CHICAGO, May 30, 2015 /PRNewswire/ -- Mirati
Therapeutics, Inc. ("Mirati") (NASDAQ: MRTX) today presented data
that demonstrated preliminary evidence of clinical activity from
its investigational targeted tyrosine kinase inhibitor candidate,
MGCD265, as part of the developmental therapeutics category at the
2015 American Society of Clinical Oncology (ASCO) Annual Meeting
being held in Chicago from
May 29-June 2, 2015. The Company also
provided updates on its other targeted tyrosine kinase inhibitor,
MGCD516, and spectrum-selective HDAC inhibitor, mocetinostat. Both
MGCD516 and mocetinostat were presented as clinical trials in
progress at the conference.
"New cancer therapies specifically targeting genetic drivers in
selected patients may represent a significant advance compared to
traditional chemotherapy," said Christian Kollmannsberger, M.D.,
British Columbia Cancer Agency, Vancouver Cancer
Centre. "MGCD265 is a receptor tyrosine kinase inhibitor that
selectively targets tumors in patients with MET or Axl gene
alterations. In an ongoing single agent expansion study of MGCD265
in non-small cell lung cancer patients with these alterations, we
have seen significant tumor regression in three patients as well as
improvement in clinical symptoms such as pain and shortness of
breath. Data from this study indicate that MGCD265 can fully
inhibit MET and Axl, is well tolerated and should be studied
further to define the benefit to patients with lung cancer."
"Data from the Phase 1/1b expansion study presented today
clearly demonstrate the anti-tumor activity of MGCD265 and support
our hypothesis that targeting MET driver alterations is a
clinically valid approach. MGCD265 is the first MET inhibitor
targeting MET mutations, MET gene amplification and Axl
rearrangements. Collectively, these driver alterations comprise up
to 8% of patients with non-small cell lung cancer," said
Charles M. Baum, M.D., Ph.D.,
president and CEO, Mirati. "We are very encouraged by the initial
results from this study. The first three non-small cell lung cancer
patients with MET exon 14 deletion mutations or MET gene
amplification showed clear tumor regression as early as the first
assessment and the trial continues to enroll additional patients.
Treatment was well tolerated in dose escalation and dose expansion
cohorts and PK/PD data demonstrated robust inhibition. These data
increase our confidence in the program and we expect to initiate a
single arm registration-enabling study in NSCLC by the end of the
year."
MGCD265 Phase 1/1b Study, Expansion Cohort:
MGCD265 is
an inhibitor of the MET and Axl receptor tyrosine kinase pathways
which, when mutated, are drivers of tumor growth. Preclinical data
have shown that MGCD265 can potently inhibit tumor cell growth in
vitro. Tumor xenograft data demonstrated that tumors with MET exon
14 deletion mutations or MET gene amplification treated with
MGCD265 resulted in complete tumor regression, and were predictive
of clinical data observed in the ongoing MGCD265 expansion study.
This open label, single agent study is designed to evaluate the
safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and
clinical activity of twice-daily (BID) MGCD265 in patients who have
failed at least one prior therapy.
This multinational study began enrollment at the end of
December 2014 and continues to enroll
NSCLC patients with MET or Axl genetic alterations.
Evidence of clinical activity
Patients receive 1050 mg
of MGCD265 BID for 21-day cycles and are assessed for response
after every second treatment cycle. At the time of this initial
analysis, the first three NSCLC patients with MET gene alterations
showed a clinical benefit, including clear tumor regression and
improvement in clinical symptoms such as pain and shortness of
breath. Currently, these patients do not meet strict criteria for
RECIST responses. Patient details are noted below. (The MGCD265
Phase 1/1b study poster presented at ASCO contains additional
information, including patient scans noted below, and can be found
on the Company's website at www.mirati.com.)
- 76-year old male: Adenocarcinoma of the lung with a MET exon 14
deletion mutation. The patient enrolled in the study with lung
metastases, retroperitoneal and retrocrural lymph nodes and pleural
effusion. The patient had undergone platinum-based chemotherapy
followed by PD-L1 inhibitor therapy with the best response to each
therapy being progressive disease. The first scan after treatment
with MGCD265 demonstrated cavitation of the lung/retroperitoneal
mass with resolution of pain and cough. The patient continues on
the study and is currently in Cycle 5.
- 70-year old female: History of refractory metastatic
adenocarcinoma of the lung with a MET exon 14 deletion mutation.
