Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial
Mené dans 22 pays sur 743 patients atteints d'un carcinome hépatocellulaire de stade avancé (durées médianes de suivi : 15,2 et 13,4 mois), cet essai de phase III compare l'efficacité, du point de vue de la survie globale, et la toxicité du nivolumab et du sorafénib en traitement de première ligne
Background : Single-agent nivolumab showed durable responses, manageable safety, and promisingsurvival in patients with advanced hepatocellular carcinoma in the phase 1–2 CheckMate040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapyin the first-line setting for patients with advanced hepatocellular carcinoma. Methods : In this randomised, open-label, phase 3 trial done at medical centres across 22 countrie sand territories in Asia, Australasia, Europe, and North America, patients at least18 years old with histologically confirmed advanced hepatocellular carcinoma not eligiblefor, or whose disease had progressed after, surgery or locoregional treatment; withno previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class Aand Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardlessof viral hepatitis status were randomly assigned (1:1) via an interactive voice responsesystem to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400mg orally twice daily) until disease progression or unacceptable toxicity. The primaryendpoint was overall survival assessed in the intention-to-treat population. Safetywas assessed in all patients who received at least one dose of study drug. This completedtrial is registered with ClinicalTrials.gov, NCT02576509. Findings : Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment(nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7–28·0) for the nivolumab group and 13·4months (5·7–25·9) in the sorafenib group. Median overall survival was 16·4 months(95% CI 13·9–18·4) with nivolumab and 14·7 months (11·9–17·2) with sorafenib (hazardratio 0·85 [95% CI 0·72–1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-definedsignificance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-relatedadverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients inthe nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase(22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patientsreceiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in thenivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation : First-line nivolumab treatment did not significantly improve overall survival comparedwith sorafenib, but clinical activity and a favourable safety profile were observedin patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considereda therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenicdrugs are contraindicated or have substantial risks.
The Lancet Oncology , 2021