Shuchi Gulati, Brian Stwalley, Viviana Del Tejo, Ella X. Du, Aozhou Wu, Andi Chin, Keith A. Betts, Stephen Huo, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadel- phia, PA; Bradford Hill Clinical Research Center, Santiago, Chile; University of Bari ’A. Moro’ and Poli- clinico Consorziale di Bari, Bari, Italy; Medical Oncology, Vall d�Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d�Hebron, Vall d�Hebron Barcelona Hospital Campus, Barcelona, Spain; Uro- logic Oncology Clinic, Instituto Nacional de Ciencias Me�dicas y Nutricio�n Salvador Zubira�n, Mexico City, DF, Mexico; Tulane Cancer Center, New Orleans, LA; University of Cincinnati Medical Center, Cin- cinnati, OH; Bristol Myers Squibb, Princeton, NJ; Analysis Group, Inc, Los Angeles, CA; Analysis Group, Inc., Los Angeles, CA; Analysis Group, New York, NY; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow- up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS. Research Sponsor: BMS.

Post-weighting efficacy comparison for N+C vs. P+A using anchor-based MAIC. N+C vs. P+A N+C vs. sunitinib P+A vs. sunitinib (anchor-based (CheckMate 9ER) (KEYNOTE-426) comparison)

PFS, HR (95% CI) 0.50 (0.40, 0.63)* 0.71 (0.60, 0.84)* 0.70 (0.53, 0.93)* ORR, Difference (95% CI) 28.7% (21.0%, 20.3% (13.8%, 8.4% (-1.7%, 18.4%) 36.4%)* 26.9%)* DOR, HR (95% CI) 0.55 (0.35, 0.85)* 0.70 (0.53, 0.92)* 0.79 (0.47, 1.31) OS, HR (95% CI) 0.67 (0.49, 0.92)* 0.68 (0.55, 0.85)* 0.99 (0.67, 1.44)

* indicates a P < 0.05.

4579 Poster Session

Patient-reported experience of diagnosis, management, and burden of renal cell carcinomas: Results from the 2020 Global Patient Survey from 41 countries.

Rachel H. Giles, Deb Maskens, Robin Martinez, Karin Kastrati, Carlos Castro, Juan Carlo Julian Mauro, Robert Bick, Malcolm Packer, Daniel Yick Chin Heng, James Larkin, Axel Bex, Eric Jonasch, Sara Jane Maclennan, Michael A.S. Jewett; International Kidney Cancer Coalition, Duivendrecht, Netherlands; Kidney Cancer Canada, Toronto, Canada; Smart Patients, Mountain View, CA; Das Lebenshaus e.V., Wo€lfersheim, Germany; Associacion Ale, Mexico City, Mexico; Alcer, Madrid, Spain; Kidney Cancer Canada, Toronto, ON, Canada; Kidney Cancer UK, Cambridge, United Kingdom; Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom; The Netherlands Cancer Institute, Amsterdam, Netherlands; The University of Texas MD Anderson Cancer Center, Houston, TX; Academic Urology Unit, Aberdeen, United King- dom; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

Background: The sustained increased global prevalence of kidney cancer (renal cell carcinoma, RCC) has increased the burden to health systems, and most of all, to individual patients and their families. Al- though individual national surveys have been held, no conclusions could be drawn about country-level variation in patient experience or best practice. Here, we report on the second biennial Global Patient Survey on the diagnosis, management, and burden of RCC. Conducted by the International Kidney Can- cer Coalition (IKCC) and involving its Affiliate Organizations worldwide, the survey aims to improve col- lective understanding and to contribute toward the reduction of the burden of kidney cancer around the world. Methods: A 35-question survey on the diagnosis, management, and burden of RCC was designed by a multi-country steering committee of patient leaders to identify geographic variations in 6 key di- mensions: patient education, experience and awareness, access to care and clinical trials, best practices, quality of life, and unmet psychosocial needs. The survey was distributed in 13 languages to patients with kidney cancer and their caregivers, through IKCC’s 46 Affiliate Organisations and social media. It was completed online or in paper form between 29 Oct 2020 and 5 Jan 2021. Results: 2,012 (1,586 patients, 417 carers, 9 undisclosed) responses were recorded from 41 countries in 13 languages. Survey results were analyzed using cross-tabulations by an independent third-party organization. The full global report will be publicly available, as well as 7 individual country reports where at least 100 responses were received. 52% lacked understanding of subtype at diagnosis. 42% reported that the likelihood of surviving their cancer beyond 5 years was not explained. 51% reported that they were involved as much as they wanted to be in developing their treatment plan. 41% indicated that No one discussed cancer clinical trials with them. 31% were invited to take part in a clinical trial. 56% experienced barriers to their treatment. 45% self-reported that they were insufficiently physically active; 15% were completely sedentary. 50% indicated that they very often’ or always’ experienced disease-related anxiety. 55% indicated that they very often’ or always’ experienced a fear of recurrence. 52% reported having talked to their doctor/healthcare professional about their concerns. Conclusions: The IKCC and its global affiliates will use these results to ensure that patient and caregiver voices are heard and acted upon, with ultimate incorporation of these findings by much broader communities into care pathways, clinical practice, or health technology assessments. Furthermore, individual countries can use their reports to advance understanding of patient experiences and to drive improvements in providing care locally. Research Sponsor: International Kidney Cancer Coalition.

4580 Poster Session

Outcomes with novel combinations in non-clear cell renal cell carcinoma(nccRCC): ORACLE study.

Deepak Kilari, Aniko Szabo, Pooja Ghatalia, Tracy L Rose, Nicole Weise, Matthew D. Tucker, Ariel Ann Nelson, Huaying Dong, Danubia Hester, Luna Acharya, Rohit K. Jain, Benjamin L. Maughan, Ajjai Shivaram Alva, Abhishek Tripathi, Arnab Basu, Vadim S Koshkin, Hamid Emamekhoo, Nancy B. Davis, Arpita Desai, Rana R. McKay; Medical College of Wisconsin, Milwaukee, WI; Fox Chase Cancer Center, Philadelphia, PA; The University of North Carolina at Chapel Hill (UNC-CH) School of Medicine and UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; UC San Diego Moores Cancer Cen- ter, La Jolla, CA; Duke University Medical Center, Durham, NC; Howard University College of Medicine, Bowie, MD; University of Iowa Cancer Center, Iowa City, IA; Lee Moffitt Cancer Center, Tampa, FL; Sid- ney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; University of Michigan Rogel Cancer Center, Ann Arbor, MI; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK; University of Alabama at Birmingham, Birmingham, AL; Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA; University of Wisconsin School of Medicine and Public Health, Madison, WI; Vanderbilt- Ingram Cancer Center, Nashville, TN; University of California San Francisco, Helen Diller Family Com- prehensive Cancer Center, San Francisco, CA; University of California San Diego, Moores Cancer Cen- ter, La Jolla, CA

Background: Despite advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of new combination therapies (including immunotherapy (IO), anti-vascular endothelial growth factor inhibitors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors) in metastatic nccRCC is not known. Methods: In this multicenter retrospective analysis, we explored the efficacy of combination systemic therapies in patients with nccRCC. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints include progression- free survival (PFS), disease control rate (DCR), median duration of response (DOR), overall survival (OS), and biomarker correlates. Results: Among 66 included patients, median age was 59 yr; 60% were male and 62% white. Histologies included papillary (38%), chromophobe (17%), unclassified (24%), translocation (12%), and other (9 %). Sarcomatoid and/or rhabdoid differentiation was present in 18%, 70% had prior nephrectomy, 86% were IMDC intermediate/poor risk, 29% and 32% had liver and bone metastasis respectively. 67% received combination treatment in the first line. Comparison of outcomes based on treatment regimen is shown in the table. Conclusions: Antitumor activity was observed with novel combinations in nccRCC which warrants further prospective studies. Response rates and survival with combination therapy in this dataset remain inferior to rates seen in clear cell RCC. Research Sponsor: None.

