Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration

Abstract

<p class="first" id="P5"> <i>MET</i> exon 14 alterations are oncogenic drivers of non-small cell lung cancers (NSCLCs). ^{<a class="xref-link" href="#R1">1</a>} These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition. ^{<a class="xref-link" href="#R2">2</a>} Crizotinib is a multikinase inhibitor with potent activity against MET. ^{<a class="xref-link" href="#R3">3</a>} The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring <i>MET</i> exon 14 alterations in an expansion cohort of an open-label phase 1 study of crizotinib ( <a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT00585195" id="d934346e355" target="xrefwindow">NCT00585195</a>). The confirmed objective response rate was 32% (95% confidence interval [CI], 21–45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by <i>MET</i> exon 14 alteration splice site region and mutation type, concurrent increased <i>MET</i> copy number, or the detection of a <i>MET</i> exon 14 alteration in ctDNA. The median duration of response was 9.1 months (95% CI, 6.4–12.7). The median progression-free survival was 7.3 months (95% CI, 5.4–9.1). <i>MET</i> exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in patients with <i>MET</i> exon 14-altered lung cancers and adds to an expanding list of genomically-driven therapies for oncogenic subsets of NSCLC. </p>