At extended follow-up, lenvatinib plus pembrolizumab showed sustained superiority over sunitinib for overall and progression-free survival as first-line treatment for advanced renal cell carcinoma.1 The majority of the benefit was observed in intermediate- and poor-risk subgroups, according to the final prespecified overall survival analysis of the phase III CLEAR trial presented at the 2023 ASCO Annual Meeting.1
At a median follow-up of about 50 months, there was a 21% reduction in risk of death favoring the combination (P = .0424). (P = .0424). The overall survival rates at 24, 36, and 48 months all favored the combination arm vs the control arm: 80.4% vs 69.6%, 66.4% vs 60.2%, and 55.9% vs 52.5%, respectively.
“There are demonstrated benefits to lenvatinib plus pembrolizumab in all risk groups, but the impact of this combination and other combinations, whether ipilimumab plus nivolumab or other immunotherapy/tyrosine kinase inhibitor combinations on overall survival in this setting, is much smaller in the favorable-risk vs the intermediate- and poor-risk subgroups,” said presenting author Thomas E. Hutson, DO, PharmD, Director of the Urologic Oncology Program and Co-Chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center.
“There are demonstrated benefits to lenvatinib plus pembrolizumab in all risk groups, but the impact of this combination ... is much smaller in the favorable-risk vs the intermediate- and poor-risk subgroups.”— Thomas E. Hutson, DO, PharmD
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“The progression-free survival and objective response rate benefit was maintained with lenvatinib plus pembrolizumab, even in the favorable-risk group. With longer follow-up, the progression-free survival benefit [of] lenvatinib plus pembrolizu-mab looks as robust as it did on the primary analysis,” Dr. Hutson added.
The combination of the pan–tyrosine kinase inhibitor lenvatinib plus the checkpoint inhibitor pembrolizumab was approved by the U.S. Food and Drug Administration as first-line treatment for adults with advanced renal cell carcinoma. Approval was based on the primary analysis of the phase III CLEAR study, demonstrating a significant improvement in median progression-free survival vs sunitinib.2
CLEAR was a prospective, randomized study with three arms: (1) lenvatinib at 20 mg/d orally plus intravenous pembrolizumab at 200 mg every 3 weeks (n = 355); (2) lenvatinib at 18 mg/d plus oral everolimus at 5 mg/d (n = 357); or (3) oral sunitinib at 50 mg/d for 4 weeks on and 2 weeks off (n = 357). Updated findings for the everolimus arm were not presented at the 2023 ASCO Annual Meeting.
At baseline, median patient age was 64 years in the experimental arm and 61 years in the sunitinib arm. Memorial Sloan Kettering Cancer Center (MSK) prognostic risk level was similar between the two arms. Around 62% had intermediate-risk disease, and 9% had poor-risk disease; approximately 29% had favorable-risk disease. The PD-L1 Combined Positive Score (CPS) was at least 1 for one-third of patients, less than 1 for one-third of patients, and not available for the remaining patients.
The objective response rate was 71.3% with lenvatinib plus -pembrolizumab compared with 36.7% with sunitinib. The complete response rate was 18.3% with the combination compared with 4.8% with sunitinib. The median duration of response was 26.7 months with lenvatinib plus pembrolizumab compared with 14.7 months with sunitinib.
In a nonprespecified analysis, according to International mRCC Database Consortium (IMDC) risk subgroup, the combination of lenvatinib plus pembrolizumab compared with sunitinib led to a 6% improvement in overall survival for favorable-risk patients and a 26% improvement in survival for intermediate- and poor-risk subgroups.
Results With Additional Follow-up
With an additional 23 or more months of follow-up, median progression-free survival was 23.9 months in patients with lenvatinib plus pembrolizumab vs 9.2 months with sunitinib (P < .0001). The 36-month progression-free survival rates in the overall cohort were 37.3% and 17.6%, respectively. According to IMDC risk subgroup, median progression-free survival was significantly higher with lenvatinib plus pembrolizumab in both the favorable-risk subgroup and the intermediate- plus poor-risk subgroup.
Objective response rate per independent review was 71.3% with lenvatinib plus pembrolizumab and 36.7% with sunitinib. Best overall response with lenvatinib plus pembrolizumab was a complete response in 18.3%, a partial response in 53.0%, and stable disease in 18.9%.
For more on the CLEAR trial of the combination of lenvatinib plus pembrolizumab in the treatment of advanced renal cell carcinoma, see a video with Thomas E. Hutson, DO, PharmD, on The ASCO Post Newsreels at ascopost.com/videos.
When adjusted for receipt of subsequent anticancer medications, the final median overall survival was not reached with lenvatinib plus pembrolizumab compared with 32.0 months with sunitinib.
“At 4 years, 68.9% of patients who received sunitinib have gone on to receive subsequent anticancer therapy, which included anti-VEGF therapy in 45% and checkpoint inhibitors in 55%,” Dr. Hutson said. “In the lenvatinib-plus-pembrolizumab arm, 51% of patients went on to subsequent therapy, with the reason being they are still on therapy with lenvatinib plus pembrolizumab.”
No new safety signals were observed with extended follow-up.
DISCLOSURE: The study was funded by Eisai and Merck Sharp & Dohme. Dr. Hutson has received honoraria from Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, Novartis, and Pfizer; has served as a consultant or advisor to Astellas Pharma, Bayer/Onyx, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, Novartis, and Pfizer; has served on the speakers bureau of Astellas Pharma, Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer; and has received institutional research funding from Bristol Myers Squibb, Eisai, Exelixis, Johnson & Johnson, and Pfizer.
1. Motzer RJ, Porta C, Eto M, et al: Final prespecified overall survival analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab vs sunitinib in patients with advanced renal cell carcinoma. 2023 ASCO Annual Meeting. Abstract 4502. Presented June 5, 2023.
2. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators: Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 384:1289-1300, 2021.
David A. Braun, MD, PhD
David A. Braun, MD, PhD, of Yale Cancer Center, was the formal discussant of the abstract on the 4-year follow-up of the CLEAR trial. “We have made remarkable progress [in advanced renal cell carcinoma] and are now in the combination era of immunotherapy-based therapy...