Complex paradigm of MET exon14 mutation: A skip beyond EGFR in lung adenocarcinoma

• Author Details:   
• Madan K ^*
• Shatarupa Das
• Loretta Ann Pereira
• Rohan Shetty
• Richa Nathani

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Lung cancer is a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 80–85% of cases. It is characterized by diverse histological subtypes and distinct molecular drivers, each with specific therapeutic implications. These include mutations in EGFR(15–30%), KRAS(25–30%), BRAF(1–2%), HER2(2–3%), and MET(3–4%), as well as gene rearrangements in ALK(5–7%), ROS1(1–2%), RET(1–2%), and NTRK(~1%). Lately, MET alterations, particularly, MET exon 14(METex14) skipping mutation occurring in approximately 3% of NSCLC cases, has emerged as a clinically actionable target. Other alterations of MET, such as point mutations, amplifications, alternative splicing events, can mimic METex14 skipping by leading to constitutive activation of MET signaling. These alterations confer resistance to EGFR inhibitors or influence treatment responses, necessitating targeted NGS panels to guide personalized therapeutic strategies in NSCLC. We present a case of a 71-year-old male, treated for rectal adenocarcinoma, now diagnosed with primary lung adenocarcinoma. Molecular testing with targeted NGS panel covering key lung cancer genes for various genomic alterations (SNVs, InDels, CNVs, and Fusions) was considered. On sequencing analysis, a tier I pathogenic variant in MET c.3028 G>C; p.Asp1010His was detected with a VAF of 35%. No other co-mutations were noted. The patient was started on radiation for painful bone metastasis, however succumbed to the widespread disease. The identification of the METex14 mutation underscores the significance of targeted therapy, particularly with MET inhibitors such as Capmatinib and Tepotinib, which have demonstrated promising efficacy. This report emphasizes the necessity of targeted multi-gene NGS panels for precision medicine in NSCLC.

Keywords:  Non-small cell lung carcinoma, Molecular alterations, MET alteration, MET exon 14 skipping mutation