Clinical trialPhase 3Liver cancer

Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

Lancet · 2017573 patients (379 regorafenib, 194 placebo)

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Lancet. 2017. 389:56-66

Study type: Clinical trial
Study name: RESORCE
Phase: Phase 3
Design: Randomised (2:1), double-blind, parallel-group, placebo-controlled trial at 152 centres in 21 countries
Sample size: 573 patients (379 regorafenib, 194 placebo)
Source: Lancet · 2017
Trial registration: NCT01774344

In plain words

This study looked at patients with advanced liver cancer whose disease had grown while on the oral drug sorafenib. Compared with a placebo, the oral drug regorafenib helped these patients live about 3 months longer on average (median 10.6 vs 7.8 months). High blood pressure, a skin reaction on the hands and feet, and tiredness were its main side effects.

Key results

10.6 vs 7.8 months

Median overall survival

HR 0.63 (95% CI 0.50–0.79); one-sided P<0.0001

3.1 vs 1.5 months

Median progression-free survival (mRECIST)

HR 0.46 (95% CI 0.37–0.56); p<0.0001; FDA label

11% vs 4%

Objective response rate (mRECIST)

By RECIST 1.1: 7% vs 3%; FDA label

Dose and schedule cards

Regorafenib (RESORCE)

Second-line after progression on sorafenib; patients who tolerated sorafenib (in the trial: Child-Pugh A, BCLC B or C)On the page “Liver cancer” · Advanced hepatocellular carcinoma: after progression

Second-line after progression on sorafenib; patients who tolerated sorafenib (in the trial: Child-Pugh A, BCLC B or C)

Drug	Dose	Route	Schedule
Regorafenib	160 mg (4 × 40-mg tablets)	Oral, after a low-fat meal	Once daily, days 1–21

Cycle length: Every 28 days (21 days on, 7 days off)
Duration: Until progression or intolerable toxicity

RESORCE excluded patients who had stopped sorafenib because of toxicity or who could not tolerate 400 mg daily.

Boxed warning for hepatotoxicity: monitor liver function before and during treatment. Dose reduction in 40-mg steps (120 mg, then 80 mg; lowest dose 80 mg); discontinue permanently for ALT/AST more than 20 times the upper limit of normal, ALT/AST more than 3 times with bilirubin more than 2 times, or intolerance of the 80-mg dose.

On the page “Liver cancer” · Advanced hepatocellular carcinoma: after progression

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Regorafenib

Regorafenib 160 mg (4 × 40 mg tablets) orally once daily on days 1 to 21 of each 28-day cycle (3 weeks on, 1 week off), with best supportive care, until clinical or radiological progression or unacceptable toxicity.

Per the FDA label: take after a low-fat meal (less than 600 calories and less than 30% fat); dose reduction in 40 mg steps (120 then 80 mg; lowest dose 80 mg per day); permanently discontinue for AST or ALT more than 20 times the upper limit of normal, or more than 3 times with bilirubin more than 2 times the upper limit of normal.

2Placebo

4 matching placebo tablets once daily in weeks 1 to 3 of each 4-week cycle, with best supportive care.

Source of the regimen details: Abstract of the paper (Lancet 2017); ClinicalTrials.gov NCT01774344 (arm descriptions); FDA label for Stivarga (DailyMed/openFDA, Dosage, Dose Modification and RESORCE study sections)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with BCLC stage B or C hepatocellular carcinoma who had tolerated sorafenib (at least 400 mg per day on at least 20 of the last 28 days of treatment), had progressed on sorafenib and had Child–Pugh A liver function. Per the FDA label, patients who had permanently stopped sorafenib because of toxicity or could not tolerate 400 mg daily were not enrolled; the median duration of prior sorafenib was 7.8 months, and ECOG was 0 in 66% and 1 in 34%.

Endpoints

Primary endpoint: overall survival (time from randomisation to death from any cause) in the intention-to-treat population.

Other outcomes (FDA label): progression-free survival, objective response rate and duration of response by RECIST 1.1 and mRECIST.

Safety and side effects

The most common clinically relevant grade 3 or 4 adverse events with regorafenib versus placebo: hypertension (15% versus 5%), hand–foot skin reaction (13% versus 1%), fatigue (9% versus 5%) and diarrhoea (3% versus 0). Drug-related deaths per investigator: 7 patients (2%) in the regorafenib group and 2 patients (1%) in the placebo group.

Per the FDA label: dose interruption was needed in 58.3% and dose reduction in 48% of patients in the regorafenib group (mostly for hand–foot syndrome); discontinuation due to adverse events 10.4% versus 3.6%.

Clinical significance and place in guidelines

The first second-line treatment with a survival benefit after sorafenib in HCC. The ESMO guideline (Asian-adapted version 2026) recommends regorafenib after sorafenib with level of evidence I, A.

Limitations

Only patients who had tolerated sorafenib and had Child–Pugh A liver function were enrolled; there are no data on use after first-line immunotherapy.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.