Capmatinib in MET Exon 14 Skipping Mutation-Positive Lung Adenocarcinoma with Extensive Central Nervous System Metastasis.

Several selective mesenchymal-epithelial transition (MET) inhibitors have recently demonstrated favorable systemic efficacy in MET exon 14 skipping mutation-positive non-small cell lung cancer. However, there are limited data on their efficacy against central nervous system (CNS) metastasis, especially leptomeningeal seeding. Recently, we encountered a case of a 65-year-old woman who was diagnosed with metastatic lung adenocarcinoma. As routine molecular testing showed no genomic alterations, including epidermal growth factor receptor mutation and anaplastic lymphoma kinase translocation, the patient received a frontline platinum-doublet followed by paclitaxel. However, the tumor did not respond to these therapies, and her condition became deleterious owing to extensive brain and leptomeningeal metastases. Plasma genotyping revealed that the tumor harbored a MET exon 14 skipping mutation, and we started capmatinib, a selective MET inhibitor. The CNS lesions markedly decreased and the performance status of the patient dramatically improved. Our report highlights the significant CNS activity of capmatinib, even in cases of leptomeningeal metastasis. In addition, this report emphasizes the importance of the active utilization of molecular profiling to detect rare but druggable genetic alterations for the better management of patients with lung cancer.

Kim TW ，Lee KM ，Lee SH 《OncoTargets and Therapy》

Lazarus Response to Tepotinib for Leptomeningeal Metastases in a Patient With MET Exon 14 Skipping Mutation-Positive Lung Adenocarcinoma: Case Report.

The spread of next-generation sequencing enables clinicians to identify rare oncogene alterations, including MET exon 14 skipping mutation, in clinical practice for NSCLC. Several tyrosine kinase inhibitors for MET exon 14 skipping mutation such as capmatinib and tepotinib have elucidated their effectiveness. Only a few reports have suggested their efficacy against central nervous system lesions, especially leptomeningeal metastases. We here report a case of a patient with NSCLC with MET exon 14 skipping mutation and poor performance status salvaged by marked leptomeningeal metastases response to tepotinib. We further provide measures of plasma/cerebrospinal fluid concentrations of tepotinib and its cerebrospinal fluid penetration rate.

Ninomaru T ，Okada H ，Fujishima M ，Irie K ，Fukushima S ，Hata A ... -  《-》

Synchronous Double Primary Lung Adenocarcinomas With EGFR L858R Point Mutation and MET Exon 14 Skipping Mutation.

Ando S ，Futami S ，Azuma K ，Nishimatsu K ，Shirasaka T ，Minami S ... -  《-》

Activity and bioavailability of tepotinib for leptomeningeal metastasis of NSCLC with MET exon 14 skipping mutation.

Tepotinib is a key drug for cancer patients with mesenchymal-epithelial transition receptor tyrosine kinase proto-oncogene (MET) exon 14 skipping mutation. However, its bioavailability in the cerebrospinal fluid (CSF) in humans has not been fully elucidated. Moreover, information about the efficacy of tepotinib in patients with leptomeningeal metastasis is limited. Here, we present the case of a 56-year-old man who was diagnosed with lung adenocarcinoma with MET exon 14 skipping mutation. He was urgently hospitalized due to leptomeningeal metastasis. We administered tepotinib 500 mg/day as the second-line therapy and observed improvement in leptomeningeal metastasis and performance status. The tepotinib concentrations reached 1,648 ng/mL in the plasma and 30.6 ng/mL in the CSF, with a penetration rate (CSF/plasma) of 1.83%. These demonstrate tepotinib could achieve a high rate of central nervous system transition and could be effective against leptomeningeal metastasis.

Tanaka H ，Taima K ，Makiguchi T ，Nakagawa J ，Niioka T ，Tasaka S ... -  《Cancer Communications》

Capmatinib for patients with non-small cell lung cancer with MET exon 14 skipping mutations: A review of preclinical and clinical studies.

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 (METex14) during mRNA splicing. Mutations leading to METex14 are found in approximately 3-4% of patients with non-small cell lung cancer (NSCLC). Accumulating evidence suggests that METex14 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 METex14 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 METex14 advanced NSCLC, respectively. These results have supported the approval of capmatinib by the US Food and Drug Administration for patients with metastatic NSCLC harboring METex14.

Wu YL ，Smit EF ，Bauer TM 《-》