MET alterations leading to exon 14 skipping occur in approximately 4% of lung carcinomas, resulting in MET activation and sensitivity to MET inhibitors in vitro.1 Crizotinib, initially developed as a MET inhibitor, is currently approved for the treatment of ALK-positive non–small-cell lung cancer (NSCLC) and has demonstrated activity in tumors harboring METexon 14 alterations. Drilon and colleagues evaluated crizotinib antitumor activity and safety in patients with advanced MET exon 14–altered NSCLC, enrolled into an expansion cohort of the ongoing phase 1 PROFILE 1001 study (NCT00585195).2 Patients received crizotinib at a starting dose of 250 mg twice daily. Responses were assessed using RECIST v1.0 criteria. A total of 21 patients with MET exon 14–altered NSCLC had enrolled and 18 were response-evaluable. Two patients discontinued treatment (1 due to an adverse event [AE], 1 preferred another treatment formulation). Tumor histology in these patients was as follows: 71% adenocarcinoma, 18% sarcomatoid adenocarcinoma, 6% adenosquamous carcinoma, and 6% squamous-cell carcinoma. Of these, 65% were former smokers and 35% were never-smokers. The duration of treatment ranged from 0.5 to 9.1+ months, with 88% of patients still receiving treatment as of this report.
The overall response rate was 44%, all with confirmed partial remissions (PRs; all seen at the first scheduled tumor assessment at 8 weeks); there were 5 unconfirmed complete responses/PRs. Median progression-free survival could not be calculated, with no deaths or progressive disease by the data cut-off. Treatment-related AEs (TRAEs) were reported in 82% of patients; the most common were edema (35%), nausea (35%), vision disorder (29%), bradycardia (24%), and vomiting (24%). Most TRAEs were grade 1/2 in severity. One grade 3 TRAE (edema) and no grade 4/5 TRAEs were reported. The authors concluded that crizotinib has antitumor activity in patients with MET exon 14–altered NSCLC. The drug had a generally tolerable AE profile, consistent with that previously reported for patients with ALK-positive or ROS1-rearranged NSCLC. It was recommended that MET exon 14 alterations are actionable cancer drivers that can be detected in the clinic and that patients with NSCLC should be screened for this mutation.