IO/VEGF IO/IO VEGF/mTOR n 19 40 7 ORR(%) 21 19 0 DCR(%) 69 46 72 Median PFS (mo.) 1st line 16.8 13.6 2.1 Median DOR (mo.) 23.6 13.6 NR Median OS (mo.) 24.7 19.2 23.1 n- number of patients; mo.-months; NR – not reached. IO/VEGF (pembrolizumab + axitinib/ atezolizumab + bevacizumab /avelumab + axitinib); IO/IO (Ipilimumab and nivolumab); VEGF/mTOR (lenvatinib plus everolimus).

4581 Poster Session

Disease-free survival as a predictor of overall survival in localized renal cell carcinoma (RCC) following first nephrectomy.

Naomi B. Haas, Yan Song, Jaqueline Willemann Rogerio, Su Zhang, Oluwakayode Adejoro, Christopher Carley, Jingjing Zhu, Rituparna Bhattacharya, James Signorovitch, Murali Sundaram; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Analysis Group, Inc., Boston, MA; Merck & Co., Inc., Kenilworth, NJ; Former Employee of Merck & Co., Inc., Kenilworth, NJ

Background: Intermediate endpoints (e.g., disease free survival [DFS]) have gained traction lately as potential surrogates for OS in oncology as they require shorter follow up to show clinical benefit. Given the high post-nephrectomy survival in patients (pts) with localized RCC, evidence on if DFS can be used as a predictor of OS in the disease is warranted. We assessed the association between DFS and OS in pts with newly diagnosed, completely resected, intermediate-high (pT2N0 high grade, pT3N0) or high-risk (pT4N0, pTanyN1) RCC post-nephrectomy. Methods: This retrospective observational study used the SEER-Medicare database (2007–2016). DFS was defined as time from initial nephrectomy date to first recurrence (diagnosis of metastatic disease, additional surgery, starting systemic treatment for advanced RCC) or death, whichever occurred first. OS from time of recurrence in pts with recurrence were compared with OS from comparable time point in pts without, using Kaplan-Meier analyses and adjusted Cox models. OS was also compared between pts with and without recurrence by landmark time points at 1, 2, 3, 4 and 5 years (yrs) post-nephrectomy; hazard ratios (HRs) between the two cohorts were estimated using adjusted Cox models. Correlation between DFS and OS was assessed using the Kendall’s s rank correlation. Monthly healthcare costs were compared between the two cohorts using generalized linear model. Results: 643 post-nephrectomy RCC pts (269 with recurrence vs 374 without) met the inclusion criteria (Median follow-up: 23 months). The mean age was 75.5 yrs, 61% male, and 86% white. The median post-nephrectomy OS and DFS was 8.61 and 4.44 yrs, respectively. Pts with and without recurrence had comparable baseline characteristics. Pts with recurrence had significantly shorter OS than those without [median: 2.53 yrs vs not reached; adjusted HR (95% confidence interval [CI]): 6.00 (4.24–8.48)]. Pts with recurrence by each landmark time point had significantly shorter OS than those without [1 yr post-nephrectomy median OS: 2.35 vs 9.66 yrs, and the OS 1, 3, and 5 after the 1 yr landmark was 69.9 vs 96.5%, 41.8 vs 83.8%, and 37.0 vs 70.1%, respectively; all Ps (log- rank test) < 0.001]. Cox models indicated that pts with recurrence by each landmark time point had 2.6–3.5 times increased risk of death compared with those without. Kendall’s s rank correlation model demonstrated a statistically significant correlation between DFS and OS (Kendall’s s = 0.70; 95% CI: 0.65–0.74; P < 0.001). Pts with recurrence had $4,924 and $1,387 higher adjusted all-cause medical costs and pharmacy costs per month (P < 0.001). Conclusions: Post-nephrectomy recurrence is associated with significantly shorter OS among pts with intermediate-high or high-risk RCC, resulting in a strong positive association between DFS and OS in the population. Higher healthcare cost was also seen among pts with recurrence. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

4582 Poster Session

Role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC).

Pooja Ghatalia, Elizabeth A. Handorf, Mengying Deng, Matthew R. Zibelman, Philip Abbosh, Fern Anari, Richard E. Greenberg, Rosalia Viterbo, David Chen, Marc C. Smaldone, Alexander Kutikov, Daniel M. Geynisman, Robert Guy Uzzo; Fox Chase Cancer Center, Philadelphia, PA; FCCC, Philadel- phia; Fox Chase Cancer Center, Department of Hematology and Oncology, Philadelphia, PA; Fox Chase Cancer Center–Temple University Health System, Philadelphia, PA

Background: The role of CN in mRCC was challenged by the results of the CARMENA trial in the targeted therapy (TT) era. We sought to evaluate the role of both upfront and deferred CN in pts receiving modern IO-based and TT regimens. Methods: Pts with synchronous mRCC who received systemic therapy (tx) for mRCC after 2011 were included from the de-identified nationwide Flatiron Health database. We evaluated 3 groups: systemic tx alone, systemic-> CN, and CN-> systemic tx. Overall survival (OS) was calculated from the time of initiation of first therapy – systemic or CN. Patient characteristics were compared using chi-squared tests or t-test. Weighted Kaplan-Meier curves, log-rank tests, and Cox proportional hazards regressions with time-varying covariates were used to assess the effect of tx on survival. Adjustment was conducted via inverse probability of treatment weighing based on the generalized propensity score, estimated via Bayesian Additive Regression Trees. Covariates in the model were age, gender, race, insurance at mRCC diagnosis, and IMDC risk group. Results: Of 1719 pts with mRCC, 972 (56.5%) received systemic tx alone, 605 (35.1%) received CN-> systemic tx, and 142 (8.2%) received systemic->CN. 310 pts received IO or IO/IO, 123 pts received IO+TT and 1152 pts received only TT. The median follow-up was 37.1 months. In adjusted analyses using propensity score weighting and time-varying covariates, CN-> systemic was significantly associated with improved OS compared with systemic tx alone (Table). When stratifying groups by type of systemic treatment (IO and TT), there was improvement of OS in the CN groups compared to systemic tx alone, although we lacked power to reach statistical significance. Among CN-treated patients, the order of systemic tx relative to CN did not change OS (hazard ratio [HR] = 1.00, 95% CI 0.76-1.32, p=0.96). Conclusions: Using a national, EHR-based cohort, which includes a large number of IO treated pts, our findings support an oncologic role for CN in select mRCC pts. The timing of CN, for pts who were able to receive both systemic therapy and CN, may not affect overall outcome. The associated improvement in survival of CN is seen in pts receiving IO and TKI based systemic tx. Research Sponsor: None.

Adjusted median OS from weighted Kaplan-Meier curves and HR from weighted time-varying Cox model. N for Systemic adjusted tx Tx analysis alone CN-systemic tx Systemic tx-CN IO, IO/IO or IO/TT 15.1 mo 40.2 mo Not reached 400 (N=255) HR=0.84 (0.56-1.27), p=0.4 HR=0.58 (0.22-1.54), (N=113) p=0.28 (N=32) TT 11.0 mo 25.4 mo 37.7 mo 1087 (N=570) HR=0.85 (0.72-1.01), HR=0.85 (0.63-1.13), p=0.06 p=0.26 (N=417) (N=100) Overall 12.1 mo 26.1 mo 37.7 mo 1615 (N=891) HR=0.82 (0.70-0.95), HR=0.82 (0.62-1.07), p=0.008 p=0.14 (N=586) (N=138)

4583 Poster Session

Effect of high-dose corticosteroid use on efficacy of immune checkpoint inhibitors in patients with renal cell carcinoma (RCC).

