EMA Validates Application for Nivolumab Plus Ipilimumab in Frontline HCC

Dana Walker, MD, MSCE

The European European Medicines Agency (EMA) has validated a type II variation application for nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma (HCC) who have not received prior systemic therapy. Validation of the application confirms the submission is complete and initiates the centralized procedure review from the EMA.1

The application was supported by data from the phase 3 CheckMate 9DW study (NCT04039607), which is evaluating the combination as a frontline treatment for patients with advanced HCC.

During the 2024 ASCO Annual Meeting, investigators presented updated findings from the trial. At a median follow-up of 35.2 months (range, 26.8-48.9), the median overall survival (OS) in patients treated with nivolumab plus ipilimumab (n = 335) vs the investigator’s choice of lenvatinib (Lenvima) or sorafenib (Nexavar; n = 333) was 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5), respectively (HR, 0.79; 95% CI, 0.65-0.96; P = .018). The 24-month OS rates in these respective arms were 49% vs 39%; the 36-month OS rates were 38% vs 24%, respectively.²

“Approximately 62,000 cases of liver cancer are diagnosed annually in the European Union, with HCC being the predominant type,” Dana Walker, MD, MSCE, vice president and global program lead of gastrointestinal and genitourinary cancers at Bristol Myers Squibb, stated in a news release. “Despite recent treatment advances, the prognosis remains poor for patients in more advanced stages which highlights the need for therapies with better clinical outcomes. We look forward to working with the EMA to advance our application for nivolumab plus ipilimumab to provide a new first-line dual immunotherapy combination treatment option for adult patients with unresectable or advanced HCC in the European Union.”

CheckMate 9DW was a global, open-label study that compared nivolumab plus ipilimumab with physician’s choice of lenvatinib or sorafenib monotherapy in patients with treatment-naive, unresectable HCC. To be eligible for the trial, patients needed to have an ECOG performance status of 1 or less, have a Child-Pugh score of 5 or 6, at least 1 measurable lesion per RECIST 1.1 criteria, and no main portal vein invasion. Patients were stratified by etiology (hepatitis B virus vs hepatitis C virus vs uninfected), microvascular invasion/extrahepatic spread (present vs absent), and alpha-fetoprotein (< 400 ng/mL vs ≥ 400 ng/mL).2

Patients were randomly assigned to receive 1 mg/kg of intravenous nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for up to 4 cycles. This was followed by either nivolumab monotherapy at 480 mg every 4 weeks, investigator’s choice of oral lenvatinib at 8 mg or 12 mg daily or sorafenib at 400 mg twice daily. Treatment in both arms continued until disease progression, unacceptable toxicity, patient withdrawal, or up to 2 years in the combination arm.

The primary end point was OS. Secondary end points included overall response rate (ORR), duration of response (DOR), and time to symptom deterioration. Key exploratory end points included progression-free survival (PFS) and safety.

Baseline patient characteristics were generally well balanced between the investigational and control arms; the median age of patients was 65 years (range, 20-86) vs 66 years (range, 20-89), respectively. Across both arms, most patients were male (81% vs 83%), had a Child-Pugh score of 5 (76% vs 79%), had BCLC stage C disease (73% vs 73%), and did not receive prior locoregional therapy (58% vs 53%).

Additional findings from CheckMate 9DW showed that the ORRs in the combination and physician’s choice arms were 36% (95% CI, 31%-42%) vs 13% (95% CI, 10%-17%), respectively (P < .0001); the complete response rates were 7% vs 2%, respectively. The median time to response was 2.2 months (range, 1.1-11.6) vs 3.7 months (range, 0.6-11.2).

The median DOR was 30.4 months (95% CI, 21.2-not evaluable) vs 12.9 months (95% CI, 10.2-31.2) in the combination and control arms, respectively. The median PFS was 9.1 months (95% CI, 6.6-10.5) compared with 9.2 months (95% CI, 7.9-11.1), respectively (HR, 0.87; 95% CI, 0.72-1.06). The 18-month PFS rates in these respective arms were 34% vs 18%; the 24-month rates were 28% vs 12%, respectively.

In terms of safety, any-grade treatment-related adverse effects (TRAEs) were reported in 84% of patients in the combination arm (n = 332) compared with 91% of those in the physician’s choice of treatment arm (n = 325). Any-grade serious TRAEs (28% vs 14%), TRAEs leading to treatment discontinuation (18% vs 10%), and treatment-related deaths (4% vs < 1%) occurred in both arms.

References

1. Bristol Myers Squibb receives European Medicines Agency validation of application for Opdivo (nivolumab) plus Yervoy (ipilimumab) for first-line treatment of unresectable or advanced hepatocellular carcinoma. News release. Bristol Myers Squibb. July 19, 2024. Accessed July 19, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-European-Medicines-Agency-Validation-of-Application-for-Opdivo-nivolumab-plus-Yervoy-ipilimumab-for-First-Line-Treatment-of-Unresectable-or-Advanced-Hepatocellular-Carcinoma/default.aspx
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