Second-Line Regorafenib Boosts Advanced HCC Survival

Hepatocellular carcinoma patients who have failed sorafenib therapy can derive an overall survival benefit from regorafenib

medwireNews: A placebo-controlled trial finds that the oral multikinase inhibitor regorafenib prolongs overall survival (OS) in hepatocellular carcinoma (HCC) patients who have progressed during first-line treatment with sorafenib .

The RESORCE study is the first in almost a decade to show an OS benefit in this patient population, the team led by Jordi Bruix, from the University of Barcelona in Spain, notes in The Lancet, adding that the findings “represent a significant advance in addressing an unmet need in the treatment of HCC.”

The study authors continue: “All previous second-line trials of novel agents have failed; thus no effective systemic therapies after progression on sorafenib are currently available.”

Commentator Jean-Charles Nault, from Institut National de la Santé et de la Recherche Médicale in Paris, France, hopes that these “positive signals […] should encourage the scientific community to persist in the long and winding road toward finding a cure for HCC.”

The phase III, double-blind trial included 573 advanced HCC patients who had tolerated sorafenib (≥400 mg/day for at least 20 of the last 28 days of treatment) before experiencing radiological progression. Participants were randomly allocated to receive either regorafenib 160 mg/day for 3 weeks of each 4-week cycle or placebo, in both cases alongside best supportive care.

After a median follow-up of 7.0 months, OS was a median of 10.6 months for the 379 regorafenib-treated patients and 7.8 months for the 194 given placebo, giving a significant hazard ratio (HR) of 0.63.

This improvement in OS was accompanied by significantly longer median progression-free survival and time to progression in the regorafenib treatment arm, at 3.1 and 3.2 months, respectively, versus 1.5 months for both outcomes in the placebo arm.

The objective response and disease control rates were similarly higher among patients given regorafenib relative to placebo, at 11% versus 4% and 65% versus 36%, respectively.

Regorafenib-treated participants were more likely than their placebo-treated counterparts to experience grade 3 or 4 hypertension (15 vs 5%), hand–foot skin reaction (13 vs 1%), fatigue (9 vs 5%) and diarrhoea (3 vs 0%).

Furthermore, 54% of patients in the regorafenib group required a dose interruption or reduction as a result of drug-related toxicity, compared with 10% of those in the placebo group. The corresponding rates for discontinuation attributable to drug-related toxicity were 10% and 4%.

The study authors conclude: “These data underscore that prolonging exposure to multikinase inhibitors such as the sequence of sorafenib and regorafenib in conjunction with proper management of adverse events can lead to an extension in survival.”

However, Jean-Charles Nault wonders why “regorafenib [has] succeeded where other treatments failed?”, and cites one reason as the trial design.

“[The] selection of patients included in the RESORCE trial was rigorous, and included Child-Pugh A patients, with stratification on five factors, including metastasis and portal thrombosis, and exclusion of patients who had discontinued sorafenib due to intolerance”, he writes.

The commentator points out that as a result “the main area of uncertainty lies in the tolerance and efficacy of regorafenib in patients not tolerating sorafenib”, warranting further research in this subpopulation of patients.


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; Advance online publication 5 December 2016. doi:

Nault J-C. The end of almost 10 years of negative RCTs in advanced hepatocellular carcinoma.Lancet; Advance online publication 5 December 2016. doi:


medwireNews ( ) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016