EMA Validates Application for Nivolumab/Ipilimumab in Liver Cancer Type

The application for the combination therapy was supported by results from the phase 3 CheckMate –9DW trial (NCT04039607), which showed a statistically significant and clinically meaningful improvement in overall survival with nivolumab/ipilimumab compared with lenvatinib or sorafenib.

The European Medicines Agency (EMA) has validated a Type II variation application for nivolumab (Opdivo) plus ipilimumab (Yervoy) as a frontline treatment for adult patients with unresectable or advanced hepatocellular carcinoma (HCC), according to a news release from the drug’s developer, Bristol Myers Squibb.¹

The application for the combination therapy was supported by results from the phase 3 CheckMate –9DW trial (NCT04039607), which showed a statistically significant and clinically meaningful improvement in overall survival (OS) for the investigational combination compared with lenvatinib (Lenvima) or sorafenib (Nexavar). Results from the phase 3 CheckMate –9DW trial were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.² Additionally, tolerability findings for the therapy were consistent with previously reported safety data, and no new safety signals were identified.

The validation of the application begins the EMA’s centralized review.

“Approximately 62,000 cases of liver cancer are diagnosed annually in the European Union, with HCC being the predominant type. Despite recent treatment advances, the prognosis remains poor for patients in more advanced stages, which highlights the need for therapies with better clinical outcomes,” said Dana Walker, MD, MSCE, vice president and global program lead of gastrointestinal and genitourinary cancers at Bristol Myers Squibb, in a news release on the application’s validation.¹ “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.”

In the phase 3 trial, 668 patients were randomly assigned to receive either nivolumab in combination with ipilimumab (n = 335) or either lenvatinib or sorafenib (n = 325), with 275 (85%) receiving lenvatinib. Patients in the combination arm received 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for up to 4 cycles and then nivolumab at 480 mg every 4 weeks. Alternatively, patients in the investigator’s choice arm received lenvatinib at 8 mg or 12 mg every day or 400 mg of sorafenib twice daily until unacceptable toxicity or disease progression.

Nivolumab treatment was administered for a maximum of 2 years.

The primary end point was OS. Secondary end points included objective response rate (ORR) and duration of response (DOR) per blinded independent central review (BICR).

Median follow-up was 35.2 months (range, 26.8-48.9), with a median OS of 23.7 months (95% CI, 18.8-29.4) for the nivolumab/ipilimumab arm vs 20.6 months (95% CI, 17.5-22.5) in the investigator’s choice arm (HR, 0.79; 95% CI, 0.65-0.96; P = .018). OS at 24 months for the investigational arm vs the comparator arm was 49% (95% CI, 44%-55%) vs 39% (95% CI, 34%-45%).

Additionally, ORR was higher in the investigational arm at 36% (95% CI, 31%-42%) vs 13% (95% CI, 10%-17%) in the lenvatinib or sorafenib arm (P < .0001), with complete responses observed in 7% vs 2% of patients. Median DOR was 30.4 months (95% CI, 21.2-not evaluable) vs 12.9 months (95% CI, 10.2-31.2) in each respective arm.

Of those evaluable in the nivolumab/ipilimumab arm (n = 332), any-grade and grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 278 (84%) and 137 (41%) of patients. Furthermore, any-grade and grade 3/4 TEAEs leading to discontinuation occurred in 59 (18%) and 44 (13%) of patients.

Of those evaluable in the investigator’s choice arm (n = 325), any-grade and grade 3/4 TEAEs occurred in 297 (91%) and 138 (42%) of patients. Additionally, any-grade and grade 3/4 TEAEs leading to discontinuation occurred in 34 (10%) and 21 (6%) of patients.

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://tinyurl.com/2nwe64rd
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