Reference Detail

Ref Type

Journal Article

PMID

(29145039)

Authors

Angevin E, Spitaleri G, Rodon J, Dotti K, Isambert N, Salvagni S, Moreno V, Assadourian S, Gomez C, Harnois M, Hollebecque A, Azaro A, Hervieu A, Rihawi K, De Marinis F

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	87		2017 12	131-139	Eur J Cancer

URL

Abstract Text

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.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.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.The MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC.NCT01391533.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SAR125844	SAR125844	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SAR125844		SAR-125844	MET Inhibitor 59	SAR125844 is a selective inhibitor of MET, which inhibits MET activation and downstream pathway signaling, and potentially results in decreased growth of MET-driven tumors (PMID: 25504634, PMID: 29145039, PMID: 29108334).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References