The latest data from the phase 3 CLEAR study (NCT02811861) showed that with about 33 months’ follow-up, the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) continued to demonstrate an overall survival (OS) advantage vs single-agent sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC).1
The updated results, which were shared at the 2022 International Kidney Cancer Symposium, also showed that the lenvatinib/pembrolizumab also maintained benefits in progression-free survival (PFS) and objective response rate (ORR) compared with sunitinib.
The PFS and OS benefits observed in the overall study population were also shown in certain subgroups. For example, patients with intermediate-/poor-risk advanced RCC favored lenvatinib and pembrolizumab vs sunitinib. Among favorable-risk patients, the median OS was not reached, and only a few OS events were seen in these patients.
Prior to the updated analysis results, lenvatinib plus pembrolizumab significantly improved PFS vs sunitinib in patients with advanced RCC (HR, 0.39; 95% CI, 0.32-0.49; P < .001). The combination also demonstrated a significant OS advantage compared with sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005). The ORR shown in the primary analysis of the CLEAR study was 71.0% in the lenvatinib plus pembrolizumab arm compared with 36.1% in the sunitinib arm (relative risk [RR], 1.97; 95% CI, 1.69-2.29; nominal P < .001).
CLEAR is a 3-arm trial of patients with advanced RCC who are treatment-naïve, presented with a Karnofsky performance score of ≥ 70, have measurable disease, and adequate organ function. Patients were randomized 1:1:1 to receive lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks, lenvatinib 18 mg once daily with everolimus (Afinitor) 5 mg once daily, or sunitinib 50 mg once daily. With patients stratified by disease risk and geographic location, PFS was the primary end point of the study. The secondary end points included OS, ORR, safety, and health-related quality of life. As exploratory end points, duration of response (DOR) and biomarkers were also assessed in the study.
The updated analysis focused on a comparison of the lenvatinib/pembrolizumab arm and the sunitinib arm. At baseline, patients had a median age of 64 years (range, 34-88) in the combination arm vs 61 years (range, 29-82) in the sunitinib arm. More than 55% percent of patient in each arm were European or North American, and the remainder were from other parts of the world. According to the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC) grouping, the majority of patients in both arms had intermediate-risk disease, and 10% or less in each arm had poor risk disease. Thirty-one percent of the combination arm had favorable risk disease vs 34.7% of the monotherapy arm.
The median follow-up for the updated analysis was 33.7 months in the lenvatinib/pembrolizumab arm vs 33.4 months in the sunitinib arm. The 12-month PFS was 70.6% (95% CI, 65.3-75.2) with the combination vs 38.4% (95% CI, 32.4-44.3) with sunitinib. At 24 months, the PFS rate was 48.6% (95% CI, 42-54.3) with lenvatinib and pembrolizumab vs 22.6% (95% CI, 17.1-28.5) with sunitinib.
OS also continued to favor lenvatinib plus pembrolizumab with extended follow-up. The median OS was not reached in the combination arm nor in the sunitinib arm (HR, 0.72; 95% CI, 0.55-0.93). The 12-month OS rate observed with lenvatinib plus pembrolizumab was 91.4% (95% CI, 87.9-93.9) vs 80.2% (95% CI, 75.5-84.1) with sunitinib. At 24-months, the OS rate was 80.2% (95% CI, 75.5-84.1) with the combination vs 69.7% (95% CI, 64.4-74.3) with sunitinib.
Notably, both PFS and OS results in the MSKCC and IMDC risk groups also favored treatment with lenvatinib and pembrolizumab vs sunitinib. The extended follow-up analysis also looked at patients who received lenvatinib and pembrolizumab who completed 2 years of treatment. These patients had OS rate of 94.5% at 36 months.
An ORR of 71.0% (95% CI, 66.3-75.7) was seen with lenvatinib/pembrolizumab compared with 36.1% (95% CI, 31.2-41.1) in the sunitinib arm (RR, 1.97; 95% CI, 1.69-2.29). In the combination arm, the complete response rate was 17.2% vs 4.2% with sunitinib, and the partial response rate was 53.8% with the combination vs 31.9% with sunitinib. The median DOR was 26.0 months (95% CI, 22.2-41.4 months) with lenvatinib/pembrolizumab vs 14.7 months (95% CI, 9.4-16.8 months) with sunitinib.
According to the study investigators, the extended follow-up data from the CLEAR study demonstrated robust efficacy that has been maintained with longer follow-up. These data support the use of frontline lenvatinib and pembrolizumab as a standard of care for patients with advanced RCC.
1. Porta CG, Masatoshi E, Motzer RJ, et al. Updated efficacy of lenvatinib + pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma in the CLEAR study. Presented at: 2022 International Kidney Cancer Symposium. November 3-5, 2022; Austin, TX.