Data Presented at the American Association for
Cancer Research 2020 Virtual Annual Meeting II Show Synergism
between FAK and RAF/MEK Inhibition Supporting Clinical Evaluation
of Defactinib with VS-6766 in Metastatic Uveal Melanoma
Verastem’s RAF/MEK Inhibitor (VS-6766) and FAK
Inhibitor (Defactinib) Currently Being Investigated Clinically in
Low-Grade Serous Ovarian and KRAS Mutant Non-Small Cell Lung
Cancers
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 a study that provides preclinical
proof-of-concept for combining VS-6766, its RAF/MEK inhibitor, with
defactinib, its focal adhesion kinase (FAK) inhibitor, for the
treatment of metastatic uveal melanoma (UM), the most prevalent eye
cancer among adults. The data comprise one of four virtual posters
with Verastem authors being presented today at the American
Association for Cancer Research (AACR) 2020 Virtual Annual Meeting
II, which is taking place June 22-24, 2020.
Uveal melanoma arises from the melanin-producing cells in the
eye, similar to how it arises in cutaneous melanoma. While it’s
considered rare, primary UM metastasizes in 50% of patients with
only 8% of patients surviving 2 years after development of
metastatic disease.1 Previously, MEK inhibitors, including
selumetinib and trametinib, have failed to show substantial
clinical benefit for patients with metastatic uveal melanoma.2,3
Indeed, no current therapies improve overall survival for
metastatic UM and there is a high unmet need for novel
therapies.4
In the current preclinical study, FAK inhibition (FAKi; e.g.,
defactinib) demonstrated synergistic growth-inhibitory effects in
UM cells when combined with a MEK inhibitor (MEKi) or the
investigational RAF/MEK inhibitor VS-6766. Additionally, MEKi
increased phosphorylation of FAK, suggesting the need for FAK
blockade in combination with MEKi for more complete antitumor
effect. Accordingly, FAKi combination with MEKi induced apoptotic
cell death leading to rapid tumor regression in UM xenografts,
whereas the MEKi or FAKi as single agents showed tumor growth
inhibition but failed to showed tumor shrinkage. Furthermore, the
FAKi/MEKi combination was successful at reducing tumor burden in
liver metastasis UM models.
“The study identified and reinforced FAK as a viable pathway to
inhibit downstream from the GNAQ pathway, which is constitutively
active in UM,” said J. Silvio Gutkind, PhD, Distinguished Professor
of Pharmacology and Associate Director for Basic Science at UC San
Diego Moores Cancer Center, and senior investigator of the study.
“We observed that co-targeting of FAK and RAF/MEK signaling led to
tumor collapse in UM xenograft and liver metastasis models in vivo.
Based on the encouraging results of this study, we are excited to
work toward clinical testing of defactinib with VS-6766 for
patients with metastatic uveal melanoma.”
“These data build on a growing body of evidence that underscore
the potential of the VS-6766/defactinib combination for treatment
of a variety of solid tumors with significant medical need,” said
Brian Stuglik, Chief Executive Officer of Verastem Oncology. “We
will continue to evaluate the combination in metastatic uveal
melanoma along with rapidly advancing our broader clinical
development program in solid tumors.”
The combination of VS-6766 and defactinib is being evaluated in
patients with Low Grade Serous Ovarian Cancer (LGSOC), and KRAS
mutant non-small cell lung cancer (NSCLC) and colorectal cancer
(CRC) in the ongoing investigator-initiated Phase I trial. The
company also plans to support a Phase II investigator-initiated
study of the combination of VS-6766 and defactinib in uveal
melanoma anticipated to begin in late 2020.
