Capmatinib for patients with non-small cell lung cancer with MET exon 14 skipping mutations: A review of preclinical and clinical studies. (April 2021) - Wu, Yi-Long
Highlights: MET exon 14 skipping is an oncogenic driver in NSCLC associated with poor prognosis. Capmatinib showed antitumor activity in preclinical models. Capmatinib demonstrated efficacy in advanced NSCLC with MET exon 14 skipping. Capmatinib has also shown encouraging preliminary activity in brain metastasis. Abstract: The mesenchymal-epithelial transition (MET) receptor tyrosine kinase binds the hepatocyte growth factor to activate downstream cell signaling pathways involved in cell proliferation, survival, and migration. Several genetic mechanisms can result in an aberrant activation of this receptor in cancer cells. One such activating mechanism involves the acquisition of gene mutations that cause MET exon 14 skipping ( MET ex14) during mRNA splicing. Mutations leading to MET ex14 are found in approximately 3–4% of patients with non-small cell lung cancer (NSCLC). Accumulating evidence suggests that MET ex14 is a true, independent oncogenic driver in NSCLC, as well as being an independent prognostic factor for poorer survival in patients with NSCLC. The successes of target therapies have relied on improved understanding of the genetic alterations that lead to the dysregulation of the molecular pathways and more advanced molecular diagnostics. Multiple efforts have been made to target the MET pathway in cancer; however, real clinical progress has only occurred since the emergence of MET ex14 as a valid biomarker for MET inhibition. Capmatinib is a highly potent and selective type Ib inhibitor of MET. Following preclinical demonstration of activity against MET-dependent cancer cell line growth and MET-driven tumor growth in xenograft models, data from a phase 1 clinical trial showed an acceptable safety profile of capmatinib and preliminary evidence of efficacy in patients with MET-dysregulated NSCLC. The multicohort GEOMETRY mono-1 phase 2 trial reported objective response rates of 68% and 41% in treatment-naïve and in pre-treated patients with MET ex14 advanced NSCLC, respectively. These results have supported the approval of capmatinib by the US Food and Drug Administration for patients with metastatic NSCLC harboring MET ex14.