Lenvatinib is a multitargeted antiangiogenic agent that has shown activity as a monotherapy in renal-cell carcinoma (RCC) and in combination with everolimus as second-line therapy for RCC. Pembrolizumab is an anti–PD-1 antibody that is used in combination with axitinib for advanced RCC.1 Lenvatinib and pembrolizumab combined have shown activity in a phase 1b/2 trial.1,2
In the phase 3 CLEAR trial, patients with previously untreated advanced RCC were randomized to 1 of 3 treatment arms: once-daily lenvatinib 20 mg plus pembrolizumab 200 mg intravenously once every 3 weeks (N = 355), once-daily lenvatinib 18 mg plus once-daily everolimus 5 mg (N = 357), or once-daily sunitinib 50 mg for 4 weeks followed by 2 weeks off treatment (N = 357). The primary end point was independent review committee–assessed progression-free survival. Secondary end points included overall survival (OS), objective response rate, and safety.1
After a median follow-up of 26.6 months, combination therapy with lenvatinib and pembrolizumab significantly extended median progression-free survival relative to sunitinib (23.9 vs 9.2 months, respectively; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.32-0.49; P <.001) as did treatment with lenvatinib and everolimus (HR, 0.65; 95% CI, 0.53-0.80; P <.001). Lenvatinib combination therapies were superior to sunitinib regardless of International Metastatic RCC Database Consortium risk group and other evaluated demographic features.1
At the time of analysis, median OS was not reached in any treatment group. Compared with sunitinib, lenvatinib plus pembrolizumab significantly extended OS by 34% (95% CI, 12%-51%; P = .005), whereas lenvatinib plus everolimus did not have a significant effect on OS relative to sunitinib (HR, 1.15; 95% CI, 0.49-0.88; P = .30).1
Objective response rate was 71.0% for lenvatinib plus pembrolizumab, 53.5% for lenvatinib plus everolimus, and 36.1% for sunitinib, with complete response rates of 16.1%, 9.8%, and 4.2%, respectively. Among those patients with confirmed responses, the median duration of response was 25.8 months.1
The most common adverse event (AE) was diarrhea, reported in 61.4% of patients treated with lenvatinib plus pembrolizumab, 66.5% of those treated with lenvatinib plus everolimus, and 49.4% of those treated with sunitinib. The most common grade 3 or 4 AEs included diarrhea, hypertension, elevated lipase levels, and hypertriglyceridemia. Discontinuation of at least 1 agent as a result of AEs was reported in 37.2% of those treated with lenvatinib plus pembrolizumab, 27.0% of those treated with lenvatinib plus everolimus, and 14.4% of those treated with sunitinib.1
The researchers concluded that lenvatinib plus pembrolizumab was a tolerable treatment option with significant efficacy benefits versus sunitinib for first-line advanced RCC.1 The results of the CLEAR trial led to the approval of lenvatinib plus pembrolizumab for previously untreated advanced RCC in August 2021.3
- Motzer R, Alekssev B, Rha S-Y, et al; for the CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289-1300.
- Taylor MH, Lee C-H, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020;38:1154-1163.
- US Food and Drug Administration. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. Updated August 11, 2021. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-plus-pembrolizumab-advanced-renal-cell-carcinoma. Accessed November 18, 2021.