Background: A TKI for hepatocyte growth factor (HGF). Overexpression, gene amplification, rearrangements, or mutations of MET protein result in alterations to MET signaling pathway, leading to downstream effects on cell growth, apoptosis, motility and invasiveness.
Detection Methods:
- MET exon 14 skipping: recommend RNA NGS, but qRT-PCR or DNA NGS are other options.
- MET amplification: NGS or FISH. Note: If a lung biopsy is not performed or not enough tissue exists to perform NGS or FISH, liquid biopsy can be used to identify markers in the blood.
Most Common Alterations:
- MET Mutation: MET mutations, specifically MET exon 14-skipping, occur in 2% to 4% of NSCLC. MET exon 14-skipping mutations result in reduced degradation of MET protein causing MET to behave in an oncogenic manner. They have been shown to be a highly aggressive subtype with poor prognosis. Current research suggests these mutations are independent drivers and are mutually exclusive of other known driver mutations. Hundreds of alterations have been identified, including point mutations, deletions, insertions or complex mutations resulting in exon 14-skipping. Loss of exon 14 due to a splicing event results in increased stability of the receptor, which leads to increased kinase activity and tumor growth.
- Clinical Features Associated: older age, smoking and no smoking history, pulmonary sarcomatoid carcinoma (PSC), adenocarcinoma histology, adenosquamous carcinoma
- MET Rearrangement/Fusion: MET fusions were first discovered in cell lines exposed to carcinogen. The true rate in NSCLC, based on NGS, is less than 1% of identified fusions effect the function of the gene in oncogenic manner.
- Includes: TPR, TRIM4, ZKSCAN1, PPFIB1, LRRFIP1, EPS15, DCTN1, PTPRZ1, NTRK1, CLIP2, TFG, HLA-DRB1, KIF5B
- MET Amplification: MET amplification can be a primary event, occurring in 2% to 5% of newly diagnosed patients with NSCLC, or a secondary event, associated with acquired resistance to TKIs, primarily EGFR TKIs (50% to 60% of first- and second-generation TKI acquired resistance). High MET amplification is very rare (<0.34%).
FDA-Approved Targeted Therapy:
- Crizotinib (Xalkori; Pfizer, EMD Serono):
- A multi-kinase, ATP-competitive TKI that confers activity againstMET, ALK and ROS1. This type 1 MET inhibitor received breakthrough approval by the FDA in 2018 for patients with MET exon 14 altered NSCLC who progressed on platinum-based chemotherapy. The approval was based on an expansion cohort of the PROFILE 1001 study of patients with MET exon 14-altered NSCLC treated with crizotinib. In 18 evaluable patients, a partial response of 44% was observed, with 50% experiencing stable disease at time of analysis.
- Most Common Adverse Events: diarrhea, abdominal pain, swelling, nausea, vision disorders, decreased heart rate, difficulty breathing, vomiting
- Capmatinib (Tabrecta, Novartis):
- Type 1 MET inhibitor received approval by the FDA in 2020 for patients with metastaticMET exon 14 skipping mutated NSCLC in front-line and refractory setting. Approval was based on the GEOMETRY mono-1 trial of patients with metastatic NSCLC confirmed MET exon 14 skipping. At time of approval, an ORR of 68% was found among treatment-naive patients with a DoR of 12.6 months. An ORR of 41% was found among previously treated patients with DoR 9.7 months.
- Most Common Adverse Events: lower limb swelling, nausea, fatigue, vomiting, difficulty breathing, decreased appetite — Of note additional adverse events include interstitial lung disease, hepatotoxicity, photosensitivity, and embryo-fetal toxicity.
- Tepotinib (Tepmetko, Merck/EMD Serono):
- Type 1 MET inhibitor granted accelerated approval by the FDA in early 2021 for patients with metastatic NSCLC with MET exon 14 skipping mutation. It is a highly selective, ATP-competitive, reversible MET TKI that may penetrate the CNS. The approval was based on the VISION trial of advanced or patients with metastatic NSCLC with MET exon 14 skipping alterations. At time of approval, an ORR of 43% was found for treatment-naive and previously treated patients with a median DoR of 10.8 months and 11.1 months, respectively.
- Most Common Adverse Events: swelling, fatigue, nausea, diarrhea, musculoskeletal pain, difficulty breathing — Of note, additional adverse events include interstitial lung disease, hepatotoxicity and embryo-fetal toxicity
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