Combination of VS-6766 and Defactinib
Demonstrates 67% (4/6 Patients) Overall Response Rate in KRAS
Mutant Low-Grade Serous Ovarian Cancer in Phase 1 Trial
Subsequent Combined Analysis (VS-6766
Monotherapy and Defactinib Combination) Demonstrates 57% (4/7
Patients) Overall Response Rate in KRASG12V Non-Small Cell Lung
Cancer
Management to Host Investor Conference Call
Today at 8:00 AM ET
Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology),
a biopharmaceutical company committed to developing and
commercializing new medicines for patients battling cancer, today
announced results from the ongoing investigator-initiated Phase 1
clinical study investigating VS-6766, its RAF/MEK inhibitor, in
combination with defactinib, its FAK inhibitor, in patients with
KRAS mutant advanced solid tumors. The data will be presented as a
virtual poster today at the American Association for Cancer
Research (AACR) 2020 Virtual Annual Meeting I.
This ongoing study is an open label, dose escalation and
expansion study. The expansion cohorts are currently ongoing in
patients with advanced solid tumors, including low-grade serous
ovarian cancer (LGSOC), KRAS mutant non-small cell lung cancer
(NSCLC) and KRAS mutant colorectal cancer (CRC). In the LGSOC
cohort, among the patients with KRAS mutant tumors (n=6), 4
patients responded, for an overall response rate (ORR) of 67%.
Median time on treatment was 20.5 months. In the KRAS mutant NSCLC
cohort (n=10), 1 patient achieved a partial response and 8 patients
achieved disease control. In this cohort, 70% of patients continued
on treatment at least 12 weeks and 30% of patients continued on
treatment at least 24 weeks.
Based on an observation of higher response rates seen in
patients with KRASG12V mutations in the investigator-initiated
Phase 1 combination study, we conducted a combined analysis with
data from the combination study and the prior single-agent study
that utilized a twice-weekly dosing schedule of VS-67661 to get a
more complete picture of activity in KRASG12V mutations. The
subsequent, combined analysis (VS-6766 monotherapy and defactinib
combination) showed a 57% ORR (4/7 patients); as a single agent
(2/5 patients) and in combination with defactinib (2/2 patients) in
KRASG12V mutant NSCLC. Similarly, the combined analysis showed a
60% ORR (3/5 patients); as a single agent (1/2 patients) and in
combination with defactinib (2/3 patients) in KRASG12V mutant
gynecologic cancers. These additional analyses were conducted by
Verastem Oncology to understand the impact that various KRAS
variants may have had on response to identify potential signals to
pursue in future prospective studies. This additional analysis was
not part of the AACR 2020 poster presentation.
“Earlier research has demonstrated MEK inhibitors can cause
upregulation of FAK in KRAS mutant tumors, which are notoriously
difficult to treat and quite common across solid tumors. The
combination of a RAF/MEK and FAK inhibitor can potentially overcome
this challenge and opens up an exciting new pathway for treatment,”
stated Professor 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 found that the combination
of VS-6766 and defactinib in low-grade serous ovarian cancer
(LGSOC) was well tolerated by the patients in the trial and shows
promising clinical activity, including durable response that is
associated with clinically meaningful benefit. The study continues
to enroll additional patients into the ovarian, lung and colorectal
expansion cohorts with additional responses seen in all
cohorts.”
“We are encouraged by these early response rates in KRAS mutant
LGSOC and in KRASG12V mutant tumors as they underscore the
significant potential of this novel approach in areas of high unmet
medical need,” said Brian Stuglik, Chief Executive Officer of
Verastem Oncology. “The potential of the combination of VS-6766 and
defactinib is rapidly evolving as we continue to gain more insights
and analyze the data. We plan to initiate discussions with
regulatory authorities as soon as possible to define a path
forward, with the goal of commencing a registration-directed
clinical trial during 2020.”
Initial Results from the Phase 1 Study Investigating the
Combination of VS-6766 and Defactinib in Patients with KRAS Mutant
Cancers and Subsequent Analyses
The poster presentation describes safety and dose response data
from the dose-escalation portion and expansion cohorts from an
open-label, investigator-initiated Phase 1 study conducted in the
United Kingdom assessing the combination of RAF/MEK and FAK
inhibitor therapy in patients with LGSOC and KRAS mutant NSCLC. The
study evaluated the combination of VS-6766 and defactinib. VS-6766
was administered using a twice-weekly dose escalation schedule and
was administered 3 out of every 4 weeks. Defactinib was
administered using a twice-daily dose escalation schedule, also 3
out of every 4 weeks. Dose levels were assessed in 3 cohorts:
cohort 1 (VS-6766 3.2mg, defactinib 200mg); cohort 2a (VS-6766 4mg,
defactinib 200mg); and cohort 2b (VS-6766 3.2mg, defactinib
400mg).
In the patients with LGSOC (n=8), the ORR was 50% (n=4). Among
the patients with KRAS mutant LGSOC (n=6), the ORR was 67% (n=4).
Of the 4 patients who have responded, 3 had a prior MEK inhibitor
and as of November 2019 had been on study for a median of 20.5
months (range 7-23 months). In the patients with NSCLC (n=10), all
of which had KRAS mutations, 1 patient achieved a partial response
and 1 patient with a 22% tumor reduction still on treatment as of
November 2019. Median time on treatment for this cohort was
approximately 18 weeks.
