A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy

Pavlos Msaouel, Sangeeta Goswami, Peter F. Thall, Xuemei Wang, Ying Yuan, Eric Jonasch, Jianjun Gao, Matthew T. Campbell, Amishi Yogesh Shah, Paul Gettys Corn, Alda L. Tam, Kamran Ahrar, Priya Rao, Kanishka Sircar, Lorenzo Cohen, Sreyashi Basu, Fei Duan, Sonali Jindal, Yuwei Zhang, Hong ChenShalini S. Yadav, Ronald Shazer, Hirak Der-Torossian, James P. Allison, Padmanee Sharma, Nizar M. Tannir

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article numbereabm6420
JournalScience translational medicine
Volume14
Issue number641
DOIs
StatePublished - Apr 20 2022
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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