Frontline Nivolumab/Ipilimumab Delivers Long-Term Efficacy in Unresectable HCC

The first-line combination of nivolumab (Opdivo) and ipilimumab (Yervoy) generated sustained efficacy and safety benefits compared with lenvatinib (Lenvima) or sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC), according to 4-year follow-up findings from the phase 3 CheckMate 9DW trial (NCT04039607), which were presented at the 2026 Gastrointestinal Cancers Symposium.¹

At a data cutoff of July 9, 2025, and a median follow-up of 52.5 months (range, 44.0-66.1), the median overall survival (OS) was 23.7 months (95% CI, 18.8-29.4) in the nivolumab/ipilimumab arm (n = 335) vs 20.6 months (95% CI, 17.7-22.5) in the control arm (n = 333; HR, 0.78; 95% CI, 0.65-0.93). In the investigational arm, the 24-, 36-, and 48-month OS rates were 50% (95% CI, 44%-55%), 39% (95% CI, 33%-44%), and 31% (95% CI, 26%-36%), respectively. These respective rates in the control arm were 39% (95% CI, 34%-45%), 25% (95% CI, 21%-30%), and 18% (95% CI, 14%-23%).

“The results continue to support nivolumab and ipilimumab as a first-line standard of care for patients with unresectable HCC,” lead study author Peter R. Galle, MD, PhD, of the Department of Internal Medicine at University Medical Center Mainz in Germany, said in a presentation of the data.

What was the design of CheckMate 9DW?

This global, randomized, open-label trial enrolled patients with unresectable HCC who had at least 1 measurable lesion per RECIST 1.1 criteria, received no prior systemic therapy, a Child-Pugh score of 5 or 6, an ECOG performance score of 0 or 1, and no main portal vein invasion. Patients were stratified by etiology (hepatitis B virus vs hepatitis C virus vs uninfected), macrovascular invasion/extrahepatic spread status (absent vs present), and alpha-fetoprotein level (< 400 ng/mL vs ≥ 400 ng/mL).

In total, 668 patients were randomly assigned 1:1 to receive intravenous (IV) nivolumab at 1 mg/kg plus IV ipilimumab at 3 mg/kg every 3 weeks for up to 4 cycles followed by nivolumab monotherapy at 480 mg every 4 weeks; or investigator’s choice of oral lenvatinib at 8 mg or 12 mg daily (n = 275), or oral sorafenib at 400 mg twice daily (n = 50). Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or a maximum treatment duration of 2 years (in the nivolumab/ipilimumab arm alone).

OS served as the primary end point. Secondary end points included overall response rate (ORR) and duration of response (DOR) by blinded independent central review and per RECIST 1.1 criteria, as well as time to symptom deterioration. Safety was a key exploratory end point.

What findings have been previously reported with nivolumab plus ipilimumab in previously untreated HCC?

In April 2025, the FDA granted full approval to frontline nivolumab plus ipilimumab for the treatment of adult patients with unresectable or metastatic HCC.² This regulatory decision was backed by prior data from CheckMate 9DW that showed that at a median follow-up of 35.2 months (range, 26.8-48.9), the median OS was 23.7 months (95% CI, 18.8-29.4) with the investigational combination compared with 20.6 months (95% CI, 17.5-22.5) with sorafenib or lenvatinib (HR, 0.79; 95% CI, 0.65-0.96; P = .018). Additionally, the ORR was 36.1% (95% CI, 31.0%-41.5%) with ipilimumab/nivolumab vs 13.2% (95% CI, 9.8%-17.3%) in the control arm (P < .0001).

What updated efficacy findings were seen in CheckMate 9DW?

Galle reported that the baseline characteristics were well balanced between the 2 arms.¹ Most notably, 27% patients in the nivolumab/ipilimumab arm had Barcelona-Clinic Liver Cancer stage B or lower disease vs 26% of those in the control arm; Galle noted that the slightly higher rate in the investigational arm may have contributed to the positive results.

In the nivolumab/ipilimumab arm, the ORR was 36% (95% CI, 31%-42%), including a complete response rate of 8% and a partial response rate of 28%. These respective rates in the control arm were 13% (95% CI, 10%-17%), 2%, and 11%. The median time to response with nivolumab/ipilimumab was 2.2 months (range, 1.1-41.7) vs 3.7 months (range, 0.6-8.0). In the nivolumab/ipilimumab arm, the median DOR was 34.3 months (95% CI, 22.6-47.7), and 37% (95% CI, 24%-50%) of patients had a DOR lasting at least 48 months. In the control arm, the median DOR was 12.9 months (95% CI, 10.2-33.9), and 12% (95% CI, 1%-38%) of patients had a DOR lasting at least 48 months.

