Mirati Therapeutics: Breaking the Resistance Against Immunotherapy in Lung Cancer

Mirati Therapeutics (MRTX) announced positive preliminary data from two ongoing clinical trials of its product sitravatinib in non-small cell lung cancer (NSCLC). Combination of sitravatinib and Bristol Myers Squibb (BMS) checkpoint inhibitor Obdivo (nivolumab) might have broken the resistance against the immunotherapy checkpoint inhibitor drug in NSCLC patients with documented progression following prior checkpoint therapy. The results of the combination sitravatinib/nivolumab demonstrated 3 confirmed Partial Responses in first 11 evaluable patients.

Also, the first evaluable NSCLC patient with CBL inactivating mutation treated with single agent sitravatinib confirmed Partial Response with 77% tumor reduction.

The promising data will be presented today, Friday, September 15t, 2017 at the IASLC 2017 Chicago Multidisciplinary Symposium in Thoracic Oncology (learn more at www.iaslc.org).

Combination of sitravatinib and nivolumab in NSCLC patients with documented progression following checkpoint therapy demonstrated 3 confirmed Partial Responses in first 11 evaluable patients

Sitravatinib (MGCD-0516) is a spectrum-selective kinase inhibitor which potently inhibits receptor tyrosine kinases (RTKs) including RET, TAM family receptors (TYRO3, Axl, Mer), and split family receptors (VEGFR2, KIT). Sitravatinib is being evaluated as a single agent in a Phase 1b expansion trial enrolling patients that harbor RET, CHR4Q12, and CBL genetic mutations in NSCLC and other tumors.

As an immuno-oncology agent, sitravatinib is being tested in combination with BMS’ anti PD-1 checkpoint inhibitor nivolumab (OPDIVO®) in NSCLC patients who have progressed after prior treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family receptors may help overcome resistance to checkpoint inhibitor therapy through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells, and myeloid-derived suppressor cells and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment.

In today’s presentation, initial safety data and efficacy information will be announced from the ongoing Phase 2 study of sitravatinib in combination with nivolumab (OPDIVO®) as a treatment for NSCLC patients with cancer progression following previous treatment with a checkpoint inhibitor.

Additionally, a case study will be presented, documenting an objective response of an NSCLC patient with a CBL inactivating mutation. This was the first evaluable NSCLC patient harboring a CBL mutation treated in the ongoing Phase 1b study of sitravatinib as a single agent.

In both clinical studies, sitravatinib alone and in combination with nivolumab was well tolerated with a manageable safety profile.

Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati Therapeutics said, “For the majority of NSCLC patients who progress following checkpoint therapy, there is a need for new therapeutic options. We are evaluating sitravatinib in combination with nivolumab in this checkpoint resistant population and are very encouraged by the responses observed, since responses would not be expected from re-treatment with a checkpoint inhibitor alone.”

“In addition, in the single agent trial, the objective partial response is the first example of clinical activity in a patient with a CBL mutation. Inactivating mutations in CBL occur in approximately 1.5% of NSCLC patients and currently represent an unmet medical need.”

Prohost Observations

Impressive news from Mirati Therapeutics about its product sitravatinib used in monotherapy and in combination with the checkpoint inhibitor immunotherapy Obdivo (nivolumab) belonging to Bristol-Myers Squibb. Sitravatinib confirmed its efficacy in small-cell lung cancer patients with the CBL inactivating mutation, which is great news that helps believe Mirati Therapeutics drug’s efficacy in combination with the checkpoint inhibitor drug.

We will be more informed following the analysis of what we will listen to at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

The news as we heard it, is nothing but impressive.

Mirati Therapeutics’ Stock is trading now at $10. Up $5.25 rallying over 100%


Today’s Presentations

Sitravatinib and Nivolumab Combination Study

Poster Presentation: Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitor Therapy  

Clinical Trial: NCT02954991, A Phase 2 study evaluating the tolerability and clinical activity of sitravatinib in combination with nivolumab in patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with checkpoint inhibitor therapy. 

Presenter: Ticiana A. Leal, M.D. 

This presentation provides a preliminary safety and efficacy update of the Phase 2 trial of sitravatinib in combination with nivolumab in NSCLC patients who have experienced progression of disease on or after treatment with checkpoint inhibitor therapy. In the efficacy data presented, 3 patients experienced a confirmed partial response out of 11 evaluable patients. Early safety data demonstrated an acceptable profile and manageable adverse events. Based on the data presented, the pre-defined criteria have been met for expansion from stage 1 to stage 2, which will enroll a combined total of 34 patients. 

This study is designed to assess the potential of sitravatinib to inhibit several important immunosuppressive pathways that may be important in overcoming resistance to checkpoint inhibitor therapy.

 Sitravatinib Single Agent Study

Poster Presentation: CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib

Clinical Trial:NCT02219711, A Phase 1b study evaluating safety, PK, metabolism, PD and clinical activity of Sitravatinib in patients with advanced solid tumor malignancies

Presenter: Lyudmila A. Bazhenova. M.D. 

The poster describes a case study of a NSCLC patient with a CBL mutation treated with sitravatinib. CBL loss of function mutations result in the increased activation of multiple oncogenic receptor tyrosine kinases (RTKs) in tumors, including PDGFRA, VEGFR2, KIT, Axl, and Mer. In preclinical models, sitravatinib has demonstrated the ability to potently inhibit these RTKs and induce tumor regression in NSCLC models harboring inactivating CBL mutations. In the case study presented, a heavily pre-treated NSCLC patient harboring an inactivating CBL mutation was treated with sitravatinib and demonstrated a confirmed partial response (PR) with a maximum decrease of 77% in target lesions. Early safety data is also provided; sitravatinib was well tolerated and the side effects observed were manageable. This trial is on-going and actively recruiting patients harboring CBL and other genetic mutations.

CBL mutations are present in 1.5% of NSCLC, 3.5% of melanoma, and 2% of cancers of unknown origin.

Both posters will be available on the Company’s website on the sitravatinib page, located in the Pipeline section, at: http://www.mirati.com/mgcd516/


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