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Clinical Trial
. 2022 Jan;23(1):77-90.
doi: 10.1016/S1470-2045(21)00604-5. Epub 2021 Dec 13.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

Thomas Yau  1 , Joong-Won Park  2 , Richard S Finn  3 , Ann-Lii Cheng  4 , Philippe Mathurin  5 , Julien Edeline  6 , Masatoshi Kudo  7 , James J Harding  8 , Philippe Merle  9 , Olivier Rosmorduc  10 , Lucjan Wyrwicz  11 , Eckart Schott  12 , Su Pin Choo  13 , Robin Kate Kelley  14 , Wolfgang Sieghart  15 , Eric Assenat  16 , Renata Zaucha  17 , Junji Furuse  18 , Ghassan K Abou-Alfa  8 , Anthony B El-Khoueiry  19 , Ignacio Melero  20 , Damir Begic  21 , Gong Chen  21 , Jaclyn Neely  21 , Tami Wisniewski  21 , Marina Tschaika  21 , Bruno Sangro  22
Affiliations
Clinical Trial

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

Thomas Yau et al. Lancet Oncol. 2022 Jan.

Abstract

Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.

Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.

Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.

Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.

Funding: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

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Conflict of interest statement

Declaration of interests TY reports consulting fees from, honoraria from, and participation on a data safety monitoring board or advisory board for, AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp and Dohme, New B Innovation, Novartis, OrigiMed, Pfizer, Sillajen, Sirtex, and Taiho Pharmaceutical. J-WP reports consulting fees from AstraZeneca, Exelixis, Genentech, Ipsen, and Roche; honoraria from Bayer, Bristol Myers Squibb, and Ono Pharmaceutical; and research funding from Bristol Myers Squibb. RSF reports consulting fees for the present manuscript (to self) from Bristol Myers Squibb; other consulting fees from AstraZeneca, Bayer, C Stone, Eisai, Eli Lilly, Exelixis, Merck Sharp and Dohme, Novartis, Pfizer, and Roche–Genentech; research funding for the present manuscript (to institution) from Bristol Myers Squibb; research funding grants or contracts from Bayer, Eisai, Eli Lilly, Merck Sharp and Dohme, Pfizer, and Roche–Genentech; honoraria from Bayer, Bristol Myers Squibb, Eisai, Merck Sharp and Dohme, Pfizer, and Roche–Genentech; expert testimony for Bayer; meeting attendance for AstraZeneca, Bayer, Eisai, Exelixis, Merck Sharp and Dohme, Pfizer, and Roche–Genentech; and participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, C Stone, Eisai, Eli Lilly, Exelixis, Merck Sharp and Dohme, Novartis, Pfizer, and Roche–Genentech. A-LC reports consulting fees and honoraria from AstraZeneca, Bayer Healthcare, BeiGene, Bristol Myers Squibb, Eisai, Hoffman-LaRoche, IPSEN Innovation, IQVIA, Merck Sharp and Dohme, Ono Pharmaceutical, and Roche–Genentech; and meeting attendance for Bayer Yakuhin and Roche. PM reports consulting fees, honoraria, and research funding from AbbVie, Bristol Myers Squibb, Eisai, Gilead Sciences, and Ipsen; consulting fees and honoraria from Bayer; and participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Lilly, Merck Sharp and Dohme, and Roche. JE reports consulting fees from AstraZeneca, Basilea, Bayer, Boston Scientific, Bristol Myers Squibb, BTG, Eisai, Ipsen, Merck Sharp and Dohme, and Roche; meeting attendance for Amgen, Bristol Myers Squibb, Merck Sharp and Dohme, and Roche; and research funding (to institution) from BeiGene and Bristol Myers Squibb. MK reports consulting fees from Bristol Myers Squibb, Eisai, Merck Sharp and Dohme, Ono Pharmaceutical, and Roche; honoraria from Bayer, Bristol Myers Squibb, Chugai, EA Pharma, Eisai, Eli Lilly, and Merck Sharp and Dohme; and research funding (to institution) from AbbVie, Chugai, EA Pharma, Eisai, Gilead Sciences, Ono Pharmaceutical, Otsuka, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, and Takeda. JJH reports consulting fees from Adaptimmune, Bristol Myers Squibb, CytomX Therapeutics, Eisai, Exelexis, Lilly, Merck Sharp and Dohme, QED Therapeutics, and Zymeworks, and research funding from Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Incyte, Lilly, Novartis, Pfizer, Polaris, Yivivia, and Zymeworks. PM reports grants (to institution) from IPSEN and participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Lilly, Merck Sharp and Dohme, and Roche. OR reports participation on a data safety monitoring