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.

Treatment of Refractory Metastatic Renal Cell Carcinoma

“…Single-agent nivolumab in the CheckMate 374 trial showed an ORR of 13.6%, including 27% pre-treated patients [ 57 ]. Several phase II trials of immunotherapy combinations show a modest effect in cohorts of metastatic nccRCC that included pretreated patients [ 32 , 58 , 59 , 60 ]. Ongoing trials will shed further light on these agents’ effectiveness in the refractory setting.…”

Kidney Cancer Models for Pre-Clinical Drug Discovery: Challenges and Opportunities

“…In line with this finding, the MET inhibitor savolitinib was found to show efficacy in MET-driven papillary RCC ( 19 ). Recent phase II trials that explore immune checkpoint inhibitors alone or in combination with cabozantinib in nccRCC show promising activity in patients with papillary RCC but at the same time highlight the therapeutic problem of chromophobe RCC ( 20 , 21 ). Most nccRCC cell line and patient-derived xenograft (PDX) models have been established for the “classical” papillary RCC ( 22 ) and there is an urgent need to further expand model systems to other, less common nccRCC entities, including chromophobe RCC, for a further optimization and individualization of pre-clinical drug discovery.…”

Current Options for Second-Line Systemic Therapy in Metastatic Renal Cell Carcinoma

“…As a result, subsequent lines of therapy after progression may include either a different TKI or/and an ICI. The combination of cabozantinib and nivolumab demonstrated promising activity in the unclassified/papillary/translocation-associated cohort of a phase II study with a median ORR of 47% and OS of 28 months ( 93 ). One third of those patients had received one prior line of therapy with a VEGF or mTOR inhibitor ( 93 ).…”

“…The combination of cabozantinib and nivolumab demonstrated promising activity in the unclassified/papillary/translocation-associated cohort of a phase II study with a median ORR of 47% and OS of 28 months ( 93 ). One third of those patients had received one prior line of therapy with a VEGF or mTOR inhibitor ( 93 ). Nivolumab monotherapy in the phase IIIb/IV CheckMate 374 study in previously treated non-ccRCC patients also demonstrated clinically meaningful activity with median ORR of 13% and OS of 16 months ( 94 ).…”