MET Y1230C

Co-fusions involved EML4-ALK (1.9%), STRN-ALK (1.2%), and CCDC6-RET (0.7%). Conclusions Comprehensive ctDNA NGS can identify METa and associated co-alterations that may inform therapeutic decisions for patients with AC in AME.

In addition, TPX-0022 exhibited potent activity against the resistance-relevant c-Met L1195F mutant and moderate activity against the c-Met G1163R, F1200I and Y1230H mutants but weak activity against the c-Met D1228N and Y1230C mutants. Overall, our study reveals the structural mechanism underlying the potency and selectivity of TPX-0022 and the ability to overcome acquire resistance mutations and provides insight into the development of selective c-Met macrocyclic inhibitors.

We corroborated these data with target engagement studies by fluorescence cross-correlation spectroscopy using KD constructs in cell lysates or full-length receptors from solubilized cellular membranes as wildtype or activated mutants (Y1235D and Y1234E/1235E). Collectively, our results provide further insight into the MET A-loop structural determinants that affect the binding of the selective inhibitor tepotinib.

We report biomarkers associated with clinical response and resistance to REGN5093 which may help with screening of aNSCLC pts in future combination studies of REGN5093 with other therapies.

MET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.

Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.

Initial screening (300 drugs, including 33 MET-TKIs) was performed using Ba/F3 cells carrying METex14 plus MET D1228A/Y because anecdotal case reports suggested that D1228X mutations were more refractory to second-line MET-TKIs than Y1230X mutations.This screening found four candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). We then performed further growth inhibitory assays using these four candidates plus other four MET-TKIs (type Ib; capmatinib and tepotinib, type II; cabozantinib and merestinib) in Ba/F3 cells carrying METex14 plus one of MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations... The type II MET-TKI foretinib may be an appropriate second-line MET-TKI for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at D1228 or Y1230 residues.212

The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.

We evaluated the antitumor activity of REGN5093-M114 in patient-derived tumor xenograft (PDX) models from EGFR-mutant NSCLC patients with acquired resistance to osimertinib plus savolitinib, including acquired MET p.Y1230C mutation. Finally, we determined whether REGN5093-M114 is able to overcome acquired resistance to the MET-TKI, tepotinib, using PDC from METex14 mutant NSCLC patients. In acquired MET-amplified EGFR-TKI resistant PDCs, PDOs, ATCC cell lines and PDX models, REGN5093-M114 alone exhibited a significant antitumor efficacy compared to MET-TKI or the MET x MET biparatopic antibody (REGN5093), but had no effect on some models with same MET copy number as the sensitive models... REGN5093-M114 has the potential to be a novel therapeutic option in NSCLC harboring MET genetic alterations, and further clinical application is highly warranted.