- Non-small-cell lung cancers comprise 85% of lung cancers and are commonly diagnosed at a later stage.
- EGFR, ALK, ROS, and BRAF mutation testing is required at the time of diagnosis as there are approved targeted therapies. Recently, MET gene mutations have been reported in addition to the EGFR, BRAF, ALK, and ROS genes mutations. MET gene mutations, activating the MET pathway, occur in 3-4% of stage IV NSCLC.
- MET exon 14 skipping mutations, copy number (GCN) gain or amplification, and MET protein overexpression are the common alterations in the MET gene.
- Considering the importance and exclusivity of these mutations, the development of the MET-inhibitors like monoclonal antibodies against MET or HGF, and small-molecule MET inhibitors targeting the MET pathway is essential.
- The anti-MET antibodies have previously shown unsatisfactory outcomes in the trials. However, small-molecule inhibitors are now being explored. While type I inhibitors block ATP binding to prevent receptor activation, type Ib inhibitors are more MET-specific. Type II inhibitors bind to the hydrophobic pocket adjacent to the ATP binding site. They are currently being evaluated for their efficacy against MET exon 14 skipping mutations and MET amplification (SAR125844 and AMG 337). Type III inhibitors bind to allosteric sites.
- The review discusses the clinical activity of capmatinib, a highly selective small-molecule MET inhibitor, which has shown promising results in the in-vitro and in-vivo trials. The trials assessed the efficacy, maximum tolerated dose, and safety of the drug.
GEOMETRY Mono-1 trial:
- The phase II GEOMETRY Mono-1 trial in EGFR-wt advanced-stage NSCLC patients and exon 14 skipping has shown favorable efficacy.
- The ORR and DCR for MET-inhibitors are in the same range or higher than those observed for the ROS, ALK, EGFR, BRAF-TKIs.
- Treatment-naïve patients showed a better response than those with prior therapies. This emphasizes the need for baseline molecular testing of MET gene alterations.
MET exon 14 skipping:
- The best-known target for capmatinib is MET exon 14 skipping. MET exon 14 skipping mutations are predictive biomarkers of the capmatinib response.
- The molecular diagnosis of all MET exon 14 skipping is challenging because MET exon 14 skipping may lead to several changes like splicing by point mutations or small deletions.
- Patients with MET exon 14 skipping have a low tumor burden, thus making the patients ineligible for immune checkpoint inhibitor therapies. With such limited treatment options, patients with exon 14 skipping have poor survival outcomes.
- Although not adequately defined, a MET GCN change also predicts the activity of the MET inhibitor. FISH detects MET amplification as GCN per cell or as a MET/CEP7 ratio. A MET/CEP7 ration ≥ 5 is considered a high-level amplification.
- Capmatinib blocks MET phosphorylation and the activation of key downstream effectors in MET-dependent tumor cell lines.
Role of MET in EGFR-TKI Resistance And Future Treatments
- MET gene changes are pivotal in the development of EGFR-TKI resistance. The resistance may be related to the C797S mutation in the EGFR exon 20 of the EGFR pathway itself or might be due to the activation of alternative pathways like HER-2 or MET amplification, mutations in the MAPK, PI3K genes, or cyclin-dependent kinase pathways.
- There is a high proportion of MET alterations in resistant tumors. MET inhibitors might therefore be the potential therapeutics in EGFR-mutated NSCLCs.
- MET inhibitors reverse the effects of MET activation on the EGFR and HER-3 pathways. It also restores the sensitivity to the EGFR-TKI, erlotinib, in EGFR-mutant NSCLC cell lines with acquired resistance. Capmatinib is effective in NSCLC patients who developed resistance after first-line EGFR-TKI treatment.
- A capmatinib dose of 400 mg BID is effective and well-tolerated. It has the potential to cross the blood-brain barrier. It has a promising efficacy in the treatment of brain metastases.
- Capmatinib may be used with other TKIs in resistant tumors. EGFR activation is responsible for developing resistance to MET-inhibitors. The review elucidated the need to assess the potential activity of combination therapy (capmatinib + EGFR inhibitors). Overall, capmatinib is an emerging therapeutic.
- Additionally, trials investigating the efficacy of crizotinib, tepotinib, tepotinib with gemcitabine, and savolitinib are ongoing.