SAN DIEGO, Oct. 25, 2020 /PRNewswire/ -- Mirati
Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted
oncology company, today announced preliminary results from the
Company's mutant KRAS selective inhibitor programs. The preliminary
results included updated clinical data of adagrasib (MRTX849), the
Company's KRAS G12C inhibitor, presented at the 32nd
EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics
("ENA") and initial preclinical in vivo data of MRTX1133,
the Company's selective and potent potential first-in-class KRAS
G12D inhibitor.
Adagrasib is a potent and selective inhibitor of KRAS G12C,
optimized for a long half-life and a significant volume of tissue
distribution to maintain continuous inhibition of KRAS-dependent
signaling for the complete dose interval to maximize efficacy
demonstrated by the depth and duration of anti-tumor activity.
"The adagrasib preliminary data presented today showed deep and
durable anti-tumor activity in non-small cell lung cancer (NSCLC),
colorectal cancer (CRC) and other solid tumors, providing renewed
hope for patients that harbor a KRAS G12C mutation. A 45%
confirmed objective response rate for adagrasib as a monotherapy in
advanced NSCLC is compelling. While this data is still maturing,
adagrasib also demonstrated clinically meaningful duration of
treatment for NSCLC patients in the Phase 1/1b cohort," said Charles
M. Baum, M.D., Ph.D., President and Chief Executive Officer
of Mirati. "Enrollment is complete in the Phase 2 cohort of
adagrasib as a monotherapy treatment for patients in 2nd
/ 3rd line NSCLC and we anticipate submitting a New Drug
Application for accelerated approval in the second half of 2021.
Adagrasib has been well tolerated as a monotherapy and in
combination with pembrolizumab, cetuximab and TNO-155, a
SHP-2 inhibitor. We are initiating
additional registration-enabling global clinical studies of
adagrasib as both a monotherapy and in combinations as we expand
the program to earlier lines of therapy in NSCLC and CRC."
Adagrasib tolerability at a dose of 600 mg BID in both
monotherapy and combination trials:
- In a pooled assessment of 110 patients harboring a G12C
mutation in NSCLC, CRC and other solid tumors, monotherapy
adagrasib has been well tolerated
-
- 4.5% of treatment-related adverse events led to
discontinuation
- Over 50 patients have been treated with adagrasib in
combination with either pembrolizumab (a PD-1 inhibitor) in NSCLC,
cetuximab (an anti-EGFR antibody) in CRC and TNO-155 (a
SHP-2 inhibitor) in NSCLC or CRC
-
- Each combination has been well tolerated
- The pembrolizumab and cetuximab combination cohorts are ongoing
and each have cleared the dose limiting toxicity evaluation period
at the full dose of each commercial agent and at a 600 mg BID dose
of adagrasib
- The TNO-155 combination dose escalation and expansion cohorts
are ongoing at a 600 mg BID dose of adagrasib
Preliminary efficacy data as of August
30, 2020 in patients with advanced NSCLC treated with
adagrasib as a monotherapy at a 600 mg BID dose:
- Patients had a median of two prior systemic treatments,
including all patients receiving prior treatment with
platinum-based chemotherapy regimens and 92% of patients receiving
prior treatment with an anti-PD-1 /L1 inhibitor
- Efficacy data from pooled Phase 1/1b cohort and Phase 2 registration-enabling
cohort (n=51):
-
- 45% (23/51) confirmed objective response rate (ORR)
-
- 70% (16/23) of responders had a best tumor response greater
than 40%
- 96% (49/51) disease control rate (DCR)
- 3.6 months median duration of follow-up
-
- 65% (33/51) of patients remain on treatment
- 83% (19/23) of responders have not progressed and remain on
treatment
- Efficacy data from the Phase 1/1b
cohort (n=14):
-
- 43% (6/14) confirmed ORR
- 100% (14/14) DCR
- 8.2 months median duration of treatment
-
- 50% (7/14) of patients remain on treatment
- 83% (5/6) of responders remain in response and on
treatment
-
- 4 of 6 responders have a duration of treatment for >11
months and all 4 patients remain on treatment
- Preliminary explorative correlative analysis of co-mutations of
KRAS G12C and STK11 in advanced NSCLC showed a 64% (9/14) ORR
across pooled Phase 1/1b and Phase 2
cohorts:
-
- Approximately 30% of all KRAS G12C mutant NSCLC patients have a
STK11 co-occurring mutation
- Co-occurring KRAS and STK11 mutations have been shown to be
significantly correlated with poor clinical outcomes when treated
with immunotherapy and platinum-based chemotherapy regimens
- In a case study presented today from the ongoing clinical trial
of adagrasib as a monotherapy, a heavily pre-treated NSCLC patient
with an unirradiated, active brain metastases observed a 67%
reduction in tumor volume including the disappearance of a
metastatic brain lesion:
-
- Preclinical studies demonstrate dose-dependent brain and
