Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates

Abstract

Purpose: To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non-clear-cell renal cell carcinoma (RCC).

Patients and methods: Patients had advanced non-clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response.

Results: A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations.

Conclusion: Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non-clear-cell RCC variants warrant further study as predictors of response.

Trial registration: ClinicalTrials.gov NCT03635892.

FIG 1.

Maximum change from baseline in target lesions in combined cohort. ^aTwo patients with rapid clinical progression had unevaluable lesions are excluded from the plot.

FIG 2.

PFS and OS in Cohort 1. (A) PFS, RECIST 1.1. There were 22 PFS events (20 progressions and two deaths with no progression). Median PFS is 12.5 months (95% CI, 6.3 to 15.9). The PFS estimate is 52.8% (95% CI, 34.1 to 68.5) at 12 months. (B) OS. There were 10 deaths in the 40-patient cohort. Median OS is 28.0 months (95% CI, 16.3 to NE). The OS estimate is 68.7% (95% CI, 46.3 to 83.3) at 18 months. Median follow-up time for survivors is 13.1 months (range, 2.2-28.6 months). NE, not evaluable; OS, overall survival; PFS, progression-free survival.

FIG 3.

Genomic analysis by targeted exome sequencing. Genomic analysis oncoprint of patients with tissue available for targeted exome sequencing by MSK-IMPACT. ^aSarcomatoid; ^bmultiple samples; ^cTFEB-amplified; ^dcollecting duct; multiple samples; ^emultiple samples.