The combination of lenvatinib plus pembrolizumab showed superiority over sunitinib in terms of overall survival, progression-free survival, and objective response rate in patients with advanced clear cell renal cell carcinoma (RCC), according to results of the phase III CLEAR trial. The CLEAR study also included an experimental arm that studied the combination of lenvatinib plus everolimus; that arm also outperformed sunitinib for progression-free survival and objective response rate but failed to show a significant survival benefit. These findings were presented by Robert J. Motzer, MD, and colleagues at the 2021 Genitourinary Cancers Symposium (Abstract 269).

“Lenvatinib plus pembrolizumab significantly improved progression-free survival, overall survival, and objective response rate vs sunitinib for the treatment of patients with advanced clear cell renal cell carcinoma. These results support lenvatinib plus pembrolizumab as first-line treatment or patients with advanced renal cell carcinoma,” said Dr. Motzer, of Memorial Sloan Kettering Cancer Center, who was lead author of the study.

Robert J. Motzer, MD

Phase II studies showed good activity for lenvatinib in combination with pembrolizumab and with everolimus, respectively, in advanced RCC.

Study Details

The multicenter, open-label, randomized, controlled, phase III CLEAR trial was a three-arm study designed to compare lenvatinib plus pembrolizumab vs sunitinib and lenvatinib plus everolimus vs sunitinib as first-line therapy for advanced RCC.

CLEAR was a global study, with approximately 56% of patients treated in Western Europe and North America and approximately 44% treated in other countries. Baseline characteristics were well-balanced across the three treatment arms. About three-quarters of the study population underwent prior nephrectomy.

The study randomly assigned 1,069 patients with previously untreated advanced RCC 1:1:1 to receive either lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib. The primary endpoint was progression-free survival; key secondary endpoints were overall survival and objective response rate.

Final progression-free survival and interim overall survival were presented in August 2020, and the current data represent updated analysis.

Updated Analysis

The primary endpoint of progression-free survival assessed by independent review was met for the lenvatinib plus pembrolizumab arm. Median progression-free survival was 23.9 months for the combination vs 9.2 months for sunitinib, a 61% improvement favoring the experimental arm (P < .001).

“This is an impressive improvement in progression-free survival,” noted Dr. Motzer.

Lenvatinib plus everolimus also met the primary endpoint, with a median progression-free survival of 14.7 months vs 9.2 months for sunitinib, which represented a 35% improvement favoring that combination (P < .001).

The progression-free survival benefit of lenvatinib plus pembrolizumab was evident across all subgroups, including all International Metastatic RCC Database Consortium (IMDC) risk groups: favorable-, intermediate-, and poor-risk.

Lenvatinib plus everolimus was also of benefit vs sunitinib in the subgroup analysis, but the confidence intervals were wider for this combination, particularly for the poor-risk group.

“Both lenvatinib combination arms met the primary endpoint of progression-free survival benefit over sunitinib,” emphasized Dr. Motzer.

An interim overall survival analysis also favored the lenvatinib plus pembrolizumab combination, with a 34% improvement compared with sunitinib (P = .005). Dr. Motzer pointed out that the P value was below the prespecified value of .015 required for significance. By contrast, there was no difference in overall survival with the combination of lenvatinib plus everolimus vs sunitinib.

Response rates were also significantly better with the lenvatinib combinations. The confirmed objective response rate was 71.0% with lenvatinib plus pembrolizumab, 53.5% with lenvatinib plus everolimus, and 36.1% with sunitinib. Dr. Motzer highlighted the high rate of complete responses with lenvatinib and pembrolizumab—16.1% compared with 4.2% with sunitinib. Patients in the lenvatinib plus pembrolizumab arm had the longest median duration of response; median duration of response was 25.8 months with lenvatinib plus pembrolizumab, 16.6 months with lenvatinib plus everolimus, and 14.6 months with sunitinib.

Grade 3 or higher treatment-related adverse events occurred in 71.6% of patients in the lenvatinib plus pembrolizumab group, 73.0% in the lenvatinib plus everolimus group, and 58.8% in the sunitinib group. Dose reductions and discontinuations due to treatment-related adverse events were more common with the lenvatinib combinations than with sunitinib, but the toxicity was comparable to that seen with these agents in other trials, and no new safety signals emerged.

Disclosure: For full disclosures of the study authors, visit coi.asco.org.