|Targets:||MET and AXL|
|Indications:||Non-Small Cell Lung Cancer (NSCLC) and other Solid Tumors
Glesatinib (MGCD265) is a tyrosine kinase inhibitor that potently and selectively targets tumors in patients with driver alterations in MET (mutations and gene amplification) and AXL (rearrangements and gene amplification) that occur in approximately 8% of patients with non-small cell lung cancer (NSCLC). Genetic alterations in these targets have been implicated as drivers of tumor growth and disease progression in NSCLC and other solid tumors. Glesatinib is being evaluated in a Phase 2 trial in NSCLC patients with MET genetic alterations to confirm and extend the data that supports the clinical benefit of glesatinib in patients with driver mutations in MET. Other tumor types are being enrolled as well.
The overall five year survival rate for patients with NSCLC is only 16.8% and NSCLC results in the greatest number of cancer deaths in the United States. Over recent years, new therapies have been approved that target gene pathways implicated in progression of NSCLC, including EGFR kinase inhibitors, EML4-ALK inhibitors, and VEGF monoclonal antibodies. However, these targets represent only a fraction of the growing list of cancer genes that play a role in NSCLC. There remains a significant unmet medical need to develop new therapies that inhibit multiple targets, particularly those that also inhibit novel targets for which no therapy exists.
Glesatinib (MGCD265) is currently in the expansion phase of a Phase 1B/2 dose escalation study. In the ongoing trial, Mirati is identifying and enrolling only those patients with targeted MET and AXL alterations, approximately 8% of NSCLC. The company is partnering with companion diagnostic developers to utilize a multiplex next generation sequencing assay capable of detecting driver mutations. The multiplex assay is being used in ongoing clinical studies to select for patients with NSCLC and other solid tumors who are most likely to respond to Glesatinib (MGCD265).
In preclinical studies, Glesatinib (MGCD265) demonstrated activity in a variety of tumor models including those exhibiting dysregulation of the MET and/or AXL pathways. Greater than additive anti-cancer activity was also demonstrated when Glesatinib (MGCD265) was combined with other anti-cancer agents such as EGFR inhibitors.
The MET and AXL receptor tyrosine kinases (RTKs) play key roles in the pathogenesis of several human cancers and are critical mediators of tumor cell survival and metastatic progression. Genetic alterations of MET and AXL are associated with a broad spectrum of cancers including NSCLC and others.
MET is one of the most frequently abnormally activated kinases in several human cancers. Inappropriate activation of MET is involved in multiple oncogenic processes including cell growth and metastasis, and MET is also implicated as a key factor in resistance to targeted therapies. MET mutations, amplifications and splice site variants have been identified as drivers of tumor growth in multiple types of cancer, including NSCLC.
Glesatinib (MGCD265) is a potent inhibitor of AXL. AXL is an oncogenic RTK whose expression has been correlated with advanced clinical stage of NSCLC and poor clinical outcomes. AXL can be dysregulated in certain cancers through increased expression or gene rearrangement resulting in abnormal tumor growth and tumor cell survival. MET and AXL are associated with the epithelial mesenchymal transition and both appear to be involved in the mechanism of resistance to EGFR inhibitors such as Tarceva® and Erbitux®. Simultaneous inhibition of the MET and AXL pathways by Glesatinib provides a rational combination strategy with EGFR inhibitors to treat, delay or prevent resistance to EGFR inhibitors.
Mirati is selecting patients whose tumors have genetic alterations of MET and AXL that are drivers of disease in order to demonstrate a high response rate and establish clinical efficacy as a single agent. Mirati believes that this approach will demonstrate maximal clinical efficacy in the most efficient way so that we can accelerate the path to regulatory approval and allow patients to access this therapy as quickly as possible.
Tarceva® is a registered trademark of OSI Pharmaceuticals, LLC.
Iressa® is a registered trademark of AstraZeneca, PLC.
Erbitux® is a registered trademark of ImClone, LLC.