merestinib (LY2801653)

P1, N=164, Completed, Eli Lilly and Company | Active, not recruiting --> Completed

Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib...While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting.

Given the common hyperactivation of MAPK in IBC tumors, including rSUM149, we evaluated Merestinib, a multikinase inhibitor in clinical trials. It effectively targeted pERK and peIF4E pathways, suppressed downstream targets, induced cell death in drug-resistant rSUM149 cells, and showed synergistic effects with another tyrosine kinase inhibitor (Lapatinib) in parental cells. This underscores its significant impact on protein synthesis signaling, crucial for combating translational dependence in cancer cells. In summary, our study elucidates adaptive changes in IBC cells in response to therapy and treatment pauses, guiding precision medicine approaches for this challenging cancer type.

P1, N=215, Active, not recruiting, Eli Lilly and Company | Trial completion date: Mar 2024 --> Jul 2024

P2; Trial completion date: Mar 2024 --> Oct 2023 | Active, not recruiting --> Terminated; Funding was pulled

P2, N=309, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Dec 2025

P1, N=215, Active, not recruiting, Eli Lilly and Company | Phase classification: P1a/1b --> P1 | Trial completion date: Dec 2023 --> Mar 2024

We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.

These findings suggest that merestinib has strong antitumor activity in GAC and exhibits an additive effect when administered with nab-paclitaxel. These results provide compelling evidence that this therapeutic approach may lead to a clinically relevant combination to improve GAC patients’ survival.

P1a/1b, N=215, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2022 --> Dec 2023

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.

P2; Trial primary completion date: Oct 2020 --> Oct 2021

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.

CCR2 and MET were significantly co-expressed in patient DCIS and IDC tissues. In summary, MET receptor activity is an important mechanism for CCL2/CCR2-mediated progression and metabolism of early-stage breast cancer, with important clinical implications.

P1a/1b, N=215, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2021 --> Dec 2022

Simultaneous inhibition of c-MET, Axl and DDR1/2 pathways by merestinib has antitumor efficacy in PDAC and it can significantly improve the standard chemotherapy response. This therapeutic approach might lead to a clinically relevant combination to increase PDAC patients’ survival.

P1a/1b, N=215, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P1a/1b, N=215, Recruiting, Eli Lilly and Company | Trial completion date: Apr 2022 --> Dec 2021 | Trial primary completion date: Oct 2020 --> Jun 2020

P2, N=12, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=25 --> 12