First-line nivolumab does not improve overall survival (OS), compared with sorafenib, in patients with advanced hepatocellular carcinoma (HCC), according to phase 3 results published in The Lancet Oncology.

The phase 3 CheckMate 459 trial ( Identifier: NCT02576509) was designed to investigate nivolumab as a potential first-line treatment option to improve survival and provide a more tolerable safety profile than sorafenib in patients with advanced HCC.  

The study included 743 patients who were randomly assigned to receive nivolumab (240 mg intravenously every 2 weeks; 371 participants) or sorafenib (400 mg orally twice daily; 372 participants).

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At the primary analysis, there were 519 deaths — 244 in the nivolumab arm and 275 in the sorafenib arm.

At a minimum follow-up of 22.8 months, the median OS was 16.4 months in the nivolumab arm and 14.7 months in the sorafenib arm (hazard ratio, 0.85; 95% CI, 0.72-1.02; P =.075).

Although nivolumab did not meet the prespecified significance boundary for superior OS, a sustained separation of the Kaplan-Meier OS curves was observed, with a greater proportion of patients in the nivolumab arm surviving at 12 months, 24 months, and 33 months. This suggests that nivolumab may confer a survival benefit, but longer follow-up is needed, according to the researchers.

The 1-year OS rate was 60% in the nivolumab arm and 55% in the sorafenib arm. The 2-year OS rate was 37% and 33%, respectively.

The 1-year progression-free survival (PFS) rate was 22% in the nivolumab arm and 14% in the sorafenib arm. The 2-year PFS rate was 14% and 6%, respectively.

The most common grade 3 or higher treatment-related adverse events (TRAEs) — in the nivolumab and sorafenib arms, respectively — were palmar-plantar erythrodysesthesia (<1% vs 14%), AST increase (6% vs 14%), and hypertension (0% vs 7%). Serious TRAEs occurred in 12% of patients receiving nivolumab and 11% of those receiving sorafenib.

There were 4 treatment-related deaths in the nivolumab arm and 1 in the sorafenib arm. The causes of death in the nivolumab arm were liver failure (n=2), hepatotoxicity, and subarachnoid hemorrhage. The cause of death in the sorafenib arm was liver failure.

Based on these results, the researchers proposed that nivolumab might be considered an option for patients in whom tyrosine kinase inhibitors and anti-angiogenic drugs are contraindicated or pose substantial risks.

Disclosures: This research was supported by Bristol Myers Squibb in collaboration with Ono Pharmaceutical. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial. Published online December 13, 2021. doi:10.1016/S1470-2045(21)00604-5