Recently, splice site alterations at MET exon 14 that result in exon skipping and activation of the c-Met pathway have been identified in ≈3% of lung adenocarcinomas. MET exon 14 alterations appear to be a true oncogenic driver of lung adenocarcinoma and appear to be mutually exclusive with other known oncogenic drivers such as EGFR and ALK. Emerging clinical data suggest that tumors with MET exon 14 alterations are sensitive to c-Met inhibition. The highly selective c-Met inhibitor tepotinib has been shown to be well tolerated and active in several phase I/Ib trials, with activity appearing greatest in c-Met-positive tumors. The recommended dose has been established as 500 mg/day. This open-label phase II trial (EudraCT 2015-005696-24) is investigating the efficacy of tepotinib in patients with lung adenocarcinoma harboring MET exon 14 alterations.
The primary objective is to assess the efficacy of tepotinib based on independently assessed objective response determined using RECIST v1.1. Key secondary objectives include further assessment of efficacy, as well as assessment of safety, pharmacokinetics, and quality of life. Eligible patients are adults with histologically confirmed advanced adenocarcinoma of the lung who have failed at least one line of systemic therapy, including a platinum doublet-containing regimen. Tumors must test positive for MET exon 14 skipping alterations as confirmed by a central laboratory. Exclusion criteria include EGFR mutations that confer sensitivity to EGFR TKIs, ALK rearrangements, and prior therapy (other than local palliative radiotherapy) within 21 days of the first dose of trial treatment. Patients receive tepotinib 500 mg/day in 21-day cycles until disease progression, intolerable toxicity, or withdrawal from treatment for other reasons. Recruitment of 60 patients in Europe, USA, and Japan is planned. This trial will establish the activity, safety, and tolerability of tepotinib in patients with lung adenocarcinoma harboring MET exon 14 alterations.
Clinical trial identification
Legal entity responsible for the study
U. Stammberger, R. Bruns: Employed by Merck KGaA, the manufacturer of tepotinib. All other authors have declared no conflicts of interest.