Clinical trialPhase 3Liver cancer

Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial

Lancet · 2025668 patients (335 nivolumab + ipilimumab, 333 lenvatinib or sorafenib)

Yau T, Galle PR, Decaens T, et al. Lancet. 2025. 405:1851-1864

Study type: Clinical trial
Study name: CheckMate 9DW
Phase: Phase 3
Design: Randomised (1:1), open-label trial, 163 centres in 25 countries; report of a preplanned interim analysis
Sample size: 668 patients (335 nivolumab + ipilimumab, 333 lenvatinib or sorafenib)
Source: Lancet · 2025
Trial registration: NCT04039607

In plain words

This study compared a combination of two immunotherapy drugs (nivolumab and ipilimumab) with the tablets commonly used at the time (lenvatinib or sorafenib) in advanced liver cancer. Overall, patients in the immunotherapy group lived longer, and after 3 years about 38% of them were alive (versus 24%). However, in the first 6 months deaths were more common in the immunotherapy group, and serious immune side effects can occur; so this treatment should be chosen carefully and given under the care of an experienced treatment team.

Key results

23.7 vs 20.6 months

Median overall survival

HR 0.79 (95% CI 0.65–0.96); p=0.018 (two-sided stratified log-rank); median follow-up 35.2 months

49% vs 39%

24-month overall survival

95% CI 44–55 vs 34–45

38% vs 24%

36-month overall survival

95% CI 32–43 vs 19–30

HR 1.65 (unfavourable for immunotherapy)

Death in the first 6 months

95% CI 1.12–2.43; thereafter HR 0.61 (0.48–0.77) in favour of nivolumab + ipilimumab

36.1% vs 13.2%

Objective response rate (independent review, RECIST 1.1)

Complete response 6.9% vs 1.8%; p<0.0001; median duration of response 30.4 vs 12.9 months; FDA label

Drugs in this study:Lenvatinib (Lenvima)Nivolumab (Opdivo)Sorafenib (Nexavar)Ipilimumab (Yervoy)

Dose and schedule cards

Nivolumab + ipilimumab (CheckMate 9DW)

Unresectable or metastatic HCC, no prior systemic therapy; in the trial: Child-Pugh A and ECOG 0–1On the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Unresectable or metastatic HCC, no prior systemic therapy; in the trial: Child-Pugh A and ECOG 0–1

Drug	Dose	Route	Schedule
Induction: up to 4 doses
Nivolumab	1 mg/kg	IV, 30-min infusion	Day 1, every 3 weeks
Ipilimumab	3 mg/kg	IV, 30-min infusion	Day 1, immediately after nivolumab
Maintenance
Nivolumab	240 mg every 2 weeks or 480 mg every 4 weeks	IV, 30-min infusion	After completion of the combination doses (in the trial: 480 mg every 4 weeks)

Cycle length: 21 days during induction; then 14 or 28 days
Duration: Nivolumab monotherapy until progression, intolerable toxicity or a maximum of 2 years

The trial excluded patients with active autoimmune disease, hepatic encephalopathy within the past 12 months, platelets below 60,000, clinically significant ascites, or HBV and HCV (or HBV and HDV) coinfection; endoscopy before enrollment was not mandatory. The excess of deaths in the first 6 months and the 12 treatment-related deaths in the combination arm make careful patient selection essential.

On the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Unresectable or metastatic hepatocellular carcinoma (CheckMate 9DW)

First line or after sorafenibOn the page “Ipilimumab (Yervoy)” · Other cancers, with nivolumab (FDA label, revised 08/2026)

First line or after sorafenib

Drug	Dose	Route	Schedule
Combination: up to 4 doses
Nivolumab	1 mg/kg	IV, 30-minute infusion	Day 1 every 3 weeks (given first)
Ipilimumab	3 mg/kg	IV, 30-minute infusion	Same day, straight after nivolumab
Maintenance
Nivolumab	240 mg every 2 weeks or 480 mg every 4 weeks	IV, 30-minute infusion	After the combination doses

Cycle length: 21 days, then 14 or 28 days
Duration: Nivolumab until progression, unacceptable toxicity or a maximum of 2 years

On the page “Ipilimumab (Yervoy)” · Other cancers, with nivolumab (FDA label, revised 08/2026)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Nivolumab + ipilimumab

Nivolumab 1 mg/kg IV infusion over 30 minutes + ipilimumab 3 mg/kg IV infusion over 30 minutes, every 3 weeks for up to 4 doses; then nivolumab monotherapy 480 mg IV over 30 minutes every 4 weeks. Total treatment until disease progression, unacceptable toxicity or a maximum of 2 years. Patients who stopped the combination because of an adverse event attributed to ipilimumab could continue nivolumab monotherapy.

2Lenvatinib or sorafenib (investigator's choice)

At the investigator's choice: lenvatinib 8 mg orally daily (body weight less than 60 kg) or 12 mg daily (body weight 60 kg or more), or sorafenib 400 mg orally twice daily. Of the treated patients in this group, 85% received lenvatinib and 15% sorafenib.

Source of the regimen details: Abstract of the paper (Lancet 2025); FDA label for Opdivo (openFDA/DailyMed, CHECKMATE-9DW study section: infusion duration, maximum 2 years, continuation of nivolumab monotherapy)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 years or older with unresectable or metastatic HCC and no previous systemic therapy, with at least one untreated measurable lesion per RECIST 1.1, a Child-Pugh score of 5 or 6 and ECOG performance status 0 or 1. According to the FDA label: histological confirmation was required and endoscopy before enrolment was not mandatory; exclusion criteria were active autoimmune disease, brain or leptomeningeal metastases, hepatic encephalopathy in the past 12 months, platelet count below 60 × 10⁹/L, clinically significant ascites, need for systemic immunosuppression, HIV, and active co-infection with HBV and HCV or HBV and HDV. In practice, the Child-Pugh score was 5 in 77% of patients, 6 in 20% and 7 in 3%.

Endpoints

Primary endpoint: overall survival in all randomised patients.

Other endpoints: objective response rate and duration of response by blinded independent central review per RECIST 1.1 (FDA label); safety was an exploratory endpoint.

Safety and side effects

Grade 3–4 treatment-related adverse events occurred in 137 (41%) of 332 patients in the nivolumab + ipilimumab group and 138 (42%) of 325 patients in the lenvatinib or sorafenib group. 12 deaths were attributed to nivolumab + ipilimumab and 3 deaths to lenvatinib or sorafenib.

According to the FDA label (nivolumab + ipilimumab group): serious adverse events 53%; serious hepatic adverse events 17% (grade 3–4 in 16%; including immune-mediated hepatitis 3% and hepatic failure 2.4%); fatal adverse events 3.6% (4 cases of immune-mediated or autoimmune hepatitis and 4 cases of hepatic failure); permanent discontinuation of nivolumab because of an adverse event 27% and interruption 62%. Regular monitoring of liver tests is essential.

Clinical significance and place in guidelines

Based on this study, the FDA approved nivolumab + ipilimumab in 2025 for first-line treatment of unresectable or metastatic HCC. This regimen is the third immunotherapy combination with an overall survival advantage in the first line (after atezolizumab + bevacizumab and STRIDE). The higher risk of early death and the treatment-related deaths highlight the importance of careful patient selection. Approval status with other regulators and its exact place in current guidelines should be checked against official sources.

Limitations

Open-label design; report based on an interim analysis; more deaths in the first 6 months with immunotherapy and more treatment-related deaths (12 versus 3); only Child-Pugh 5 or 6 patients enrolled; the control group received tyrosine kinase inhibitors rather than the immunotherapy combinations that are now the first-line standard.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.