LBA34 - Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC)

Background

The global, randomized, double-blind, Ph3 LEAP-002 study (NCT03713593) evaluated the efficacy and safety of lenvatinib + pembrolizumab (lenva + pembro) vs lenvatinib (lenva) + placebo as 1L therapy for aHCC.

Methods

Eligible pts with aHCC were randomized 1:1 to lenva (8 mg/day if BW<60 kg or 12 mg/day if BW≥60 kg) plus pembro (200 mg IV Q3W) or lenva plus placebo. Dual primary endpoints OS and PFS (per RECIST 1.1 by BICR) were assessed using the stratified log-rank test. ORR (per RECIST 1.1 by BICR) was a key secondary endpoint. The protocol specified 2 interim analyses (IAs) and a final analysis (FA) for OS. Prespecified efficacy boundaries were one-sided P = 0.002 for PFS at IA1 (prespecified final PFS analysis) and 0.0185 for OS at FA.

Results

794 pts were randomized (lenva + pembro, 395; lenva, 399). At FA (data cutoff 21 June 2022; median follow-up 32.1 mo), 534 OS events had occurred and 36 pts (9.1%) in the lenva + pembro arm and 24 pts (6.1%) in the lenva arm remained on study treatment. The median OS with lenva + pembro was 21.2 mo vs 19.0 mo with lenva, and the HR was 0.840 (95% CI: 0.708-0.997, P=0.0227, Table). HR for PFS at IA1 (data cutoff 5 April 2021) was 0.867 (95% CI: 0.734-1.024, P=0.0466, Table). ORR at FA was 26.1% for lenva + pembro vs 17.5% for lenva. Grade 3-5 treatment-related adverse events (TRAEs) were 62.5% in the lenva + pembro arm and 57.5% in the lenva arm (grade 5 TRAEs, 1.0% vs 0.8%). Post-study systemic anti-cancer treatments were used in 44.1% vs 52.1% of pts, in each arm, respectively. Table: 000LBA34

Conclusions

LEAP-002 primary endpoints of OS (at FA) and PFS (at IA1) did not meet pre-specified statistical significance. The combination of lenva + pembro achieved the longest median OS ever reported in 1L HCC Ph3 studies (21.2 mo) with no new safety signals observed. The median OS of 19.0 mo with lenva monotherapy supports its role as a standard of care in 1L aHCC.

Clinical trial identification

NCT03713593.

Editorial acknowledgement

Medical writing assistance was provided by Yue Liu of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

