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

  • Eur J Cancer. 2017 Dec:87:131-139. doi: 10.1016/j.ejca.2017.10.016.
Eric Angevin  1 ,  Gianluca Spitaleri  2 ,  Jordi Rodon  3 ,  Katia Dotti  4 ,  Nicolas Isambert  5 ,  Stefania Salvagni  6 ,  Victor Moreno  7 ,  Sylvie Assadourian  8 ,  Corinne Gomez  9 ,  Marzia Harnois  10 ,  Antoine Hollebecque  11 ,  Analia Azaro  12 ,  Alice Hervieu  13 ,  Karim Rihawi  14 ,  Filippo De Marinis  15
Affiliations
  • 1. Drug Development Department, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Université Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: [email protected].
  • 2. Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Electronic address: [email protected].
  • 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: [email protected].
  • 4. Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy. Electronic address: [email protected].
  • 5. Centre Georges-François Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France. Electronic address: [email protected].
  • 6. Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: [email protected].
  • 7. START MADRID - FJD., Hospital Universitario Fundación Jiménez Díaz, vda. Reyes Católicos, 2, 28040, Madrid, Spain. Electronic address: [email protected].
  • 8. SANOFI, 54, Rue La Boétie, 75008 Paris, France. Electronic address: [email protected].
  • 9. SANOFI, 54, Rue La Boétie, 75008 Paris, France. Electronic address: [email protected].
  • 10. SANOFI, 54, Rue La Boétie, 75008 Paris, France. Electronic address: [email protected].
  • 11. Drug Development Department, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Université Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: [email protected].
  • 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: [email protected].
  • 13. Centre Georges-François Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France. Electronic address: [email protected].
  • 14. Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: [email protected].
  • 15. Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Electronic address: [email protected].
PMID: 29145039 DOI: 10.1016/j.ejca.2017.10.016
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.

Keywords
Advanced solid tumours; Dose escalation; MET-amplified; MET-inhibitor; NSCLC; Phase I.
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