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

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

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: 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.
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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