Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

Masatoshi Kudo, Richard S. Finn, Shukui Qin, Kwang Hyub Han, Kenji Ikeda, Fabio Piscaglia, Ari Baron, Joong Won Park, Guohong Han, Jacek Jassem, Jean Frederic Blanc, Arndt Vogel, Dmitry Komov, T. R.Jeffry Evans, Carlos Lopez, Corina Dutcus, Matthew Guo, Kenichi Saito, Silvija Kraljevic, Toshiyuki TamaiMin Ren, Ann Lii Cheng

Research output: Contribution to journalArticlepeer-review

1563 Citations (Scopus)

Abstract

Background: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. Methods: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice–web response system—with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors—to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. Findings: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1–14·9) was non-inferior to sorafenib (12·3 months, 10·4–13·9; hazard ratio 0·92, 95% CI 0·79–1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. Interpretation: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. Funding: Eisai Inc.

Original languageEnglish
Pages (from-to)1163-1173
Number of pages11
JournalThe Lancet
Volume391
Issue number10126
DOIs
Publication statusPublished - 2018 Mar 24

Bibliographical note

Funding Information:
MK reports honoraria from Bayer, Eisai, MSD, and EA Pharma. RSF reports grants, personal fees and non-financial support from Eisai, Bayer, Pfizer, Novartis, Bristol Myers Squibb (BMS), and Merck outside the submitted work. K-HH reports grants and consultant fees from Eisai and KOWA, and consultant fees from Bayer, all outside the submitted work. KI reports honoraria from Eisai and Dainippon Sumitomo Pharma. FP reports personal fees from Eisai during the conduct of the study, and grants and personal fees from Bayer, and personal fees from Bracco, both outside the submitted work. AB reports research funding from Eisai. JJ reports personal fees from AstraZeneca, Roche, Pfizer, G1 Therapeutics, Pierre Fabre, Celgene, Merck, and BMS outside the submitted work. JFB reports personal fees from Bayer SP, Eli Lilly Oncology, Novartis, and BMS outside the submitted work. TRJE reports other fees (reimbursement of study costs of this clinical trial [to the institution]; advisory board honorarium [payable to the institution]) from Eisai during the conduct of the study, and other fees from BMS (financial support for clinical trials of novel anti-cancer drugs, honoraria for consultancies or speaker's fees, and support to attend international conferences), Clovis (support for clinical trials [to institution] and honorarium for advisory board), Karus Therapeutics (scientific advisory board [payable to the institution]), Baxalta (advisory board honorarium [payable to the institution]), Bayer (support for clinical trials and advisory board honorarium [payable to the institution]), Celgene (support for clinical trials and advisory board honorarium [payable to the institution]), GlaxoSmithKline (support for clinical trials and advisory board honorarium [payable to the institution]), Otsuka (support for clinical trials and advisory board honorarium [payable to the institution]), Roche/Genentech (support for clinical trials and advisory board honorarium [payable to the institution]), TC Biopharm (support for clinical trials), Immunova (advisory board honorarium [payable to the institution]), Basilea (support for clinical trials), e-Therapeutics (support for clinical trials), Immunocore (support for clinical trials), Vertex (support for clinical trials), Verastem (support for clinical trials), Daiichi (support for clinical trials), and Merck (support for clinical trials) outside the submitted work. CL reports grants, personal fees, non-financial support and advisory board fees from Eisai, Bayer, Lilly, and Daiichi Sankyo during the conduct of the study. CD, MG, KS, SK, TT, and MR are employees of Eisai. A-LC reports personal fees from BMS, Ono, Novartis, Bayer, Merck, and MSD during the conduct of the study. SQ, J-WP, GH, AV, and DK declare no competing interests.

Funding Information:
The study was funded by Eisai Inc, (Woodcliff Lake, NJ, USA) and designed in collaboration with the principal investigators. The funder employed CD, MG, KS, SK, TT, and MR, who played a significant part in study design, data collection, data analysis, data interpretation, and writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2018 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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