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

Funding

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

Disclosure

R.S. Finn: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, CStone, Bayer, BMS, Exelixis, Eli Lilly, Eisai, Hengrui, Merck, Pfizer, Roche/ Genenentech; Financial Interests, Institutional, Research Grant: Adaptimmune, Bayer, BMS, Eli Lilly, Eisai, Merck, Pfizer, Roche/ Genentech; Non-Financial Interests, Principal Investigator: Eisai, Merck, BMS, Pfizer, Roche/Genentech. M. Kudo: Financial Interests, Personal, Invited Speaker: Eisai, Chugai, Eli Liiy, Bayer, Takeda, MSD; Financial Interests, Institutional, Research Grant: Otsuka, Sumitomo Dainippon Pharma, EA Pharma, Taiho, Eisai, AbbVie, Gilead Sciences, Takeda, GE Healthcare, Chugai. P. Merle: Financial Interests, Personal and Institutional, Advisory Board: Roche, BMS, MSD, EISAI, AstraZeneca, BAYER, IPSEN; Financial Interests, Institutional, Research Grant: Ipsen. T. Meyer: Financial Interests, Personal, Advisory Board: Ipsen, AstraZeneca, Eisai, Bayer, Roche, Adaptimmune, Boston Scientific; Financial Interests, Institutional, Research Grant: Bayer, BTG. S. Qin: Non-Financial Interests, Personal and Institutional, Principal Investigator: Cina . M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, NIHON SERVIER, Novartis, Ono, Takeda, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, Nihon Servier, Takeda; Financial Interests, Institutional, Invited Speaker: Bayer, Bristol-Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, Nihon Servier, Delta-Fly Pharma, Syneos Health, Merus.N.V.. J. Edeline: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, Bayer, Boston Scientific, Eisai, Ipsen, Servier, MSD; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, Bayer, Merck Serono, Eisai, Ipsen, BMS, Basilea, Servier, Incyte, Beigene; Financial Interests, Institutional, Invited Speaker: BMS, Beigene, BMS, MSD, Roche, Beigene, Bayer, Novartis, Taiho, Servier, Agios; Non-Financial Interests, Principal Investigator: Unicancer. Z. Ren: Financial Interests, Personal, Advisory Board: AstraZeneca Roche Merch Sharp & Dohme. A. Cheng: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Merck Sharp Dohme, BeiGene, Ltd., Exelixis Ltd., Ipsen Innovation, F. Hoffmanna-La Roche Ltd; Financial Interests, Personal, Invited Speaker: Eisai, Ono Pharmaceutical, Bayer Yakuhin Ltd., Novartis, Amgen Taiwan, Chugai Pharmaceutical; Financial Interests, Personal, Other, Travel: IQVIA. P.R. Galle: Financial Interests, Personal, Invited Speaker: Bayer, Boston Scientific, Adaptimmune, Eisai, MSD, Sirtex, Lilly, Roche, Ipsen.; Financial Interests, Personal, Writing Engagements: BMS, Roche, AstraZeneca; Financial Interests, Personal, Expert Testimony: BMS, Roche; Financial Interests, Personal, Speaker’s Bureau: Bayer, Boston Scientific, Adaptimmune, Eisai, MSD, Sirtex, Lilly, Roche, Ipsen; Financial Interests, Personal, Advisory Board: Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen.; Financial Interests, Institutional, Research Grant: Bayer, Roche; Financial Interests, Personal and Institutional, Principal Investigator: Bayer, Roche. S. Kaneko: Financial Interests, Personal, Invited Speaker: Bayer Eisai Avi pharma Sumitomo pharma Takeda Eli lily; Financial Interests, Personal, Advisory Board: Bayer Eisai Eli lily; Financial Interests, Personal and Institutional, Research Grant: Bayer Eisai Avi pharma Sumitomo pharma Takeda Eli lily Pfizer Otuka. H. Kumada: Financial Interests, Personal, Invited Speaker: AbbVie Eisai Gilead Sciences Sumitomo Dainippon Pharma; Financial Interests, Personal, Full or part-time Employment: Toranomon Hospital. A. Wang: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co. Inc.. 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.. A.B. Siegel: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. J. Llovet: Non-Financial Interests, Personal and Institutional, Invited Speaker: ESMO, ASCO, AASLD, ILCA, AACR, AEEH, EASL; Financial Interests, Personal and Institutional, Advisory Board: BMS MINA Therapeutics Merck Medscape Eversana; Financial Interests, Personal and Institutional, Full or part-time Employment: ICREA Universitat de Barcelona ICAHN Mount Sinai School Of Medicine; Financial Interests, Personal and Institutional, Research Grant: R01 - NIH, R01 – NIDDK, Samuel Waxman Cancer Research, Eisai INC, Alex’s Lemonade StandFoundation For Childhood Cancer, Bayer Pharmaceuticals, Accelerator Award Cancer Research UKAECC- AIRC, Ipsen Pharma, National Health Institute (SPAIN); Non-Financial Interests, Personal and Institutional, Member: EASL, AACR, ASCO, AEEH, AASLD, ILCA, ESMO; Financial Interests, Personal and Institutional, Advisory Role: Eli Lilly, Bayer Healthcare Pharmaceutical, Eisai Inc, Merck, Bristol Myers-Squibb, Ipsen, Glycotest, Nucleix, Genentech, Roche, AstraZeneca, Omega Therapeutics, Iylon., Mina Alpha, Boston Scientific. All other authors have declared no conflicts of interest.