2022 World Conference on Lung Cancer (ePosters)-EP08.02-146. Proposal of Foretinib as Second-Line TKI after Capmatinib/Tepotinib Treatment Failure in NSCLC with MET Exon 14 Mutation

EP08.02-146. Proposal of Foretinib as Second-Line TKI after Capmatinib/Tepotinib Treatment Failure in NSCLC with MET Exon 14 Mutation

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The study focused on identifying effective type II MET kinase inhibitors (MET-TKIs) for non-small-cell lung cancer (NSCLC) patients who have developed resistance mutations to type I MET-TKIs, namely MET exon14 skipping mutations (METex14) with D1228X and Y1230X mutations. The researchers conducted in vitro and in vivo experiments using various cell models to evaluate the activity of different MET-TKIs against these resistant mutations.<br /><br />They initially screened 300 drugs, including 33 MET-TKIs, and identified four candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib, and sitravatinib) that showed activity against both D1228X and Y1230X mutations. Further growth inhibitory assays were performed using these candidates and other MET-TKIs, and it was found that only foretinib showed potent activity against D1228X mutations.<br /><br />In in vitro and in vivo models, foretinib demonstrated significant activity against D1228X mutations compared to other MET-TKIs, such as cabozantinib and merestinib. Molecular dynamics simulations suggested that the long tail of foretinib played a crucial role in binding with D1228X MET through interaction with a residue at the solvent front (G1163).<br /><br />The study concluded that foretinib could be a suitable second-line MET-TKI for NSCLCs with METex14 after capmatinib/tepotinib treatment failure due to secondary mutations at D1228 or Y1230 residues.<br /><br />These findings provide valuable insights into potential treatment strategies for NSCLC patients with resistance mutations to type I MET-TKIs, with foretinib showing promise in overcoming such resistance. Further clinical studies are required to validate these results and establish the efficacy of foretinib as a second-line treatment option.

Asset Subtitle

Toshio Fujino

Meta Tag

Speaker Toshio Fujino

Topic Metastatic Non-small Cell Lung Cancer - Molecular Targeted Treatments

Keywords

type II MET kinase inhibitors

non-small-cell lung cancer

resistance mutations

METex14

D1228X mutations

foretinib

in vitro experiments

in vivo experiments

second-line MET-TKI

treatment strategies