A phase II trial of sitravatinib plus nivolumab after progression on prior immune checkpoint inhibitor (ICI) in patients with metastatic clear cell renal cell carcinoma (ccRCC).
Authors: Dizman Nazli , Adra Nabil , Vaishampayan Ulka N. , Xiao Lianchun , Yuan Ying , Campbell Matthew T , Gao Jianjun , Zurita Amado J. , Jonasch Eric , Tannir Nizar M. , Shah Amishi Yogesh , Msaouel Pavlos , Hahn Andrew Warren 
Published: July 2024

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Background: Sitravatinib, an oral multi-kinase inhibitor targeting VEGFR, TAM, and MET, has been shown to resensitize the tumor microenvironment to ICI by reducing immune-suppressive myeloid cells in metastatic ccRCC (Msaouel, Sci Transl Med 2022). ICI is the standard first-line (1L) treatment of metastatic ccRCC, and there is unmet need for improved treatment outcomes after progression on ICI. We hypothesized that sitravatinib plus nivolumab would revert an immunosuppressive tumor microenvironment (TME) to improve objective response rate (ORR) and survival in patients with metastatic ccRCC whose disease progressed on or after ICI. Methods: In this investigator-initiated, phase II, multicenter trial (NCT04904302), patients with progressive metastatic ccRCC after 1-2 lines of treatment were enrolled into three cohorts: Cohort A) progression on 1L nivolumab + ipilimumab, Cohort B) progression on 1L pembrolizumab + axitinib or 2L anti-PD-1 therapy after receiving 1L VEGF-targeted monotherapy, Cohort C) progression on 1L or 2L cabozantinib or lenvatinib +/- everolimus either before, after, or in combination with anti-PD-1 ICI. Starting dose of sitravatinib was 100 mg PO daily and nivolumab was 480 mg IV every 4 weeks. The co-primary endpoints were ORR [complete response (CR) + partial response (PR)] and disease control rate [DCR; CR, PR or stable disease (SD) at 24 weeks]. The study was designed to enroll 88 patients with an interim analysis for futility in each cohort using a BOP2 design, but it was terminated early due to discontinuation of sitravatinib development by the sponsor. Results: 14 patients were enrolled with 2 in cohort A, 6 in cohort B and 6 in cohort C. Most patients had IMDC intermediate risk disease (n=11, 78.6%), 7 patients had prior nephrectomy (50%), and sarcomatoid dedifferentiation was present in the tumors of 2 patients (7.1%). Across all cohorts, the ORR was 15.4% (2/13, 1 patient not evaluable) and DCR at 24 weeks was 35.7% (5/14). The 2 patients who experienced a PR were pre-treated with nivolumab + ipilimumab and pembrolizumab + axitinib. DCR at 24 months was 63% for Cohort A+B and 0% for Cohort C. After a median follow up of 11.9 months (mo), 10 patients had discontinued treatment (71.4%), all due to disease progression, and 6 patients had died (42.9%). Median progression free survival was 5.5 mo [ 95% CI 3.8 – not reached (NR)], and median overall survival was 13.3 mo (95% CI 8.77 – NR). Six patients (42.9%) experienced a grade 3-4 adverse event (AE) and 2 patients (14.3%) experienced an immune-mediated AE. Conclusions: In this small phase 2 trial with limited sample size due to early termination, sitravatinib plus nivolumab demonstrated a manageable safety profile and produced modest clinical benefit. The observed responses occurred in patients who did not receive prior treatment with cabozantinib or lenvatinib. Clinical trial information: NCT04904302 .