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

5016Sitravatinib (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).

IASLC 2016 TiP Poster #4109

Click to view “A study of MGCD516, a receptor tyrosine kinase (RTK) inhibitor, in molecularly selected patients with NSCLC or other advanced solid tumors”

IASLC 2016 TiP Poster #4795

Click to view “Phase 2 Study of Glesatinib or Sitravatinib with Nivolumab in Non-Small Cell Lung Cancer (NSCLC) after Checkpoint Inhibitor Therapy”

ASCO 2016 Poster #2575

Click to view “A First-in-Human Phase 1 Study of Receptor Tyrosine Kinase (RTK) Inhibitor MGCD516 in Patients with Advanced Solid Tumors

<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  targets or genetic alterations activating multiple sitravatinib targets. Prospectively selecting for patients that harbor these genetic drivers of disease will potentially enable sitravatinib 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.