The patient enrolled in the study with extensive liver metastases,
right pulmonary lesion and had undergone neoadjuvant
chemoradiation, radical pneumonectomy for T3N1 disease, received
chemoradiation for pleural and bone metastases, Stereotactic Body
Radiation Therapy (SBRT) for pulmonary metastatis, and resection of
recurrence in the colon. The first scan after treatment with
MGCD265 showed extensive tumor necrosis and regression. The patient
continues on the study and is currently in Cycle 6.
- 51-year old female: Adenocarcinoma of the lung with MET
amplification. The patient enrolled in the study with extensive
lung disease, bone and brain metastases. The patient had received
an EGFR inhibitor, undergone chemotherapy and whole brain
radiation. The first scan after treatment with MGCD265 demonstrated
regression of tumors in the lung. The patient continues on the
study and is currently in Cycle 3.
Safety and tolerability
In the dose escalation phase
of the study, the maximum tolerated dose of MGCD265 was 1050 mg
BID. This dose was shown to result in >90% inhibition of MET and
Axl based on preclinical predictions and biomarkers sMET and sAxl.
The dose limiting toxicities were grade 3 fatigue in one patient
and grade 3 diarrhea in one patient. In the dose escalation cohort,
MGCD265 was well tolerated at the 1050 mg BID dose and diarrhea in
subsequent patients is managed with standard doses of the
anti-diarrhea agent loperamide.
The Company expects to initiate a single arm Phase 2
registration-enabling study in NSCLC by the end of the year.
"While the initial focus of the single agent MGCD265 program is
on non-small cell lung cancer, MET is a critical driver in other
solid tumors. As approximately five percent of gastric cancer
patients have MET gene amplification, gastric cancer represents a
significant area for expanded development and, we believe, that
MGCD265 could result in clinically meaningful responses in this
underserved patient population," said Charles M. Baum, M.D., Ph.D., president and CEO,
Mirati. "In addition to the single agent opportunity in NSCLC,
there is a strong scientific rationale for the combination of
MGCD265 with a third-generation EGFR inhibitor. Recent data
have reinforced the hypothesis that MET and Axl may play an
important role in resistance to EGFR inhibition. We are
exploring our options and plan to start a combination study in
patients who are becoming resistant to EGFR inhibition."
The MGCD265 Phase 1/1b study poster presented at ASCO can be
found on the Company's website at www.mirati.com. Additional
information about this clinical trial of MGCD265 is available
at www.clinicaltrials.gov using identifier:
NCT00697632.
Mocetinostat Phase 2 Study in Urothelial Bladder Cancer
(UC):
Mocetinostat is a spectrum-selective histone
deacetylase (HDAC) inhibitor. This single arm, single agent Phase 2
clinical trial is designed to evaluate the efficacy, safety,
tolerability and PK of mocetinostat as a treatment for a select
group of patients with advanced urothelial carcinoma of the
bladder.
The primary objective of the study is to determine the clinical
activity of mocetinostat in patients with previously treated,
locally advanced, unresectable or metastatic urothelial carcinoma
of the bladder harboring inactivating mutations or deletions of the
histone acetyltransferase genes CREBBP and/or EP300 (estimated to
occur in approximately 20% of bladder cancer
patients). Secondary objectives include evaluation of safety,
secondary efficacy endpoints and PK. Mocetinostat is administered
orally three times per week on a 28-day cycle.
The mocetinostat Phase 2 study poster presented at ASCO can be
found on the Company's website at www.mirati.com. Additional
information about this clinical trial of mocetinostat is available
at www.clinicaltrials.gov using identifier: NCT02236195.
MGCD516 Phase 1 Study in NSCLC:
MGCD516 is a receptor
tyrosine kinase (RTK) inhibitor targeting the RET, DDR and Trk
tyrosine kinase signaling pathways, which are reported to be
oncogenic drivers. This Phase 1, open label, single agent study is
designed to evaluate the safety, PK/PD and clinical activity of
MGCD516 in patients with advanced solid tumors, with an initial
focus on NSCLC.
The primary objective of the dose escalation phase of the study
is to characterize the safety of MGCD516, determine a Phase 2 dose
and establish the maximum tolerated dose. MGCD516 is orally
administered to unselected patients with advanced solid tumors once
daily (QD) on a 21-day cycle. The study is exploring escalating
doses of 10 mg, 20 mg, 40 mg, 80 mg and 110 mg to date. Patients
have been enrolled across all dosing cohorts and dose escalation
will continue until a maximum tolerated dose is established.
The MGCD516 Phase 1 study poster presented at ASCO can be found
on the Company's website at www.mirati.com. Additional information
about this clinical trial of MGCD516 is available at
www.clinicaltrials.gov using identifier:
NCT02219711.
