LBA-3 CheckMate 459: Long-term (minimum follow-up 33.6 months) survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma

Abstract

Patients with advanced hepatocellular carcinoma (aHCC) not amenable to surgical resection or locoregional therapy may be treated with multitargeted kinase inhibitors or immuno-oncology–based combination therapy. Sorafenib is approved as first-line (1L) therapy but provides only a modest survival benefit. Despite approved 1L therapies for aHCC, there remains an unmet need to prolong survival while improving treatment tolerability. The phase 3 CheckMate 459 study compared 1L nivolumab versus sorafenib in patients with aHCC; initial efficacy and safety data were previously presented (Yau et al. ESMO 2019; NCT02576509). The protocol-defined statistical significance threshold for overall survival (OS) was not met, although nivolumab showed clinical benefit. Here, we present long-term follow-up results from CheckMate 459. In CheckMate 459, 743 systemic therapy–naive patients ≥ 18 years of age with aHCC and Child-Pugh A liver function were randomized 1:1 to nivolumab (240 mg intravenous every 2 weeks; n = 371) or sorafenib (400 mg oral twice daily; n = 372). The primary endpoint was OS. Secondary endpoints were objective response rate and progression-free survival by blinded independent central review per Response Evaluation Criteria in Solid Tumors v1.1; efficacy by programmed death ligand 1 (PD-L1) tumor cell expression; and safety. At a minimum follow-up of 33.6 months, nivolumab demonstrated a clinically meaningful improvement in OS versus sorafenib (median OS, 16.4 months [95% CI, 14.0–18.5] vs 14.8 months [95% CI, 12.1–17.3], respectively; hazard ratio [HR], 0.85 [95% CI, 0.72–1.00]; nominal P value = 0.0522). The 33-month OS rates for nivolumab and sorafenib were 29% (95% CI, 25–34) and 21% (95% CI, 17–25), respectively. A consistent benefit was observed with nivolumab regardless of baseline PD-L1 expression (PD-L1 ≥ 1% HR, 0.80 [95% CI, 0.54–1.17]; PD-L1 < 1% HR, 0.84 [95% CI, 0.70–1.01]). Median OS (mOS) in patients with PD-L1 ≥ 1% was longer with nivolumab versus sorafenib (16.1 months [95% CI, 8.4–22.3] vs 8.6 months [95% CI, 5.7–16.3], respectively). Among patients with hepatitis C virus (HCV) and hepatitis B virus (HBV) etiology, mOS was numerically longer with nivolumab versus sorafenib (17.5 vs 12.7 months; HR, 0.72 [95% CI, 0.51–1.02] for HCV and 16.1 vs 10.4 months; HR 0.79 [95% CI, 0.59–1.07] for HBV, respectively). Nivolumab demonstrated greater liver function preservation over time than sorafenib as evidenced by albumin-bilirubin levels and Child-Pugh scores. Seven patients (2%) in the nivolumab arm and 77 patients (21%) in the sorafenib arm received subsequent immuno-oncology therapy. Nivolumab demonstrated a more favorable safety profile compared with sorafenib, with grade 3–4 treatment-related adverse events occurring in 82 patients (22.3%) and 180 patients (49.6%), respectively. At a minimum follow-up of 33.6 months, 1L nivolumab monotherapy continued to demonstrate clinically meaningful survival benefit in aHCC. Nivolumab had a more favorable and manageable safety profile and greater preservation of liver function over time compared with sorafenib, consistent with previous reports, with no new or unexpected safety signals observed.