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

Abstract

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 MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. 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 splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. 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 people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC. Results from an expansion cohort of the PROFILE 1001 trial describe the anti-tumor activity of crizotinib in people with non-small-cell lung cancer harboring a MET exon 14 alteration.