Mirati to Present at Jefferies 2015 Global Healthcare
Conference
Mirati will also be presenting at the Jefferies
2015 Global Healthcare Conference on Wednesday, June 3 at 8:00
a.m. ET/5:00 a.m. PT in
New York. Charles M. Baum, M.D., Ph.D., president and CEO
of Mirati, will provide a corporate overview.
A live audio webcast of the presentation will be accessible on
the "Investors" page of Mirati's corporate website at
www.mirati.com. A replay of the presentation will be available at
the same location for 60 days following the conference.
About NSCLC
Despite available treatment options, the
overall five year survival rate for patients with NSCLC is only
16.8% 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, and VEGF
monoclonal antibodies. 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.
MET is highly expressed in NSCLC tumors and higher MET receptor
expression rates correlate with advanced stages of tumor
progression, and poor clinical outcomes. Recent data indicate that
MET is a driver of tumor growth when it is genetically altered and
activated by point mutations, exon 14 deletions, and gene
amplification in a significant fraction (6-7%) of NSCLC patients.
MET exon 14 deletion mutations and MET amplification were recently
identified in a significant number of patients with lung
adenocarcinoma in The Cancer Genome Altas consortium project
(TCGA-2014a). MET mutations, including exon 14 deletion mutations,
and MET gene amplification each exhibit the key characteristics of
driver oncogenes in NSCLC. Rearrangements of the Axl tyrosine
kinase gene also appear to be a driver of tumor growth and occur in
~1% of patients with NSCLC.
Extensive preclinical and clinical data indicate that activation
of the MET pathway can result in resistance to EGFR inhibitors, as
well as the third-generation EGFR inhibitors that are active
against tumors with T790 mutations. Resistance is mediated through
mutation and/or overexpression of alternative RTK targets and
pathways, including MET and Axl. In certain tumors, MET may
actually substitute for, or cooperate with, EGFR to drive tumor
growth and progression. MET activation is believed to mediate
resistance to EGFR inhibitors by bypassing EGFR dependence and
activating downstream signaling. In this setting, MET activation
and EGFR mutations function as co-oncogenic drivers. Research has
shown that EGFR inhibitor resistance can be reversed in vivo
by combined EGFR and MET inhibition, a finding that validates
combination therapy with EGFR and MET inhibitors to address
therapeutic resistance.
About MGCD265
MGCD265 is a tyrosine kinase inhibitor
that is expected to potently and selectively target tumors in
patients with driver alterations in MET (mutations and gene
amplification) and Axl (rearrangements) that occur in approximately
8% of patients with non-small cell lung cancer (NSCLC). MGCD265 is
in the expansion phase of a Phase 1/1b dose escalation study for
NSCLC patients with MET or Axl genetic alterations. Genetic
alterations in these targets have been implicated as drivers of
tumor growth and disease progression in NSCLC, gastroesophageal
cancer and other solid tumors. MET and Axl are also implicated as
drivers of tumor progression in patients whose tumors have become
resistant to EGFR inhibitors. Therefore, the combination of MGCD265
with an EGFR inhibitor could treat patients who have become
resistant to agents targeting EGFR. Mirati retains worldwide
rights to MGCD265.
About Mocetinostat
Mocetinostat is an
orally-bioavailable, spectrum-selective HDAC inhibitor.
Mocetinostat is currently in a Phase 2 trial for the treatment of
patients with bladder cancer that carry inactivating mutations of
the histone acetyltransferase
genes CREBBP and EP300. An investigator-sponsored
Phase 2 study evaluating mocetinostat as a treatment for diffuse
large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) is
underway. The U.S. FDA has granted Orphan Drug
Designation to mocetinostat as a treatment for DLBCL. Mirati
retains worldwide rights to mocetinostat with the exception of
certain Asian territories where the program is partnered
with Taiho Pharmaceutical Co., Ltd.
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. These kinases and their 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 in a Phase 1 dose escalation study in advanced solid
tumors with an initial focus on NSCLC. Mirati retains worldwide
rights to MGCD516.
About Mirati Therapeutics
Mirati Therapeutics develops
molecularly targeted cancer treatments that are intended to inhibit
tumor growth. 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 targeted oncology 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 www.mirati.com.
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.
Company Contact:
Anne
Erickson
Mirati Therapeutics Inc.
Investor Relations and Corporate Communications
858-332-3532
ericksona@mirati.com
Investor Relations and Media Relations:
Jason Spark
Canale Communications
619-849-6005
jason@canalecomm.com
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