Amethyst NSCLC trial: Phase 2, parallel-arm study of receptor tyrosine kinase (RTK) inhibitor, MGCD265, in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) with activating genetic alterations in mesenchymal-epithelial transition factor (MET).

Background: MGCD265 is an oral, potent, small molecule RTK inhibitor of MET and Axl, which are important for mediating signals for cell growth, survival, and migration. M≤Tmutations and/or gene amplification have been reported in approximately 7% of NSCLC and function as oncogenic drivers that promote cancer development and progression. AffiTsplice site mutations that result in the deletion of exon 14 (METex14del) represent a novel class of genetic alterations that have been implicated as oncogenic drivers in a subset of NSCLC. METex14del contains the Y1003 CBL ubiquitin ligase regulatory binding site that mediates CBL-dependent MET degradation and signal attenuation. Deletion of this region results in sustained activation of MET and its downstream signaling pathways. MGCD265 has demonstrated anti-tumor efficacy with robust tumor regression in xenograft models ofMETex14del and MET amplification. Additionally, confirmed partial responses have been observed in pts with MET-altered NSCLC treated with MGCD265 in the Phase 1 setting. Methods: This global Phase 2 trial is enrolling pts with NSCLC characterized by activating genetic MET alterations in tumor tissue or blood and who have received at least one prior platinum-containing regimen for advanced disease. Pts will be enrolled to one of four study arms based on the type of MET dysregulation: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in blood, and 4) amplification in blood. The primary endpoint is Obj ective Response Rate (ORR) in accordance with RECIST 1.1; a Bayesian Predictive Probability Design is applied independently to each treatment arm. Secondary objectives are safety and tolerability, response duration, survival, correlations between tissue and blood testing, and PK/PD. Pts are treated with MGCD265 in 21-day cycles until RECIST-defined progression or unacceptable toxicity. The study is open for enrollment and recruitment is ongoing. (Table Presented).