Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking as the sixth most frequently diagnosed cancer and the third leading cause of cancer-related deaths worldwide, primarily attributed to its late-stage diagnosis, limited therapeutic options, and poor prognosis.^1-3 While tyrosine kinase inhibitors (TKIs) and anti-vascular endothelial growth factor (anti-VEGF) therapies are commonly used, their long-term efficacy is limited and clinical benefits are restricted to a subset of patients.^2,3 Nivolumab, a programmed cell death protein 1 (PD-1) immune checkpoint inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, are monoclonal antibodies that are proven to enhance antitumor immune response.^3,4 The United States (US) Food and Drug Administration (FDA) recently approved their combination for treating unresectable or metastatic HCC in patients who have not received prior systemic therapy, based on the results of phase 3 CheckMate 9DW trial.³ 

In advanced HCC, the tumor microenvironment fosters immune evasion by upregulating inhibitory pathways that suppress cytotoxic T-cell activity.² Nivolumab + ipilimumab enhance antitumor immune responses by blocking these inhibitory signals and restoring T-cell function.^3,4 Nivolumab + ipilimumab has demonstrated superior overall survival (OS) and durable responses compared to sorafenib in untreated advanced HCC.³ Based on these findings, the dual immunotherapy has been approved by the FDA as a first-line treatment for patients with unresectable or metastatic HCC without prior systemic therapy, offering a promising alternative to kinase inhibitor-based therapies.³ 

The CheckMate 9DW trial was a global, randomized, open-label phase 3 study that evaluated the efficacy and safety of nivolumab + ipilimumab vs. standard first-line treatments, lenvatinib or sorafenib, in patients with previously untreated advanced HCC.³ Eligible study participants were adults with histologically confirmed advanced HCC without prior systemic therapy.³ Patients were required to have at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, a Child-Pugh score of 5 or 6, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.³ A total of 668 patients from 163 sites in 25 countries were enrolled.³ Patients were randomized 1:1 to receive either nivolumab 1mg/kg + ipilimumab 3mg/kg every 3 weeks for four doses, followed by nivolumab 480mg monotherapy every 4 weeks, or investigator’s choice of either lenvatinib (8mg or 12mg daily depending on body weight) or oral sorafenib (400mg twice daily).³ The primary endpoint was OS.3 Secondary endpoints included objective response rate (ORR), duration of response (DoR) and time to symptom deterioration.³ Safety was assessed as an exploratory endpoint.³ 

At a median follow-up of 35.2 months, overall OS was significantly longer in the nivolumab + ipilimumab group compared with the lenvatinib or sorafenib group (23.7 months vs. 20.6 months; HR=0.79; 95% CI: 0.65-0.96; two-sided stratified log-rank p=0.018).³ OS rates at 24 and 36 months were also higher with nivolumab + ipilimumab (49% and 38%) vs. lenvatinib or sorafenib (39% and 24%), respectively.³ The ORR was 36% with nivolumab + ipilimumab and 13% with lenvatinib or sorafenib (p<0.001).³ Durable responses were observed with a median DoR of 30.4 months in the nivolumab + ipilimumab group compared to 12.9 months in the control group.³ Furthermore, 47% of responders in the nivolumab + ipilimumab group had an ongoing response at 36 months.³ 

The primary and secondary endpoint results were consistent across most subgroups, although early deaths within the first 6 months were higher in the nivolumab + ipilimumab arm (HR=1.65; 95% CI: 1.12-2.43).³ Long-term survival benefit was evident with sustained separation of OS curves favoring nivolumab + ipilimumab group thereafter (HR=0.61; 95% CI: 0.48-0.77).³ Safety profiles were comparable between treatment arms, with grade 3-4 treatment-related adverse events (TRAEs) in 41% of patients receiving nivolumab + ipilimumab and 42% of those receiving lenvatinib or sorafenib.³ Treatment-related deaths were reported in 12 patients in the nivolumab + ipilimumab group and three in the comparator group.³ No new safety signals were identified, and the safety profile remained manageable and aligned with prior reports of this regimen in second-line HCC and other indications.³ 

In summary, nivolumab + ipilimumab was shown to provide a significant OS benefit with a manageable safety profile in patients with previously unresectable HCC, supporting the dual immunotherapy as an important first-line treatment option and a viable alternative to existing TKIs.3