TY - JOUR
T1 - A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma
AU - Msaouel, Pavlos
AU - Sweis, Randy F.
AU - Bupathi, Manojkumar
AU - Heath, Elisabeth
AU - Goodman, Oscar B.
AU - Hoimes, Christopher J.
AU - Milowsky, Matthew I.
AU - Davis, Nancy
AU - Kalebasty, Arash Rezazadeh
AU - Picus, Joel
AU - Shaffer, David
AU - Mao, Shifeng
AU - Adra, Nabil
AU - Yorio, Jeffrey
AU - Gandhi, Sunil
AU - Grivas, Petros
AU - Siefker-Radtke, Arlene
AU - Yang, Rui
AU - Latven, Lisa
AU - Olson, Peter
AU - Chin, Curtis D.
AU - Der-Torossian, Hirak
AU - Mortazavi, Amir
AU - Iyer, Gopa
N1 - Publisher Copyright:
Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PY - 2024/8/1
Y1 - 2024/8/1
N2 - BACKGROUND AND OBJECTIVE: 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. METHODS: 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). KEY FINDINGS AND LIMITATIONS: 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. CONCLUSIONS AND CLINICAL IMPLICATIONS: 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. PATIENT SUMMARY: 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.
AB - BACKGROUND AND OBJECTIVE: 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. METHODS: 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). KEY FINDINGS AND LIMITATIONS: 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. CONCLUSIONS AND CLINICAL IMPLICATIONS: 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. PATIENT SUMMARY: 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.
KW - Nivolumab
KW - Sitravatinib
KW - Urothelial carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85199224246&partnerID=8YFLogxK
U2 - 10.1016/j.euo.2023.12.001
DO - 10.1016/j.euo.2023.12.001
M3 - Article
C2 - 38105142
AN - SCOPUS:85199224246
SN - 2588-9311
VL - 7
SP - 933
EP - 943
JO - European Urology Oncology
JF - European Urology Oncology
IS - 4
ER -