In the phase III RESORCE trial reported in The Lancet, Jordi Bruix, MD, Head of the Barcelona Clinic Liver Cancer Group, University of Barcelona, and colleagues found that regorafenib (Stivarga) improved overall survival vs placebo in patients with hepatocellular carcinoma who had progressed on sorafenib (Nexavar) treatment.1
In this double-blind trial, 573 patients from 152 sites in 21 countries were randomized 2:1 between May 2013 and December 2015 to receive best supportive care plus regorafenib at 160 mg/d (n = 379) or placebo (n = 194) during weeks 1 to 3 of 4-week cycles. Eligible patients had Barcelona Clinic Liver Cancer stage B or C disease; could not benefit from resection, local ablation, or chemoembolization; had tolerated sorafenib at ≥ 400 mg/d for at least 20 of the past 28 days of treatment; had progressed on sorafenib; and had Child-Pugh A liver function. Randomization was stratified by geographic region, Eastern Cooperative Oncology Group (ECOG) performance status, macrovascular invasion, extrahepatic disease, and alpha-fetoprotein level. The primary endpoint was overall survival analyzed by intent to treat.
In the regorafenib and placebo groups, median age was 64 and 62 years, 88% in both groups were male, 38% in both groups were from Asia, ECOG performance status was 0 for 65% and 67% and 1 for 35% and 33%, 29% and 28% had macrovascular invasion, 70% and 76% had extrahepatic disease, and 43% and 45% had an alpha-fetoprotein level ≥ 400 ng/mL.
Improved Overall Survival
Median follow-up was 7.0 months. Median overall survival was 10.6 months (95% confidence interval [CI] = 9.1–12.1 months) in the regorafenib group vs 7.8 months (95% CI = 6.3–8.8 months) in the placebo group (hazard ratio [HR] = 0.63, P < .0001). The benefit of regorafenib was consistent across stratification factors and other subgroups. Median progression-free survival on modified Response Evaluation Criteria in Solid Tumors was 3.1 months vs 1.5 months (HR = 0.46, P < .0001), and median time to disease progression was 3.2 months vs 1.5 months (HR = 0.44, P < .0001). An objective response occurred in 11% (including 2 complete responses) vs 4%, and disease control rates were 65% vs 36%, respectively.
The most common adverse events of any grade in the regorafenib group were hand-foot skin reaction (53% vs 8% in placebo group), diarrhea (41% vs 15%), fatigue (40% vs 32%), hypertension (31% vs 6%), and anorexia (31% vs 15%). Grade 3 or 4 adverse events occurred in 67% vs 39%, with the most common clinically relevant events being hypertension (15% vs 5%), hand-foot skin reaction (13% vs 1%), fatigue (9% vs 5%), and diarrhea (3% vs 0%). Serious adverse events occurred in 44% vs 47% and were considered related to study treatment in 10% vs 3%. Adverse events led to treatment interruption or dose reduction in 68% vs 31% and treatment discontinuation in 25% vs 19%. Seven deaths in the regorafenib group and two deaths in the placebo group were considered related to study treatment.
The investigators concluded: “Regorafenib is the only systemic treatment shown to provide survival benefit in [hepatocellular carcinoma] patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib.” ■
Disclosure: This study was funded by Bayer. For full disclosures of the study authors, visit www.thelancet.org.
1. Bruix J, Qin S, Merle P, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389:56-66, 2017.
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