A phase 2 study presented at the 2025 ESMO Congress compared lenvatinib plus everolimus with cabozantinib in patients with metastatic clear cell renal cell carcinoma whose disease progressed after PD-1 immunotherapy. The study included 86 patients, most of whom had previously received nivolumab or ipilimumab. The combination of lenvatinib and everolimus significantly improved progression-free survival, with a median of 15.7 months compared to 10.2 months for cabozantinib. The objective response rate was higher with the combination (52.6% vs. 38.6%), although this difference was not statistically significant.
The lenvatinib/everolimus combination was associated with higher toxicity. Grade 3 or 4 adverse events occurred in 67.5% of patients on the combination versus 50% on cabozantinib. Common side effects included diarrhea, fatigue, proteinuria, and hypertension. Serious adverse events and treatment discontinuations were also more frequent with the combination (20% vs. 10.9%).
This study was the first head-to-head randomized comparison of these two treatments in the post-PD-1 setting. Overall survival data are still immature. Experts suggest lenvatinib plus everolimus may be particularly suitable for patients where achieving a tumor response is a priority and the higher risk of side effects is acceptable. The combination was first FDA-approved for advanced RCC after prior anti-angiogenic therapy in 2016.
Overall, the study indicates that lenvatinib plus everolimus offers superior disease control and response rates compared with cabozantinib after PD-1 therapy, but with increased toxicity.