What was the updated safety profile of nivolumab plus ipilimumab in previously untreated, unresectable HCC?

Galle noted that the safety profile of nivolumab plus ipilimumab was consistent with prior reports and continued to be manageable with no new safety signals.

Among all treated patients, the median duration of treatment was 4.7 months (range, < 0.1-24.4) in the nivolumab/ipilimumab arm (n = 332) vs 6.9 months (range, < 0.1-50.6) in the control arm. In the nivolumab/ipilimumab arm, any-grade treatment-related adverse effects (TRAEs), serious TRAEs, and TRAEs leading to discontinuation were reported at rates of 83%, 28%, and 18%, respectively; the respective rates of grade 3/4 AEs in these categories were 41%, 25%, and 13%. In the control arm, the rates of any-grade AEs in these categories were 91%, 14%, and 10%; the respective rates of grade 3/4 AEs were 42%, 13%, and 6%. Notably, 12 treatment-related deaths occurred in the nivolumab/ipilimumab arm vs 3 in the control arm.

In the nivolumab/ipilimumab arm, the most common TRAEs included (hypertension (any-grade, 2%; grade 3/4, 0%), diarrhea (14%; 1%), palmar-plantar erythrodysesthesia (PPE) syndrome (2%; 0%), pruritus (28%; 2%), hypothyroidism (12%; 0%), decreased appetite (7%; < 1%), rash (20%; 2%), increased aspartate aminotransferase (AST) levels (19%; 6%), increased alanine aminotransferase (ALT) levels (19%; 5%), asthenia (10%; < 1%), fatigue (8%; 0%), decreased weight (2%; 0%), increased lipase levels (11%; 5%), nausea (6%; 0%), and hyperthyroidism (10%; < 1%). In the control arm, the most common TRAEs included (hypertension (any-grade, 42%; grade 3/4, 12%), diarrhea (35%; 3%), PPE syndrome (30%; 3%), pruritus (3%; 0%), hypothyroidism (26%; 0%), decreased appetite (22%; 2%), proteinuria (20%; 5%), rash (9%; < 1%), increased AST levels (9%; < 1%), increased ALT levels (6%; < 1%), asthenia (16%; 2%), fatigue (16%; 2%), decreased weight (11%; 2%), increased lipase levels (6%; 1%), nausea (10%; < 1%), and hyperthyroidism (1%; 0%).

Notably, among patients treated with ipilimumab/nivolumab, immune-mediated hepatitis occurred at any grade in 19% and grade 3/4 in 15%. In total, 17% of patients received high-dose steroids, and 6% of patients discontinued therapy due to this AE. The median time to onset of any-grade immune-mediated hepatitis was 6.0 weeks (range, 0.9-88.9). This event resolved in 75% of patients, and the median time to resolution was 10.3 weeks (range, 0.9-129.3+).

“That’s something we have to pay attention to, [and it] can be a problem, but if you intervene early on, it’s something quite manageable,” Galle explained.

Disclosures: Galle reported receiving honoraria from Adaptimmune, AstraZeneca/MedImmune, Bayer Schering Pharma, Bristol-Myers Squibb, Ipsen, MSD, Roche/Genentech, and Sirtex Medical; performing consulting or advisory roles for Adaptimmune, Bayer Schering Pharma, Boston Scientific, Bristol-Myers Squibb, Lilly, MSD, Roche/Genentech, and Sirtex Medical; performing speakers’ bureau roles for AstraZeneca, Bayer Schering Pharma, BMS GmbH & Co. KG, Ipsen, Lilly, and Roche; receiving research funding from Roche/Genentech; and receiving coverage of travel, accommodations, or expenses from AstraZeneca, Bayer Schering Pharma, Lilly, Roche/Genentech, and Sirtex Medical.

References

1. Galle PR, Sangro B, Decaens T, et al. Nivolumab plus ipilimumab vs lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC): 4-year follow-up of CheckMate 9DW. J Clin Oncol. 2026;44(suppl 2):LBA479. doi:10.1200/JCO.2026.44.2_suppl.LBA479
2. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. FDA. April 11, 2025. Accessed January 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma