Meeting an un-MET need: Targeting MET in non-small cell lung cancer

Abstract

The MET pathway can be activated by MET exon 14 skipping mutations, gene amplification, or overexpression. Mutations within this pathway carry a poor prognosis for patients with non-small cell lung cancer (NSCLC). MET exon 14 skipping mutations occur in 3-4% of patients with NSCLC, while MET amplifications are found in 1-6% of patients. The most effective method for detection of MET amplification is fluorescent in situ hybridization (FISH) and of MET exon 14 skipping mutations is RNA-based next generation sequencing (NGS). Immunohistochemistry (IHC) is an alternative method of diagnosis but is not as reliable. Early studies of MET tyrosine kinase inhibitors (TKIs) demonstrated limited clinical benefit. However, newer selective MET TKIs, such as capmatinib and tepotinib, have improved efficacy. Both drugs have an acceptable safety profile with the most common treatment-related adverse event being peripheral edema. One of the most frequent resistance mechanisms to EGFR inhibition with osimertinib is MET amplification. There is interest in combining EGFR inhibition plus MET inhibition in an attempt to target this resistance mechanism. Additional ways of targeting MET alterations are currently under investigation, including the bi-specific antibody amivantamab. Additional research is needed to further understand resistance mechanisms to MET inhibition. There is limited research into the efficacy of immune checkpoint inhibition for MET-altered NSCLC, though some data suggests decreased efficacy compared with wild-type patients and increased toxicity associated with the combination of immunotherapy and MET TKIs. Future directions for research will include combination clinical trials and understanding rational combinations for MET alterations.

Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors

“…It is believed that there are more co-occurring mutations in MET-amplified tumors compared with the MET Δex14-mutated tumors, and the co-mutation type depends on the degree of MET amplification. 20 Therefore, maybe we should pay much more attention to MET amplification. MET amplification, caused by an increase in the GCN of the MET gene, is a common mechanism of resistance to treatment with EGFR TKIs in addition to the occurrence of T790 M mutation, with MET amplification or MET-based resistance occurring in up to 10% to 25% of patients with NSCLC who progress from first- to third-generation EGFR TKIs.…”

Advancements in NSCLC

“…Notably, peripheral edema emerged as the predominant adverse event in patients experiencing grade 3 or higher toxicities. Concurrently, emerging MET-targeted inhibitors like savolitinib and cabozantinib are advancing through clinical trials, [88][89][90] with their therapeutic potential yet to be ascertained.…”

Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?

“…Therefore, their binding is independent of interactions with the A-loop. Type III MET TKIs are non-ATP competitive inhibitors, binding allosterically outside the ATP pocket [ 6 , 7 , 23 ]. An overview of the main published clinical trials with MET TKIs in NSCLC is shown in Table 1 .…”

“…MET-directed therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting MET, MET ligands, or the hepatocyte growth factor (HGF) [ 5 , 6 , 7 ], have been tested in patients with advanced NSCLC with MET deregulation, mainly due to exon 14 skipping mutations ( MET ex14) or MET amplification ( MET -amp).…”

“…Currently, two selective MET TKIs, capmatinib and tepotinib, have been demonstrated to be highly effective in this molecularly defined subgroup of patients, as showed in the GEOMETRY Mono-1 and VISION trials, respectively, and have obtained FDA and EMA approval. Moreover, other similar agents are being tested in early-phase clinical trials with promising anti-tumor activity [ 7 , 8 , 9 ] ( accessed on 14 May 2023).…”