Msaouel and Goswami et al. report the results of phase 1-2 study of sitravatinib and nivolumab combination in immunotherapy-naive patients with advanced ccRCC that was refractory to prior antiangiogenic therapies. The combination demonstrated manageable toxicity and high clinical activity, with an ORR of 35.7% and a median PFS of 11.7 months, and with 80.1% of patients alive at a median follow-up of 18.7 months. Lead-in sitravatinib treatment led to downregulation of VISTA+ and CD38+ suppressive myeloid cells in the periphery and TME, which were sustained after the addition of nivolumab. Tumor burden was also reduced in patients with liver metastases.
Contributed by Shishir Pant
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.