Lorenza Rimassa1, Eric Assenat2, Markus Peck-Radosavljevic3, Marc Pracht4, Vittorina Zagonel5, Philippe Mathurin6, Elena Rota Caremoli7, Camillo Porta8, Bruno Daniele9, Luigi Bolondi10, Vincenzo Mazzaferro11, William Harris12, Nevena Damjanov13, Davide Pastorelli14, María Reig15, Jennifer Knox16, Francesca Negri17, Jörg Trojan18, Carlos López López19, Nicola Personeni20, Thomas Decaens21, Marie Dupuy2, Wolfgang Sieghart22, Giovanni Abbadessa23, Brian Schwartz23, Maria Lamar23, Terri Goldberg24, Dale Shuster24, Armando Santoro25, Jordi Bruix26. 1. Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy. 2. Service d'Oncologie Médicale, CHRU Saint Eloi, Montpellier, France. 3. Department of Internal Medicine III, Section of Gastroenterology/Hepatology, Medizinische Universitaet Wien, Wien, Austria; Department of Internal Medicine and Gastroenterology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria. 4. Centre Eugène Marquis et CH Saint Malo, Rennes, France. 5. Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy. 6. Service des Maladies de l'Appareil Digestif, Hôpital Claude Huriez, Lille Cedex, France. 7. Oncologia Medica, AO Papa Giovanni XXIII Hospital, Bergamo, Italy. 8. IRCCS San Matteo University Hospital Foundation, Pavia, Italy. 9. Department of Oncology and Medical Oncology Unit, AO G Rummo Hospital, Benevento, Italy. 10. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Center for Applied Biomedical Research, Sant'Orsola-Malpighi Hospital, Bologna, Italy. 11. Department of Gastro-Intestinal Surgery and Liver Transplantation, University of Milan, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 12. University of Washington School of Medicine, Seattle, WA, USA. 13. Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. 14. Department of Oncology, Santa Maria del Prato Hospital, Feltre, Italy. 15. Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 16. Solid Tumor Medical Oncology, McCain Centre for Pancreatic Cancer, University Health Network, Princess Margaret Cancer Center at the OPG, Toronto, ON, Canada. 17. Medical Oncology Unit, University Hospital of Parma, Parma, Italy. 18. Universitätsklinikum Frankfurt, Medizinische Klinik 1, Frankfurt, Germany. 19. Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain. 20. Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. 21. Institute for Advanced Biosciences-INSERM U1209, CNRS UMR 5309 and Department of Hepatogastroenterology Université Grenoble-Alpes, Grenoble, France; Clinique Universitaire d'Hépato-gastroentérologie, Pôle Digidune, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France. 22. Department of Internal Medicine III, Section of Gastroenterology/Hepatology, Medizinische Universitaet Wien, Wien, Austria. 23. ArQule Inc, Burlington, MA, USA. 24. Daiichi Sankyo Inc, Basking Ridge, NJ, USA. 25. Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy. 26. Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. Electronic address: jbruix@clinic.cat.
Abstract
BACKGROUND:Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated withsorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS:Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION:Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).
RCT Entities:
BACKGROUND:Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION:Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).
Authors: Aiwu Ruth He; Roger B Cohen; Crystal S Denlinger; Ashwin Sama; Ariel Birnbaum; Jimmy Hwang; Takami Sato; Nancy Lewis; Michelle Mynderse; Michele Niland; Jennifer Giles; Johan Wallin; Brian Moser; Wei Zhang; Richard Walgren; Elizabeth R Plimack Journal: Oncologist Date: 2019-03-04
Authors: B M Meyers; J Knox; R Cosby; J R Beecroft; K K W Chan; N Coburn; J Feld; D Jonker; A Mahmud; J Ringash Journal: Curr Oncol Date: 2020-05-01 Impact factor: 3.677