Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring <i>MET</i> Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Abstract

<b>Purpose:</b><i>MET</i> exon 14 deletion (<i>MET</i>ex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in <i>MET</i>ex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.<b>Experimental Design:</b> As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing <i>in vitro</i> and <i>in vivo</i> models and in glesatinib clinical trials.<b>Results:</b> Glesatinib inhibited MET signaling, demonstrated marked regression of <i>MET</i>ex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a <i>MET</i>ex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the <i>MET</i> activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. <i>In vivo</i> models exhibiting <i>MET</i>ex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a <i>MET</i>ex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a <i>MET</i> Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.<b>Conclusions:</b> Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. <i>Clin Cancer Res; 23(21); 6661-72. ©2017 AACR</i>.