Chris Labaki, Sarah Abou Alaiwi, Andrew Lachlan Schmidt, Talal El Zarif, Ziad Bakouny, Pier Vitale Nuzzo, Wenxin Xu, David A. Braun, Bradley Alexander McGregor, Toni K. Choueiri; Dana Farber Cancer Institute - (Individuals), Boston, MA; Dana Farber Cancer Institute, Boston, MA; Liz Plummer Cancer Centre, Cairns and Hinterland Hospital and Health Service, Cairns, QLD, Australia; Lank Center for Gen- itourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Bos- ton, MA

Background: The use of High-Dose Corticosteroids (HDC) has been linked to poor outcomes in patients with lung cancer treated with immune checkpoint inhibitors (ICIs) (Ricciuti B, JCO, 2019). There is no data on the effect of HDC on renal cell carcinoma patients (RCC) treated with immunotherapy. We hypothesized that HDC use would be associated with worse outcomes in RCC patients receiving ICIs. Methods: This study evaluated a retrospective cohort of patients with RCC at Dana-Farber Cancer Insti- tute in Boston, MA. Clinical information including demographics, IMDC risk score, RCC histology, ste- roid administration, ICI regimen, line of therapy, time to treatment failure (TTF) and overall survival (OS) were collected. Patients were divided into those receiving HDC (prednisone $10 mg or equivalent for $ 1 week, HDC group) or not receiving HDC (No-HDC group). HDC administration was evaluated in relation to TTF and OS in a univariate analysis (Log-rank test) and a multivariate analysis (Cox regression). Results: 190 patients with RCC receiving ICIs were included, with a median age of 59 years. HDC were administered to 56 patients and 134 patients received no (N= 116) or only low-dose (N=18) steroids. In the HDC group, 40 patients received steroids for immune-related adverse events, 8 for other cancer-related indications, and 8 for non-oncological indications. There was no difference in TTF between the HDC and No-HDC groups (12-mo TTF rate: 34.8 vs. 32.3%, respectively; log-rank p=0.65). Similarly, there was no difference in OS between the HDC and No-HDC groups (36-mo OS rate: 56.7 vs. 62.4%, respectively; log-rank p=0.97). After adjusting for IMDC risk group, RCC histology, ICI regimen type, and line of therapy, TTF and OS did not differ in the HDC group as compared to No-HDC group (HR=1.14 [95%CI: 0.80-1.62], p=0.44 and HR=1.17 [95%CI: 0.65-2.11], p=0.59, respectively). Conclusions: In this retrospective study of patients with RCC treated with ICIs, administration of high-dose corticosteroids was not associated with worse outcomes. Research Sponsor: None.

Clinical characteristics, 12-mo TTF and 36-mo OS rates in study groups. Patients receiving Patients not receiving P- Variable Category HDC (n=56) HDC (n=134) value*

IMDC groups Intermediate risk, n(%) 24 (42.8) 89 (66.4) Ref. Favorable risk, n(%) 19 (34.0) 24 (18.0) 0.005 Poor risk, n(%) 13 (23.2) 21 (15.6) 0.04 Histology ccRCC, n(%) 48 (85.7) 107 (79.8) Ref. nccRCC, n(%) 8 (14.3) 27 (20.2) 0.34 Line of therapy 1st line, n(%) 46 (82.1) 94 (70.1) Ref. 2nd line, n(%) 10 (17.9) 40 (29.9) 0.09 Regimen ICI + anti-VEGF, n(%) 25 (44.7) 58 (43.3) Ref. Dual ICI therapy, n(%) 17 (30.3) 33 (24.6) 0.64 ICI monotherapy, n(%) 14 (25.0) 43 (32.1) 0.47 Survival 12-month TTF rate, % [95%CI] 34.8 [24.1-50.1] 32.3 [24.9-41.9] 0.65 36-month OS rate, % [95%CI] 56.7 [41.2-78.0] 62.4 [53.2-73.1] 0.97

*Logistic regression for clinical variables, log-rank test for survival outcomes.

4584 Poster Session

An open-label, single-arm, multicenter, phase II study of RC48-ADC to evaluate the efficacy and safety of subjects with HER2 overexpressing locally advanced or metastatic urothelial cancer (RC48-C009).

Xinan Sheng, Zhisong He, Weiqing Han, Ai-Ping Zhou, Hong Luo, Yanxia Shi, Changlu Hu, Ziling Liu, Hongqian Guo, Xin Yao, Benkang Shi, Jiyan Liu, Zhigang Ji, Jianming Guo, Yi Hu, Shi Ying Yu, Guohua Yu, Jianming Ying, Jianmin Fang, Jun Guo; Department of Renal Cancer and Melanoma, Peking Univer- sity Cancer Hospital & Institute, Beijing, China; Department of Urology, Peking University First Hospi- tal, Institute of Urology, Peking University, Beijing, China; Urinary Surgery Center, Hunan Cancer Hospital, Changsha, China; Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China; Department of Urology Surgery, Chongqing Cancer hospital, Chongqing, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; Anhui Provincial Cancer Hospital, Hefei, China; Department of Cancer Centre, First Hospital of Jilin University, Changchun, China; Urinary Surgery Center, Nanjing Drum Tower Hospital, Nanjing, China; Tianjin Cancer Hospital, Tianjin, China; Qilu Hospital of Shandong University, Jinan, China; West China Hospital, Sichuan University, Chengdu, China; Peking Union Medical College Hospi- tal, Beijing, China; Zhongshan Hospital, Fudan University, Shanghai, China; Chinese PLA General Hos- pital, Beijing, China; Tongji Hospital, Wuhan, China; Weifang People0s Hospital, Weifang, China; Pathology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; School of Life Science and Technology, Tongji University, Shanghai, China; Key Laboratory of Carcino- genesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China

Background: There is still urgent medical needs in the patients with locally advanced or metastatic urothelial cancer (mUC) post to the failure of at least one line chemotherapy. RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC), has proved its efficacy in these patients (RC48-C005, NCT03507166), most of whom had received gemcitabine and platinum. Taking into consideration that taxane is another possible active agent for mUC, this study aims to further evaluate the efficacy of RC48-ADC in HER2 overexpressing mUC post to the failure of platinum, gemcitabine and taxane. Meth- ods: This study was an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria included: histologically confirmed UC, HER2 overexpressing (IHC 2+ or 3+), ECOG PS 0-1, failed platinum, gemcitabine and taxane. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, death or study termination. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC) according to RECIST v1.1. Progress-free survival (PFS), duration of response (DOR), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study started in December 2018 and completed in September 2020. A total of 64 patients were enrolled, with a median age of 62.5 years. At baseline, most patients (82.8%) had visceral metastasis. Fifty-five patients (85.9%) had received $ 2 lines treatment and 19 (29.7%) patients had prior immune checkpoint inhibitor (CPI) therapy. As of Nov 30, 2020, the confirmed ORR assessed by BIRC was 46.9% (95% CI: 34.3%, 59.8%) and the median DOR was 8.3 months (95% CI: 4.3, NE), the median PFS was 4.3 months (95% CI: 4.0, 6.8). The median OS was 14.8 months (95% CI: 8.7, 21.1). The ORR was 60.0% (15/25) in patients with HER2 IHC3+ or FISH test positive, 45.3% (24/53) in patients with visceral metastasis, 42.1% (8/19) in patients post to CPI therapy. The ORR was 55.6% (5/9), 50.0% (21/ 20) and 30.8% (4/13), in patients who had received 1 line, 2 lines and $ 3 lines treatment, respectively. Most commonly reported TRAEs were leukopenia (45.3%), AST increase (43.8%), neutropenia (42.2%), hypoesthesia (42.2%), ALT increase (37.5%) and fatigue (35.9%); Most commonly reported $ grade 3 TRAEs were neutropenia (9.4%) and hypoesthesia (6.3%). Conclusions: In patients with HER2 overexpressing (IHC 2+ or 3+) mUC who had failed platinum, gemcitabine and taxane, and the great majority of whom had received $2 prior lines treatment, RC48-ADC has demonstrated consistently excellent efficacy and benefit-risk profile compared with the RC48-C005 study which enrolled patients with mUC who had received $1 line prior chemotherapy. Clinical trial information: NCT03809013. Research Sponsor: remegen.

