Immunotherapy–tyrosine kinase inhibitor combinations are now listed in the NCCN guidelines for advanced non–clear cell renal cell carcinoma (nccRCC) following encouraging results from single-arm trials of lenvatinib plus pembrolizumab and cabozantinib plus nivolumab.
Both trials showed overall response rates in the low-50% range across histologies, though the lenvatinib/pembrolizumab study included patients with chromophobe histology while the cabozantinib/nivolumab trial did not. Median progression-free survival for frontline patients was about 18 months with lenvatinib/pembrolizumab and about 11 months with cabozantinib/nivolumab. Median overall survival was longer in the lenvatinib/pembrolizumab study, noting that the cabozantinib/nivolumab trial included some second-line patients.
Safety and tolerability influenced regimen assessment. Treatment-related discontinuation of either study drug occurred in roughly 22% of patients on lenvatinib/pembrolizumab, compared with about 50% on cabozantinib/nivolumab; fewer patients receiving lenvatinib/pembrolizumab discontinued both agents.
Lenvatinib plus everolimus remains an option some clinicians use for chromophobe RCC based on a small study that included nine chromophobe patients, four of whom responded (44%). Biological rationale includes possible mTOR or TSC pathway alterations in chromophobe tumors, but the regimen has been used less frequently since newer IO/TKI data emerged.
Programmatic questions about incorporating single-arm phase 2 data into guidelines were resolved after extended follow-up showed prolonged PFS and overall survival signals. Those results supported NCCN inclusion and have not posed consistent barriers to insurance coverage. The evolving evidence base raises questions for trial design going forward, including whether future randomized studies should use cabozantinib or an IO/TKI combination as the control arm.
A randomized phase 2 trial of ipilimumab plus nivolumab (SUNNIFORECAST) met its primary endpoint of 12-month overall survival—approximately 87% for ipilimumab/nivolumab versus 77% for standard-of-care—but yielded lower objective response rates (about 25%), a median progression-free survival of 5.5 months, and more than one-third of patients with primary disease progression. Higher PD‑L1 expression correlated with greater benefit from ipilimumab/nivolumab. Those efficacy limitations help explain why the combination has not been embraced in NCCN recommendations for nccRCC despite meeting the survival endpoint.
Disclosure: Moshe C. Ornstein, MD, MA, discussed these findings; he has reported consulting or advisory roles for several companies and institutional research support from multiple industry sponsors.
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