In a phase III trial (CheckMate 9DW) reported in The Lancet, Yau et al evaluated whether first-line nivolumab plus ipilimumab improved overall survival vs investigator's choice of lenvatinib or sorafenib in patients with unresectable hepatocellular carcinoma.
Study Details
In the open-label trial, 668 patients from 25 countries in Asia, Australia, Europe, North America, and South America were randomly assigned between January 2020 and November 2021 to receive nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for up to four doses, followed by nivolumab at 480 mg every 4 weeks (n = 335); or lenvatinib at 8 or 12 mg daily (depending on bodyweight) or sorafenib at 400 mg twice daily (n = 333; 85% lenvatinib and 15% sorafenib). Treatment was continued until progression (or beyond progression if clinical benefit was still observed) or unacceptable toxicity. The primary endpoint was overall survival.
Key Findings
Prior to crossing the Kaplan-Meier curves at 6 months, overall survival was poorer in the nivolumab/ipilimumab group vs the lenvatinib or sorafenib group (hazard ratio [HR] = 1.65, 95% confidence interval [CI] = 1.12–2.43). Thereafter, a sustained separation of curves was observed favoring nivolumab/ipilimumab (HR = 0.61, 95% CI = 0.48–0.77).
After a median follow-up of 35.2 months (interquartile range = 31.1–39.9 months), median overall survival was 23.7 months (95% CI = 18.8–29.4 months) among patients who received nivolumab/ipilimumab vs 20.6 months (95% CI = 17.5–22.5 months) among those who received lenvatinib or sorafenib (HR = 0.79, 95% CI = 0.65–0.96, P = .018). Rates at 24 and 36 months were 49% vs 39% and 38% vs 24%. Post hoc analysis showed significant benefit of nivolumab/ipilimumab vs both lenvatinib (HR = 0.77, 95% CI = 0.62–0.95) and sorafenib (HR = 0.42, 95% CI = 0.24–0.73).
Median progression-free survival was 9.1 months in the nivolumab/ipilimumab group vs 9.2 months in the lenvatinib or sorafenib group (HR = 0.87, 95% CI = 0.72–1.06). Subsequent systemic anticancer therapy was received by 38% vs 52% of patients, including immunotherapy in 13% vs 35%.
Grade 3 or 4 treatment-related adverse events occurred in 41% of the nivolumab/ipilimumab group and 42% of the lenvatinib or sorafenib group; the most common were increased aspartate transaminase (6%), increased alanine transaminase (5%), and increased lipase (5%) in the nivolumab/ipilimumab group and hypertension (12%) and proteinuria (5%) in the lenvatinib or sorafenib group. Treatment-related death occurred in 12 patients in the nivolumab/ipilimumab group (due to immune-mediated hepatitis in four patients, hepatic failure in three, and hepatic insufficiency, decompensated cirrhosis, diarrhea-colitis, autoimmune hemolytic anemia, and dysautonomia in one patient each) and in three patients in the lenvatinib or sorafenib group (due to hepatorenal syndrome, ischemic stroke, and acute kidney injury in one patient each).
The investigators concluded: “Nivolumab plus ipilimumab showed a significant overall survival benefit versus lenvatinib or sorafenib and manageable safety in patients with previously untreated unresectable hepatocellular carcinoma. These results support nivolumab plus ipilimumab as a first-line treatment in this setting.”
Peter R. Galle, MD, of the University Medical Center, Mainz, Germany, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of all study authors, visit thelancet.com.
