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

医学 恶心 内科学 不利影响 胃肠病学 实体瘤疗效评价标准 酪氨酸激酶抑制剂 肺癌 队列 免疫组织化学 肿瘤科 呕吐 便秘 癌症 进行性疾病 化疗
作者
Eric Angevin,Gianluca Spitaleri,Jordi Rodón,Katia Dotti,Nicolás Isambert,Stefania Salvagni,Víctor Moreno,Sylvie Assadourian,Corinne Gomez,Marzia Harnois,Antoine Hollebecque,Analía Azaro,Alice Hervieu,Karim Rihawi,Filippo de Marinis
出处
期刊:European Journal of Cancer [Elsevier BV]
卷期号:87: 131-139 被引量:37
标识
DOI:10.1016/j.ejca.2017.10.016
摘要

PurposeDysregulated 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.MethodsThis 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.ResultsIn 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.ConclusionThe 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
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