glesatinib (MGCD265)

P2, N=161, Terminated, Mirati Therapeutics Inc. | Completed --> Terminated; This study was terminated as a result of Sponsor portfolio reprioritization.

Glesatinib had an acceptable safety profile in patients with advanced, pre-treated NSCLC with MET activating alterations. Modest clinical activity was observed, which likely reflects suboptimal drug bioavailability suggested by previously reported Phase I data, and pharmacodynamic findings of lower than anticipated increases in circulating soluble shed MET ectodomain (s-MET).

The safety profile of single-agent glesatinib was acceptable. SDD 750 mg twice daily was selected as the preferred glesatinib formulation and dose based on clinical activity, safety, and PK data. Observations from this study led to initiation of a phase II study of glesatinib in patients with NSCLC stratified by type of MET alteration (NCT02544633).

This is clinically applicable to a variety of TKIs targeting MET such as crizotinib, capmatinib, carbozantinib, savolitinib, tepotinib, glesatinib, merestinib or monoclonal antibody drug classes.4.Conclusions :-MET gene alternations have many forms, now there are important targets for MET: MET Ex14 Skipping, MET Amplifications, MET point mutations.-There are many medecines suitable for these targets. This leads to the need to diagnose these MET gene mutations with next-generation sequencing techniques.

These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume)...Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.

Treatment patterns were heterogeneous across therapy lines and included available and experimental treatments (immune checkpoint inhibitor [ICI] therapy; MET inhibitors [crizotinib, cabozantinib, and glesatinib])...Conclusions Pts were generally at advanced age, were frequent smokers and had high-PD-L1 expression. Findings from this study help better characterize this rare population; treatment patterns and effectiveness outcomes underline the high unmet medical need.