Giorgio Scagliotti1, Joachim von Pawel2, Silvia Novello2, Rodryg Ramlau2, Adolfo Favaretto2, Fabrice Barlesi2, Wallace Akerley2, Sergey Orlov2, Armando Santoro2, David Spigel2, Vera Hirsh2, Frances A Shepherd2, Lecia V Sequist2, Alan Sandler2, Jeffrey S Ross2, Qiang Wang2, Reinhard von Roemeling2, Dale Shuster2, Brian Schwartz2. 1. Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ. giorgio.scagliotti@unito.it. 2. Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ.
Abstract
PURPOSE: Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety. RESULTS: The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%). CONCLUSION: E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
RCT Entities:
PURPOSE:Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety. RESULTS: The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%). CONCLUSION: E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
Authors: Osamu Tetsu; Matthew J Hangauer; Janyaporn Phuchareon; David W Eisele; Frank McCormick Journal: Chemotherapy Date: 2016-02-25 Impact factor: 2.544
Authors: James I Geller; John P Perentesis; Xiaowei Liu; Charles G Minard; Rachel A Kudgus; Joel M Reid; Elizabeth Fox; Susan M Blaney; Brenda J Weigel Journal: Pediatr Blood Cancer Date: 2017-04-27 Impact factor: 3.167
Authors: Magda Bahcall; Taebo Sim; Cloud P Paweletz; Jyoti D Patel; Ryan S Alden; Yanan Kuang; Adrian G Sacher; Nam Doo Kim; Christine A Lydon; Mark M Awad; Michael T Jaklitsch; Lynette M Sholl; Pasi A Jänne; Geoffrey R Oxnard Journal: Cancer Discov Date: 2016-09-30 Impact factor: 39.397