board or advisory board for Bayer, Eisai, and Sitrex. SPC reports a research grant from Bristol Myers Squibb; honoraria from AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, Ipsen, Novartis, Roche, Shire, and Sirtex Medical; meeting attendance for Amgen, Bristol Myers Squibb, and Merck Sharp and Dohme; and stock or stock options from Bristol Myers Squibb. RKK reports research support (to institution) from Adaptimmune, Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech–Roche, MedImmune, Merck Sharp and Dohme, Novartis, Partner Therapeutics, QED Therapeutics, Relay Therapeutics, and Taiho Pharmaceutical; consulting fees (to institution) from Agios, AstraZeneca, Bristol Myers Squibb, Genentech–Roche, and Merck Sharp and Dohme; consulting fees (to self) from Exact Sciences, Genentech–Roche, and Gilead Sciences; participation on a data safety monitoring board or advisory board for Genentech–Roche (uncompensated after October 2020, formerly compensated to self), Merck Sharp and Dohme (uncompensated); and meeting attendance for Ipsen. JF reports consulting fees from Astellas Pharma, AstraZeneca, Bayer Yakuhin, Chugai Pharma, Eisai, Fujifilm, J-Pharma, Lilly Japan, Merck Sharp and Dohme, Novartis, Ono Pharmaceutical, Otsuka, Shire, Sumitomo Dainippon, Taiho Pharmaceutical, Takara Bio, and Yakult Honsha; honoraria from AbbVie, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Fujifilm, J-Pharma, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, Mochida Pharmaceutical, Merck Sharp and Dohme, Nihon Servier, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, Sawai Pharmaceutical, Shionogi, Shire, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult Honsha; and research funding (to institution) from Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Daiichi Sankyo, Eisai, J-Pharma, Kyowa Hakko Kirin, Lilly Japan, Mochida Pharmaceutical, Merck Sharp and Dohme, NanoCarrier, Ono Pharmaceutical, Pfizer, Sanofi, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, and Yakult Honsha. GKA-A reports research support to institution from Arcus, Agios, AstraZeneca, Bayer, BioNTech, Bristol Myers Squibb, Celgene, Flatiron, Genentech–Roche, Genoscience, Incyte, Polaris, Puma, QED Therapeutics, Sillajen, and Yiviva; and consulting support from Adicet, Agios, AstraZeneca, Alnylam, Autem, Bayer, BeiGene, Berry Genomics, Cend, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech–Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck Sharp and Dohme, MiNA Therapeutics, QED Therapeutics, Rafael, Redhill, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, twoXAR, Vector, and Yiviva. ABE-K reports grants or contracts from AstraZeneca, Astex, and Fulgent Genetics; consulting fees from ABL Bio, Agenus, AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck Sharp and Dohme, Pieris Pharmaceuticals, and Roche–Genentech; participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck Sharp & Dohme, Pieris Pharmaceuticals, QED Therapeutics, and Roche–Genentech; and research funding from Astex Pharmaceuticals, AstraZeneca, and Merck Sharp and Dohme. IM reports consulting fees from AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, EMD Serono, F-Star, Genmab, Gossamer Bio, Lilly, Merck Sharp and Dohme, Numab, PharmaMar, Roche, and Tusk Therapeutics; honoraria from Alligator Biosciences, AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, Lilly, Roche–Genentech, and Tusk Therapeutics; meeting attendance for Bristol Myers Squibb, Incyte, Merck Sharp and Dohme, Roche–Genentech; and research grants (to institution) from Alligator Biosciences, Bristol Myers Squibb, Genmab, Pfizer, Roche–Genentech. DB, JN, TW, and MT reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. GC reports employment with Bristol Myers Squibb. BS reports grants or contracts (to institution) from Bristol Myers Squibb and Sirtex; consulting fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Eli Lilly, H3 Biomedicine, Incyte, Ipsen, Roche, Sirtex Medical, and Terumo; honoraria from and meeting attendance for Bayer, Bristol Myers Squibb, Incyte, Ipsen, Sirtex, and Terumo; and participation on a data safety monitoring board or advisory board for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, H3 Biomedicine, Incyte, Ipsen, Lilly, Roche, Sirtex, and Terumo. LW, ES, WS, EA, and RZ declare no competing interests.

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