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

  • Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
Masatoshi Kudo  1 ,  Richard S Finn  2 ,  Shukui Qin  3 ,  Kwang-Hyub Han  4 ,  Kenji Ikeda  5 ,  Fabio Piscaglia  6 ,  Ari Baron  7 ,  Joong-Won Park  8 ,  Guohong Han  9 ,  Jacek Jassem  10 ,  Jean Frederic Blanc  11 ,  Arndt Vogel  12 ,  Dmitry Komov  13 ,  T R Jeffry Evans  14 ,  Carlos Lopez  15 ,  Corina Dutcus  16 ,  Matthew Guo  16 ,  Kenichi Saito  16 ,  Silvija Kraljevic  17 ,  Toshiyuki Tamai  16 ,  Min Ren  16 ,  Ann-Lii Cheng  18
Affiliations
  • 1. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan. Electronic address: [email protected].
  • 2. Geffen School of Medicine at UCLA, Santa Monica, CA, USA.
  • 3. Nanjing Bayi Hospital, Nanjing, Jiangsu, China.
  • 4. Severance Hospital, Yonsei University, Seoul, South Korea.
  • 5. Toranomon Hospital, Tokyo, Japan.
  • 6. University of Bologna, Bologna, Italy.
  • 7. California Pacific Medical Center, San Francisco, CA, USA.
  • 8. National Cancer Center Korea, Goyang-si, South Korea.
  • 9. Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 10. Medical University of Gdansk, Gdansk, Poland.
  • 11. University of Bordeaux, Bordeaux, France.
  • 12. Hannover Medical School, Hannover, Germany.
  • 13. N N Blokhin Cancer Research Center, Moscow, Russia.
  • 14. University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
  • 15. Marqués de Valdecilla University Hospital, Santander, Spain.
  • 16. Eisai, Woodcliff Lake, NJ, USA.
  • 17. Eisai, Hatfield, UK.
  • 18. National Taiwan University Hospital, Taipei, Taiwan.
PMID: 29433850 DOI: 10.1016/S0140-6736(18)30207-1
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.

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