Details for all abstracts selected for presentation at the
AACR 2020 Virtual Meeting II are as follows:
Title: FAK and MEK co-targeting: A new multimodal
precision therapy for GNAQ-driven uveal melanoma Lead
author: Justine S. Paradis Poster #: 6406/30
Session: PO.ET06.05 Date and Time: Monday, June 22,
2020; 9:00 a.m. to 6:00 p.m. EDT URL:
https://www.abstractsonline.com/pp8/#!/9045/presentation/5323
Title: The dual PI3K-δ/PI3K-γ inhibitor duvelisib
inhibits signaling and proliferation of solid tumor cells
expressing PI3K-δ and/or PI3K-γ Lead author: Silvia Coma
Poster #: 663/10 Session: PO.ET06.06 Date and
Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL:
https://www.abstractsonline.com/pp8/#!/9045/presentation/1880
Title: Single cell expression analysis of PIK3 genes to
direct solid tumor treatment with the dual PI3K-δ,γ inhibitor
duvelisib Lead author: Samantha Hidy Poster #: 1552/3
Session: PO.TB06.02 Date and Time: Monday, June 22,
2020; 9:00 a.m. to 6:00 p.m. EDT URL:
https://www.abstractsonline.com/pp8/#!/9045/presentation/7806
Title: PEGylated recombinant human hyaluronidase,
PEGPH20, significantly enhances the anti-tumor activity of the
combination of focal adhesion kinase Inhibitor and anti-PD-1
antibody by targeting CXCR4-expressing myeloid cells in a murine
model of PDAC Lead author: Arsen Osipov Poster #:
1588/9 Session: PO.TB06.04 Date and Time: Monday,
June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT URL:
https://www.abstractsonline.com/pp8/#!/9045/presentation/7864
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).6 The ongoing clinical study of
the VS-6766/defactinib combination is supported by single-agent
Phase 2 studies which investigated defactinib in KRAS mutant NSCLC7
and VS-6766 in KRAS mutant NSCLC and LGSOC.5
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.8,9
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).6
The ongoing clinical study of the VS-6766/defactinib combination is
supported by single-agent Phase 2 studies which investigated
defactinib in KRAS mutant NSCLC7 and VS-6766 in KRAS mutant NSCLC
and LGSOC.8 Defactinib is also in clinical testing in combination
with pembrolizumab for treatment of patients with pancreatic
cancer, NSCLC and mesothelioma.10
About COPIKTRA® (duvelisib)
COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase
(PI3K), and the first approved dual inhibitor of PI3K-delta and
PI3K-gamma, two enzymes known to help support the growth and
survival of malignant B-cells. PI3K signaling may lead to the
proliferation of malignant B-cells and is thought to play a role in
the formation and maintenance of the supportive tumor
microenvironment.11,12,13 COPIKTRA is indicated for the treatment
of adult patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two
prior therapies and relapsed or refractory follicular lymphoma (FL)
after at least two prior systemic therapies. COPIKTRA is also being
developed by Verastem Oncology for the treatment of peripheral
T-cell lymphoma (PTCL), for which it has received Fast Track status
and Orphan Drug Designation, and is being investigated in
combination with other agents through investigator-sponsored
studies.14 For more information on COPIKTRA, please visit
www.COPIKTRA.com. Information about duvelisib clinical trials can
be found on www.clinicaltrials.gov.
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. 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 Clin Ophthalmol. 2017; 11: 279–289. Published online 2017 Jan
31. doi: 10.2147/OPTH.S89591.
2 Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM,
Kudchadkar RR, et al. Effect of selumetinib vs chemotherapy on
progression-free survival in uveal melanoma: a randomized clinical
trial. Jama. 2014 Jun 18;311(23):2397-405.
3 Alexander Noor Shoushtari, Ragini Reiney Kudchadkar, Katherine
Panageas, Rashmi Krishna Murthy, Maria Jung, Roshani Shah, et al. A
randomized phase 2 study of trametinib with or without GSK2141795
in patients with advanced uveal melanoma. Journal of Clinical
Oncology 34(15_suppl):9511-9511 · May 2016
4 Feng, Arang et al. Cancer Cell 2019
5 Jiang H et al. Targeting focal adhesion kinase renders
pancreatic cancers responsive to checkpoint immunotherapy. Nat Med
2016: Aug 22(8) 851-60.
6 Sulzmaier F.J. et al. FAK in cancer: mechanistic findings and
clinical applications. Nature Rev Cancer. 2014 14: 598-610.
7 https://clinicaltrials.gov, NCT03875820.
8 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.
9 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.
10 www.clinicaltrials.gov, NCT02758587.
11 Winkler D.G., Faia K.L., DiNitto J.P. et al. PI3K-delta and
PI3K-gamma inhibition by IPI-145 abrogates immune responses and
suppresses activity in autoimmune and inflammatory disease models.
Chem Biol 2013; 20:1-11.
12 Reif K et al. Cutting Edge: Differential Roles for
Phosphoinositide 3 kinases, p110-gamma and p110-delta, in
lymphocyte chemotaxis and homing. J Immunol 2004:173:2236-2240.
13 Schmid M et al. Receptor Tyrosine Kinases and TLR/IL1Rs
Unexpectedly activate myeloid cell PI3K, a single convergent point
promoting tumor inflammation and progression. Cancer Cell
2011;19:715-727.
14 www.clinicaltrials.gov, NCT03372057.
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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
781-292-4205
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