Based on an observation of higher response rates seen in
patients with KRASG12V mutations in the investigator-initiated
Phase 1 combination study, we conducted a combined analysis with
data from the combination study and the prior single-agent study
that utilized a twice-weekly dosing schedule of VS-67661 to get a
more complete picture of activity in KRASG12V mutations. The
subsequent, combined analysis (VS-6766 monotherapy and defactinib
combination) showed a 57% ORR (4/7 patients); as a single agent
(2/5 patients) and in combination with defactinib (2/2 patients) in
KRASG12V mutant NSCLC. Similarly, the combined analysis showed a
60% ORR (3/5 patients); as a single agent (1/2 patients) and in
combination with defactinib (2/3 patients) in KRASG12V mutant
gynecologic cancers. These additional analyses were conducted by
Verastem Oncology to understand the impact that various KRAS
variants may have had on response to identify potential signals to
pursue in future prospective studies. This additional analysis was
not part of the AACR 2020 poster presentation.
The most common side effects seen in the Phase 1 study were
rash, creatine kinase elevation, nausea, hyperbilirubinemia and
diarrhea, most being NCI CTC Grade 1/2 and all were reversible. The
recommended Phase 2 dose was determined to be cohort 1 (VS-6766
3.2mg, defactinib 200mg).
The preliminary data reported in the study suggest that a novel
intermittent dosing schedule of RAF/MEK and FAK inhibitor
combination therapy has promising clinical activity in patients
with KRAS mutant LGSOC and KRASG12V mutant NSCLC, including
patients previously treated with a MEK inhibitor. Expansion cohorts
remain ongoing.
Details for the AACR 2020 Virtual Meeting I presentation are
as follows:
Title: Phase 1 study of the combination of a RAF-MEK
inhibitor CH5126766 (VS-6766) and FAK inhibitor defactinib in an
intermittent dosing schedule with expansions in KRAS mutant cancers
Lead author: Udai Banerji, The Institute of Cancer Research
and The Royal Marsden Poster #: CT143 Session:
VPO.CT01 - Phase I Clinical Trials Date and Time: Monday,
April 27, 2020; 9:00 a.m. to 6:00 p.m. ET URL:
https://www.abstractsonline.com/pp8/#!/9045/presentation/10642
Conference Call and Webcast Information
The Verastem Oncology management team will host a conference
call and webcast on Monday, April 27, 2020, at 8:00 AM ET to
discuss the Phase 1 RAF/MEK/FAK combination data. The call can be
accessed by dialing (877) 341-5660 (U.S. and Canada) or (315)
625-3226 (international), five minutes prior to the start of the
call and providing the passcode 8390795.
The live, listen-only webcast of the conference call can be
accessed by visiting the investors section of the Company's website
at www.verastem.com. A replay of the webcast will be archived on
the Company's website for 90 days following the call.
About VS-6766
VS-6766 (formerly known as CH5126766, CKI27 and RO5126766) 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. The combination of VS-6766 and the focal
adhesion kinase (FAK) inhibitor defactinib is currently being
investigated in an investigator-initiated Phase 1 dose escalation
and expansion study. The expansion cohorts are currently ongoing in
patients with KRAS mutant advanced solid tumors, including low
grade serous ovarian cancer (LGSOC), non-small cell lung cancer
(NSCLC) and colorectal cancer (CRC).2 The ongoing clinical study of
the VS-6766/defactinib combination is supported by single-agent
Phase 2 studies which investigated defactinib in KRAS mutant NSCLC3
and VS-6766 in KRAS mutant NSCLC and LGSOC.1
About Defactinib
Defactinib 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.4,5 Additionally, in
both preclinical and clinical studies, FAK activation has been
shown to occur as a potential resistance mechanism in response to
MEK inhibitor treatment, and synergy of a FAK inhibitor with a
RAF/MEK inhibitor has been shown in several preclinical models. The
combination of defactinib and VS-6766 is currently being
investigated in an investigator-initiated Phase 1 dose escalation
and expansion study. The expansion cohorts are currently ongoing in
patients with KRAS mutant advanced solid tumors, including low
grade serous ovarian cancer (LGSOC), non-small cell lung cancer
(NSCLC) and colorectal cancer (CRC).2 The ongoing clinical study of
the VS-6766/defactinib combination is supported by single-agent
Phase 2 studies which investigated defactinib in KRAS mutant NSCLC3
and VS-6766 in KRAS mutant NSCLC and LGSOC.4 Defactinib is also in
clinical testing in combination with pembrolizumab for treatment of
patients with pancreatic cancer, NSCLC and mesothelioma.6
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a commercial
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
phosphoinositide 3-kinase (PI3K), focal adhesion kinase (FAK) and
RAF/MEK inhibition.
Our first FDA approved product is available for the treatment of
patients with certain types of indolent non-Hodgkin’s lymphoma
(iNHL).
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 timing of commencing a
registration-directed trial for the RAF/MEK/FAK combination. 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.
References
1 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.
2 https://clinicaltrials.gov, NCT03875820
3 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.
4 Jiang H et al. Targeting focal adhesion kinase renders
pancreatic cancers responsive to checkpoint immunotherapy. Nat Med
2016: Aug 22(8) 851-60.
5 Sulzmaier F.J. et al. FAK in cancer: mechanistic findings and
clinical applications. Nature Rev Cancer. 2014 14: 598-610.
6 www.clinicaltrials.gov, NCT02758587
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version on businesswire.com: https://www.businesswire.com/news/home/20200426005068/en/
Investors: John Doyle Vice President, Investor Relations &
Finance +1 781-469-1546 jdoyle@verastem.com
Media: Lisa Buffington Corporate Communications +1 781-292-4205
lbuffington@verastem.com
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