Antitumor Activity of Crizotinib in Lung Cancers Harboring a MET Exon 14 Alteration

MET exon 14 alterations are oncogenic drivers of non-small cell lung cancers (NSCLCs).(1) These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition.(2) Crizotinib is a multikinase inhibitor with potent activity against MET.(3) The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations in an expansion cohort of an open-label phase 1 study of crizotinib (NCT00585195). 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 MET exon 14 alteration splice site region and mutation type, concurrent increased MET copy number, or the detection of a MET 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). MET 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 MET exon 14-altered lung cancers and adds to an expanding list of genomically-driven therapies for oncogenic subsets of NSCLC.