4585 Poster Session

Circulating tumor DNA (ctDNA) in patients with advanced adrenocortical carcinoma.

Bassel Nazha, Hiba I. Dada, Leylah Drusbosky, Jacqueline T Brown, Deepak Ravindranathan, Bradley Curtis Carthon, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen; Emory University Depart- ment of Hematology and Medical Oncology, Atlanta, GA; Guardant Health, Inc., Redwood City, CA; NantHealth, Culver City, CA; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Winship Cancer Institute of Emory University, Atlanta, GA; Emory Uni- versity Hospital Midtown, Atlanta, GA

Background: Adrenocortical Carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited treatments in the advanced setting. Molecular pathways with tumor suppressor genes (e.g. TP53, CDKN2A) and oncogenes (e.g. CTNNB1 and RAS) are implicated in oncogenesis. To our knowledge, the genomic landscape of ctDNA alterations for ACC has not been described in a large cohort. We report plasma-based ctDNA alterations in patients with advanced ACC. Methods: We retrospectively evaluated genomic data from 102 patients with ACC who had ctDNA testing between 12/2016 – 10/ 2020 using Guardant360 (Guardant Health, CA). ctDNA analysis interrogated single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes. We evaluated the frequency of genomic alterations, the landscape of co-occurring mutations, and pathogenic or likely pathogenic alterations with potential targeted therapies. The prevalence of alterations identified in ctDNA were compared to those detected in tissue using a publicly available database (cBioPortal). Re- sults: The median age was 54 years (range 24-81), and 55% of patients were male. Among the entire cohort, 84 pts (82.4%) had $1 somatic alteration detected. Mutations were most frequently detected in TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%). The frequencies detected in ctDNA were similar to the results detected in tissue. Pathogenic and/or likely pathogenic mutations in therapeutically relevant alterations were observed in 36 patients (35%), including EGFR, BRAF, MET, CDKN2A, and CDK4/6 (Table 1). The most frequently co-occurring mutations were EGFR + TP53 (14%), EGFR + MET (11%), BRAF + MET (10%). Conclusions: Blood-based ctDNA profiling in advanced ACC provided comprehensive genomic data in most patients, with a similar profile to tumor tissue analyses. Over one third of patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options for this aggressive malignancy. Research Sponsor: None.

ACC patients with mutations in the rapeutically relevant alterations Gene N % EGFR 10 11.9% BRAF 9 10.7% MET 9 10.7% CDKN2A 7 8.3% NF1 7 8.3% CDK4 7 8.3% CDK6 6 7.1% GNAS 6 7.1% FGFR 1 or FGFR2 5 6.0% ATM 4 4.8%

TPS4586 Poster Session

A phase 3, multicenter, randomized study evaluating the efficacy of TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy in participants with muscle-invasive urothelial carcinoma of the bladder.

Stephen B. Williams, Christopher Cutie, Kirk A Keegan, Bradley Raybold, Milin Acharya, Wei Zhu, Xiang Li, Lang A O’Dondi, Neil Beeharry, Daniel Eidelberg Spratt; University of Texas Medical Branch (UTMB), Galveston, TX; TARIS Biomedical, Lexington, MA; Janssen Research & Development, Raritan, NJ; Janssen Research & Development, Spring House, PA; Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH

Background: The standard of care for patients with muscle-invasive bladder cancer (MIBC) consists of neoadjuvant chemotherapy and radical cystectomy (RC) or chemoradiotherapy (CRT). However, RC is associated with potential morbidity or mortality from the procedure. TAR-200 is an intravesical drug-delivery system designed for the local continuous release of gemcitabine within the bladder. Cetrelimab is an investigational immunoglobulin G4 anti–programmed cell death protein-1 antibody. In patients with MIBC, this clinical trial will evaluate whether combination treatment with intravesical TAR-200 and systemic cetrelimab will result in enhanced local and systemic antitumor activity versus concurrent CRT. Methods: SunRISe-2 (NCT04658862) is a prospective, multicenter, open-label, randomized phase 3 study evaluating the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab versus CRT in participants with MIBC. Eligible participants are aged 318 years with an ECOG performance status of 0, 1, or 2, and histologically proven, cT2-T4a, N0, M0 urothelial carcinoma of the bladder diagnosed within 90 days of the randomization date, and who refuse or are ineligible for RC. Approximate- ly 550 participants will be randomized in a 1:1 ratio and with stratification by 2 factors: transurethral resection of bladder tumor screening results (visibly complete vs incomplete) and screening tumor stage (T0 vs Ta/T1/Tis vs T2-T4a). Participants in Arm 1 will receive intravesical TAR-200 every 3 weeks for the first 18 weeks on study; and, beginning at week 24, every 12 weeks through study year 3. Cetreli- mab will be dosed every 3 weeks until month 18. Participants in Arm 2 will receive standard of care CRT (with either cisplatin or gemcitabine, for up to 6 weeks). A primary disease assessment will be performed at week 18 to evaluate treatment response in both arms. Subsequent assessments (axial imaging and cystoscopy) will occur at week 24 and every 12 weeks thereafter through study year 2, and then every 24 weeks through study year 5. The primary endpoint is bladder intact event-free survival. Key secondary endpoints include metastasis-free survival, overall survival, overall response rate (at week 18), and safety and tolerability. Other/exploratory end points include assessments of cancer-specific survival, time to symptomatic progression, pharmacokinetics, immunogenicity, health-related quality of life, healthcare resource utilization, and biomarkers. Participants are being enrolled at approximately 272 study sites worldwide. The study opened for enrollment in December 2020. Clinical trial information: NCT04658862. Research Sponsor: Janssen Research & Development, LLC.

TPS4587 Poster Session

KEYNOTE-B15/EV-304: Randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle- invasive bladder cancer (MIBC).

Christopher J. Hoimes, Jens Bedke, Yohann Loriot, Hiroyuki Nishiyama, Xiao Fang, Ritesh S. Kataria, Blanca Homet Moreno, Matt D. Galsky; Duke University, Durham, NC; Eberhard Karls Universita€t Tu€bingen, Tu€bingen, Germany; Gustave Roussy, Cancer Campus, Villejuif, France; University of Tsuku- ba, Ibaraki, Japan; Merck & Co., Inc., Kenilworth, NJ; Icahn School of Medicine at Mount Sinai, New York, NY

Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND); however, in time, patients experience disease recurrence or progression. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. The KEYNOTE-869/EV-103 phase 1/2 study (NCT03288545) showed that the PD-1 inhibitor pembrolizumab + EV had encouraging antitumor activity and acceptable safety as first- line treatment for cisplatin-ineligible patients with metastatic urothelial cancer (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044). Based on these data, investigating EV + pembrolizumab in an earlier setting such as MIBC and in a perioperative fashion is appropriate. KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Methods: Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant ($50%) urothelial histology, have nonmetastatic disease ($N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS $10 or CPS < 10), and geographic region (United States or Europe or most of world). Imaging (CT or MRI) will be performed #6 weeks before cystectomy and 6 weeks after cystectomy. After postcys- tectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathological complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathological downstaging, and safety and tolerability. Clinical trial information: NCT04700124. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

TPS4588 Poster Session

Consolidative radiotherapy for metastatic urothelial bladder cancer patients without progression and with no more than three residual metastatic lesions following first line systemic therapy: A prospective randomized comparative phase II trial (BLAD RAD01/ GETUG-AFU V07).

