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

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.

Fig. 1.. Illustration of trial conduct to determine the optimal starting dose of sitravatinib in combination with nivolumab.

Each circle represents a cohort of three patients whose dose-limiting toxicity (DLT) and early efficacy outcomes are indicated by different colors. The first cohort of three patients started at a sitravatinib dose of 80 mg daily, and subsequent cohorts started at a sitravatinib dose selected by the LO-EffTox design based on the DLT and early efficacy outcomes of all prior cohorts. The starting sitravatinib dose of 60 mg daily was never selected, whereas the dose of 150 mg was only selected on cohort 7 and subsequently found to be too toxic to be selected again based on the pre-specified trade-off between DLT and early efficacy.

Fig. 2.. Efficacy outcomes of sitravatinib in combination with nivolumab in patients with advanced clear cell renal cell carcinoma that progressed on prior anti-angiogenic therapy.

(A) Waterfall plot showing the maximum change in the sum of the longest dimensions in each of the 42 evaluable patients treated with sitravatinib + nivolumab. The international metastatic renal cell carcinoma database consortium (IMDC) risk category and neutrophil-to-lymphocyte ratio (NLR) for each patient are also shown. (B) Swimmer plot showing the durability of responses to therapy. Patients with liver metastases are highlighted with asterisks. The IMDC risk category and NLR for each patient are also shown. (C) Peripheral blood NLR from all patients (n=42) at baseline, after sitravatinib treatment (week 2), and during treatment with sitravatinib and nivolumab (weeks 4 and 6). P values were estimated by paired sample t-tests. (D) Representative images from a patient with multiple liver metastases (shown by red arrows on the baseline image) demonstrating durable complete response in the liver metastases and partial overall response following therapy with sitravatinib (120 mg) in combination with nivolumab.

Fig. 3.. Effect of sitravatinib plus nivolumab in the peripheral blood and tumor tissues.

(A) PBMC samples harvested from patients (n =34) at baseline, after sitravatinib treatment (week 2), and during treatment with sitravatinib and nivolumab (weeks 4 to 18) were analyzed by mass cytometry. Major subsets were gated by flowjo. (B to D) Clustering analysis on peripheral blood CD45⁺ cells by FlowSOM. tSNE of all clusters in CD45⁺ cells is shown in (B). Two myeloid clusters identified by FlowSOM clustering are shown in (C) (C24: CD14⁺CD68⁺CD38⁺VISTA⁺ monocytic macrophages) and (D) (C25: CD11c⁺HLA-DR⁺CD14⁻CD68⁻VISTA⁺CD38⁺ dendritic cell). (E and F) Tumor samples harvested from patients at baseline and after treatment were analyzed by mass cytometry (week 2: sitravatinib; week 6: sitravatinib and nivolumab). Clustering analysis by FlowSOM identified two macrophage clusters: C5: CD11b⁺CD14⁺CD68⁺CSF1R⁺VISTA⁺PDL2⁺PDL1⁺CD38⁺CD163⁺CD206⁺ (E) and C12: CD11b⁺VISTA⁺CD38⁺ (F). P values in (A to F) were estimated by unpaired t tests. (G and H) NanoString analysis of tumor samples harvested from patients at baseline (n=9) and after treatment (n=7). (G) Bar plots showing differentially activated pathways in tumor tissues samples at baseline (blue bar) and after treatment (red bar). (H) Volcano plots illustrating differentially expressed genes (DEGs) after sitravatinib treatment at week 2 (Left) and after treatment with sitravatinib and nivolumab at week 6 (Right) compared with baseline. Red dots show DEGs associated with the VEGF signaling pathway and the antigen processing–cross presentation pathway.