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Sitravatinib (MGCD516)

Targets: Receptor tyrosine kinases including RET, CHR4q12, CBL, Trk, and DDR families.
Indications: Solid tumors with an initial focus on Non-Small Cell Lung Cancer (NSCLC)
Status: Phase 1B basket trial in patients with solid tumors, once daily oral dose

Sitravatinib (MGCD516) is being evaluated in a Phase 1b dose expansion cohort in selected patients with specific genetic alterations that are drivers of tumor growth, with an initial focus on NSCLC and in other solid tumors where sitravatinib may confer a benefit. Sitravatinib is a tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4q12, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression.  Based on our experience to date, the PK is well-behaved and a convenient, once daily dosing regime is being explored.  

Mirati owns the worldwide rights to Sitravatinib (MGCD516).

Click to see: A First-in-Human Phase 1 Study of Receptor Tyrosine Kinase (RTK) Inhibitor MGCD516 in Patients with Advanced Solid Tumors, poster #2575, ASCO 2016

<p><img src="/assets/001/5058.png" alt="A Novel Multi-Targeted Kinase Inhibitor Targeting Driver Mutations" title="A Novel Multi-Targeted Kinase Inhibitor Targeting Driver Mutations" /></p>


Clinical Development

Sitravatinib (MGCD516) is in Phase 1b development for the potential treatment of advanced solid tumors. Mirati plans to identify the maximum tolerated dose of Sitravatinib (MGCD516) and initiate expansion cohorts in selected patients with NSCLC who have genetic alterations in Sitravatinib (MGCD516) RTK targets or their key regulatory pathways in the first quarter of 2015.

In vitro, the compound has demonstrated potent inhibition of cell survival in cell lines that are driven by RET, CHR4q12, CBL, Trk, or DDR mutations. In animal studies, Sitravatinib (MGCD516) shows good oral bioavailability in mice, rats and dogs, and demonstrated tumor regression in multiple human xenograft tumor models in mice.

Sitravatinib (MGCD516) Clinical Trials

Scientific Rationale

The receptor tyrosine kinases in the RET, CHR4q12, CBL, Trk, and DDR families are key regulators of signaling pathways leading to cell growth, survival and migration. RET, CHR4q12, CBL, Trk, and DDR are dysregulated in many cancers through overexpression or genetic alteration and act as oncogenic drivers promoting cancer development and progression. Preclinically, Sitravatinib (MGCD516) has demonstrated tumor growth inhibition and regression in several animal models, including models with genetic alterations of Sitravatinib (MGCD516)'s targets.

Collectively, the genetic alterations of the Sitravatinib (MGCD516) tyrosine kinase targets provide clinical development opportunities in multiple indications. Activating mutations and gene rearrangements of RET have been identified as oncogenic drivers in a subset of lung adenocarcinoma and were found to be mutually exclusive with other known driver alterations. Trk family kinases are also genetically altered in multiple cancers including gene rearrangements in lung adenocarcinoma and other solid tumors. In addition, activating oncogenic mutations involving DDR have been identified in lung cancer.

The clinical development of Sitravatinib (MGCD516) will select for patients whose tumors have genetic alterations of Sitravatinib (MGCD516) targets or genetic alterations activating multiple Sitravatinib (MGCD516) targets. Prospectively selecting for patients that harbor these genetic drivers of disease will potentially enable Sitravatinib (MGCD516) to demonstrate a high response rate and rapidly establish clinical efficacy. Mirati believes that this approach is the most efficient way to achieve regulatory approval, ultimately bringing the drug to patients as quickly as possible.

Select Background Reading

  1. Hammerman, P. et al., 'Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer', 1 ( 1 ): Cancer Discovery 2012 ; 78 - 89
  2. Ramos, A.H., et al., 'Amplification of chromosomal segment 4q12 in non-small cell lung cancer', Cancer Biol Ther. 2009 November ; 8(21): 2042–2050
  3. Hammerman, P. et al., 'Protein tyrosine kinase regulation by ubiquitination: Critical roles of Cbl-family ubiquitin ligases' , Biochimica et Biophysica Acta 1833 (2013) 122–139
  4. An, S. et al., 'Identification of Enriched Driver Gene Alterations in Subgroups of Non-Small Cell Lung Cancer Patients Based on Histology and Smoking Status', 7 ( 6 ): PLOS One 2012
  5. Lipson , D. et al., 'Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies', 18 ( 3 ): Nature Medicine 2012 ; 382 - 384
  6. Kohno, T. et al., 'KIF5B-RET fusions in lung adenocarcinoma', 18 ( ): Nature Medicine 2012 ; 375 - 377
  7. Vaishnavi, A. et al., 'Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer', 19 ( 11 ): Nature Medicine 2013 ; -
  8. Marchetti, A. et al., 'Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung.', 29 ( 5 ): Human Mutation2008 ; 609 - 616
  9. Harada, T. et al., 'Role and relevance of TrkB mutations and expression in non-small cell lung cancer', 17 ( 9 ): Clinical Cancer Research 2011 ; 2638 - 2645