Novartis Announces FDA Approval of Tabrecta (capmatinib), the First MET Inhibitor for NSCLC with MET Exon 14 Skipping Mutation

On May 6, the FDA approved Novartis’ Tabrecta (capmatinib) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping (METex14) mutations. The FDA also approved FoundationOne CDx (F1CDx) as a companion diagnostic for Tabrecta.

Chemical Structure of Capmatinib

The FDA’s approval was primarily based on data from the Phase II study coded GEOMETRY mono-1. This open-label, multicenter, single-arm study enrolled 97 patients with non-small cell lung cancer (NSCLC) confirmed by RNA-based clinical testing to harbor MET exon 14 skipping mutations. Patients received capmatinib 400 mg until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR), and additional endpoints included duration of response (DOR).

The Independent Data Monitoring Committee assessment results showed that the objective response rate (ORR) for capmatinib in treatment-naïve patients was 68%, including a complete response (CR) rate of 4% and a partial response (PR) rate of 64%; the proportion of patients with a duration of response (DOR) exceeding 12 months was 47%. In previously treated patients, the ORR was 41%, and the proportion of patients with a DOR exceeding 12 months was 32%.

In terms of safety, the most common adverse reactions to capmatinib were peripheral edema (42%), nausea (33%), increased creatinine (20%), vomiting (19%), fatigue (14%), decreased appetite (13%), and diarrhea (11%). The majority of adverse events (AEs) were Grade 1 or 2.

Lung cancer is the most common type of cancer globally. In 2018, there were 2.1 million newly diagnosed cases of lung cancer worldwide, resulting in 1.8 million deaths. Lung cancer is primarily classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for approximately 85% of all lung cancer cases. MET exon 14 skipping mutations occur in 3%-4% of newly diagnosed advanced NSCLC cases.

c-Met is a receptor expressed on the cell surface, with hepatocyte growth factor (HGF) as its ligand. Extensive research has demonstrated that overactivation of c-Met may initiate the transformation of normal cells into tumor cells and further drive subsequent events such as invasion, metastasis, and dissemination. A hallmark of cellular carcinogenesis is the epithelial-to-mesenchymal transition (EMT), in which c-Met is considered to play a pivotal driving role. Furthermore, the c-Met gene serves as a critical regulatory node for the self-renewal and clonal aggregation of cancer stem cells.