Jonathan Khalifa, Damien Pouessel, Mathieu Roumiguie, Paul Sargos, Genevieve Loos, Ulrike Schick, Naji Salem, Nathalie Mesgouez-Nebout, Yohann Loriot, Christophe Hennequin, Emmanuel Meyer, Pierre Blanchard, Valentine Guimas, Laurent Votron, Pierre Graff-Cailleaud, Gilles Crehange, Muriel Mounier, Ange�lique Massoubre, Leonor Chaltiel, Thomas Filleron; Institut Claudius Regaud/IUCT-On- copole, Toulouse, France; Institut Claudius Regaud/IUCT-Oncopole, CHU Rangueil, Toulouse, France; Institut Bergonie�, Bordeaux, France; Centre Jean Perrin, Clermont-Ferrand, France; Institut de Can- ce�rologie et d’He�matologie CHRU de Brest, Brest, France; Department of Radiotherapy, Institut Paoli- Calmettes, Marseille, France; Institut de Cance�rologie de l’Ouest-site Paul Papin, Angers, France; De- partment of Cancer Medicine, Gustave Roussy, Universite� Paris-Saclay, Villejuif, France; Hopital Saint- Louis, Paris, France; Department of Radiation Oncology, Centre Francois Baclesse, Caen, France; Gus- tave Roussy, Villejuif, France; Institut de Cance�rologie de l’Ouest, Nantes Saint-Herblain, France; Clini- que Claude Bernard, Albi, France; Institut Curie, Paris, France

Background: Consolidative local treatment of the primary tumor in the treatment of metastatic malignancies has shown promising results in several types of tumors, mostly relying on the seed-and-soil theory. Furthermore, the local treatment of the residual metastases following systemic treatment is a promising approach, in part due to the high incidence of progression at prior sites of disease in patients who had initially responded to chemotherapy. To date, no prospective data exists on such consolidative approach in metastatic urothelial bladder cancer (mUBC). The phase II trial BLAD-RAD01 GETUG-AFU V07 was designed to investigate the role of local consolidative radiotherapy in patients with limited mUBC and without progression following the initial phase of first-line systemic therapy. Methods: This is a phase II, multicenter, randomized open-label and comparative study. Patients with mUBC (excluding brain and liver metastases), without progression following standard first-line systemic therapy according to RE- CIST v1.1, and with no more than 3 residual metastatic lesions on 18FDG-PET scanner and/or contrast-enhanced CT-scanner are eligible for the study. After the completion of systemic treatment, an estimated 130 patients will be randomized in a 1:1 ratio between consolidative local treatment (pelvic radiotherapy +/- previous transurethal resection of bladder tumor, associated with stereotactic body radiotherapy (SBRT) to the residual metastases) plus standard of care (arm B) and standard of care only (arm A). Stratification is performed based upon: the center, the ECOG performance status, the administration of immunotherapy or not, the number of residual metastatic lesions and the imaging modality for assessment of the number of residual lesions. To date, standard of care for this population is maintenance treatment with avelumab. Radiotherapy regimens consist in conventionally fractionated (64Gy in 32 fractions) or hypofractionated (55Gy in 20 fractions) irradiation of the bladder, optional pelvic nodes irradiation, and 3 to 5 fractions of 6 to 18 Gy in SBRT for metastases, depending on the location. The main objective is to detect an increase in 20-month overall survival rate following chemotherapy from 50% (based upon the JAVELIN 100 trial) to 66%; this corresponds to a hazard ratio of 0.6. A total of 83 events are necessary for 85% power to detect this difference if it is true using a one-sided logrank test at the 10% of significance. Target difference, type I and II error rates are relaxed and compatibles with recommendations for comparative phase II trials. Key secondary endpoints are progression free survival, safety and quality of life. To date, one patient has been enrolled and eight centers are open for accrual. Clinical trial information: NCT04428554. Research Sponsor: PHRC-K 2019 (programme hospitalier de recherche clinique national en cance�rologie).

TPS4589 Poster Session

AUREA study: Atezolizumab (Atezo) combined with split-dose gemcitabine plus cisplatin (s-GC) in locally advanced or metastatic urothelial cancer (LA/mUC): A SOGUG study.

Alfonso Gomez De Liano Lista, Georgia Anguera, Emilio Esteban, Ovidio Fernandez Calvo, Iciar Garc�ıa- Carbonero, Xavier Garcia del Muro, Iria Gonza�lez Maeso, David Lorente-Estelles, Esther Mart�ınez Ortega, Alvaro Pinto, Javier Puente, Guillermo de Velasco; Medical Oncology Department, Complejo Hospitalario Universitario Insular-Materno Infantil, Las Palmas, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Hospital Universitario Central de Asturias, Oviedo, Spain; Medical Oncology De- partment-Complejo Hospitalario Universitario de Ourense, Ourense, Spain; Medical Oncology, Hospital Virgen De La Salud, Toledo, Spain; Medical Oncology. Institut Catala� d’Oncologia (ICO) L’Hospitalet del Llobregat, Barcelona, Spain; Hospital Son Lla�tzer, Palma De Mallorca, Spain; Hospital Provincial de Castellon, Castello�n de la Plana, Spain; Medical Oncology, Complejo Hospitalario de Jae�n, Jae�n, Spain; Medical Oncology Department, Hospital Universitario La Paz, Instituto de Investigacion Sanitar- ia Hospital La Paz (IdiPAZ), Madrid, Spain; Hospital Cl�ınico San Carlos, Instituto de Investigacio�n Sani- taria del Hospital Cl�ınico San Carlos (IdISSC), CIBERONC, Madrid, Spain; Department of Oncology, Hospital 12 de Octubre, Madrid, Spain

Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky�s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression $5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/ mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age > 70 years, PS ECOG 0-2, creatinine Clearance >30 and <60 mL/min per Cockroft- Gault formula or by 24-hour urine collection. Other reasons for cisplatin ineligibility as considered by investigator, including those uncovered by Galsky�s criteria, will be allowed, prior discussion with PI. Ex- clusion criteria include prior systemic therapy for LA/mUC (adjuvant/neoadjuvant allowed if finished > 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078. Research Sponsor: Roche, Spanish Oncology Genito Urinary Group (SOGUG).

TPS4590 Poster Session

EA8185: Phase 2 study of bladder-sparing chemoradiation (chemoRT) with durvalumab in clinical stage III, node positive urothelial carcinoma (INSPIRE)—An ECOG-ACRIN and NRG Collaboration.

