Non-Small Cell Lung Cancer (NSCLC) and other Solid Tumors


Phase 2

Glesatinib (MGCD265) is a tyrosine kinase inhibitor that potently and selectively targets tumors in patients with driver alterations in MET (mutations and gene amplification) andAXL (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 METgenetic 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.

Mirati owns the worldwide rights to glesatinib (MGCD265).

A Selective Inhibitor of MET and Axl

Understanding the MET Gene and
Receptor Tyrosine Kinase Glesatinib (MGCD265):
Potent Multi-Targeted Tyrosine Kinase Inhibitor
of MET and Axl

The Patient Need

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.

Clinical Development

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.

Glesatinib (MGCD265) Clinical Trials

Image: Glesatinib (MGCD265) Graph

Scientific Rationale

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.


MET Publications

  1. Cancer Research Atlas Research Network, ‘Comprehensive molecular profiling of lung adenocarcinoma’ , 511 ( ): Nature2014 ; 543 – 550
  2. Frampton G.M., et al., ‘Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors’ , Cancer Discov. 2015 Aug;5(8):850-9.
  3. Awad M.M., et al., ‘MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression’ J Clin Oncol. 2016 Mar 1;34(7):721-30.
  4. Knowles, L. et al., ‘HGF and c-Met Participate in Paracrine Tumorigenic Pathways in Head and Neck Squamous Cell Cancer’ , 15 ( 11 ): Clinical Cancer Research 2009 ; 3740 – 3750
  5. Kong-Beltran, M. et al., ‘Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer’ , ( 66 ): Cancer Research 2006 ; 283 – 289
  6. Onozato, R. et al., ‘Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers’ , 4 ( 1 ): Journal of Thoracic Oncology 2009 ; 5 – 11
  7. Turke, A. et al., ‘Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC’ , 17 ( 1 ): Cancer Cell 2010 ; 77 – 88
  8. Yu , H. et al., ‘Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers’ , 19 ( 8 ): Clinical Cancer Research 2013 ; 2240 – 2247

AXL Publications

  1. Sholl, Lynette M. et al., ‘Institutional implementation of clinical tumor profiling on an unselected cancer population’JCI Insight 2016;1(19):e87061
  2. Averett Byers, L. et al., ‘An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance’ , 19 ( 1 ): Clinical Cancer Research 2013 ; 279 – 290
  3. Levin, P.A., et al., ‘AAxl Receptor Axis: A New Therapeutic Target in Lung Cancer’, Journal of Thoracic Oncology, 2016.04.015
  4. Graham, D.K., et al., ‘The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer’, Nature Reviews Cancer Vol 14 December 2014
  5. Byers, L.A., et al., ‘An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance’, 19 ( 1 ): Clin Cancer Res 2013; 279-90
  6. Rothlin, C. V., Ghosh, S., Zuniga, E. I., et al., ‘TAM receptors are pleiotropic inhibitors of the innate immune response’, Cell 131, 1124–1136 (2007)
  7. Lu, Q., Lemke, G., ‘Homeostatic regulation of the immune system by receptor tyrosine kinases of the TYRO3 family’, Science 293, 306–311 (2001)
  8. Ye, X. et al., ‘An anti-AXL monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies’, Oncogene 29, 5254–5264 (2010)
  9. Cook, R.S. et al., ‘MERTK inhibition in tumor leukocytes decreases tumor growth and metastasis’, J. Clin. Invest. 123, 3231–3242 (2013)
  10. Paolino, M. et al., ‘The E3 ligase Cbl b and TAM receptors regulate cancer metastasis via natural killer cells’, Nature 507, 508–512 (2014)
  11. Postel-Vinay, S. et al., ‘AXL and acquired resistance to EGFR inhibitors’, 44: Nature Genetics 2012; 835-836
  12. Seo, J. et al., ‘The transcriptional landscape and mutational profile of lung adenocarcinoma’ , 22 ( 11 ): Genome Research 2012 ; 2109 – 2119
  13. Zhang , Z. et al., ‘Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer’ , 44 ( 8 ): Nature Genetics 2013 ; 852 – 860

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.