Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Trial registration: ClinicalTrials.gov NCT02811861.

FIG 1.

Kaplan-Meier plots of final analysis of (A) OS (unadjusted), (B) PFS by IIR per RECIST v1.1, and (C) duration of response by IIR per RECIST v1.1. The 95% CIs are estimated using a generalized Brookmeyer and Crowley method. HR is based on a Cox proportional hazards model including the treatment group as a factor; the Efron method was used for ties and stratified by geographic region (region 1: Western Europe and North America; region 2: Rest of the world) and MSKCC prognostic groups (favorable, intermediate, and poor risk) in IxRS. CR, complete response; DOR, duration of response; HR, hazard ratio; IIR, independent imaging review; IxRS, interactive voice/web response system; LEN, lenvatinib; MSKCC, Memorial Sloan Kettering Cancer Center; NE, not estimable; OS, overall survival; PEMBRO, pembrolizumab; PFS, progression-free survival; PR, partial response; SUN, sunitinib.

FIG 2.

Kaplan-Meier plots of (A) final OS and (B) PFS analysis in favorable-risk and intermediate- plus poor-risk IMDC subgroups. PFS was determined by independent imaging review per RECIST v1.1. The IMDC risk group was not a stratification factor, and relevant data were derived programmatically. Medians were estimated using the Kaplan-Meier method, and 95% CIs were estimated using a generalized Brookmeyer and Crowley method. HR is based on a Cox proportional hazards model including the treatment group as a factor; the Efron method was used for ties. Stratification factors were geographic region (region 1: Western Europe and North America, region 2: Rest of the world) and MSKCC prognostic groups (favorable, intermediate, and poor risk) in IxRS. HR, hazard ratio; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IxRS, interactive web/voice-response system; LEN, lenvatinib; MSKCC, Memorial Sloan Kettering Cancer Center; NE, not estimable; NR, not reached; OS, overall survival; PEMBRO, pembrolizumab; PFS, progression-free survival; SUN, sunitinib.