cerebrospinal fluid (CSF) exposure
- The Phase 2 cohort of adagrasib as a monotherapy is currently
enrolling additional NSCLC patients with active brain metastases to
further explore this patient population which has a high unmet
medical need
In a case study presented today from the ongoing clinical trial
of adagrasib in combination with TNO-155 (investigational
SHP-2 inhibitor) in collaboration
with Novartis, a heavily pre-treated NSCLC patient treated in the
combination trial of adagrasib and TNO-155 (investigational
SHP-2 inhibitor) observed a 60%
reduction in tumor volume:
- Data was from a scan on August 24,
2020
- Prior therapy included treatment with a non-adagrasib
monotherapy G12C direct inhibitor (with initial partial response
followed by disease progression) and in combination with another
SHP-2 inhibitor with chemotherapy
(which was discontinued due to an adverse event)
Preliminary efficacy data as of August
30, 2020 in heavily pretreated patients with advanced CRC
treated with adagrasib as a monotherapy at a 600 mg BID dose:
- Median of 4 prior systemic treatments
-
- Efficacy data from pooled Phase 1/1b and Phase 2 cohorts (n=18)17% (3/18) confirmed
ORR with 2 of 3 responders remaining on treatment
- 94% (17/18) DCR
- 67% (12/18) of patients remain on treatment
-
- 55% (10/18) have a duration of treatment of >4 months
Preliminary efficacy data as of August
30, 2020 in patients with advanced solid tumors, other than
NSCLC and CRC, treated with adagrasib as a monotherapy at 600 mg
BID dose from a Phase 1/1b
cohort:
- One patient each (n=4) with pancreatic, ovarian, endometrial
and cholangiocarcinoma tumors were treated, and each patient had a
confirmed partial response to therapy
- 2 appendiceal cancer patients had stable disease
- All 6 eligible patients remain on treatment
MRTX1133 Preclinical Summary
MRTX1133, the Company's potent, selective and reversible
inhibitor of KRAS G12D, binds to and inhibits mutant KRAS protein
in both its active and inactive states. MRTX1133 exhibits single
digit nanomolar potency and is >1000-fold selective for KRAS
G12D compared with wild-type KRAS in cellular assays. Based on
preclinical analyses, MRTX1133 has a projected human half-life
exceeding 50 hours and exhibits a low propensity for drug
interactions or off-target pharmacology. MRTX1133 demonstrated
tumor regression in multiple in vivo tumor models, including
pancreatic and colorectal cancers.
"MRTX1133, a potential first-in-class compound, continues to
advance toward an Investigational New Drug filing in the first half
of 2021. The drug properties and antitumor activity we've observed
in preclinical tumor models continue to show promise," said
James G. Christensen, Ph.D.,
Executive Vice President and Chief Scientific Officer at Mirati.
"MRTX1133 has a low predicted target plasma concentration, based on
its potency and high unbound fraction, and our goal is to achieve
near complete and sustained target inhibition and maximal
anti-tumor activity. To ensure sustained therapeutic levels are
achieved, we are pursuing both oral and parenteral routes of
administration in parallel as we plan for a Phase 1 clinical trial
and intend to select the route that results in the optimal KRAS
G12D inhibition. We are driven by the opportunity to positively
impact the lives of patients with KRAS mutant cancers who have
limited treatment options."
ENA Presentations on Adagrasib Clinical Data:
Pasi A. Janne, M.D., Ph.D.,
Director of the Lowe Center for Thoracic Oncology at Dana-Farber
Cancer Institute, Professor of Medicine, Harvard University and the Scientific Director of
the Belfer Center for Applied Cancer Science, presented updated
data for adagrasib in NSCLC patients from MRTX849-001. The
presentation is titled, "KRYSTAL-1: Activity and Safety of
Adagrasib (MRTX849) in Advanced/Metastatic Non-Small Cell Lung
Cancer (NSCLC) Harboring KRAS G12C Mutation"
(LBA-03).
Melissa L. Johnson, M.D.,
Associate Director of the Lung Cancer Research Program at Sarah
Cannon Research Institute and Partner, Tennessee Oncology, PLLC,
presented updated data for adagrasib in other solid tumors
harboring a KRAS G12C mutation from MRTX849-001. The presentation
is titled, "KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849)
in Patients with Colorectal Cancer (CRC) and Other Solid Tumors
Harboring a KRAS G12C Mutation" (LBA-04).
"It's an inspiring and exciting time in the oncology field to
see potential targeted therapeutic options for patients with the
KRAS G12C mutation, a patient population that has historically
faced limited treatment options. The clinical outcomes presented
today, including the depth and maturing duration of responses in
non-small cell lung cancer, colorectal cancers, and other solid
tumors, along with the overall favorable safety profile, are highly
encouraging," said Dr. Pasi Jänne.
