MGCD265 is a potent, orally available, small molecule RTK inhibitor of mutant and wild-type forms MET and of Axl, both of which mediate signals for cell growth, survival, and migration. Alterations in MET, including mutations and/or gene amplification, occur in approximately 7% of NSCLC and function as oncogenic drivers that promote cancer development and progression. Recently, various mutations located at or near the exon 14 splice site of MET (METex14del) have been identified and result in absence of expression of exon 14. Importantly, this non-expressed region encodes the Y1003 CBL ubiquitin ligase regulatory binding site that is required for CBL-dependent MET degradation and signal attenuation. Absence of this receptor domain results in sustained MET signaling, which has been implicated as an oncogenic driver in a subset of NSCLC. Furthermore, in xenograft models of NSCLC where METex14del and MET amplification are putative oncogenic drivers, MGCD265 induces robust tumor regression, and confirmed partial responses have been observed in patients with MET-altered NSCLC treated with MGCD265 in the Phase 1 setting.
Pts with NSCLC characterized by activating genetic MET alterations identified in tumor tissue or circulating tumor DNA (ctDNA) and who have received at least one prior platinum-containing regimen for advanced disease are eligible for this global Phase 2 trial and are assigned to one of four cohorts based on the type of MET dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue, 3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is Objective Response Rate (ORR) in accordance with RECIST 1.1. A Bayesian Predictive Probability Design is applied independently to each cohort of up to 45 patients, assuming p0 = 0.20 and p1 = 0.40. Secondary objectives include safety, tolerability, response duration, survival, correlation between tissue and ctDNA testing, and PK/PD. This study is currently open, and recruitment is ongoing.
Clinical trial identification
EudraCT: 2015-002070-21; Clinical trial registry number: NCT02544633
Legal entity responsible for the study
J. Christensen, R. Chao, D. Faltaos: Employee of Mirati Therapeutics; stocks ownership in Mirati Therapeutics. V. Tassell: Employee of Mirati Therapeutics and own stock. All other authors have declared no conflicts of interest.