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Mirati Therapeutics Doses First Patient In Expansion Cohorts Of MGCD516 Phase 1b Trial In Genetically Selected Patients


SAN DIEGO, Dec. 17, 2015 /PRNewswire/ -- Mirati Therapeutics, Inc. (NASDAQ: MRTX) today announced that the first patient with Non-Small Cell Lung Cancer (NSCLC) has been dosed in a Phase 1b clinical trial of MGCD516. The trial will evaluate select patients exhibiting genetic alterations in the tyrosine kinase signaling pathways, RET, DDR and Trk, which are known oncogenic drivers. The study will also explore other mechanisms that may play a role in regulating tumor growth, including selecting for patients with CBL mutations and chromosome 4 amplicon alterations.

"As we continue to better understand and pinpoint genetic alterations driving different types of cancer, we are able to more effectively identify patients who may benefit from specific molecularly-targeted therapies," said Todd Bauer, M.D., associate director of drug development and physician lead of personalized medicine, Sarah Cannon Research Institute. "Results from the dose escalation phase in unselected patients indicate that MGCD516 is tolerable and we look forward to continuing this study with patients selected by specific genetic driver mutations to help advance treatment options."

"We have identified the dose that achieved serum levels associated with tumor regressions in preclinical models and, we believe, will fully inhibit the genetic alterations that MGCD516 targets," said Charles M. Baum, M.D., Ph.D., president and CEO of Mirati. "By selecting and treating cancer patients, whose tumors carry driver mutations, we could see proof of concept in 2016 and the data could support accelerated development."

The purpose of the Phase 1b open-label trial is to evaluate the safety and efficacy of 150 mg once-daily (QD) MGCD516, administered orally, in patients with the genetic driver alterations of interest, including RET fusions, DDR mutations, Trk fusions and Trk mutations, CBL mutations and CHR4q12 gene amplification. The trial will enroll patients with NSCLC as well as patients with advanced solid tumors that carry the genetic alterations of interest. Additional information about this clinical trial of MGCD516 is available at using identifier: NCT02219711.

Despite available treatment options, the overall five year survival rate for patients with NSCLC is only 17.8% and NSCLC results in the greatest number of cancer deaths in the U.S. Moreover, the five year overall survival rate for Stage 4 metastatic disease is a mere 4.0% (SEER Lung and Bronchus Cancer-2011). Over recent years, new therapies have been approved that target gene pathways implicated in progression of NSCLC, including EGFR kinase inhibitors, EML4-ALK inhibitors, VEGF monoclonal antibodies and PD-1 inhibitors. However, these targets represent only a fraction of the growing list of cancer genes that play a role in NSCLC. Given these factors, there remains a significant unmet medical need to develop new therapies that inhibit multiple targets, particularly those that also inhibit novel targets for which no therapy exists.

About MGCD516
MGCD516 is a tyrosine kinase inhibitor that has demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression. MGCD516 also targets other signaling pathways that may play a role in tumor growth. These key regulatory pathways are genetically altered in multiple cancer indications and act as oncogenic drivers that promote cancer development and progression in solid tumors, including NSCLC. MGCD516 is being evaluated in a Phase 1b dose expansion cohort in selected patients with specific genetic alterations that are drivers of tumor growth. The initial focus for MGCD516 is on NSCLC. Mirati retains worldwide rights to MGCD516.

About the Genetic Alterations that MGCD516 Targets
Genetic alterations in the RET, DDR and Trk family receptor tyrosine kinase (RTK) signaling pathways are oncogenic drivers.

Multiple independent genomics studies have identified RET gene rearrangements (fusions) as oncogenic drivers in approximately 2% of non-small cell lung cancer (NSCLC). RET fusions function as transforming oncogenes, and transgenic mice exhibiting RET fusions develop NSCLC. RET fusions are largely mutually exclusive with genetic alterations in other oncogenic drivers, such as EGFR, KRAS, ALK, and ROS1. As with ALK and ROS1 rearrangements, RET fusions are not associated with a history of smoking or adenocarcinoma histology, and typically occur in younger patients. Multiple clinical case studies have reported objective responses of RET fusion-positive patients to selected RET inhibitors.

