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- Title
A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy.
- Authors
Msaouel, Pavlos; Goswami, Sangeeta; Thall, Peter F.; Wang, Xuemei; Yuan, Ying; Jonasch, Eric; Gao, Jianjun; Campbell, Matthew T.; Shah, Amishi Yogesh; Corn, Paul Gettys; Tam, Alda L.; Ahrar, Kamran; Rao, Priya; Sircar, Kanishka; Cohen, Lorenzo; Basu, Sreyashi; Duan, Fei; Jindal, Sonali; Zhang, Yuwei; Chen, Hong
- Abstract
The accumulation of immune-suppressive myeloid cells is a critical determinant of resistance to anti–programmed death-1 (PD-1) therapy in advanced clear cell renal cell carcinoma (ccRCC). In preclinical models, the tyrosine kinase inhibitor sitravatinib enhanced responses to anti–PD-1 therapy by modulating immune-suppressive myeloid cells. We conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab in 42 immunotherapy-naïve patients with ccRCC refractory to prior antiangiogenic therapies. The combination demonstrated no unexpected toxicities and achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80.1% of patients alive after a median follow-up of 18.7 months. Baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with response to sitravatinib and nivolumab. Patients with liver metastases showed durable responses comparable to patients without liver metastases. In addition, correlative studies demonstrated reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib treatment. This study provides a rationally designed combinatorial strategy to improve outcomes of anti–PD-1 therapy in advanced ccRCC. Success with sitravatinib: Immune checkpoint blockade benefits a subset of patients with clear cell renal cell carcinoma (ccRCC), but accumulation of immune-suppressive myeloid cells can lead to treatment resistance. The combination of sitravatinib, a tyrosine kinase inhibitor shown to decrease immune-suppressive myeloid cells, with immune checkpoint blockade might therefore improve clinical outcomes. Here, Msaouel and colleagues conducted a phase 1-2 clinical trial using a late-onset efficacy-toxicity design to identify an optimal dose of sitravatinib in combination with nivolumab in immunotherapy-naïve patients with advanced ccRCC. The combination led to a response rate of 35.7% and an 88.1% disease control rate, with a reduction in immune-suppressive myeloid cells in the peripheral blood and the tumor microenvironment. Phase 3 studies using this combination are now underway.
- Subjects
RENAL cell carcinoma; NIVOLUMAB; MYELOID cells; IMMUNE checkpoint proteins; PROTEIN-tyrosine kinase inhibitors; PROGRAMMED cell death 1 receptors
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 641, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abm6420