Eric Angevin1, Gianluca Spitaleri2, Jordi Rodon3, Katia Dotti4, Nicolas Isambert5, Stefania Salvagni6, Victor Moreno7, Sylvie Assadourian8, Corinne Gomez9, Marzia Harnois10, Antoine Hollebecque11, Analia Azaro12, Alice Hervieu13, Karim Rihawi14, Filippo De Marinis15. 1. Drug Development Department, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Université Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: eric.angevin@gustaveroussy.fr. 2. Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Electronic address: gianluca.spitaleri@ieo.it. 3. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, Barcelona, 08035, Spain. Electronic address: jrodon@vhio.net. 4. Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy. Electronic address: katia.dotti@istitutotumori.mi.it. 5. Centre Georges-François Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France. Electronic address: NIsambert@cgfl.fr. 6. Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: stefania.salvagni@aosp.bo.it. 7. START MADRID - FJD., Hospital Universitario Fundación Jiménez Díaz, vda. Reyes Católicos, 2, 28040, Madrid, Spain. Electronic address: Victor.Moreno@start.stoh.com. 8. SANOFI, 54, Rue La Boétie, 75008 Paris, France. Electronic address: Sylvie.Assadourian@sanofi.com. 9. SANOFI, 54, Rue La Boétie, 75008 Paris, France. Electronic address: Corinne.Gomez@sanofi.com. 10. SANOFI, 54, Rue La Boétie, 75008 Paris, France. Electronic address: Marzia.Harnois@sanofi.com. 11. Drug Development Department, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Université Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: Antoine.HOLLEBECQUE@gustaveroussy.fr. 12. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, Barcelona, 08035, Spain. Electronic address: aazaro@vhio.net. 13. Centre Georges-François Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France. Electronic address: ahervieu@cgfl.fr. 14. Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: karim.rihawi@aosp.bo.it. 15. Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Electronic address: filippo.demarinis@ieo.it.
Abstract
PURPOSE: Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. METHODS: This was a phase I dose-escalation (3 + 3 design [50-740 mg/m2]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. RESULTS: In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m2, five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. CONCLUSION: The MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01391533.
PURPOSE: Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. METHODS: This was a phase I dose-escalation (3 + 3 design [50-740 mg/m2]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. RESULTS: In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m2, five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. CONCLUSION: The MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01391533.
Authors: Siddhartha Devarakonda; Sumithra Sankararaman; Brett H Herzog; Kathryn A Gold; Saiama N Waqar; Jeffrey P Ward; Victoria M Raymond; Richard B Lanman; Aadel A Chaudhuri; Taofeek K Owonikoko; Bob T Li; John T Poirier; Charles M Rudin; Ramaswamy Govindan; Daniel Morgensztern Journal: Clin Cancer Res Date: 2019-07-12 Impact factor: 12.531
Authors: John H Strickler; Christel N Rushing; Hope E Uronis; Michael A Morse; Donna Niedzwiecki; Gerard C Blobe; Ashley N Moyer; Emily Bolch; Renee Webb; Sherri Haley; Ace J Hatch; Ivy P Altomare; Gary B Sherrill; David Z Chang; James L Wells; S David Hsu; Jingquan Jia; S Yousuf Zafar; Andrew B Nixon; Herbert I Hurwitz Journal: Oncologist Date: 2021-02-09
Authors: Edwin Choy; Gregory M Cote; M Dror Michaelson; Lori Wirth; Justin F Gainor; Alona Muzikansky; Lecia V Sequist; Ryan J Sullivan; Panagiotis M Fidias; Alice Shaw; Rebecca S Heist Journal: Oncologist Date: 2022-07-05 Impact factor: 5.837