LBA3 - Transarterial chemoembolization (TACE) with or without lenvatinib (len) + pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): Phase III LEAP-012 study

Background

TACE remains standard of care for intermediate-stage HCC. We present results from LEAP-012, a randomized, multicenter, double-blind, phase 3 trial evaluating len + pembro + TACE vs placebo + TACE in intermediate-stage HCC.

Methods

Eligible patients (pts) with HCC not amenable to curative treatment and Child-Pugh class A, no portal vein invasion, and ECOG PS of 0 or 1 were randomized 1:1 to len 12 mg (body weight ≥60 kg) or 8 mg (body weight <60 kg) QD PO + pembro 400 mg Q6W IV or to placebo PO + IV for up to 2 years; len/oral placebo alone continued until progression or discontinuation. The first TACE occurred 2-4 weeks after the start of systemic therapy, with a maximum of 2 treatments per tumor (4 total), no more than once per month. Randomization was stratified by study site, AFP, ECOG PS, ALBI grade, and tumor burden. Primary end points were PFS per RECIST v1.1 by BICR and OS; HR and 95% CIs were estimated using a stratified Cox proportional hazards model with the Efron method of tie handling.

Results

480 pts were randomly assigned to len + pembro (n = 237) or placebo PO + IV (n = 243); both groups received TACE. At this first interim analysis, median time from randomization to data cutoff (Jan 30, 2024) was 25.6 months (range, 12.6-43.5). With 286 events, PFS was significantly improved for len + pembro vs placebo (HR, 0.66, 95% CI, 0.51-0.84; P = 0.0002; significance threshold, P = 0.025); median PFS was 14.6 months (95% CI, 12.6-16.7) vs 10.0 months (95% CI, 8.1-12.2). With 151 events (47.5%), OS was immature and the significance threshold was not met (HR, 0.80; 95% CI, 0.57-1.11; P = 0.0867; significance threshold, P = 0.0012). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 71.3% of pts in the len + pembro group vs 31.5% in the placebo group; TRAEs led to the discontinuation of both study drugs in 8.4% vs 1.2% of pts, respectively.

Conclusions

LEAP-012 met its primary end point. Len + pembro + TACE showed a statistically significant, clinically meaningful improvement in PFS and an early trend toward improvement in OS vs placebo + TACE in pts with intermediate-stage HCC. The AE profile was consistent with known safety profiles of len, pembro, and TACE. OS will be retested in future analyses.

Clinical trial identification

NCT04246177, first posted January 29, 2020.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by David K Edwards V, PhD, CMPP, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Shane Walton, PhD, CMPP, and Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, PA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eisai Inc., Nutley, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Eisai Inc., Nutley, NJ, USA.

Disclosure

J. Llovet: Financial Interests, Personal, Other, Consultancy: Bayer Healthcare Pharmaceuticals, Eisai Inc., Merck, Bristol Myersd Squibb, Eli Lilly, Roche, Genentech, Glycotest, AstraZeneca, Omega Therapeutics Inc., Mina Alpha, Boston Scientific, Exelixis, Bluejay, Captor Therapeutics; Financial Interests, Institutional, Research Grant: Bayer Healthcare Pharmaceuticals, Eisai Inc, Bristol Myers Squibb, Ipsen. R.S. Finn: Financial Interests, Institutional, Research Grant: Esia, Merck, Bayer, Bristol Myers Squibb, Eli Lilly, Novartis, Pfizer, Roche, Genentech, Adpatimmune; Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting fees: Esia, Merck, Bayer, Bristol Myers Squibb, Eli Lilly, Novartis, Pfizer, Roche, Genentech, Zai Labs, CStone; Financial Interests, Personal, Other, Honoraria: Genentech; Financial Interests, Personal, Other, Travel arranged for meeting: Genentech; Financial Interests, Personal, Advisory Board, Data Safety Monitoring Board: AstraZeneca DSMB. Z. Ren: Non-Financial Interests, Personal, Advisory Board: AstraZeneca, Merck Sharp & Dohme, Roche. S. Ogasawara: Financial Interests, Personal and Institutional, Invited Speaker: Eisai; Financial Interests, Personal and Institutional, Speaker’s Bureau: Eisai, Chugai Pharma, AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: Eisai, Chugai Pharma, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Eisai, Chugai Pharma, AstraZeneca; Financial Interests, Personal, Advisory Board: MSD. D.C. Madoff: Non-Financial Interests, Personal, Advisory Role: Merck. R.M. Ghobrial: Financial Interests, Personal, Other, Consultancy: Sanofi; Financial Interests, Personal, Other, Honoraria: Sanofi; Financial Interests, Personal, Advisory Board: Sirtex, Transmedics, LyGenesis; Financial Interests, Leadership Role, ILTS: Treasurer, president, past president; ASTS, member of Foundation Board: ILTS and ASTS Foundation Board; Financial Interests, Personal, Stocks/Shares: Transmedics, Eli Lilly. A.B. El-Khoueiry: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche/Genentech, BMS, Eisai, Exelixis, Qurient, Senti Biosciences, Tallac Therapeutics, Agenus, ABL Bio, Bayer; Financial Interests, Personal, Principal Investigator: Affimed, Roche/Genentech; Financial Interests, Institutional, Research Grant: AstraZeneca, Astex, Fulgent, Auransa. A. Vogel: Financial Interests, Personal, Other, Honoraria: Roche, Amgen, Lilly, Bristol Myers Squibb, MSD, Pierre Fabre, Ipsen, Janssen, Incyte, AstraZeneca/MedImmune, Sirtex Medical, Daiichi Sankyo, Terumo, Taiho Oncology, Eisai, BeiGene, Boehringer Pharma GmbH, GSK, Boston Scientific, Servier; Financial Interests, Personal, Advisory Role: Novartis, Lilly, Roche, Amgen, Baxalta, AstraZeneca, Eisai, BTG, Ipsen, Pierre Fabre, Terumo, Daiichi Sankyo, Sirtex Medical, Boehringer Pharma GmbH, Incyte, Taiho Oncology; Financial Interests, Personal, Research Funding: Novartis; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Ipsen, Astraeneca, MSD, Lilly. X. Peng: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC. K. Mody: Financial Interests, Personal, Full or part-time Employment: Eisai Inc.. L. Dubrovsky: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. M. Kudo: Financial Interests, Personal and Institutional, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K.; Financial Interests, Personal and Institutional, Expert Testimony: Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd.; Financial Interests, Personal and Institutional, Research Grant: Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd.; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca K.K.; Financial Interests, Institutional, Research Grant: Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., GE Healthcare Japan Corporation, AbbVie GK; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche. All other authors have declared no conflicts of interest.