ASCO 2021: Nivolumab Plus Cabozantinib in Patients With Non-Clear Cell Renal Cell Carcinoma: Results of a Phase 2 Trial

(  While there have been transformational changes in first-line therapy for patients with advanced renal cell carcinoma (RCC) in the past three years, these studies have focused on patients with clear cell histology. As a result, there have been little direct data to guide care for patients with non-clear cell histologies and we have had to rely primarily on extrapolation from data derived among patients with clear cell disease. As such, sunitinib has remained the NCCN guideline-recommended first line treatment. First presented at ESMO 2020 and subsequently published, the CheckMate9ER study demonstrated that cabozantinib and nivolumab was associated with improved outcomes compared to sunitinib. In the Kidney and Bladder Poster Discussion session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Lee presented results of a phase II trial of nivolumab and cabozanitinb in patients with non-clear cell renal cell carcinoma (NCT03635892).

The authors enrolled patients with advanced non-clear cell RCC who had received either no prior systemic therapy or a single line of treatment other than immune checkpoint inhibitors. Patients also had to have measurable disease by RECIST. These patients were then divided into two cohorts - Cohort 1 comprised papillary, unclassified, or translocation associated RCC while Cohort 2 comprised chromophobe RCC.


All patients received cabozantinib 40 mg/day plus nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. The primary endpoint was objective response rate (ORR) by RECIST with secondary endpoints including progression-free survival, overall survival, and safety. Methodologically, the authors used a single stage design for Cohort 1. As this met its primary endpoint, it was expanded to produce more precise estimates of ORR. Cohort 2 utilized a Simon two-stage design which, due to lack of efficacy, was closed early. In addition to these clinical outcomes, the authors performed correlative analyses by next generation sequencing.

As of a data cut-off of January 20, 2021, 40 patients were treated in Cohort 1 and 7 patients were treated in Cohort 2. The median follow up time was 13.1 months (range 2.2 – 28.6).

In Cohort 1, the majority of patients (n=26, 65%) were previously untreated while 14 (35%) patients had 1 prior line of treatment, with 10 (25%) having received prior VEGF-targeted therapy and 8 (20%) having received prior mTOR-targeted therapy. In this cohort, ORR was 48% (95% CI 31.5–63.9%) with a median PFS of 12.5 months (95% CI 6.3–16.4) and median OS of 28 months (95% CI 16.3–NE). In Cohort 2, no responses were seen among these 7 patients with chromophobe histology.


The toxicity profile, specifically grade 3/4 treatment-emergent adverse events, were in keeping with what was observed in the CheckMate 9ER trial (any treatment related AEs in 87% and grade 3/4 events in 32%). Grade 3/4 elevations in AST and ALT seen in 9% and 15% of patients, respectively. Further, cabozantinib and nivolumab were discontinued due to toxicity in 17% and 19% of patients, respectively.

The authors additionally performed targeted exome sequencing among 32 patients in cohort 1 and 5 patients in cohort 2. Five of 6 patients with NFS 2 mutations and four of 5 patients with FH mutations had objective responses, while only one of 6 with SETD2 mutations had objective response.

The authors concluded that the combination of cabozantinib and nivolumab had an acceptable safety profile and showed promising efficacy in patients with metastatic non-clear cell RCC with papillary, unclassified, or translocation associated histology whereas activity was not observed in patients with chromophobe RCC.

Presented by: Chung-Han Lee, MD, PhD, Medical Oncologist, Memorial Sloan Kettering Cancer Center

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