Robert J. Motzer, MD

As reported in The New England Journal of Medicine by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center (MSK), and colleagues, the phase III CLEAR trial has shown prolonged progression-free survival with lenvatinib/pembrolizumab and with lenvatinib/everolimus vs sunitinib and prolonged overall survival with the lenvatinib/pembrolizumab combination in first-line treatment of advanced renal cell carcinoma.¹

Study Details

In the open-label trial, 1,069 patients with no prior systemic therapy from sites in 20 countries were randomly assigned 1:1:1 between October 2016 and July 2019 to receive lenvatinib at 20 mg once daily plus pembrolizumab at 200 mg once every 3 weeks (n = 355), lenvatinib at 18 mg once daily plus everolimus at 5 mg once daily (n = 357), or sunitinib at 50 mg once daily, 4 weeks on/2 weeks off (n = 357). Randomization was stratified according to geographic region (Western Europe and North America or the rest of the world) and MSK prognostic risk group (favorable, intermediate, or poor risk) The primary endpoint was progression-free survival assessed by an independent review committee using Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population.

Across all three groups, the median patient age was 61 to 64 years (total range = 29–88 years; 55%–63% < 65 years), 72% to 77% were male, and 56% were from Western Europe or North America and 44% from the rest of the world. Karnofsky performance status score was 90 to 100 in 80% to 83%. MSK prognostic group was favorable in 27%, intermediate in 64%, and poor in 9%. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group analysis was favorable in 31% to 35%, intermediate in 54% to 59%, and poor in 9% to 12%.

Progression-Free Survival

Data cutoff was in August 2020 for the final analysis of progression-free survival with a median follow-up for overall survival of 26.6 months. Compared with the sunitinib group (median = 9.2 months, 95% confidence interval [CI] = 6.0–11.0 months), median progression-free survival was significantly prolonged in the lenvatinib/pembrolizumab group (median = 23.9 months, 95% CI = 20.8–27.7 months; hazard ratio [HR] = 0.39, 95% CI = 0.32–0.49, P < .001) and in the lenvatinib/everolimus group (median = 14.7 months, 95% CI = 11.1–16.7 months; HR = 0.65; 95% CI = 0.53–0.80, P < .001).

The results for progression-free survival favored the two combination regimens over sunitinib across all evaluated subgroups. Among stratification subgroups, hazard ratios for lenvatinib/pembrolizumab vs sunitinib were: 0.42 (95% CI = 0.32–0.57) for Western Europe/North America and 0.36 (95% CI = 0.26–0.49) for the rest of the world; and 0.36 (95% CI = 0.23–0.54), 0.44 (95% CI = 0.34–0.58), and 0.18 (95% CI = 0.08–0.42) for MSK risk of favorable, intermediate, and poor. Hazard ratios for lenvatinib/everolimus vs sunitinib were: 0.74 (95% CI = 0.56–0.97) for Western Europe/North America and 0.56 (95% CI = 0.42–0.76) for the rest of the world; and 0.55 (95% CI = 0.38–0.81), 0.67 (95% CI = 0.51–0.88), and 0.73 (95% CI = 0.42–1.29) for MSK risk of favorable, intermediate, and poor.

Subsequent systemic anticancer treatment was received by 54.9% of the lenvatinib/pembrolizumab group, 68.2% of the lenvatinib/everolimus group, and 71.0% in the sunitinib group. The most common treatments consisted of antiangiogenic therapy in 50.7%, 40.8%, and 41.4% and PD-1/PD-L1 inhibitors in 13.6%, 51.4%, and 53.1%.

Median overall survival was not reached in any treatment group. Overall survival at 2 years was 79.2% in the lenvatinib/pembrolizumab group, 66.1% in the lenvatinib/everolimus group, and 70.4% in the sunitinib group, with a significant benefit vs sunitinib observed for lenvatinib/pembrolizumab (HR = 0.66, 95% CI = 0.49–0.88, P = .005) but not for lenvatinib/everolimus (HR = 1.15, 95% CI = 0.88–1.50, P = .30). The hazard ratios favored lenvatinib/pembrolizumab vs sunitinib in most subgroups, including patients with PD-L1–positive or –negative tumors, but not among patients in the IMDC favorable-risk group.

Objective response rates were 71.0% with lenvatinib/pembrolizu-mab (relative risk = 1.97, 95% CI =1.69–2.29 vs sunitinib), 53.5% with lenvatinib/everolimus (relative risk = 1.48, 95% CI = 1.26–1.74 vs sunitinib), and 36.1% with sunitinib. Complete response was observed in 16.1%, 9.8%, and 4.2% of the three groups. Median durations of response were 25.8 months (95% CI = 22.1–27.9 months), 16.6 months (95% CI = 14.6–20.6 months), and 14.6 months (95% CI = 9.4–16.7 months).

Adverse Events

Grade ≥ 3 adverse events occurred in 82.4% of the lenvatinib/pembrolizumab group, 83.1% of the lenvatinib/everolimus group, and 71.8% of the sunitinib group. The most common were hypertension (27.6%), increased lipase (12.8%), and diarrhea (9.7%) in the lenvatinib/pembrolizumab group; hypertension (22.5%), diarrhea (11.5%), and hypertriglyceridemia (11.3%) in the lenvatinib/everolimus group; and hypertension (18.8%), increased lipase (8.8%), and hypertriglyceridemia (6.5%) in the sunitinib group.

Adverse events led to discontinuation of treatment in 37.2% of the lenvatinib/pembrolizumab group (lenvatinib in 25.6%, pembrolizumab in 28.7%, both in 13.4%), 27.0% of the lenvatinib/everolimus group (lenvatinib in 22.0%, everolimus in 24.8%, both in 18.9%), and 14.4% of the sunitinib group. Fatal adverse events not attributed to disease progression occurred in 11 patients in the lenvatinib/pembrolizumab group, 10 patients in the lenvatinib/everolimus group, and 2 patients in the sunitinib group. Potential immune-mediated adverse events of any grade occurred in 60.8% of the lenvatinib/pembrolizumab group vs 30.9% of the sunitinib group and were grade ≥ 3 in 14.8% vs 1.2%.

The investigators concluded: “Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib.” 

DISCLOSURE: The study was funded by Eisai and Merck Sharp and Dohme. Dr. Motzer has served as a consultant or advisor to AstraZeneca, Calithera Biosciences, 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, accommodations, or other expenses by Bristol Myers Squibb.

REFERENCE

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