Scientific Rationale

Why Resistance Happens: The Tumor Microenvironment

Checkpoint inhibitor resistance means that even if tumors are treated with a checkpoint inhibitor, they use other mechanisms to protect themselves from immune attack. One of these mechanisms is an immunosuppressive tumor microenvironment (TME). The TME is like a protective nest that surrounds tumors. It includes a collection of various cell types that have switched sides and now protect the cancer from immune system attacks. Various receptor tyrosine kinases (RTKs) have been implicated in creating and maintaining an immunosuppressive TME.

Sitravatinib Can Target RTKs to Assist Checkpoint Inhibitors

Uncovering the mechanisms behind checkpoint inhibitor-resistance has placed the drug development spotlight onto RTK-inhibitors. One such inhibitor is sitravatinib. Sitravatinib is a potent, spectrum-selective RTK inhibitor. It inhibits several closely related RTKs, including the TAM family (TYRO3, AXL and MER), VEGFR2 and KIT. This inhibition weakens the cancer’s defenses in the tumor microenvironment.

  • Tyro3/Axl/MER – enhances immune responses through activation of key innate immune cell types including macrophages, dendritic cells and Natural Killer (NK) cells.
  • VEGFR2 & KIT –   suppresses immune cells that reduce the anti-tumor response including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) leading to the increased activity of adaptive immune cells (CD4+ and CD8+ cells).

By targeting these specific RTK receptors with sitravatinib, the immunosuppressive TME is converted to an immune-supportive TME and cancers are more likely to respond to checkpoint inhibitor treatment.

Mirati researchers drew a connection: could sitravatinib be paired with a checkpoint inhibitor? The hypothesis was that sitravatinib and checkpoint inhibitors could work as a team, with the former targeting RTKs to reverse the immunosuppressive TME clearing the path for checkpoint inhibitors to take down cancer cells. Early clinical studies demonstrated encouraging data that support this hypothesis.

Program Summary

  • Targets

    RTKs implicated in suppressing the immune response to tumors, including receptors TYRO3, Axl, Mer, VEGFR2, and KIT

  • Indications

    Non-Small Cell Lung Cancer (NSCLC) and Bladder Cancer

  • Status

    Phase II / III

Sitravatinib Immuno-Oncology Combo Mechanism if Action

Sitravatinib in the Tumor Microenvironment – May Restore Immune Response

One of the most important breakthroughs in cancer treatment over the last decade has focused on cancer immunotherapies that utilize the body’s own immune system to target and destroy cancer cells. Checkpoint inhibitors, a type of immunotherapy, block PD-1/PD-L1 signaling, letting the immune system do its job and target the cancer cell. Unfortunately, they aren’t effective in the majority of patients with cancer.

Some cancer cells use a cell-surface protein (known as PD-L1) to block these attacks from the immune system. While blocking this pathway is effective in some patients, most patients are resistant to checkpoint inhibitors, significantly limiting their efficacy as a cancer treatment.

Patient Population

Sitravatinib is being tested in several cancers including non-small-cell lung cancer patients who have developed checkpoint inhibitor therapy resistance meaning that the tumor microenvironment is non-responsive to treatment. Checkpoint inhibitor resistance is a frequent problem for NSCLC patients as 60-70% of patients do not respond to single agent checkpoint inhibitor therapy or relapse after treatment.

Clinical Development

Mirati is currently evaluating the safety and efficacy of sitravatinib in combination with nivolumab, an anti-PD-1 immune checkpoint inhibitor, in patients with NSCLC that have progressed following prior treatment with a checkpoint inhibitor. Typically, re-treating these patients with a checkpoint inhibitor would not show meaningful benefit. However, Mirati’s interim Phase 2 data, presented in October 2018 at the European Society for Medical Oncology (ESMO) showed promising results that combining sitravatinib and nivolumab could provide these patients with another treatment option:

A Phase 3 randomized trial was initiated in Q2 2019 comparing the sitravatinib and nivolumab combination against docetaxel, the current 2nd line standard of care treatment, in checkpoint inhibitor-refractory NSCLC patients. The Phase 3 trial is currently enrolling and interim data is projected to be available by H2 2021. Stay updated >

Beyond NSCLC

Mirati is conducting and participating in additional clinical trials in several cancer patient populations. We are currently enrolling a phase 2 clinical trial of sitravatinib in combination with nivolumab in patients with advanced or metastatic urothelial carcinoma and also enrolling a phase 2 clinical trial of sitravatinib in combination with nivolumab in pre-surgical patients with clear cell renal cell cancer (RCC). In addition, investigator sponsored trials (ISTs) are ongoing at multiple centers, including a clinical trial in head and neck squamous cell carcinoma (HNSCC) at Princess Margaret Cancer Centre in Toronto, Canada.

In January 2018, Mirati entered into an exclusive license agreement with BeiGene for the development, manufacturing and commercialization of sitravatinib in Asia (excluding Japan), Australia and New Zealand. Mirati retained exclusive rights for the development, manufacturing and commercialization of sitravatinib for the rest of world. Ongoing clinical trials in BeiGene’s territory include the combination of sitravatinib and tislelizumab (BeiGene’s checkpoint inhibitor) in patients with NSCLC, RCC, hepatocellular (HCC), gastric and ovarian cancers.

Select Background Reading

  1. Whitepaper: Rationale for Sitravatinib in Combination with Checkpoint Inhibitor Therapy. Aug. 2019
  2. 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
  3. 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
  4. 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
  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