Jordi Bruix1, Shukui Qin2, Philippe Merle3, Alessandro Granito4, Yi-Hsiang Huang5, György Bodoky6, Marc Pracht7, Osamu Yokosuka8, Olivier Rosmorduc9, Valeriy Breder10, René Gerolami11, Gianluca Masi12, Paul J Ross13, Tianqiang Song14, Jean-Pierre Bronowicki15, Isabelle Ollivier-Hourmand16, Masatoshi Kudo17, Ann-Lii Cheng18, Josep M Llovet19, Richard S Finn20, Marie-Aude LeBerre21, Annette Baumhauer22, Gerold Meinhardt23, Guohong Han24. 1. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, IDIBAPS-Hospital Clínic de Barcelona, CIBERehd, Universitat de Barcelona, Catalonia, Spain. Electronic address: jbruix@clinic.ub.es. 2. Chinese People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing, China. 3. Groupement Hospitalier Lyon Nord, Hepatology Unit, Lyon, France. 4. Department of Medical and Surgical Sciences, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy. 5. Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. 6. St Laszlo Teaching Hospital, Budapest, Hungary. 7. Service d'Oncologie Médicale, Centre Eugène Marquis, Rennes, France. 8. Department of Gastroenterology and Nephrology, Chiba University, Chiba, Japan. 9. Department of Hepatology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris and Université Pierre et Marie Curie, Sorbonne Universités, Paris, France. 10. Russian Cancer Research Center n.a.N.Blokhin, Moscow, Russia. 11. CHU Timone, Université de la Méditerranée, Marseille, France. 12. Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. 13. King's College Hospital NHS Foundation Trust, London, UK. 14. Tianjin Medical University Cancer Hospital, Tianjin, China. 15. INSERM 954, CHU de Nancy, Université de Lorraine, Nancy, France. 16. Service d'Hépatogastroentérologie, CHU, Caen, France. 17. Kindai University Faculty of Medicine, Osaka, Japan. 18. Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan. 19. Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, IDIBAPS-Hospital Clínic de Barcelona, CIBERehd, Universitat de Barcelona, Catalonia, Spain; Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. 20. Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 21. Bayer HealthCare SAS, Loos, France. 22. Bayer Pharmaceuticals, Bayer Vital GmbH, Leverkusen, Germany. 23. Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA. 24. The First Affiliated Hospital (Xijing Hospital) of the Fourth Military Medical University, Xi'an, China.
Abstract
BACKGROUND: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. METHODS: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by 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 α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. FINDINGS:Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 receivedregorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) 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. FUNDING: Bayer.
RCT Entities:
BACKGROUND: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment. METHODS: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by 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 α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344. FINDINGS: Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) 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. FUNDING: Bayer.
Authors: Ying Fu; Daniel J Urban; Roger R Nani; Yi-Fan Zhang; Nan Li; Haiying Fu; Hamzah Shah; Alexander P Gorka; Rajarshi Guha; Lu Chen; Matthew D Hall; Martin J Schnermann; Mitchell Ho Journal: Hepatology Date: 2019-02-19 Impact factor: 17.425
Authors: Michelle Dow; Rachel M Pyke; Brian Y Tsui; Ludmil B Alexandrov; Hayato Nakagawa; Koji Taniguchi; Ekihiro Seki; Olivier Harismendy; Shabnam Shalapour; Michael Karin; Hannah Carter; Joan Font-Burgada Journal: Proc Natl Acad Sci U S A Date: 2018-10-04 Impact factor: 11.205