In CheckMate 459 study nivolumab monotherapy did not significantly prolong overall survival (OS) compared with sorafenib as first-line treatment for patients with advanced hepatocellular carcinoma. However, nivolumab showed durable clinical activity in terms of response frequency and durability, with encouraging long-term survival, a differentiated and favourable safety profile with no new safety signals. The findings are published on 13 December 2021 in The Lancet Oncology by Dr. Thomas Yau of the Department of Medicine, University of Hong Kong, Hong Kong SAR, China and colleagues.

The authors commented that since the CheckMate 459 commenced, several studies have investigated PD1 or PD-L1 inhibitors alone or in combination with other drugs as first-line therapy for advanced hepatocellular carcinoma with atezolizumab plus bevacizumab being currently the standard of care in that setting. Until 2020, the only approved first-line therapies for advanced hepatocellular carcinoma included the multikinase inhibitors sorafenib and lenvatinib.  However, treatment with these drugs results in a high proportion of treatment-related adverse events (TRAEs) which often require dose interruption or reduction.

Based on clinical activity of PD1 inhibitors in second-line treatment for advanced hepatocellular carcinoma, there is a strong rationale for their investigation in first-line setting. Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase I/II CheckMate 040 study.

The confirmatory phase III CheckMate 459 study investigated nivolumab monotherapy compared with sorafenib monotherapy in patients with advanced hepatocellular carcinoma in the first-line setting. In this randomised, open-label, phase III study conducted in 22 countries, patients with no previous systemic therapy for advanced hepatocellular carcinoma with Child-Pugh class A and ECOG performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned 1:1 to nivolumab or sorafenib until disease progression or unacceptable toxicity. The study primary endpoint was OS assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug.

In total, 743 patients were randomly assigned, 371 to nivolumab and 372 to sorafenib. Median OS was 16.4 months (95% confidence interval [CI] 13.9–18.4) with nivolumab and 14.7 months (11.9–17.2) with sorafenib (hazard ratio 0.85, 95% CI 0.72–1.02; p = 0·075). However, the protocol-defined significance level of p = 0.0419 was not reached.

The most common grade 3 or worse TRAEs were palmar-plantar erythrodysaesthesia (<1% in the nivolumab group versus 14% patients in the sorafenib group), aspartate aminotransferase increase (6% versus 4%), and hypertension (0 versus 7%). Serious TRAEs were reported in 12% patients receiving nivolumab and 11% patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were treatment related.

The study did not meet the prespecified boundary for significance for OS as the primary endpoint. However, improvement in response and sustained separation of the OS curves suggest a prolonged survival benefit with nivolumab at longer follow-up. Nivolumab had a manageable safety profile and no new safety signals were observed. The proportion of patients with grade 3–4 TRAEs and any-grade TRAEs leading to discontinuation was lower with nivolumab than with sorafenib.

The authors commented that based on the results from CheckMate 459, nivolumab monotherapy is included in the NCCN Clinical Practice Guidelines in the US as a first-line systemic therapy option for patients with Child-Pugh score of A or B who are ineligible for anti-angiogenic drugs or tyrosine kinase inhibitors.

The CheckMate 459 study was supported by Bristol Myers Squibb and Ono Pharmaceutical. The authors thanked Dako (an Agilent Technologies company) for collaborative development of the PD-L1 IHC 28-8 pharmDx assay.


Yau T, Park J-W, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. The Lancet Oncology; Published online 13 December 2021. DOI: