期刊
EUROPEAN JOURNAL OF CANCER
卷 87, 期 -, 页码 131-139出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2017.10.016
关键词
MET-inhibitor; Advanced solid tumours; NSCLC; MET-amplified; Phase I; Dose escalation
类别
资金
- Sanofi
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/m(2)]) 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/m(2) 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/m(2), 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/m(2); SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. (C) 2017 The Author(s). Published by Elsevier Ltd.
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