Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial.

Background: Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma.
Methods: In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting.
Findings: Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]).
Interpretation: In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice.
Funding: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.
Competing Interests: Declaration of interests JML reports serving in a consulting or advisory role for AstraZeneca, Bayer HealthCare Pharmaceuticals, Bluejay, Boston Scientific, Bristol Myers Squibb, Captor Therapeutics, Eisai, Exelixis, Genentech, Glycotest, Ipsen, Eli Lilly, Merck, MiNA Alpha, Omega Therapeutics, and Roche; and receiving research funding paid to his institution from Bayer Pharmaceuticals, Bristol Myers Squibb, Eisai, and Ipsen. MKu reports receiving honoraria from Bayer, Chugai–Roche, Eisai, Lilly Japan, and Takeda and receiving research funding paid to his institution from AbbVie, Chugai–Roche, EA Pharma, Eisai, GE Healthcare, Otsuka, and Taiho Pharmaceutical. PM reports serving in a consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, and Roche and receiving research funding from Ipsen. TM reports serving in a consulting or advisory role for Bayer, Beigene, BTG, Eisai, Ipsen, MSD, and Roche and receiving research funding from Bayer, BTG, and Ipsen. MI reports receiving honoraria from Abbott Laboratories, AbbVie, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharma, EA Pharma, Eisai, Fujifilm, Guardant Health Japan, Incyte, Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, SERVIER, Taiho Pharmaceutical, Taisho Pharmaceutical Holdings, Takeda, Teijin Pharma, and Yakult Pharmaceutical; reports serving in a consulting or advisory role for AbbVie, AstraZeneca, Boehringer Ingelheim, Boston Scientific, Chugai Pharma, Eisai, Guardant Health Japan, Lilly Japan, MSD, Novartis, Ono Pharmaceutical, and SERVIER; and reports receiving research funding paid to his institution from AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharma, Delta-Fly Pharma, Eisai, InVitae, J-Pharma, Lilly Japan, Merck, Merus, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, and Pfizer. JE reports serving in a consulting or advisory role for AstraZeneca, Basilea, Bayer, BeiGene, Boston Scientific, Bristol Myers Squibb, BTG, Eisai, Ipsen, Merck Serono, MSD, Roche, SERVIER, and Taiho Oncology; receiving research funding paid to his institution from Beigene, Boston Scientific, and Bristol Myers Squibb; and receiving travel accommodations, and expenses from Amgen, Bristol Myers Squibb, and Roche. ZR reports serving in a consulting or advisory role for AstraZeneca, Merck Sharp & Dohme, and Roche. GM reports receiving support for the present manuscript from MSD and Eisai; consulting fees from MSD, Roche, Eisai, and Terumo; receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Eisai and AstraZeneca; receiving support for attending meetings or travel from MSD, Eisai, AstraZeneca, and Roche; and participation on a data safety monitoring board or advisory board for Roche, Eisai, MSD, and AstraZeneca. HYL reports receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche and participation on a data safety monitoring board or advisory board for Bayer, Eisai, Roche, and Ipsen. JHK reports receiving grants or contracts paid to his institution from Ono Pharmaceutical and Roche; receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, MSD, Roche, Roche Diagnostics, Pfizer, AstraZeneca, Eisai, Lilly, and Sanofi; receiving support for meetings or travel from Roche; participation in a data safety monitoring board or advisory board for Bixink, Eisai, Yuhan, Novartis, Daiichi Sankyo, Pfizer, Roche, and Everest Medicine; and receiving equipment, materials, drugs, medical writing, gifts or other services from Eisai, Ono Pharma, and Roche. VB reports receiving consulting fees from Eisai, Novartis, and Bayer, honoraria for lectures, presentations, and educational events from Bristol Myers Squibb, Roche, Eisai, Ipsen, and Bayer, and support for attending meetings or travel from Bristol Myers Squibb, Ipsen, and Roche. HK is an employee of Toranomon Hospital and reports other relationships with AbbVie, Eisai, Gilead Sciences, Sumitomo Chemical, and Sumitomo Dainippon Pharma. A-LC reports receiving honoraria from AstraZeneca, Bayer Yakuhin, Eisai, and Genentech/Roche and serving in a consulting or advisory role for AstraZeneca, Bayer Schering Pharma, BeiGene, Bristol Myers Squibb, Eisai, Genentech–Roche, Ipsen, IQVIA, MSD, Ono Pharmaceutical, and Roche. PRG reports receiving honoraria from Adaptimmune, AstraZeneca–MedImmune, Bayer Schering Pharma, Boston Scientific, Bristol Myers Squibb, Guerbet, Ipsen, Lilly, MSD, Roche–Genentech, and Sirtex Medical; serving in a consulting or advisory role for Adaptimmune, Bayer Schering Pharma, Boston Scientific, Bristol Myers Squibb, Lilly, MSD, Roche–Genentech, and Sirtex Medical; serving on a speaker's bureau for Bayer Schering Pharma, Ipsen, Lilly, and Roche; receiving research funding from Roche–Genentech; and receiving travel, accommodation, and expenses from Bayer Schering Pharma, Lilly, and Sirtex Medical. SK serves in a consulting or advisory role for Bayer, Eisai, and Lilly; reports receiving research funding from AVI Pharma, Bayer, Eisai, Lilly, Otsuka, Pfizer, Sumitomo Dainippon Pharma, and Takeda; and other relationships with AVI Pharma, Bayer, Eisai, Lilly, Sumitomo Dainippon Pharma, and Takeda. AW is an employee of Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA; has stock and other ownership interests in Merck, Rahway, NJ, USA. KM is an employee of Eisai and reports receiving travel, accommodations, and expenses from Eisai. CD is an employee of Eisai. LD is an employee of Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA; and has stock and other ownership interests in Merck, Rahway, NJ, USA. ABS is an employee of and has received travel, accommodations, and expenses from Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA and has stock and other ownership interests in Merck, Rahway, NJ, USA. RSF reports serving in a consulting or advisory role for AstraZeneca, Bayer, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai, Exelixis, Genentech–Roche, Hengrui Therapeutics, Lilly, Merck, Novartis, and Pfizer; reports receiving research funding paid to his institution from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and Roche–Genentech; and providing expert testimony for Bayer. SQ, RX, B-YR, MKw declare no competing interests.
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