There are no proven or approved second-line systemic treatment options for HCC. We evaluated regorafenib, an oral multikinase inhibitor, in patients with HCC who had disease progression on sorafenib.
Adults with BCLC stage B or C HCC who had radiological progression on sorafenib, Child-Pugh A liver function, and ECOG PS 0–1 were randomized 2:1 to regorafenib 160 mg/day or placebo on weeks 1–3 of each 4-week cycle until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). HRQoL was assessed by the FACT-Hep and EQ-5D questionnaires.
A total of 573 patients were randomized (regorafenib 379; placebo 194) and baseline characteristics were balanced. The regorafenib group had a 37% reduction in the risk of death (HR 0.63; 95%CI 0.50–0.79; p < 0.001); median OS (regorafenib vs placebo) was 10.6 vs 7.8 months. Regorafenib improved progression-free survival (HR 0.46; 95%CI 0.37–0.56; p < 0.001), time to progression (HR 0.44; 95%CI 0.36–0.55; p < 0.001), and the disease control rate (65.2% vs 36.1%; p < 0.001). Rates of grade ≥3 adverse events were 79.7% with regorafenib and 58.5% with placebo. Most common grade ≥3 adverse events occurring more frequently with regorafenib included hypertension (15.2% vs 4.7%), hand–foot skin reaction (12.6% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0%). The EQ-5D index, EQ-5D VAS, and FACT-G scores were similar in the treatment groups (Table). Although the FACT-Hep total score favored placebo, the difference did not meet the established minimally important threshold of 8–9 points.
|Least square mean (LSM) time-adjusted AUC (95% CI)||Regorafenib||Placebo||P-value|
|EQ-5D index||0.76 (0.75–0.78)||0.77 (0.75–0.79)||0.47|
|EQ-5D visual analogue scale (VAS)||71.68 (70.46–72.90)||73.45 (71.84–75.06)||0.06|
|Functional Assessment of Cancer Therapy-General (FACT-G)||75.14 (74.12–76.16)||76.55 (75.20–77.90)||0.07|
|FACT-Hep total||129.31 (127.84–130.79)||133.17 (131.21–135.12)|
Regorafenib significantly improved OS in patients with HCC who progressed during sorafenib treatment. Adverse events were consistent with the known safety profile of regorafenib with no clinically meaningful differences in HRQoL between groups.
Clinical trial identification
Clinicaltrials.gov ID: NCT01774344
Legal entity responsible for the study
J. Bruix: Advisory board membership: Bayer, BMS, Arqule, Roche, Gilead, AbbVie, Terumo, BTG, Kowa, Glaxo, Novartis Corporate-sponsored research: Bayer. G. Bodoky: I am advisory board member of: Novartis, Bayer, Roche, Janssen, Pfizer. O. Rosmorduc: One-time fee or honoraria from Bayer, Sirtex, Ipsen and BMS. V. Breder: Honoraria for lectures - Roche, Boeringher, Lilly, Astra Zeneca, BMS, MSD, Novartis. R. Gerolami: Member of an advisory board for Bayer. P.J. Ross: Advisory Boards: Bayer, Celgene, Baxalta (now Shire), BMS, Amgen Travel/meeting attendance support: Bayer, Amgen, Celgene, Merck Serono Speakers Bureau: Merck Serono, Celgene, Roche, Sirtex Grant funding for Research: Sanofi. J-P. Bronowicki: Membership on an advisory board: yes, Bayer Corporate; sponsored research: yes Grant to my institution for phase II or III studies: Bayer. I. Ollivier-Hourmand: I disclose financial support from Bayer for a medical congress but no other conflict or interest in relation with this work. M. Kudo: Lecture: Bayer, Kowa, Taiho Grant: Chugai, Otsuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai. M-A. Leberre, A. Baumhauer, G. Meinhardt: Employee of Bayer. All other authors have declared no conflicts of interest.