Abstract
SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260–570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m2. Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m2 in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m2 has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer.
Highlights
IntroductionAberrant activation of the hepatocyte growth factor (HGF)/c-Met pathway has been observed in various solid tumors, including gastric cancer, most commonly via MET gene amplification
Interactions between the receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met), encoded by the MET proto-oncogene, and its ligand, the hepatocyte growth factor (HGF), trigger a broad spectrum of biologic processes involved in tumorigenesis [1].Aberrant activation of the HGF/c-Met pathway has been observed in various solid tumors, including gastric cancer, most commonly via MET gene amplification
No dose-limiting toxicities (DLTs) were observed in the dose-escalation phase, and 570 mg/m2 was selected as the recommended dose (RD) based on comparable exposure and safety in Asian and Western populations [9]
Summary
Aberrant activation of the HGF/c-Met pathway has been observed in various solid tumors, including gastric cancer, most commonly via MET gene amplification. A systematic review of 15 studies in gastric cancer showed that both Asian and Western patients with a high level of c-Met have significantly poorer outcomes than do those with low levels of c-Met [2]. Other studies have shown that MET gene amplification in gastric cancer is significantly associated with unfavorable clinical outcomes, including substantially shorter survival [3, 4]. SAR125844 (SAR) is a potent and highly selective, small-molecule c-Met kinase inhibitor. It has a halfmaximal inhibitory concentration of 4.2 nM and an inhibitory constant of 2.8 nM [8]. SAR had an acceptable toxicity profile [8]
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