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Clinical Trial
. 2024 Jun;35(6):537-548.
doi: 10.1016/j.annonc.2024.03.005. Epub 2024 May 22.

Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040

I Melero  1 , T Yau  2 , Y-K Kang  3 , T-Y Kim  4 , A Santoro  5 , B Sangro  6 , M Kudo  7 , M-M Hou  8 , A Matilla  9 , F Tovoli  10 , J Knox  11 , A R He  12 , B El-Rayes  13 , M Acosta-Rivera  14 , H Y Lim  15 , S Soleymani  16 , J Yao  17 , J Neely  18 , M Tschaika  19 , C Hsu  20 , A B El-Khoueiry  21
Affiliations
Free article
Clinical Trial

Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040

I Melero et al. Ann Oncol. 2024 Jun.
Free article

Abstract

Background: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort.

Patients and methods: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1.

Results: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis.

Conclusions: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Keywords: advanced hepatocellular carcinoma; checkpoint inhibitor; immunotherapy; ipilimumab; nivolumab; sorafenib.

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Conflict of interest statement

Disclosure IM reports consultancy fees from AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, EMD Serono, F-Star, Genmab, Gossamer Bio, Lilly, Merck Sharp & Dohme, Numab, PharmaMar, Roche, Tusk Therapeutics, Highlight Therapeutics, Alligator Bioscience, Genentech, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., and Monopteros Therapeutics; honoraria from Alligator Biosciences, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Lilly, Roche/Genentech, Tusk Therapeutics, Moderna, and CatalYm GmbH; travel support from Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, and Roche/Genentech; and research grants from Alligator Biosciences, Bristol Myers Squibb, AstraZeneca, Genmab, Pfizer, and Roche/Genentech. TY reports consultancy fees from AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme Oncology. YKK reports consulting fees from ALX Oncology, Amgen, Blueprint, Bristol Myers Squibb, Daehwa, MacroGenics, Merck, Novartis, Roche, Surface Oncology, and Zymeworks. TYK is the founder of IMBdx, Inc. and has received research funds from Bayer Korea. AS reports consulting role at Bayer, Bristol Myers Squibb, Eisai, Gilead Sciences, Incyte, Merck Sharp & Dohme, Pfizer, Sanofi, and Servier; and speakers’ bureau participation for AbbVie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Gilead Sciences, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda. BS reports consultancy fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eisai, Eli Lilly, Incyte, Ipsen, Novartis, Roche, Sirtex Medical, Terumo; speaker fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Incyte, Ipsen, Roche, Sirtex Medical, and Terumo; and research grants (to institution) from Bristol Myers Squibb and Sirtex Medical. MK reports consultancy fees from Chugai, Roche, Eisai, and AstraZeneca; speaker fees from Eli Lilly, Bayer, Eisai, Chugai, Takeda, and AstraZeneca; research grants (to institution) from Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare, and Ono Pharmaceutical Company. AM reports consulting role at Bayer, Eisai, Merck Sharp & Dohme, Roche, and Sirtex Medical; and speakers’ bureau participation for Bayer, Boston Biologics, Eisai, Merck Sharp & Dohme. FT reports consultancy role for Ipsen, Eisai, and Roche. JK reports consultancy fees from AstraZeneca, Ibsen, Taiho, and Hoffman-La Roche; and research support from AstraZeneca, Merck, Ibsen, and Roche. ARH reports consulting role at Eisai, Genentech/Roche, and Merck; speakers’ bureau participation for Bristol Myers Squibb, Eisai, and Exelixis; and research grants from Genentech and Merck. BER reports research grants from AstraZeneca, Bristol Myers Squibb, EUSA Pharmaceuticals, Exelixis, Merck, Novartis, and Xencor; consulting fees from AstraZeneca, Bristol Myers Squibb, Deciphera, Ipsen, NeoGenomics, Roche, and Seagen; and advisory role at Exelixis. HYL reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/Medarex, Eisai, and MSD Oncology; consulting role at AstraZeneca, Bayer, Bristol Myers Squibb, and Eisai; and speakers’ bureau participation for Bayer. SS, JY, JN, and MT report being employees of and owning stock in Bristol Myers Squibb. CH reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Ono Pharmaceuticals, Eisai, Ipsen, Merck Sharp & Dohme, Novartis, PharmaEngine, Roche, and TTY Biopharm. ABEK reports consultancy fees from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Gilead Sciences, Merck, Pieris Pharmaceuticals, QED Therapeutics, Qurient, Roche, Senti Biosciences, Servier, and Tallac Therapeutics; honoraria from ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, Exelixis, EMD Serono, Gilead Sciences, Merck, Roche/Genentech, QED Therapeutics, Qurient, Roche, Senti Biosciences, Servier, and Tallac Therapeutics; and research grants from AstraZeneca, Astex Pharmaceuticals, and Fulgent Genetics. All other authors have declared no conflicts of interest.

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