Multikinase Inhibitor Crizotinib Is Active in MET Exon 14–Altered Lung Cancer

Alterations affecting exon 14 of the proto-oncogene MET, encoding a receptor tyrosine kinase, have been identified as drivers of non–small cell lung cancer (NSCLC), and preclinical studies imply that these alterations may confer increased tumor susceptibility to MET inhibition. In a report from an expansion cohort of the phase I PROFILE 1001 trial, Drilon and colleagues detail preliminary results from sixty-nine patients with advanced NSCLC carrying alterations in MET exon 14 (as identified by DNA- or RNA-based next-generation sequencing)—largely former smokers with lung adenocarcinomas—treated with the multikinase inhibitor crizotinib. Among the 65 patients who were tumor-evaluable, the objective response rate (ORR) was 32%, with 3 patients (5%) exhibiting a complete response. Notably, the ORR was not affected by the by the type of MET exon 14 mutation or the copy number of MET. The median progression-free survival was 7.3 months, and the median overall survival at the time of the report was 20.5 months; however, these data were not complete due to the large number of surviving patients still being monitored in the follow-up period. Crizotinib was generally well tolerated in this cohort, and side effects were comparable with those of patients with NSCLC harboring rearrangements in ALK or ROS1, for whom crizotinib is already approved. The most common treatment-emergent adverse effects were edema, vision disorders, and gastrointestinal side effects, and 7% of patients permanently discontinued study treatment due to treatment-emergent adverse effects. As this was the first prospective trial to evaluate the activity of a MET inhibitor specifically in patients with NSCLC with MET exon 14 alterations, its results illustrate the potential value of clinical testing for such alterations and the need for further study of the possible role of alterations in MET exon 14 in response to crizotinib treatment.

Drilon A, Clark JW, Weiss J, Ou SI, Camidge DR, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med 2020;26:47–51.

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