FDA Approves Nivolumab With Ipilimumab for First-Line Treatment of Adult Patients With HCC

The FDA approved nivolumab (Opdivo, Bristol Myers Squibb Company) with ipilimumab (Yervoy, Bristol Myers Squibb Company) for adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) in the first-line setting. This approval is supported by efficacy data from the CHECKMATE-9DW phase 3 clinical trial (NCT04039607).^1,2

Nivolumab is an immunotherapy that helps the patient’s body fight against different types of cancer. Because it is an immunotherapy, nivolumab works with the body’s immune system to fight disease. It can be used alone or in combination with other therapies, such as ipilimumab. Earlier in April 2025, the combination of nivolumab and ipilimumab was approved for the treatment of unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer in adult and pediatric patients aged 12 years and older.^3,4

The FDA recommends that the combination be administered intravenously (IV) in 1-mg/kg (nivolumab) and 3-mg/kg (ipilimumab) doses every 3 weeks for a maximum of 4 doses, followed by 240 mg of IV nivolumab every 2 weeks or 480 mg of IV nivolumab as a single agent every 4 weeks.¹

The efficacy of the combination treatment was evaluated in the randomized, open-label, multicenter phase 3 clinical trial, CHECKMATE-9DW (NCT04039607), to compare the overall survival (OS) with the standard of care—either sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals Inc.) or lenvatinib (Lenvima; Eisai Co., Ltd.)—when used as a first-line treatment in 668 adult patients with unresectable or metastatic HCC. Patients had histologically confirmed HCC, Child-Pugh Class A, Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior systemic therapy for advanced disease. Additionally, patients were ineligible for enrollment if they had known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; a prior liver transplant; and active brain or leptomeningeal metastases.^1,2

Patients were randomly assigned to receive either nivolumab 1 mg/kg as an IV infusion with ipilimumab 3 mg/kg IV every 3 weeks for a maximum of 4 doses, followed by single-agent nivolumab 480 mg IV every 4 weeks (n = 335), or the investigator’s choice of lenvatinib or sorafenib (n = 333). The primary end point was OS, which was measured up to 4 years, and secondary end points were objective response rate (ORR), duration of response, and time to symptom deterioration, which were also assessed up to 4 years.^1,2,5

The median OS was about 23.7 months (95% CI: 18.8, 29.4) in the nivolumab plus ipilimumab arm and 20.6 months (95% CI: 17.5, 22.5) in the lenvatinib or sorafenib arm (HR 0.79 [95% CI: 0.65, 0.96]; p < .0180) at a median follow-up of 35.2 months, according to results published in the Journal of Clinical Oncology. Additionally, the nivolumab and ipilimumab regimen also demonstrated a favorable ORR (36.1% [95% CI: 31.0, 41.5]) when compared with standard of care (13.2% [95% CI: 9.8, 17.3]; p < .0001).^1,5

Further, the data also showed 24-month OS rates of 49% (95% CI: 44, 55) and 39% (95% CI: 34, 45) in the nivolumab plus ipilimumab and standard of care groups, respectively. In these respective groups, median DOR was about 30.4 months and 12.9 months, with complete response observed in 7% and 2% of patients.⁵

The most common adverse events (AE; >20%) were rash, pruritus, fatigue, and diarrhea, according to the FDA news release.¹ Grade 3 and 4 treatment-emergent AEs were observed in 137 (41%) of patients receiving nivolumab and ipilimumab and 138 (42%) of patients receiving standard of care. Additionally, these led to the discontinuation of treatment in 44 (13%) and 21 (6%) of patients in these respective groups.⁵

REFERENCES

1. US Food & Drug Administration. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. News release. 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. A Study of Nivolumab in Combination With Ipilimumab in Participants With Advanced Hepatocellular Carcinoma (CheckMate 9DW). ClinicalTrials.gov identifier: NCT04039607. Updated May 2, 2024. Accessed April 11, 2025. https://www.clinicaltrials.gov/study/NCT04039607

3. Opdivo (nivolumab). Accessed April 11, 2025. https://www.opdivo.com/

4. Ferruggia K. Nivolumab Plus Ipilimumab Receives FDA Approval for MSI-H/dMMR mCRC. Pharmacy Times. April 8, 2025. Accessed April 11, 2025. https://www.pharmacytimes.com/view/nivolumab-plus-ipilimumab-receives-fda-approval-for-msi-h-dmmr-mcrc

5. 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. JCO. 2024;42(Number 17 suppl):LBA4008-LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008