Monika Joshi, Se Eun Kim, Abhishek A Solanki, David Tomoaki Miyamoto, David Degraff, Jennifer Wei Zou, Joshua J Meeks, Timur Mitin, Sean P. Collins, Edouard John Trabulsi, Noah M. Hahn, Jason A. Efstathiou, Michael Anthony Carducci; Penn State Cancer Institute, Hershey, PA; Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA; Loyola University Chicago, Maywood, IL; Mas- sachusetts General Hospital/ Harvard Medical School, Boston, MA; Pennsylvania State University Col- lege of Medicine, Hershey, PA; University of Pennsylvania, Philadelphia, PA; Jesse Brown VA Medical Center, Chicago, IL; Department of Radiation Medicine, Oregon Health and Science University, Port- land, OR; Department of Radiation Medicine, Georgetown University, Washington, DC; Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA; Departments of Oncology and Urology, Johns Hopkins School of Medicine, Baltimore, MD; Massachusetts General Hos- pital, Boston, MA; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Balti- more, MD

Background: Patients [pts] withlymph node positive (LN+), non-metastatic bladder cancer (BC) have a better prognosis than those with metastatic (M1) disease. However, this population is under-represented in advanced bladder trials and ineligible for bladder-sparing trials. Therefore, there have been no larger prospective trials establishing the standard of care in LN+ BC. Given the promise of immunotherapy in advanced BC and potential synergy between immunotherapy and radiation, INSPIRE was designed to determine the role of concurrent and adjuvant durvalumab (durva) in this patient population when treated with induction chemotherapy (IC) followed by concurrent chemoRT. Methods: This is a randomized phase II study that is enrolling BC pts with stage III [N1-2 M0], pure or mixed urothelial cancer. Pts must have received $3 cycles of IC [either before or after registration, prior to randomization] without progression. LN+ is defined as radiologically LN $1.0 cm in short axis, with or without biopsy prior to IC. As long as pts do not progress on induction chemotherapy, they will be randomized to chemoRT+/- durva using 5 stratification factors (Simon Pocock minimization method) a) IC prior vs. post registration b) cisplatin vs non-cisplatin regimen during RT c) LN size d) response to IC e) extent of TURBT. Pts on the chemoRT+durva arm will get chemotherapy per physician choice + IMRT + 3 x doses of Q3wk durva for 6.5-8 wks, whereas those on the control arm will get chemoRT alone. The primary end point is clinical complete response [CR], defined as no radiologically measurable disease in the LNs and negative cystoscopy and bladder biopsy 8-10 weeks post-chemoRT +/- durva. Pts on the che- moRT + durva arm who have a CR or clinical benefit ( > T0 and #T2 in bladder per cystoscopy, biopsy + CR/PR/SD in LN by imaging) will get adjuvant Q4wk durva for 9 doses, while those on the chemoRT arm will undergo observation. Secondary end points include OS, PFS, bladder-intact event-free survival, rate of toxicity and salvage cystectomy. This study is designed to detect an improvement of 25% in clinical CR between both arms (37.5% to 62.5%). A total accrual of 114 pts (in order to enroll 92 evaluable pts) will provide 81% power to detect this difference using a Fisher’s exact test (assuming 10% drop out + anticipating that 20% chemotherapy-nave pts will progress post IC). We are banking blood and primary tumor tissue pre- and post-chemoRT in both groups. The study was activated in August 2020 and accrual is ongoing. INSPIRE is the first prospective study designed for only LN+ BC and will define both short-term and long-term outcomes for bladder sparing in this patient population and has the potential to define a new treatment strategy for stage III BC. Clinical trial information: NCT04216290. Research Sponsor: U.S. National Institutes of Health.

TPS4591 Poster Session

A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer (HCRN GU18-343) ABATE study.

Deepak Kilari, Aniko Szabo, Kathryn A. Bylow, Robert S. Alter, Ariel Ann Nelson, Emily Lemke, William Adrian Hall, Scott Johnson, Peter Langenstroer, Kenneth Jacobsohn, Nancy B. Davis, Chunkit Fung, Matthew I. Milowsky; Medical College of Wisconsin, Milwaukee, WI; John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; NRG Oncology and Medical College of Wis- consin, Milwaukee, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; University of North Carolina Department of Medicine, Division of Hematology/Oncology, Chapel Hill, NC

Background: ABACUS and PURE-01 trials demonstrated the activity of single agent atezolizumab and pembrolizumab respectively as neoadjuvant therapy for muscle invasive urothelial carcinoma (MIUC). However, downstaging to non-muscle invasive disease was noted in only 50 percent of patients. Resis- tance to programmed death (PD)- 1/L-1 antibodies is likely to include factors such as impaired dendritic cell maturation/function, infiltration of T-Regs and myeloid derived suppressor cells, impaired T-cell priming and T-cell trafficking in tumors. Cabozantinib is a tyrosine kinase inhibitor which targets MET, AXL, MER, Tyro3 and VEGFR2. Cabozantinib has a unique immunomodulatory profile and has demonstrated clinical activity as monotherapy and in combination with PD-1/L1 antibodies in various solid tumors including UC, renal cell cancer, castrate- resistant prostate cancer, and non-small cell lung cancer. We hypothesize that the combination of cabozantinib and atezolizumab as neoadjuvant therapy for MIUC would improve rates of pathologic downstaging compared to single-agent checkpoint inhibitors. Methods: ABATE(NCT04289779) is an open-label, single arm, multi-center study to assess the efficacy and safety of cabozantinib with atezolizumab as neoadjuvant therapy for cT2-T4aN0/xM0 MIUC. An estimated 38 patients will be enrolled and receive cabozantinib 40 mg PO daily with atezolizumab 1200mg every 3 weeks for a total duration of 9 weeks followed by radical cystectomy. Adults ($18 years) with resectable UC who are either cisplatin-ineligible or decline cisplatin are eligible. Patients are required to have an ECOG PS of 0-2 and provide tumor tissue for PD-L1 analysis. UC should be predominant component ($ 50%). Previous systemic anticancer therapies for MIUC are not permitted. CT/ MRI will be performed before investigational therapy and cystectomy. Primary endpoint is pathologic response rate defined as the absence of residual muscle-invasive cancer in the surgical specimen ( < pT2). Secondary endpoints are safety and toxicity, pathologic complete response rate and event-free survival. Exploratory end points include patient-reported outcomes and outcome associations with biomarkers. Accrual began May 2020. Clinical trial information: NCT04289779. Research Sponsor: Exe- lixis and Genentech.

TPS4592 Poster Session

Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) (CaNI) for advanced renal cell carcinoma with variant histology (aRCCVH).

Bradley Alexander McGregor, Wanling Xie, Mehmet Asim Bilen, David A. Braun, Wenxin Xu, Praful Ravi, Elisabeth I. Heath, David F. McDermott, Rana R. McKay, Hans J. Hammers, Toni K. Choueiri; Dana-Farber Cancer Institute, Boston, MA; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Karmanos Cancer Institute, Depart- ment of Oncology, Wayne State University School of Medicine, Detroit, MI; Beth Israel Deaconess Medi- cal Center, Dana-Farber/Harvard Cancer Center, Boston, MA; University of California San Diego, Moores Cancer Center, La Jolla, CA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medi- cal Center, Dallas, TX; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Bos- ton, MA

