Phase II trial of neoadjuvant sitravatinib plus nivolumab in patients undergoing nephrectomy for locally advanced clear cell renal cell carcinoma

Abstract

Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 inhibitors such as nivolumab. We report a single-arm, interventional, phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints were safety; pharmacokinetics (PK) of sitravatinib; immune effects, including changes in programmed cell death-ligand 1 expression; time-to-surgery; and disease-free survival (DFS). Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0). There were no grade 4/5 treatment-related adverse events. Sitravatinib PK did not change following the addition of nivolumab. Correlative blood and tissue analyses showed changes in the tumour microenvironment resulting in an immunologically active tumour by the time of surgery (median time-to-surgery: 50 days). The primary endpoint of this study was not met as short-term neoadjuvant sitravatinib and nivolumab did not substantially increase ORR.

Fig. 1. Trial design and conduct.

a Study schema. b CONSORT diagram. ^*Retroperitoneal lymph nodes ≤1 cm in size each considered N0. ^#Nivolumab 240 mg Q2W (Day 15, Day 29, and potentially Day 43); patients received nivolumab on Day 43 only if their surgery was expected to occur more than a week from that date; last dose of any drug was administered ≥72 h prior to surgery. ccRCC clear cell renal cell carcinoma, Q2W every 2 weeks, QD once daily, RCC renal cell carcinoma.

Fig. 2. Treatment response.

a Swimmer plot. b Waterfall plot. c Disease-free survival. *Censored. PR partial response, SD stable disease. Source data are provided in the Source Data file.

Fig. 3. Sitravatinib plasma concentrations.

At predose, 30 min, 4 h and 15 days after the first sitravatinib monotherapy dose, as well as 4 weeks following the addition of nivolumab (day 43). Reported are mean values with error bars indicating standard deviation. D day. Source data are provided in the Source Data file.

Fig. 4. Percentage change in tumour size in efficacy-evaluable patients.

a With negative versus positive PD-L1 tumour expression at baseline. b Example IHC images of PD-L1 expression at baseline (left) versus post-combination therapy at the time of surgery, at which time PD-L1 expression reached 5% (right) in subject 001, who had a 31% reduction in tumour size. c Percentage change in tumour size versus percentage change in tumour PD-L1 expression from baseline to time of surgery. IHC immunohistochemistry, PD-L1 programmed cell death ligand-1. Source data are provided in the Source Data file.

Fig. 5. Immune recruitment to the tumour tissue on therapy.

a–f Flow cytometry analyses of tumor tissue collected longitudinally. Total immune cell frequencies at baseline, post-sitravatinib, and at surgery post-combination therapy for live CD45+ cells (a), CD3 + CD4+ T cells (b), CD3 + CD8+ T cells (c), the CD4:CD8 T cell ratio (d), CD56 dim natural killer cells (e), and CD8 + Ki67+ T cells (f). Statistical significance between time points assessed was determined using a two-tailed, Wilcoxon matched pairs signed rank test and is indicated with a line at the top of the graph. The number of samples analysed per time point is shown for each graph. CD cluster of differentiation, NK natural killer. Source data are provided in the Source Data file.

Fig. 6. Macrophage infiltration and expression of PD-L1 is not modulated on-treatment.

a Multiplex IF results showing CD68+ macrophage densities at baseline, post-sitravatinib monotherapy, and at surgery post-combination therapy. The median density is indicated with the black line. b Percentage PD-L1 expression by CD68+ myeloid cells at baseline, post-sitravatinib monotherapy, and post-combination therapy. The median is indicated with the dashed line in the violin plot. c Example images of cases with low and high macrophage infiltration into tumour. A paired, two-tailed Student’s t test was used to assess changes from baseline to post-sitravatinib. The number of samples analysed per time point is shown for each graph. Abbreviations: CD cluster of differentiation, CK cytokeratin, DAPI 4, 6-diamidino-2-phenylindole, IF immunofluorescence, PD-L1 programmed cell death ligand-1. Source data are provided in the Source Data file.

Fig. 7. Gene expression profiling.

a Top angiogenesis-associated genes downregulated post-sitravatinib versus baseline. b Top genes differentially expressed post-combination therapy versus baseline. Differential expression analysis was performed using limma-trend. FDR values are adjusted p-values for multiple comparisons using the Benjamini & Hochberg method. c Top Hallmark Gene Set Enrichment Analysis (GSEA) pathways regulated post-sitravatinib and post-combination therapy versus baseline including immune (allograft rejection, complement, inflammatory response) and tumour (E2F, G2M) pathways regardless of tumour response. GSEA was used to determine the NES (normalized enrichment score) and FDR. FDR is adjusted for both gene set size and multiple hypotheses testing. Precision Immuno-Oncology panel on the HTG EdgeSeq platform, analysed using Limma V. 3.40.9. *FDR < 0.25. FDR false discovery rate, IFN interferon, logFC log fold change, NES normalised enrichment score, TNF tumour necrosis factor, UV ultraviolet. Source data are provided in the Source Data file.