Nivolumab/Ipilimumab Approaches EU Approval in Unresectable or Advanced HCC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of nivolumab (Opdivo) paired with ipilimumab (Yervoy) for the frontline treatment of adult patients with unresectable or advanced hepatocellular carcinoma (HCC).1

The positive opinion is based on data from the phase 3 CheckMate -9DW trial (NCT04039607) in which the doublet (n = 335) led to a median overall survival (OS) of 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5) with investigator’s choice of lenvatinib (Lenvima) or sorafenib (Nexavar; n = 333; HR, 0.79; 95% CI, 0.65-0.96; P = .018).2 The 24- and 36-month OS rates with nivolumab plus ipilimumab at 49% and 38%, respectively; in the control arm, these respective rates were 39% and 24%.

“HCC is the predominant type of liver cancer globally, including in the European Union, and when diagnosed at the advanced or unresectable stage, prognosis and overall survival remain sub-optimal with conventional therapy,” Dana Walker, MD, MSCE, vice president of the Opdivo global program lead at Bristol Myers Squibb, stated in a news release.1 “The positive opinion received by the CHMP is a significant step forward in providing patients with additional treatment options, and we look forward to the upcoming European Commission review and the potential to expand the treatment landscape for adult patients with unresectable or advanced HCC.”

Checking Out CheckMate -9DW

The global, open-label, phase 3 CheckMate -9DW trial enrolled patients with unresectable HCC who were naive to systemic therapy and had at least 1 measurable lesion per RECIST 1.1 criteria.2 Patients were required to have a Child-Pugh score of 5 or 6 and an ECOG performance status of 0 or 1 without main portal vein invasion.

Participants were randomly assigned 1:1 to receive 1 mg/kg of intravenous (IV) nivolumab plus 3 mg/kg of IV ipilimumab every 3 weeks for up to 4 cycles followed by 480 mg of nivolumab every 4 weeks or investigator’s choice of 8 mg or 12 mg of lenvatinib once daily or 400 mg of sorafenib twice daily. Treatment continued until progressive disease, intolerable toxicity, withdrawn consent, or maximum treatment duration was reached. They were stratified by etiology (hepatitis B virus vs hepatitis C virus vs uninfected), microvascular invasion/extrahepatic spread (present vs absent), and alpha-fetoprotein level (<400 ng/mL vs ≥400 ng/mL).

OS served as the trial’s primary end point, and secondary end points included objective response rate (ORR) and duration of response (DOR) by blinded independent central review (BICR) and RECIST 1.1 criteria, as well as time to symptom deterioration. Exploratory end points included progression-free survival (PFS) by BICR and RECIST 1.1 criteria and safety.

Additional Efficacy Revelations

The data cutoff date for the first results of the trial shared during the 2024 ASCO Annual Meeting was January 31, 2024; the median follow-up was 35.2 months (range, 26.8-48.9). The ORR achieved with the doublet was 36% (95% CI, 31%-42%) vs 13% (95% CI, 10%-17%) with investigator’s choice of lenvatinib or sorafenib (P < .0001). The median time to response (TTR) with nivolumab plus ipilimumab was 2.2 months (range, 1.1-11.6) and the median DOR was 30.4 months (95% CI, 21.2-not evaluable); with investigator’s choice of lenvatinib or sorafenib, the median TTR was 3.7 months (range, 0.6-11.2) and the median DOR was 12.9 months (95% CI, 10.2-13.2).

The median PFS with the doublet was 9.1 months (95% CI, 6.6-10.5) vs 9.2 months (95% CI, 7.9-11.1) with lenvatinib or sorafenib (HR, 0.87; 95% CI, 0.72-1.06). The 18- and 24-month PFS rates with ipilimumab plus nivolumab were 34% and 28%, respectively; with lenvatinib or sorafenib, these respective rates were 28% and 12%.

Updated data from expanded analyses were shared during the 2025 Gastrointestinal Cancers Symposium.3

Safety Spotlight

The median duration of treatment with the doublet was 4.7 months (range, <1 to 24.4) vs 6.9 months (range, <1 to 45.8) with lenvatinib or sorafenib. Treatment-related adverse effects (TRAEs) occurred in 84% and 91% of patients, respectively; they were grade 3 or 4 for 41% and 42% of patients, respectively.2 Serious TRAEs were experienced by 28% and 14% of patients, respectively, with 25% and 13% of these effects grade 3 or 4 in severity. Any TRAEs led to discontinuation for 18% of those given the doublet and 10% of those who received investigator’s choice of treatment. Twelve treatment-related deaths occurred in the doublet arm vs 3 in the control arm.

The most common any-grade TRAEs reported in the investigative and control arms, respectively, were pruritus (28% vs 3%), increased aspartate aminotransferase (20% vs 8%), increased alanine aminotransferase level (19% vs 6%), rash (19% vs 9%), hypothyroidism (12% vs 24%), diarrhea (14% vs 35%), asthenia (10% vs 16%), hyperthyroidism (10% vs 2%), fatigue (8% vs 15%), decreased appetite (7% vs 22%), nausea (6% vs 10%), hypertension (2% vs 41%), Palmar-Plantar erythrodysesthesia syndrome (2% vs 30%), decreased weight (2% vs 11%), and dysphonia (<1% vs 15%).

Navigating Beyond Today’s News

In August 2024, the FDA accepted a supplemental biologics license application seeking the approval of nivolumab plus ipilimumab for first-line use in adult patients with unresectable HCC based on CheckMate -9DW data.4 The regulatory agency will make a decision by April 21, 2025, under the Prescription Drug User Fee Act.

References

1. Bristol Myers Squibb receives positive CHMP opinion for Opdivo (nivolumab) plus Yervoy (ipilimumab) as a first-line treatment option for adult patients with unresectable or advanced hepatocellular carcinoma. News release. Bristol Myers Squibb. January 31, 2025. Accessed January 31, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-for-Opdivo-nivolumab-plus-Yervoy-ipilimumab-as-a-First-Line-Treatment-Option-for-Adult-Patients-with-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
3. Kudo M, Yau T, Decaens T, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses. J Clin Oncol. 2025;43(suppl 4):520. doi:10.1200/JCO.2025.43.4_suppl.520
4. 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 January 31, 2025. 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