Lenvatinib Plus Pembrolizumab Shows Durable Efficacy Benefits vs Sunitinib in Renal Cell Carcinoma

A follow-up analysis of the phase 3 CLEAR trial (NCT02811861) showed durable overall survival (OS) benefits with first-line lenvatinib plus pembrolizumab versus sunitinib for patients with advanced renal cell carcinoma (RCC). The findings were published in The Lancet Oncology.

The open-label randomized CLEAR trial included patients with clear-cell advanced RCC who were naïve to systemic anti-cancer therapy for RCC. A total of 1069 patients were eligible for the study and were randomized to receive lenvatinib plus pembrolizumab (n = 355), sunitinib (n = 357), or lenvatinib plus everolimus (n = 357). The lenvatinib plus everolimus group was not included in the updated analysis.

Initial results of the CLEAR study had a data cutoff of August 28, 2020, and the median survival follow-up was 26.6 months. The new study is a prespecified updated OS analysis with a data cutoff of March 31, 2021, and median survival follow-up of approximately 33 months.

Median follow-up for progression-free survival (PFS) was 27.8 months in the lenvatinib plus pembrolizumab group and 19.4 months in the sunitinib group. Median PFS was 23.3 months (95% CI, 20.8-27.7) in the combination therapy cohort and 9.2 months (95% CI, 6.0-11.0) in the sunitinib cohort, with a stratified hazard ratio (HR) of 0.42 (95% CI, 0.34-0.52).

For OS, median follow-up was 33.7 months in the lenvatinib plus pembrolizumab group and 33.4 months in the sunitinib group. In the lenvatinib plus pembrolizumab group, OS was improved versus sunitinib with an HR of 0.72, although the median OS was not reached in either group.

PFS improvements were seen across all Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups in the lenvatinib plus pembrolizumab group versus the sunitinib group, although the study authors noted that subgroup data should be interpreted with caution because there were a small number of events. In the poor- and intermediate-risk groups, OS was improved in the combination therapy group versus the sunitinib group, but median OS was not estimable in the favorable-risk groups.

“A smaller proportion of patients in the lenvatinib plus pembrolizumab group received subsequent anti-cancer medications during survival follow-up compared with those in the sunitinib group,” the authors noted. “Additionally, the median time from randomization to subsequent anti-cancer medication was longer in the lenvatinib plus pembrolizumab group than in the sunitinib group for patients who received subsequent anticancer medications at the time of this analysis.”

The extended follow-up results are consistent with the primary analysis, supporting the increased efficacy of first-line lenvatinib plus pembrolizumab compared with sunitinib in patients with advanced RCC. Another preplanned final OS analysis will provide further insight into longer term outcomes in this patient population.

“Overall, this extended follow-up analysis shows the durable and clinically meaningful efficacy benefit with lenvatinib plus pembrolizumab over sunitinib,” the authors concluded. “Previously observed benefits in overall survival, progression-free survival, and objective response rate were maintained, with more patients in the lenvatinib plus pembrolizumab group reported to achieve a complete response.”

Reference

Choueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023;24(3):228-238. doi:10.1016/S1470-2045(23)00049-9