Investigator-Initiated Phase 1 Study is First
to Evaluate a Dual RAF/MEK Inhibitor Using Innovative Intermittent
Dosing Schedules in Patients Harboring RAS/RAF Pathway
Mutations
Study Finds VS-6766 Regimen is Tolerable and
Shows Antitumor Activity in Recommended Phase 2 Single Agent
Dose
Phase 2 Registration-Directed Trials with
VS-6766 Alone and in Combination with Defactinib in Low-Grade
Serous Ovarian Cancer and KRAS Mutant Non-Small Cell Lung Cancer
Expected to Commence by Year-End 2020
Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology),
a biopharmaceutical company committed to advancing new medicines
for patients battling cancer, today announced new data have been
published today in The Lancet Oncology. The study evaluated the
intermittent dosing schedule of VS-6766 (formerly known as
CH5126766) to inform further testing of VS-6766 as both a single
agent in RAS/RAF-mutant cancers such as KRAS mutant non-small cell
lung cancer (NSCLC) or in combination with small molecules
including the FAK inhibitor defactinib in KRAS mutant solid tumors
(NCT03875820). In this dose-escalation study, tolerability and
antitumor activity were observed across various cancers with
RAS/RAF/MEK pathway mutations.
“The positive results observed with this innovative intermittent
dosing regimen of VS-6766 demonstrate its significant potential
across various cancers with RAS/RAF/MEK pathway mutations,” stated
Udai Banerji, Professor of Molecular Cancer Pharmacology at The
Institute of Cancer Research, London, and Honorary Consultant in
Medical Oncology, MBBS, MD, DNB, PhD, FRCP at The Royal Marsden NHS
Foundation Trust, London, and lead investigator of the clinical
study. “We were encouraged by the data, demonstrating both
antitumor activity and tolerability of VS-6766, and this
intermittent schedule can be used alone or for combination therapy
schedules with other anticancer agents for a variety of
difficult-to-treat cancers.”
The full manuscript, titled “Intermittent schedules of the oral
RAF–MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant
solid tumours and multiple myeloma: a single-centre, open-label,
phase 1 dose-escalation and basket dose-expansion study,” can be
accessed here.
“These results support the potential of VS-6766 as a treatment
for a variety of cancers where conventional approaches have been
sub-optimal and there is significant unmet need. We believe VS-6766
has the potential to be the backbone of RAS therapy by addressing
the multiple points of resistance and toxicity issues that have
made advancing new options difficult,” said Brian Stuglik, Chief
Executive Officer of Verastem Oncology. “Our Phase 2
registration-directed trials with VS-6766 in low grade serous
ovarian cancer and KRAS mutant NSCLC are scheduled to begin by the
end of this year. These adaptive design trials are a capital
efficient approach to rapidly evaluate VS-6766 alone or in
combination with defactinib to determine which regimen to take
forward into the expansion phase of the trial.”
Results from the Phase 1 Study Investigating Intermittent
Dosing of VS-6766 in Patients with RAS/RAF-mutated Solid Tumors and
Multiple Myeloma
Between June 2013 to January 2019, 58 patients, including 51
patients with solid tumors and seven patients with multiple
myeloma, were enrolled in a study conducted at The Institute of
Cancer Research (ICR) and The Royal Marsden Hospital in the U.K.
The study consisted of two parts; 1) dose escalation part to
determine the recommended dosage (29 patients) and 2) basket
expansion part to investigate efficacy and safety of the
recommended dosage determined in the dose escalation part (29
patients).
Four mg twice weekly was established as the recommended Phase 2
dose for VS-6766 monotherapy and was deemed tolerable based on
clinician’s assessment with several patients remaining on study for
more than six months.
In the subsequent basket expansion part, seven (26.9%) of 26
response-evaluable patients with RAS mutations in the basket
expansion achieved objective responses, with response rates in
patients with NSCLC, gynecological malignancies, colorectal cancer
(CRC), melanoma, and multiple myeloma being 3/10 (30%), 3/5 (60%),
0/4 (0%), 0/1 (0%), and 1/6 (16.7%), respectively. In all six
responders with solid tumors, tumor shrinkage was observed at the
time of the first restaging scan after two cycles of treatment,
with partial responses confirmed after two to four cycles. Five of
the six responses lasted more than six months.
Among the 57 safety-evaluable patients, the most common Grade
3/4 treatment related adverse events (TRAEs) were rash (19%), CPK
elevation (11%), hypoalbuminemia (11%), and fatigue (7%). Five (9%)
patients experienced treatment-related serious adverse events. In
the study, TRAEs were manageable, resolved spontaneously or
reversed with dose modification. There were no treatment-related
deaths. The study also confirmed a long half-life of 55 hours and
target engagement in the form of reduction of both p-ERK and p-MEK
in three patients who underwent paired biopsies, supporting
intermittent dosing schedules.
This study was supported by Chugai Pharmaceutical Co., Ltd.
Verastem in-licensed VS-6766 from Chugai in January 2020.
About VS-6766
VS-6766 (formerly known as CH5126766 and CKI27) is a unique
inhibitor of the RAF/MEK signaling pathway. In contrast to other
MEK inhibitors in development, VS-6766 blocks both MEK kinase
activity and the ability of RAF to phosphorylate MEK. This unique
mechanism allows VS-6766 to block MEK signaling without the
compensatory activation of MEK that appears to limit the efficacy
of other inhibitors.
