TARGETS: Receptor tyrosine kinases (RTKs) implicated in suppressing the immune response to tumors, including TAM family receptors (TYRO3, Axl, Mer) and split family receptors (VEGFR2, KIT).
INDICATIONS: Sitravatinib in combination with Checkpoint Inhibitor therapy:

  • Non-Small Cell Lung Cancer (NSCLC): Following progression after treatment with the combination of a checkpoint inhibitor and chemotherapy.
  • Bladder Cancer: Following progression after treatment with a checkpoint inhibitor.

Sitravatinib as a single agent:

  • NSCLC and Melanoma: Tumors that test positive for CBL mutations.
STATUS: Mirati sponsored combination trials:

  • Phase 3 trial of sitravatinib in combination with nivolumab in patients with second line NSCLC after treatment with the combination of a checkpoint inhibitor and chemotherapy (to be initiated in Q2 2019).
  • Phase 2 trial of sitravatinib in combination with nivolumab in patients with bladder cancer after treatment with a checkpoint inhibitor

Mirati sponsored single agent trials:

  • Phase 1b trial of sitravatinib in patients with solid tumors that harbor a CBL mutation.

Mechanism of Action Studies:

  • Clinical mechanism of action studies: Sitravatinib in combination with nivolumab in pre-surgical (neo-adjuvant) head and neck cancer and renal cell cancer.

5016

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO®), an anti-PD-1 checkpoint inhibitor, in patients whose cancers have progressed despite treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion clinical trial emphasizing enrollment of patients whose tumors harbor specific mutations in the CBL protein. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma. Sitravatinib potently inhibits these RTKs and is being investigated as a treatment option for cancer patients with CBL mutations.

As part of a strategic alliance with BeiGene, sitravatinib is also being tested in a number of additional clinical trials in China and Australia.

Sitravatinib (MGCD516) Publications

IASLC WCLC 2019

Click to view “Phase 3 Trial of Sitravatinib plus Nivolumab vs Docetaxel for Treatment of NSCLC after Platinum-Based Chemoimmunotherapy”

ASCO Genitourinary Cancers Symposium

Click to view “Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma (UC) after Checkpoint Inhibitor Therapy (CIT)”

Click to view “Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients Undergoing Nephrectomy for Locally-Advanced Clear Cell Renal Cell Carcinoma (ccRCC)”

SITC 2018

Click to view “Preliminary Biomarker Analysis of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor”

ASCO 2018

Click to view “Evaluation of the spectrum selective RTK inhibitor in clear cell renal cell carcinoma (ccRCC) refractory to anti-angiogenic therapy”

World Conference on Lung Cancer 2017

Click to view “Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor Therapy”
Click to view “CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib”

IASLC 2017 CHICAGO

Click to view “Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor Therapy”

Click to view “CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib”

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.

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
  10. Wenting Du et al., ‘Sitravatinib potentiates immune checkpoint blockade in refractory cancer models’, JCI Insight. 2018;3(21):e124184