A subset of lung adenocarcinomas (3-4%) harbor oncogenic alterations in the MET exon 14 (METex14) splice sites that cause exon 14 skipping. These alterations are associated with increased tumor aggressiveness and poor prognosis. However, emerging data suggest that lung adenocarcinomas harboring METex14-skipping alterations are sensitive to c-Met kinase inhibitors. On 25 March 2020, the Japanese Ministry of Health, Labour and Welfare (MHLW) granted regulatory approval for the highly selective, oral MET inhibitor, tepotinib (Tepmetko®, Merck KGaA), for the treatment of patients with advanced NSCLC harboring METex14–skipping alterations.

This approval is based on results from the ongoing, single-arm phase II VISION trial that includes treatment naive and previously treated patients with advanced METex14-positive NSCLC. METex14 alterations were determined in tissue and liquid biopsy by a next generation sequencing companion diagnostic assay (Archer®MET, ArcherDX) that gained simultaneous regulatory approval. Data from 99 patients enrolled in the study, including 15 Japanese patients, demonstrated a clinically meaningful benefit with a once-daily dose of 500 mg tepotinib, across different lines of treatment. The overall response rate, assessed by an Independent Review Committee, was 42.4% in patients whose MET status was determined by either tissue or liquid biopsy, and the median duration of response was 12.4 months. Tepotinib was well tolerated; the most common treatment-related adverse events (TRAEs) of any grade were peripheral edema (53.8%), nausea (23.8%), and diarrhea (20.8%). Eleven patients (8.5%) discontinued treatment due to TRAEs.

Currently, tepotinib is only approved in Japan. In the United States, tepotinib was granted breakthrough therapy designation by the Food and Drug Administration (FDA) in September 2019 for the treatment of patients with metastatic NSCLC harboring METex14-skipping alterations whose cancer has progressed following platinum-based chemotherapy. The designation was based on interim data from the VISION trial. Hot on the heels of tepotinib is another selective MET inhibitor, capmatinib (Novartis), which received priority review by the FDA in February 2020 based on the results of the phase II GEOMETRY study. These two MET inhibitors, along with other emerging MET-targeted agents evaluated in clinical trials, may improve outcomes for patients with this rare molecular subtype of aggressive lung cancer.