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

Author(s): Chung-Han Lee, MD, PhD1,2; Martin H. Voss, MD1,2; Maria Isabel Carlo, MD1,2; Ying-Bei Chen, MD3; Mark Zucker, PhD4; Andrea Knezevic, MS4; Robert A. Lefkowitz, MD5; Natalie Shapnik, BS1; Chloe Dadoun, MD1; Ed Reznik, PhD4; Neil J. Shah, MD1,2; Colette Ngozi Owens, MD1; Deaglan Joseph McHugh, MD1,2; David Henry Aggen, MD, PhD1,2; Andrew Leonard Laccetti, MD1,2; Ritesh Kotecha, MD1,2; Darren R. Feldman, MD1,2; and Robert J. Motzer, MD1,2
Source: DOI: 10.1200/JCO.21.01944 Journal of Clinical Oncology 40, no. 21 (July 20, 2022) 2333-2341.
Lucio Gordan MD

The combination of cabozantinib/nivolumab remains a powerful combination in the RCC space. This article brings together data on histology and genomics to predict response in NCC-RCC with improved efficacy in tumors expressing NF2 and FH, and decreased activity in chromophobic histology. The role and utilization of data continue to evolve and become prevalent in day-to-day practice.


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 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.


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.


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.

Author Affiliations

1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 2Department of Medicine, Weill Cornell Medical College, New York, NY 3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 4Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 5Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY

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