DDR2 mutations have been found to occur in up to 4% of lung squamous cell carcinomas and have been shown to be sensitive to a tyrosine kinase inhibitor in xenograft models.

While TrkA (NTRK1) fusions were originally detected in thyroid cancers, genetic alterations of this RTK have also been found in NSCLC and colorectal cancer patients. Although frequencies are not yet well understood, oncogenic TrkA fusions have been shown to occur in NSCLC patients. Clinical case studies have reported objective responses of TrkA fusion-positive patients to selected TrkA inhibitors. In addition,TrkC (NTRK3) genetic alterations have been identified, although infrequently, in cases of sporadic breast and colorectal cancers and were found to comprise a significant fraction of large cell neuroendocrine lung cancers (a subset of NSCLC). Fusion events involving TrkC were also identified in secretory breast cancers, fibrosarcoma, and acute myeloid leukemias. 

Exploring Novel Targets
Focal amplification of the 4q12 region of chromosome 4 has been detected in approximately 3% of NSCLC (including 5% lung squamous cell carcinoma). Preclinical xenograft models have shown that treatment with MGCD516, as a single agent, can result in clear tumor responses which provide additional support that amplification of 4q12 can be a driver in NSCLC.

CBL is a tumor suppressor gene that is implicated in the normal regulation of receptor processing and attenuation of ligand-dependent activation of a subset of RTKs, including MET, PDGFRA, KIT, and TAM. CBL mutations have been identified in approximately 2.5% of NSCLC patients, which has been shown to result in the inappropriate activation of these RTKs, and a corresponding contribution to tumor growth and progression.

About Mirati Therapeutics
Mirati Therapeutics develops molecularly targeted, single agent and immuno-oncology combination therapies intended to treat cancer. Mirati's approach combines the three most important factors in oncology drug development, 1) researching and developing drug candidates that target genetic and epigenetic drivers of cancer, 2) designing creative and agile clinical development strategies that select for patients whose tumors are dependent on specific driver alterations, and 3) leveraging a highly accomplished oncology precision medicine leadership team. The Mirati team uses a blueprint - proven by their prior work - for developing potential breakthrough cancer therapies, with accelerated development paths, in order to improve outcomes for patients. Mirati is advancing three drug candidates through clinical development for multiple oncology indications. More information is available at

Forward Looking Statements
Certain statements contained in this news release, other than statements of fact that are independently verifiable at the date hereof, contain "forward-looking" statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that involve significant risks and uncertainties. For more detailed disclosures and discussions regarding such forward looking statements, please refer to Mirati's filings with the U.S. Securities and Exchange Commission ("SEC"), including without limitation Mirati's filings on Forms 10-K, 10-Q, and 8-K. Forward looking statements are based on the current expectations of management and upon what management believes to be reasonable assumptions based on information currently available to it. Such statements can usually be identified by the use of words such as "may," "would," "believe," "intend," "plan," "anticipate," "estimate," "expect," and other similar terminology, or by statements that certain actions, events or results "may" or "would" be taken, occur or be achieved. Such statements include, but are not limited to, statements regarding Mirati's development plans and timelines, potential regulatory actions, expected use of cash resources, the timing and results of clinical trials, and the potential benefits of and markets for Mirati's product candidates. Forward looking statements involve significant risks and uncertainties and are neither a prediction nor a guarantee that future events or circumstances will occur. Such risks include, but are not limited to, potential delays in development timelines or negative clinical trial results, reliance on third parties for development efforts, changes in the competitive landscape, changes in the standard of care, as well as other risks described in Mirati's filings with the SEC. We are including this cautionary note to make applicable, and to take advantage of, the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 for forward-looking statements. The information in this news release is given as of the date above and Mirati expressly disclaims any obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, unless required by law.


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SOURCE Mirati Therapeutics, Inc.

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