Kudo M.Finn R.S.Qin S.Han K.-H.Ikeda K.Piscaglia F.Baron A.Park J.-W.Han G.Jassem J.Blanc J.F.Vogel A.Komov D.Evans T.R.J.Lopez C.Dutcus C.Guo M.Saito K.Kraljevic S.Tamai T.Ren M.ANN-LII CHENG2021-08-312021-08-3120180140-6736https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042855944&doi=10.1016%2fS0140-6736%2818%2930207-1&partnerID=40&md5=e8b4243ac34c8dab49ec223962a6b08bhttps://scholars.lib.ntu.edu.tw/handle/123456789/580076Background: 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. ? 2018 Elsevier Ltd[SDGs]SDG3lenvatinib; sorafenib; antineoplastic agent; carbanilamide derivative; lenvatinib; nicotinamide; quinoline derivative; sorafenib; adult; aged; Article; body weight loss; controlled study; decreased appetite; diarrhea; drug withdrawal; female; hand foot syndrome; hazard ratio; hepatic portal vein; human; hypertension; liver cell carcinoma; major clinical study; male; median survival time; multicenter study; overall survival; phase 3 clinical trial; randomized controlled trial; side effect; tumor invasion; analogs and derivatives; clinical trial; comparative study; liver cell carcinoma; liver tumor; middle aged; mortality; survival rate; treatment outcome; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Quinolines; Survival Rate; Treatment Outcomejournal article10.1016/S0140-6736(18)30207-1294338502-s2.0-85042855944