FDA Approves Nivolumab Plus Ipilimumab for Unresectable or Metastatic Hepatocellular Carcinoma

US FDA

The FDA has approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC).¹

This regulatory decision was supported by findings from the phase 3 CheckMate 9DW trial (NCT04039607), which demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) with the dual immunotherapy regimen compared with investigator’s choice of sorafenib (Nexavar) or lenvatinib (Lenvima) monotherapy. At a median follow-up of 35.2 months (range, 26.8-48.9), patients who received nivolumab plus ipilimumab (n = 335) achieved a median OS of 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5) for those treated with sorafenib or lenvatinib (n = 333), translating to a 21% reduction in the risk of death (HR, 0.79; 95% CI, 0.65-0.96; P = .018).^1,2

This full approval builds upon the March 2020 accelerated FDA approval that was granted to nivolumab plus ipilimumab for the treatment of patients with HCC who had received prior sorafenib, based on data from the phase 1/2 CheckMate 040 trial (NCT01658878).³

"This is a very effective regimen, and I think it adds to additional options for patients with this disease," said Aiwu Ruth He, MD, PhD, in an interview with OncLive^®. "For sure, [this regimen] has its place in the frontline setting as a very potent regimen for advanced HCC [because of its] survival benefit, high response rate, rapid time to response, and prolonged disease control."

CheckMate 9DW: Trial Overview

CheckMate 9DW was a global, randomized, open-label study evaluating nivolumab plus ipilimumab vs investigator’s choice of standard TKI therapy in patients with unresectable HCC who were naive to systemic therapy.² Eligible patients (n = 668) had at least 1 measurable lesion per RECIST 1.1 criteria, a Child-Pugh score of 5 or 6, and ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive either nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for up to 4 cycles followed by nivolumab at 480 mg every 4 weeks, or investigator’s choice of sorafenib (at 400 mg twice daily) or lenvatinib (at 8 mg or 12 mg daily, based on body weight). Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent, with a maximum duration of 2 years in the experimental arm.

OS was the primary end point of the study, with key secondary end points including blinded independent central review (BICR)–assessed overall response rate (ORR) and duration of response (DOR). Exploratory end points included progression-free survival (PFS) and safety.

Additional Efficacy Findings

In CheckMate 9DW, treatment with nivolumab plus ipilimumab led to a confirmed ORR of 36% (95% CI, 31%-42%) vs 13% (95% CI, 10%-17%) with sorafenib or lenvatinib (P < .0001). The complete and partial response rates in the immunotherapy arm were 7% and 29%, respectively, compared with 2% and 11% in the control group.

The median DOR was 30.4 months (95% CI, 21.2–NE) with the combination vs 12.9 months (95% CI, 10.2-31.2) with SOC therapy. The median PFS in these respective populations was 9.1 months (95% CI, 6.6-10.5) vs 9.2 months (95% CI, 7.9-11.1). In the investigational arm, the 18- and 24-month PFS rates were 34% and 28% compared with 18% and 12%, respectively, in the control arm.

Safety Profile of Nivolumab Plus Ipilimumab in HCC

The combination had a manageable safety profile consistent with safety findings from prior studies of immune checkpoint inhibitors. The median treatment duration was 4.7 months with nivolumab plus ipilimumab and 6.9 months with standard-of-care therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 84% of patients in the immunotherapy arm vs 91% of those in the control arm, with grade 3/4 TRAEs reported in 41% and 42% of patients, respectively.

Immune-mediated AEs occurred in 58% of patients receiving the combination, with 28% of patients in this arm experiencing grade 3/4 events. Hepatitis (any-grade, 19%; grade 3/4, 15%), rash (15%; 4%), and hypothyroidism/thyroiditis (19%; < 1%) were among the most commonly reported AEs. Treatment discontinuation due to TRAEs occurred in 18% of patients in the combination arm compared with 10% of those in the control arm.

References

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma.FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinomaFDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinomaFDA 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
2. 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
3. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. March 10, 2020. Accessed April 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-ca