Cabozantinib Plus Nivolumab in Advanced Non–Clear Cell Renal Cell Carcinoma

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In a single-institution phase II study reported in the Journal of Clinical Oncology, Chung-Han Lee, MD, PhD, and colleagues found that the combination of cabozantinib and nivolumab was active in patients with advanced non–clear cell renal cell carcinoma (RCC) variants, particularly those with papillary histology variants; little activity was observed in chromophobe RCC.

As noted by the investigators, preclinical data have associated chromophobe histology with immune cell exclusion, which may result in resistance to immune checkpoint inhibitors.

Chung-Han Lee, MD, PhD

Chung-Han Lee, MD, PhD

Study Details

The study enrolled 47 patients who had received none or one prior systemic therapy and no prior immune checkpoint inhibitors between August 2018 and October 2020. Patients were enrolled in two cohorts: cohort 1 consisted of 40 patients with papillary (n = 32), unclassified without papillary features (n = 6), and translocation-associated (n = 2) RCC; cohort 2 consisted of 7 patients with chromophobe RCC. Patients received cabozantinib at 40 mg once daily plus nivolumab at 240 mg once every 2 weeks or 480 mg once every 4 weeks.  


At data cutoff (January 2021), median follow-up was 13.1 months (range = 2.2–28.6 months). Objective responses (all partial) were observed in 19 (47.5%, 95% confidence interval [CI] = 31.5%–63.9%) of 40 patients in cohort 1, including responses in 15 (47%) of 32 with papillary histology, 3 of 6 with unclassified RCC without papillary features, and 1 of 2 with translocation-associated RCC. Stable disease was observed in an additional 20 patients (50%). Median duration of response was 13.6 months (95% CI = 9.7–19.8 months). In cohort 1, median progression-free survival was 12.5 months (95% CI = 6.3–16.4 months) and median overall survival was 28 months (95% CI = 16.3 months–not evaluable). No objective responses were observed among seven patients in cohort 2, with five having stable disease.

Among 32 patients in cohort 1 and 5 in cohort 2 with sequencing data, common mutations included those in NF2 (19%) and FH (16%) in cohort 1 and TP53 (80%) and PTEN (40%) in cohort 2. Objective responses were observed in 10 of 12 patients in cohort 1 with either NF2 or FH mutations.


  • Cabozantinib/nivolumab produced objective responses in 47.5% of patients with disease other than chromophobe RCC.
  • Activity was limited in patients with chromophobe RCC.

Adverse Events

The most common treatment-related adverse events of any grade were fatigue (57%), palmar-plantar erythrodysesthesia (57%), and diarrhea (53%). Grade 3 or 4 treatment-related adverse events were observed in 32% of patients, most commonly hypertension (13%), diarrhea (6%), and palmar-plantar erythrodysesthesia (4%). Adverse events led to discontinuation of cabozantinib in 13% of patients and nivolumab in 17%.  

The investigators concluded, “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.”

Dr. Lee, of the Department of Medicine, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bristol Myers Squibb and Exelixis, National Cancer Institute, and Academy of Kidney Cancer Investigators of the CDMRP/DOD. For full disclosures of the study authors, visit

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