FDA Approves Nivolumab/Ipilimumab for Metastatic or Unresectable HCC

The FDA announced its approval of frontline nivolumab (Opdivo) plus ipilimumab (Yervoy) for use in adult patients with unresectable or metastatic hepatocellular carcinoma (HCC), according to an announcement from the agency.¹

The approval is based on data from the CHECKMATE-9DW (NCT04039607) trial, which had a primary endpoint of overall survival (OS) and a secondary end point of overall response rate (ORR) per RECIST 1.1 criteria and assessed by blinded independent central review.

The open-label trial randomized 668 participants 1:1 to receive either 1 mg/kg of nivolumab intravenously plus 3 mg/kg of ipilimumab intravenously every 3 weeks for a maximum of 4 doses, followed by 480 mg of intravenous nivolumab monotherapy every 4 weeks, or investigator’s’ choice of lenvatinib (Lenvima) or sorafenib (Nexavar).

The investigated dosage is recommended by the FDA.

Efficacy

Median OS was 23.7 months (95% CI, 18.8-29.4) in the nivolumab/ipilimumab arm and 20.6 months (95% CI, 17.5-22.5) in the lenvatinib or sorafenib arm (hazard ratio [HR], 0.79; 95% CI, 0.65-0.96; P < .0180).

ORRs in the experimental arm and control arm were 36.1% (95% CI, 31.0%-41.5%) and 13.2% (95% CI, 9.8%-17.3%; P < .0001), respectively.

The FDA accepted a supplemental biologics license application (sBLA) for first-line nivolumab plus ipilimumab in unresectable HCC in August 2024.² Prior to that, the FDA granted accelerated approval to the treatment indication in March 2020. Both decisions were based on data from various stages of the CHECKMATE trial.³

Patients enrolled in CHECKMATE-9DW had histologically confirmed HCC, Child Pugh Class A, with an ECOG performance status of 0 or 1 and no previous systemic therapy for advanced disease.¹

Adverse Reactions

The adverse events (AEs) most frequently reported, occurring in over 20% of patients, were rash, pruritic, fatigue, and diarrhea.

At the time of the accelerated approval’s announcement, the most common TRAEs of any grade reported in at least 10% of patients treated with nivolumab plus ipilimumab vs investigator’s choice included hypertension (2% vs 41%, respectively), diarrhea (14% vs 35%), Palmar-plantar erythrodysesthesia syndrome (2% vs 30%), pruritus (28% vs 3%), hypothyroidism (12% vs 24%), decreased appetite (7% vs 22%), increased aspartate aminotransferase (20% vs 8%), proteinuria (0% vs 20%), increased alanine aminotransferase (19% vs 6%), rash (19% vs 9%), asthenia (10% vs 16%), fatigue (8% vs 15%), dysphonia (<1% vs 15%), increased lipase (11% vs 6%), decreased weight (2% vs 11%), hyperthyroidism (10% vs 2%), and nausea (6% vs 10%).⁴

Likewise, the most common immune-mediated AEs reported in the experimental arm included hepatitis (any grade, 19%; grade 3/4, 15%), hypothyroidism/thyroiditis (19%; <1%), rash (15%; 4%), hyperthyroidism (11%; <1%), diarrhea/colitis (8%; 5%), adrenal insufficiency (5%; 2%), hypophysitis (3%; 1%), pneumonitis (2%; <1%), nephritis and renal dysfunction (2%; <1%), hypersensitivity (1%; 0%), and diabetes mellitus (<1%; <1%).⁴

Reference

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. FDA. April 11, 2025. Accessed April 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma?utm_medium=email&utm_source=govdelivery
2. Bristol Myers Squibb receives US Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. August 21, 2024. Accessed August 21, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-U.S.-Food-and-Drug-Administration-sBLA-Acceptance-for-First-Line-Treatment-of-Unresectable-Hepatocellular-Carcinoma/default.aspx
3. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. March 10, 2020. Accessed August 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-carcinoma
4. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): first results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008