A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor,in patients with advanced solid tumours with MET amplification
Affiliation:
1. Drug Development Department, Département d''Innovation Thérapeutique et des Essais Précoces (DITEP), Université Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France;2. Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy;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;4. Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy;5. Centre Georges-François Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France;6. Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy;7. START MADRID – FJD., Hospital Universitario Fundación Jiménez Díaz, vda. Reyes Católicos, 2, 28040, Madrid, Spain;8. SANOFI, 54, Rue La Boétie, 75008 Paris, France
Abstract:
PurposeDysregulated 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.MethodsThis 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.ResultsIn 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.ConclusionThe 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
