A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification

Eric Angevin, Gianluca Spitaleri, Jordi Rodon, Katia Dotti, Nicolas Isambert, Stefania Salvagni, Victor Moreno, Sylvie Assadourian, Corinne Gomez, Marzia Harnois, Antoine Hollebecque, Analia Azaro, Alice Hervieu, Karim Rihawi, Filippo De Marinis

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Pages (from-to)131-139
Number of pages9
JournalEuropean Journal of Cancer
Volume87
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • Advanced solid tumours
  • Dose escalation
  • MET-amplified
  • MET-inhibitor
  • NSCLC
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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