Background: There aren’t any systemic treating patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to evaluate the effectiveness and safety of regorafenib in patients with HCC who’ve progressed during sorafenib treatment.

Methods: Within this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (?Y400 mg/day for ?Y20 of last 4 weeks of treatment), progressed on sorafenib, coupled with Child-Pugh A liver function were enrolled. Participants were at random assigned (2:1) with a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and |¨¢-fetoprotein level to best supportive care plus dental regorafenib 160 mg or placebo once daily during days 1-3 of every 4-week cycle. Investigators, patients, and also the funder were masked to treatment assignment. The main endpoint was overall survival (understood to be time from randomisation to dying because of any cause) and analysed by intention to deal with. This trial is registered with ClinicalTrials.gov, number NCT01774344.

Findings: Between May 14, 2013, and 12 , 31, 2015, 843 patients were screened, who 573 were enrolled and randomised (379 to regorafenib and 194 to placebo population for effectiveness analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo population for safety analyses). Regorafenib improved overall survival having a hazard ratio of 0?¡è63 (95% CI 0?¡è50-0?¡è79 one-sided p<0?¡è0001) median survival was 10?¡è6 months (95% CI 9?¡è1-12?¡è1) for regorafenib versus 7?¡è8 months (6?¡è3-8?¡è8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.

Interpretation: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC 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.