Background: Despite advances in therapy of clear cell renal cell carcinoma, outcomes for patients with aRCCVH remain poor and these patients have typically been excluded from pivotal phase III studies. COSMIC-313 (NCT03937219) exploring C/N/I vs N/I excludes those with aRCCVH. Given responses seen with C as well as N/I in aRCCVH, there is reason to explore this triplet combination in this population. Methods: NCT04413123 is single arm phase 2 trial multi-institutional study involving Dana-Farb- er Cancer Institute, Beth Israel Deaconess Medical Center, Winship Cancer Institute, Karmanos Cancer Center, University of California in San Diego and University of Texas Southwestern. The primary objective is to assess the objective response rate (ORR) by investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of C in combination with N/I in aRCCVH. Key secondary endpoints are progression-free survival (PFS), overall survival (OS) and toxicity by Common Terminology Cri- teria for Adverse Events (CTCAE) version 5. Mandatory pretreatment biopsy (unless medically infeasible) is required for correlative analysis to define the composition and transcriptional states of tumor and immune cells within the aRCCVH microenvironment in addition to determining the number and state of tumor-infiltrating T cell clones in aRCCVH and relation to response. Any variant histology is allowed, including clear-cell RCC with over 80% sarcomatoid features. Patients may be treatment nave or received prior therapy including up to one anti-vascular endothelial growth factor agent not including C; prior therapy with immune checkpoint inhibitors is exclusionary. All International Metastatic RCC Da- tabase Consortium risk classifications are allowed; patients should have adequate organ function with performance status 0-1. C will be administered at a starting dose of 40 mg daily. N will be dosed at 3 mg/kg with I 1 mg/kg every 3 weeks followed by maintenance N 480 mg IV every 4 weeks and will be continued until progressive disease or unacceptable toxicity. C can be reduced to. 20 mg daily or 20 mg every other day as needed for toxicity. Dose reductions of N or I are not permitted but delays up to 12 weeks are allowed; N may be continued without I if toxicity can be directly attributed to I. Radiographic imaging is performed at baseline with first scheduled assessment at 12 weeks then every 8 weeks thereafter. A one-stage design is employed to enroll 40 eligible patients, which provides 93% power at 1- sided alpha of 0.09 to distinguish an ORR of 40% versus 20%. 12 or more responses are required to deem treatment promising. Seven of the planned 40 patients have been enrolled as of 2/1/2021. Clinical trial information: NCT04413123. Research Sponsor: Exelixis, Pharmaceutical/Biotech Company.

TPS4593 Poster Session

A randomized trial of radium-223 (Ra-223) dichloride and cabozantinib in patients (pts) with advanced renal cell carcinoma (RCC) with bone metastases (RADICAL/Alliance A031801).

Rana R. McKay, Heather Jacene, Pamela J. Atherton, Gabriela Perez Burbano, Archana Ajmera, Shiva Baghaie, Janet Koball, Tyler J. Zemla, Ronald C. Chen, Atish Dipankar Choudhury, Joshua Michael Lang, Suzanne Cole, Tareq Al Baghdadi, Young Kwok, Himisha Beltran, Daniel J. George, Michael J. Morris, Toni K. Choueiri; University of California San Diego, Moores Cancer Center, La Jolla, CA; Dana- Farber Cancer Institute, Boston, MA; Mayo Clinic, Rochester, MN; University of California, San Diego, La Jolla, CA; Alliance for Clinical Trials in Oncology, Chicago, IL; University of Kansas, Kansas City, KS; University of Wisconsin Carbone Cancer Center, Madison, WI; UT Southwestern Medical Center, Dallas, TX; IHA Hematology Oncology Consultants, Ypsilanti, MI; University of Maryland Medical Center, Balti- more, MD; Dana Farber Cancer Institute, Boston, MA; Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncology, Boston, MA

Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with $2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of $60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade $3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided a = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223. Research Sponsor: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org. U10CA180820 and UG1CA233302 (ECOG-ACRIN).

TPS4594 Poster Session

A phase 1b/2 umbrella study of investigational immune and targeted combination therapies as first-line therapy for patients with advanced renal cell carcinoma (RCC).

Elizabeth R. Plimack, Hans J. Hammers, Toni K. Choueiri, Brian I. Rini, Robert J. Motzer, Leah Suttner, Rodolfo F. Perini, Jaqueline Willemann Rogerio, Laurence Albiges; Fox Chase Cancer Center, Philadelphia, PA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX; Dana-Farber Cancer Institute, Boston, MA; Vanderbilt University Medical Center, Nashville, TN; Memorial Sloan Kettering Cancer Center, New York, NY; Merck & Co., Inc., Kenilworth, NJ; Gustave Roussy, Villejuif, France

Background: For advanced clear cell RCC (ccRCC), first-line treatment with PD-1/PD-L1 inhibitors in combination with CTLA-4 inhibitors or VEGF TKIs are established treatment options. However, patients eventually experience progression; therefore, more effective therapies are needed. This umbrella platform study is an open-label, rolling-arm, multicenter, phase 1b/2 trial with an adaptive design that will evaluate the safety and efficacy of experimental combinations of investigational agents in advanced ccRCC based on their mechanisms of action and toxicity profile. Substudy 03A (NCT04626479) will evaluate treatment combinations as first-line therapy for patients with advanced ccRCC. Given promising results of the phase 1b/2 KEYNOTE-146 (NCT02501096) and phase 3 KEYNOTE-581/CLEAR (NCT02811861) studies, pembrolizumab (400 mg IV Q6W) + lenvatinib (20 mg orally QD) will be used as the reference arm. Methods: Patients must be aged $18 years with histologically confirmed ccRCC, measurable disease per RECIST v1.1, and KPS score $70 and must have not received prior systemic therapy for advanced RCC (neoadjuvant therapy is acceptable if completed $12 mo before randomization). The study will comprise a safety lead-in phase for experimental combinations with investigational agents without an established recommended phase 2 dose (RP2D) and an efficacy phase. Patients will be randomly assigned 2:1 to an experimental arm or a reference arm. Each experimental arm will contain approximately 80 patients. During the efficacy phase, if more than 1 experimental arm is open for enrollment, patients in the reference arm can be shared. Treatments in the experimental arms are composed of the following: MK-1308A (coformulation of quavonlimab [MK-1308] 25 mg + pembrolizumab 400 mg IV Q6W) + lenvatinib (20 mg orally QD), MK-4280A (coformulation of MK- 4280 800 mg + pembrolizumab 200 mg IV Q3W) + lenvatinib (20 mg orally QD), and pembrolizumab (400 mg Q6W IV) + belzutifan (MK-6482, 120 mg orally QD) + lenvatinib (20 mg orally QD). Treatment with pembrolizumab (including coformulations with MK-1308 and MK-4280) will continue up to 2 years, whereas treatment with lenvatinib and belzutifan will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by IMDC risk group (favorable vs intermediate/poor). Tumor imaging will occur 12 weeks after randomization, then Q6W until week 54, and Q12W thereafter. Coprimary end points are safety and tolerability, establishing the RP2D during the safety lead-in phase (if applicable) and objective response rate per RECIST v1.1 by blinded independent central review (BICR) during the efficacy phase. Secondary end points during the efficacy phase are duration of response, progression-free survival and clinical benefit rate per RECIST v1.1 (BICR), and overall survival. Clinical trial information: NCT04626479. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA.

TPS4595 Poster Session

KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).

Chung-Han Lee, Chenxiang Li, Rodolfo F. Perini, Daniela Hoehn, Laurence Albiges; Memorial Sloan Kettering Cancer Center, New York, NY; Merck & Co., Inc., Kenilworth, NJ; Gustave Roussy, Villejuif, France

Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEY- NOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/ metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no pri- or systemic therapy for nccRCC, and KPS score $70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219. Research Sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA.

TPS4596 Poster Session

PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG- ACRIN EA8143).

Mohamad E. Allaf, Se Eun Kim, Viraj A. Master, David F. McDermott, Sabina Signoretti, David Cella, Rajan T. Gupta, Suzanne Cole, Brian M. Shuch, Primo Lucky N. 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, Michael Anthony Carducci, Naomi B. Haas; James Buchanan Brady Urological In- stitute, Dept. of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA; Winship Cancer Institute of Emory University, Atlanta, GA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Brigham and Women’s Hospital, Boston, MA; Robert H. Lurie Comprehensive Cancer Cen- ter, Northwestern University, Chicago, IL; Duke University Medical Center, Durham, NC; UT Southwest- ern Medical Center, Dallas, TX; Yale School of Medicine, New Haven, CT; University of California, Sacramento, CA; Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Mayo Clinic, Rochester, MN; Massachusetts General Hospital, Boston, MA; Dana-Farber Cancer Institute, The Lank Center for Genitourinary Oncolo- gy, Boston, MA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Kidney Cancer Canada, Toronto, Canada; Stanford University School of Medicine, Stanford, CA; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; Abramson Can- cer Center, University of Pennsylvania (ECOG-ACRIN), Philadelphia, PA

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. Ran- domized 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 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013. Research Sponsor: U.S. National Institutes of Health, Bristol Myers Squibb.

