Frontline Nivolumab/Ipilimumab Prolongs OS in Unresectable HCC

Treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) yielded a statistically significant and clinically meaningful overall survival (OS) benefit vs lenvatinib (Lenvima) or sorafenib (Nexavar) in the frontline setting for patients with unresectable hepatocellular carcinoma (HCC) who were naive to systemic therapy, according to data from the phase 3 CheckMate 9DW study (NCT04039607).1

At a median follow-up of 35.2 months (range, 26.8-48.9), findings presented at the 2025 Gastrointestinal Cancers Symposium showed that patients treated with the combination of nivolumab plus ipilimumab (n = 335) experienced a median OS of 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5) with lenvatinib or sorafenib (n = 333; HR, 0.79; 95% CI, 0.65-0.96; P = .018). The 24- and 36-month OS rates in the combination arm were 49% (95% CI, 44%-55%) and 38% (95% CI, 32%-43%) compared with 39% (95% CI, 34%-45%) and 24% (95% CI, 19%-30%) in the control arm.1

“In CheckMate 9DW, nivolumab/ipilimumab demonstrated clinical benefit in terms of [improved] OS, higher objective response rate [ORR], and higher complete response [CR] rate, and also [had] an acceptable safety profile,” Masatoshi Kudo, MD, PhD, professor and chairman in the Department of Gastroenterology and Hepatology at Kindai University in Osaka, Japan, said during a presentation of data. “These results support nivolumab [plus] ipilimumab as a new first-line standard of care for patients with unresectable HCC.”

Nivolumab plus ipilimumab also generated a significantly higher ORR of 36% (95% CI, 31%-42%) compared with 13% (95% CI, 10%-17%) in the lenvatinib/sorafenib arm (P < .0001). The median duration of response (DOR) was significantly longer for nivolumab plus ipilimumab vs lenvatinib/sorafenib at 30.4 months (95% CI, 21.2-not estimable [NE]) compared with 12.9 months (95% CI, 10.2-31.2), respectively. The ORR benefit seen with the combination was consistent across various subgroups.

In August 2024, the FDA accepted the supplemental biologics license application seeking the approval of nivolumab plus ipilimumab for the first-line treatment of adult patients with unresectable HCC based on findings from CheckMate 9DW. The Prescription Drug User Fee Act target action date of April 21, 2025, was set.2

Background on the Trial

CheckMate 9DW was a global, randomized, open-label trial evaluating the frontline combination of nivolumab, a PD-1 inhibitor, and ipilimumab, a CTLA-4 inhibitor, vs the standard of care TKIs lenvatinib and sorafenib in patients with unresectable HCC.1 Eligible patients had at least 1 measurable lesion by RECIST 1.1 criteria, a Child-Pugh score of 5 or 6, and an ECOG performance status of 0 or 1. Key exclusion criteria included receipt of prior systemic therapy and main portal vein invasion.

Patients were randomly assigned 1:1 to the investigative vs control arm and were stratified by etiology, macrovascular invasion/extrahepatic spread, and alpha-fetoprotein. They received 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; lenvatinib at 8 or 12 mg daily; or sorafenib at 400 mg twice daily. Additionally, most patients received lenvatinib (85%) rather than sorafenib. Nivolumab was administered for a maximum of 2 years and treatment in the control arm continued until disease progression, unacceptable toxicity, or consent withdrawal.

The primary end point was OS, and secondary end points included ORR, DOR, safety, and time to symptom deterioration with response assessed by blinded independent central review (BICR) using RECIST 1.1 criteria. Progression-free survival and safety represented key exploratory end points.

Additional Data: OS by Best ORR

At the 24-week landmark analysis, the median OS for patients in the nivolumab plus ipilimumab arm who achieved a CR or partial response (PR; n = 101) was not reached (95% CI, 44.4-NE) vs 16.0 months (95% CI, 12.0-18.7) among those with progressive disease (PD; n = 47; HR, 0.14; 95% CI, 0.08-0.24). Patients with stable disease (SD; n = 105) experienced a median OS of 30.0 months (95% CI, 23.5-37.8) and had superior survival outcomes compared with those who had PD (HR, 0.40; 95% CI, 0.26-0.60).

Furthermore, in the lenvatinib/sorafenib arm, the median OS for patients who achieved a CR/PR (n = 28) was 28.3 months (95% CI, 20.6-NE) compared with 13.5 months (95% CI, 8.7-25.3) among those who experienced PD (n = 31; HR, 0.45; 95% CI, 0.23-0.86). Patients with SD (n = 212) had a median OS of 22.5 months (95% CI, 20.5-24.8) and also experienced superior survival outcomes compared with those who had PD (HR, 0.69; 95% CI, 0.45-1.08).

Diving into Tolerability

The safety profile of nivolumab plus ipilimumab was consistent with data from prior studies, with Kudo noting adverse effects (AEs) were generally manageable and no new safety signals were identified. Most treatment-related AEs were grade 1 or 2 and did not lead to treatment discontinuation. In the combination arm, 12 patients experienced treatment-related deaths, and most deaths (n = 9) occurred in patients with severe and underlying liver disease; disease progression per BICR was confirmed in 1 patient and was suspected in 3 additional patients.

Regarding common any-grade treatment-related AEs, hepatobiliary disorders included immune-mediated hepatitis occurring in 2% of patients receiving nivolumab plus ipilimumab and hyperbilirubinemia in 2% of those receiving lenvatinib or sorafenib. Additionally, hypertension (2% vs 41%, respectively) was reported. Overall, in the investigative vs control arms any-grade and grade 3-4 treatment-related included hepatobiliary disorders (13% and 11% vs 5% and 3%), cardiovascular events (3% and < 1% vs 42% and 12%), and hemorrhagic events (< 1% and < 1% vs 6% and 2%), respectively.

Disclosures: Dr Kudo reported serving in a consulting or advisory role for AstraZeneca, Chugai/Roche, Eisai, and Roche, and has received honoraria from all of the above plus Bayer, Lilly Japan, and Takeda. He has also received institutional research funding from Abbvie, Chugai/Roche, Eisai, GE Healthcare, Otsuka, and Taiho Pharmaceutical.

References

1. 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
2. Bristol Myers Squibb receives U.S. Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. August 21, 2024. Accessed January 24, 2025. bit.ly/40AsrJ5