Virtual Investor Event
Mirati will host a virtual investor event on October 25, 2020, at 1:30
p.m. PT/4:30 p.m. ET. Company
executives will provide an overview of the adagrasib clinical data
presented at the EORTC-NCI-AACR conference and share initial
preclinical data for MRTX1133, the Company's KRAS G12D selective
inhibitor.
Investors and the general public are invited to listen to a live
webcast of the event through the "Investors" section of the Mirati
corporate website at http://ir.mirati.com/events-and-presentations.
Materials related to the webcast will be available at the same
website prior to the event. A replay of the event will be available
shortly after the conclusion of the event.
About Adagrasib (MRTX849)
Adagrasib is an investigational, orally available small molecule
that is designed to potently and selectively inhibit a form of KRAS
which harbors a substitution mutation (G12C). KRAS G12C mutations
are frequently linked to negative prognoses and are present in
approximately 14% of non-small cell lung cancer (NSCLC)
adenocarcinoma patients, 3-4% of colorectal cancer patients (CRC),
and subsets of other types of cancer. Adagrasib is being evaluated
as a monotherapy to treat patients with KRAS G12C-positive advanced
solid tumors, including a registration enabling cohort in NSCLC.
Adagrasib is also currently being evaluated in various combination
cohorts in NSCLC and CRC with a PD-1 inhibitor, EGFR inhibitor,
pan-EGFR inhibitor and SHP2
inhibitor.
About MRTX1133
MRTX1133 is designed to potently and selectively inhibit a form
of KRAS which harbors a substitution mutation (G12D).
MRTX1133 is in investigational new drug (IND)-enabling
studies. KRAS G12D mutations impact an estimated 180,000
patients in the U.S. and Europe.
The prevalence of the G12D oncogenic mutation is much higher than
others including G12C, ALK, RET and TRK. G12D is present in
approximately 36% of pancreatic patients, 12% of colorectal
patients, 4% of NSCLC adenocarcinoma patients and 6% of endometrial
patients.
About Mirati Therapeutics
Mirati Therapeutics (NASDAQ: MRTX) is a San Diego-based late-stage biotechnology
company relentlessly focused on translating drug discovery and
research into new treatments for patients by advancing and
delivering novel therapeutics that target the genetic and
immunologic drivers of cancer. Mirati is advancing a novel pipeline
to treat large patient populations across multiple programs and
tumor types, including two programs, adagrasib and sitravatinib, in
registration-enabling studies to treat non-small cell lung cancer
(NSCLC).
Adagrasib is an investigational small molecule and selective
KRAS G12C inhibitor in clinical development as a monotherapy and in
combinations. MRTX1133 is an investigational small
molecule and selective KRAS G12D inhibitor in preclinical
development.
Sitravatinib is an investigational spectrum-selective inhibitor
of receptor tyrosine kinases (RTK) designed to enhance immune
responses through the inhibition of immunosuppressive signaling.
Sitravatinib is being evaluated in multiple clinical trials to
treat patients who are refractory to prior immune checkpoint
inhibitor therapy, including a Phase 3 trial of sitravatinib in
combination with nivolumab in NSCLC.
For more information, visit www.mirati.com.
Forward Looking Statements
This press release contains forward-looking statements regarding
the business of Mirati Therapeutics, Inc. ("Mirati"). Any statement
describing Mirati's goals, expectations, financial or other
projections, intentions or beliefs, development plans and the
commercial potential of Mirati's drug development pipeline,
including without limitation adagrasib (MRTX849), sitravatinib and
MRTX1133, is a forward-looking statement and should be considered
an at-risk statement. Such statements are subject to risks and
uncertainties, particularly those challenges inherent in the
process of discovering, developing and commercializing new drug
products that are safe and effective for use as human therapeutics,
and in the endeavor of building a business around such drugs. These
and other risks concerning Mirati's programs are described in
additional detail in Mirati's quarterly reports on Form 10-Q and
annual reports on Form 10-K, which are on file with the U.S.
Securities and Exchange Commission (the "SEC") available at the
SEC's Internet site (www.sec.gov).
Mirati's forward-looking statements also involve assumptions
that, if they never materialize or prove correct, could cause its
results to differ materially from those expressed or implied by
such forward-looking statements. Although Mirati's forward-looking
statements reflect the good faith judgment of its management, these
statements are based only on facts and factors currently known by
Mirati. As a result, you are cautioned not to rely on these
forward-looking statements. These forward-looking statements are
made as of the date of this press release, and Mirati assumes no
obligation to update the forward-looking statements, or to update
the reasons why actual results could differ from those projected in
the forward-looking statements, except as required by law.
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