TPS4597 Poster Session

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, John B. A. G. Haanen, Ekaterini Boleti, Marine Gross Goupil, Marc- Oliver Grimm, Sylvie Negrier, Philippe Barthelemy, Gwenaelle Gravis, Philipp Ivanyi, Jens Bedke, Daniel Castellano, Andrej Panic, Begona Mellado, Pablo Maroto-Rey, Sylvie Rottey, Stefanie Zschaebitz, Dorothee Deckbar, Arndt Hartmann, Lothar Bergmann; Medical Clinic II, University Hospi- tal, Frankfurt Am Main, Germany; Gustave Roussy, Villejuif, France; Netherlands Cancer Institute, Am- sterdam, Netherlands; Royal Free London NHS Foundation Trust, London, United Kingdom; CHU Bordeaux, Bordeaux, France; Department of Urology, Universitaetsklinikum Jena, Jena, Germany; De- partement of Medical Oncology, Centre Le�on Be�rard, Lyon, France; Institut de Cance�rologie Strasbourg Europe,Strasbourg, France, Strasbourg, France; Institut Paoli-Calmettes, Aix-Marseille Universite�, Mar- seille, France; Department Hematology, Hemostaseology, Oncology & Stem Cell Transplantation, Hano- ver Medical School, Hannover, Germany; Eberhand Karls University Tu€bingen, Tu€bingen, Germany; Hospital Universitario 12 de Octubre, Madrid, Spain; Clinic for urology, University Hospital, Essen, Ger- many; Translational Genomics and Targeted Therapeutics in Solid Tumours Lab, Institut d’Investiga- cions Biome�diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; Ghent University Hospital, Heymans Institute of Pharmacology, Ghent, Belgium; NCT/Heidelberg University Hospital, Heidelberg, Germany; Universi- ty Hospital Frankfurt, Frankfurt, Germany; Institute of Pathology, Universitatsklinikum Erlangen, Frie- drich-Alexander-Universitat Erlangen-Nu€rnberg, Erlangen, Germany

Background: Non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of RCC patients (pts.). Data on treatment strategies for this heterogenous group of RCC are still limited, since most clinical trials focus on clear-cell RCC (ccRCC) histology. Recently combination therapies with immune checkpoint inhibitors (IO, avelumab or pembrolizumab) and tyrosinekinaseinhibitors (TKI) (axitinib) have been approved for treatment in RCC in all International Metastatic RCC Database Consortium (IMDC) risk groups. Additionally nivolumab and ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to sunitinib. Moreover retrospective analysis in nccRCC pts. have shown promising results for IO-based therapies 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 re- viewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non- papillary non-clear cell histology and by the 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 fixed dose 480mg IV every 4 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 214 patients (132 pts with papillary, 76 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423. Research Sponsor: Bris- tol-Myers Squibb.

TPS4598 Poster Session

Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).

Karie Runcie, Eric A. Singer, Moshe Chaim Ornstein, Christopher B. Anderson, Matthew Dallos, Jessica Hawley, Emerson A. Lim, Charles G. Drake, Benjamin Izar, Hiram A. Shaish, Mark N. Stein; Columbia University Medical Center, New York, NY; Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ; Cleveland Clinic Cancer Center, Cleveland, OH; Department of Urology, Columbia University Irving Medical Center, New York, NY; Columbia University, New York, NY; Columbia University-Herbert Irving Comprehensive Can- cer Center, New York, NY; Herbert Irving Comprehensive Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Department of Radiology, Columbia University Irving Medical Center, New York, NY

Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy re- moves a large portion of the tumor which may be a source of immunosuppression driven by tumor cell- intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition gen- erated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- nave subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post- operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluores- cence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: NCT04322955. Research Sponsor: Exelixis, Bristol-Myers Squibb.

TPS4599 Poster Session

A phase I study of bintrafusp alfa (M7824) and NHS-IL12 (M9241) alone and in combination with stereotactic body radiation therapy (SBRT) in adults with metastatic non- prostate genitourinary malignancies.

Scot Anthony Niglio, Daniel da Motta Girardi, Lisa M. Cordes, Lisa Ley, Marissa Mallek, Olena Sierra Ortiz, Jacqueline Cadena, Carlos Diaz, Heather Chalfin, Andre Kydd, Rene Costello, Ariel E. Marciscano, Jennifer C Jones, Kilian Elizabeth Salerno, Vladimir Valera, William Douglas Figg, William L. Dahut, James L. Gulley, Jeffrey Schlom, Andrea B. Apolo; National Cancer Institute, National Institutes of Health, Bethesda, MD; Genitourinary Malignancies Branch, NCI, NIH, Bethesda, MD; Na- tional Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Genitourinary Ma- lignancies Branch, National Cancer Institute, Bethesda, MD; Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD; Memorial Sloan Kettering Cancer Center, New York, NY; Department of Radiation Oncology, Center for Cancer Research, National Insti- tutes of Health, Bethesda, MD; Roswell Park Cancer Institute, Buffalo, NY; Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD; Clinical Pharmacology Program, National Institutes of Health, Bethesda, MD; Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Laboratory of Tumor Immunology and Bi- ology, NCI, NIH, Bethesda, MD

Background: The majority of non- prostate genitourinary (GU) cancers are lethal when metastatic and rare GU cancers have limited treatment options. Bintrafusp alfa is a bifunctional fusion protein composed of human TGF-b receptor II, which sequesters or traps all three TGF-b isoforms and a monoclonal PD-L1 antibody. NHS-IL12 is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double- stranded DNA (dsDNA) allowing for targeted delivery of pro-inflammatory cytokine, IL-12, to necrotic portions of tumor with DNA exposure to promote local immunomodulation. Preclinical data suggest synergy between these two agents. There is also evidence suggesting that stereotactic body radiation therapy (SBRT) can promote anti-tumor immune responses both locally and systemically while also synergizing with immune checkpoint inhibitors. Therefore, the combination of Bintrafusp alfa, NHS- IL12 and radiation is a potential strategy for metastatic non-prostate GU tumors. Methods: This is an open label, non-randomized, three-stage phase I trial of bintrafusp alfa and NHS-IL12 or bintrafusp alfa and NHS-IL12 in combination with either sequential or concurrent SBRT. Bintrafusp alfa (IV 1200 mg q2w) and SBRT (8 Gy x 3 fractions) are planned with a deescalating NHS-IL12 (subQ q4w) dose schedule. The accrual ceiling has been set at 66 patients. The trial will enroll patients with a pathologi- cally confirmed diagnosis of metastatic non-prostate genitourinary cancer with an ECOG # 2 (KPS $60%). Participants may have had prior cancer immunotherapy but excluding prior treatment with bintrafusp alfa and/or NHS-IL12. 9 patients will receive treatment in cycles consisting of 4 weeks. The primary objective is to determine the safety and highest tolerated doses with acceptable toxicity (recommended phase II dose) of bintrafusp alfa and NHS-IL12 alone or in combination with SBRT administered sequentially or concurrently in patients with metastatic non-prostate genitourinary cancers. Secondary objectives are objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Exploratory objectives are to determine peripheral immune modulation and the status of the immune microenvironment using cytokine analysis, circulating tumor cells, multiplex immunohisto- chemistry, T-cell receptor sequencing, and RNA-sequencing. The study is open and enrolling. Clinical trial information: NCT04235777. Research Sponsor: U.S. National Institutes of Health.