About Defactinib
Defactinib (VS-6063) is an oral small molecule inhibitor of FAK
and PYK2 that is currently being evaluated as a potential
combination therapy for various solid tumors. The Company has
received Orphan Drug designation for defactinib in ovarian cancer
and mesothelioma in the US, EU and Australia. Preclinical research
by Verastem Oncology scientists and collaborators at world-renowned
research institutions has described the effect of FAK inhibition to
enhance immune response by decreasing immuno-suppressive cells,
increasing cytotoxic T cells, and reducing stromal density, which
allows tumor-killing immune cells to enter the tumor.1,2
About the VS-6766/Defactinib Combination
RAS mutant tumors are present in 30% of all human cancers and
have historically presented a difficult treatment challenge and are
often associated with significantly worse prognosis. Challenges
associated with identifying new treatment options for these types
of cancers include resistance to single agents, identifying
tolerable combination regimens with MEK inhibitors and new RAS
inhibitors in development addressing only a minority of all RAS
mutated cancers.
The combination of VS-6766 and defactinib has been found to be
clinically active in patients with KRAS mutant tumors. In an
ongoing investigator-initiated Phase 1/2 FRAME study, the
combination of VS-6766 and defactinib is being evaluated in
patients with LGSOC, KRAS mutant NSCLC and colorectal cancer (CRC).
Updated interim data from this study presented at the 2nd Annual
RAS-Targeted Drug Development Summit in September 2020 demonstrated
a 56% overall response rate and long duration of therapy among
patients with KRAS-G12 mutant LGSOC. Based on an observation of
higher response rates seen in NSCLC patients with KRAS-G12V
mutations in the study, Verastem will also be further exploring the
role of VS-6766 and defactinib in KRAS-G12V NSCLC. The FRAME study
was expanded in August 2020 to include new cohorts in pancreatic
cancer, KRAS mutant endometrial cancer and KRAS-G12V NSCLC.
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a development-stage
biopharmaceutical company committed to the development and
commercialization of new medicines to improve the lives of patients
diagnosed with cancer. Our pipeline is focused on novel small
molecule drugs that inhibit critical signaling pathways in cancer
that promote cancer cell survival and tumor growth, including
RAF/MEK inhibition and focal adhesion kinase (FAK) inhibition. For
more information, please visit www.verastem.com.
Forward-Looking Statements Notice
This press release includes forward-looking statements about
Verastem Oncology’s strategy, future plans and prospects, including
statements related to the potential clinical value of the
RAF/MEK/FAK combination and the anticipated timeline for Phase 2
registration-directed trials with VS-6766 in low grade serous
ovarian cancer and KRAS mutant NSCLC. The words "anticipate,"
"believe," "estimate," "expect," "intend," "may," "plan,"
"predict," "project," "target," "potential," "will," "would,"
"could," "should," "continue," “can,” “promising” and similar
expressions are intended to identify forward-looking statements,
although not all forward-looking statements contain these
identifying words. Each forward-looking statement is subject to
risks and uncertainties that could cause actual results to differ
materially from those expressed or implied in such statement.
Applicable risks and uncertainties include the risks and
uncertainties, among other things, regarding: the success in the
development and potential commercialization of our product
candidates, including defactinib in combination with VS-6766; the
occurrence of adverse safety events and/or unexpected concerns that
may arise from additional data or analysis or result in
unmanageable safety profiles as compared to their levels of
efficacy; our ability to obtain, maintain and enforce patent and
other intellectual property protection for our product candidates;
the scope, timing, and outcome of any legal proceedings; decisions
by regulatory authorities regarding labeling and other matters that
could affect the availability or commercial potential of our
product candidates; whether preclinical testing of our product
candidates and preliminary or interim data from clinical trials
will be predictive of the results or success of ongoing or later
clinical trials; that the timing, scope and rate of reimbursement
for our product candidates is uncertain; that third-party payors
(including government agencies) may not reimburse; that there may
be competitive developments affecting our product candidates; that
data may not be available when expected; that enrollment of
clinical trials may take longer than expected; that our product
candidates will experience manufacturing or supply interruptions or
failures; that we will be unable to successfully initiate or
complete the clinical development and eventual commercialization of
our product candidates; that the development and commercialization
of our product candidates will take longer or cost more than
planned; that we or Chugai Pharmaceutical Co., Ltd. will fail to
fully perform under the VS-6766 (CH5126766) license agreement; that
we may not have sufficient cash to fund our contemplated
operations; that we may be unable to make additional draws under
our debt facility or obtain adequate financing in the future
through product licensing, co-promotional arrangements, public or
private equity, debt financing or otherwise; that we will be unable
to execute on our partnering strategies for defactinib in
combination with VS-6766; that we will not pursue or submit
regulatory filings for our product candidates, and that our product
candidates will not receive regulatory approval, become
commercially successful products, or result in new treatment
options being offered to patients.
Other risks and uncertainties include those identified under the
heading “Risk Factors” in the Company’s Annual Report on Form 10-K
for the year ended December 31, 2019 as filed with the Securities
and Exchange Commission (SEC) on March 11, 2020 and in any
subsequent filings with the SEC. The forward-looking statements
contained in this press release reflect Verastem Oncology’s views
as of the date hereof, and the Company does not assume and
specifically disclaims any obligation to update any forward-looking
statements whether as a result of new information, future events or
otherwise, except as required by law.
1 Gerber D. et al. Phase 2 study of the focal adhesion kinase
inhibitor defactinib (VS-6063) in previously treated advanced KRAS
mutant non-small cell lung cancer. Lung Cancer 2020: 139:60-67. 2
Chénard-Poirier, M. et al. Results from the biomarker-driven basket
trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS-
or RAF-mutated malignancies including multiple myeloma. Journal of
Clinical Oncology 2017: 35. 10.1200/JCO.2017.35.15_suppl.2506.
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Investors: John Doyle Vice President, Investor Relations &
Finance +1 781-469-1546 jdoyle@verastem.com
Media: Lisa Buffington Corporate Communications +1
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