Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC.
The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously).
The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients.
Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied.
In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.
European urology oncology. 2023 Dec 16 [Epub ahead of print]
Pavlos Msaouel, Randy F Sweis, Manojkumar Bupathi, Elisabeth Heath, Oscar B Goodman, Christopher J Hoimes, Matthew I Milowsky, Nancy Davis, Arash Rezazadeh Kalebasty, Joel Picus, David Shaffer, Shifeng Mao, Nabil Adra, Jeffrey Yorio, Sunil Gandhi, Petros Grivas, Arlene Siefker-Radtke, Rui Yang, Lisa Latven, Peter Olson, Curtis D Chin, Hirak Der-Torossian, Amir Mortazavi, Gopa Iyer
University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ., University of Chicago Medicine, Chicago, IL, USA., Rocky Mountain Cancer Centers - Littleton, Littleton, CO, USA., Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA., Comprehensive Cancer Centers of Nevada - Southwest, Las Vegas, NV, USA., Duke University Hospital, Durham, NC, USA., UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA., Vanderbilt - Ingram Cancer Center, Nashville, TN, USA., University of California Irvine, Irvine, CA, USA., Washington University School of Medicine, Siteman Cancer Center, Saint Louis, MO, USA., New York Oncology Hematology - Albany Medical Center, Albany, NY, USA., Allegheny General Hospital, Pittsburgh, PA, USA., Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA., Texas Oncology - Austin Central, Austin, TX, USA., Florida Cancer Specialists and Research Institute - North Region (SCRI), Tampa Bay, FL, USA., Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA., University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mirati Therapeutics, Inc., San Diego, CA, USA., Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, and the Comprehensive Cancer Center, Columbus, OH, USA., Memorial Sloan Kettering Cancer Center, New York, NY, USA.