A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma

In this phase 2 study, sitravatinib plus nivolumab demonstrated a manageable safety profile, but did not result in clinically meaningful response rates across eight cohorts representing different prior systemic treatment lines in patients with advanced or metastatic urothelial carcinoma. Checkpoint...

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Veröffentlicht in:European urology oncology 2024-08, Vol.7 (4), p.933-943
Hauptverfasser: Msaouel, Pavlos, Sweis, Randy F., Bupathi, Manojkumar, Heath, Elisabeth, Goodman, Oscar B., Hoimes, Christopher J., Milowsky, Matthew I., Davis, Nancy, Kalebasty, Arash Rezazadeh, Picus, Joel, Shaffer, David, Mao, Shifeng, Adra, Nabil, Yorio, Jeffrey, Gandhi, Sunil, Grivas, Petros, Siefker-Radtke, Arlene, Yang, Rui, Latven, Lisa, Olson, Peter, Chin, Curtis D., Der-Torossian, Hirak, Mortazavi, Amir, Iyer, Gopa
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container_issue 4
container_start_page 933
container_title European urology oncology
container_volume 7
creator Msaouel, Pavlos
Sweis, Randy F.
Bupathi, Manojkumar
Heath, Elisabeth
Goodman, Oscar B.
Hoimes, Christopher J.
Milowsky, Matthew I.
Davis, Nancy
Kalebasty, Arash Rezazadeh
Picus, Joel
Shaffer, David
Mao, Shifeng
Adra, Nabil
Yorio, Jeffrey
Gandhi, Sunil
Grivas, Petros
Siefker-Radtke, Arlene
Yang, Rui
Latven, Lisa
Olson, Peter
Chin, Curtis D.
Der-Torossian, Hirak
Mortazavi, Amir
Iyer, Gopa
description In this phase 2 study, sitravatinib plus nivolumab demonstrated a manageable safety profile, but did not result in clinically meaningful response rates across eight cohorts representing different prior systemic treatment lines in patients with advanced or metastatic urothelial carcinoma. 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.
doi_str_mv 10.1016/j.euo.2023.12.001
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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.</description><identifier>ISSN: 2588-9311</identifier><identifier>EISSN: 2588-9311</identifier><identifier>DOI: 10.1016/j.euo.2023.12.001</identifier><identifier>PMID: 38105142</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Carcinoma, Transitional Cell - drug therapy ; Carcinoma, Transitional Cell - mortality ; Carcinoma, Transitional Cell - pathology ; Carcinoma, Transitional Cell - secondary ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Nivolumab ; Nivolumab - therapeutic use ; Sitravatinib ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - pathology ; Urologic Neoplasms - drug therapy ; Urologic Neoplasms - mortality ; Urologic Neoplasms - pathology ; Urothelial carcinoma</subject><ispartof>European urology oncology, 2024-08, Vol.7 (4), p.933-943</ispartof><rights>2023 European Association of Urology</rights><rights>Copyright © 2023 European Association of Urology. 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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. 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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.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>38105142</pmid><doi>10.1016/j.euo.2023.12.001</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6505-8308</orcidid></addata></record>
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identifier ISSN: 2588-9311
ispartof European urology oncology, 2024-08, Vol.7 (4), p.933-943
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2588-9311
language eng
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subjects Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Carcinoma, Transitional Cell - drug therapy
Carcinoma, Transitional Cell - mortality
Carcinoma, Transitional Cell - pathology
Carcinoma, Transitional Cell - secondary
Female
Humans
Male
Middle Aged
Neoplasm Metastasis
Nivolumab
Nivolumab - therapeutic use
Sitravatinib
Urinary Bladder Neoplasms - drug therapy
Urinary Bladder Neoplasms - pathology
Urologic Neoplasms - drug therapy
Urologic Neoplasms - mortality
Urologic Neoplasms - pathology
Urothelial carcinoma
title A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma
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