Cabozantinib Plus Nivolumab Trial Review

A recent single-institution phase 2 study evaluated the combination of nivolumab and cabozantinib in patients with non–clear cell renal cell carcinoma (RCC). This trial, while small with only 40 participants, offered valuable long-term follow-up data. The study included a mix of papillary, unclassified, and translocation RCC in one cohort, while chromophobe RCC was studied separately but ultimately excluded due to limited efficacy signals. At a 34-month follow-up, the combination demonstrated a 48% objective response rate, with a median progression-free survival of 13 months and overall survival of 28 months.

Though the efficacy data are promising, particularly for a historically underrepresented population, the toxicity profile raised questions. Approximately 40% of patients discontinued either nivolumab or cabozantinib, and about one-third discontinued both drugs, which is higher than expected when compared with similar trials in clear cell RCC. These findings may reflect the small sample size or patient characteristics, such as a higher burden of disease and poorer baseline status, rather than an inherent increase in regimen toxicity.

Clinicians involved in the discussion noted that in their own practices, the tolerability of the cabozantinib-nivolumab combination does not appear significantly worse in non–clear cell RCC patients compared to those with clear cell histology. Instead, the higher discontinuation rate in this trial may stem from the frailty or complexity of this patient population. Despite its limitations, the study reinforces the potential of tyrosine kinase inhibitor/immune-oncology combinations in non–clear cell RCC and highlights the importance of continued research to better define treatment strategies across these diverse histologic subtypes.