Lenvatinib/Pembrolizumab Combination Improves Outcomes vs Sunitinib in Renal Cell Carcinoma

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The combination of lenvatinib plus pembrolizumab was superior to sunitinib for progression-free and overall survival as well as other key endpoints in patients with advanced clear cell renal cell carcinoma (RCC), according to results of the phase III CLEAR trial presented at the 2021 Genitourinary Cancers Symposium.1 The data were simultaneously published in The New England Journal of Medicine.2

The CLEAR study also included an experimental arm of lenvatinib plus everolimus. That arm outperformed sunitinib as well for progression-free survival and objective response rate but failed to show a significant survival benefit.

“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 of patients with advanced renal cell carcinoma,” said lead author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, who presented the results.

Robert J. Motzer, MD

Robert J. Motzer, MD

Phase II studies had shown activity for lenvatinib in combination with pembrolizumab and with everolimus, respectively, in advanced RCC. The new CLEAR study compared both lenvatinib plus pembrolizumab and lenvatinib plus everolimus vs sunitinib as first-line treatment for advanced clear cell 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 had a prior nephrectomy.

The study randomly assigned 1,069 patients with previously untreated advanced RCC 1:1:1 to receive 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 a 2020 press release,3 and the current data represent an 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,” Dr. Motzer noted. 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. 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,” Dr. Motzer emphasized.

An interim overall survival analysis also favored the lenvatinib plus pembrolizumab combination, with a 34% improvement compared with sunitinib. (P = .005). However, 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, at 16.1% compared with 4.2% with sunitinib.

Patients given lenvatinib plus pembrolizumab had the longest median duration of response. The 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.

Safety Profile

Nearly all patients in each treatment arm—lenvatinib plus pembrolizumab (96.9%), lenvatinib plus everolimus (97.7%), and sunitinib (92.1%)—experienced a treatment-related adverse event. Patients given lenvatinib plus pembrolizumab (67.3%) and lenvatinib plus everolimus (69.3%) were more likely than those given sunitinib (49.7%) to experience treatment-related adverse events that led to dose reductions.

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 treatment 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.


  • As first-line treatment for advanced renal cell cancer, lenvatinib plus pembrolizumab improved overall survival, progression-free survival, and response rates compared with sunitinib, the former standard of care for advanced renal cell carcinoma.
  • The toxicity of the combination was reported to be manageable.
  • Lenvatinib plus everolimus improved progression-free survival and response rates compared with sunitinib but failed to improve overall survival.
  • These results support the combination of lenvatinib plus pembrolizumab as a new first-line option for advanced renal cell carcinoma.

“Attractive features of this combination [ie, lenvatinib and pembrolizumab] are the relatively low rates of hepatotoxicity and myelosuppression,” Dr. Motzer commented.

The treatment discontinuation rate for lenvatinib was 18.5% in the pembrolizumab-containing arm and 16.1% in the everolimus-containing arm. The discontinuation rate of both drugs in the lenvatinib-plus-pembrolizumab arm was 9.7%.


DISCLOSURE: The study was sponsored by Eisai and Merck. Dr. Motzer has served as a consultant or advisor to AstraZeneca, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, and Pfizer; has received institutional research funding from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Novartis, and Pfizer; and has been reimbursed for travel or other expenses by Bristol Myers Squibb.


1. Motzer RJ, Porta C, Eto M, et al: Phase 3 trial of lenvatinib plus pembrolizumab or everolimus versus sunitinib monotherapy as a first-line treatment for patients with advanced renal cell carcinoma (CLEAR study). 2021 Genitourinary Cancers Symposium. Abstract 269. Presented February 13, 2021.

2. Motzer R, Alekseev B, Rha SY, et al: Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. February 13, 2021 (early release online).

3. Eisai: Lenvima Plus Keytruda Demonstrated Statistically Significant Improvement in Progression-Free Survival, Overall Survival and Objective Response Rate Versus Sunitinib as First-Line Treatment for Patients With Advanced Renal Cell Carcinoma. November 10, 2020. Available at Accessed March 4, 2021.

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