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Verastem Announces Presentation of VS-6063 Clinical and Preclinical Study Results at the 2013 AACR-NCI-EORTC International Conference
“The combination of VS-6063 and paclitaxel was well tolerated in the
Phase 1 dose escalation and we are actively enrolling patients in the
expansion cohort,” said Dr.
“The six VS-6063 and VS-5584 posters presented at this meeting expand
our understanding of the activity and underlying biological mechanisms
of these promising compounds,” said Dr.
“These presentations build upon a growing body of scientific evidence
that VS-6063 and VS-5584 are potent inhibitors of cancer stem cells and
provide further support for a robust clinical development program for
each,” said
A summary of the data presented by
Title: Phase 1/1b Study of the FAK Inhibitor Defactinib
(VS-6063) in Combination with Weekly Paclitaxel for Advanced Ovarian
Cancer
Abstract #: 937
Date and Time:
Session: Poster Session A;
Clinical Trials 1
Location: Exhibit Hall C-D
Summary:
Results from the Phase 1 dose escalation portion of the study were
presented. Six patients with advanced or refractory ovarian cancer, all
of whom had prior taxane exposure and were platinum resistant, were
enrolled. VS-6063 was orally administered continuously at a dose of
200mg BID in the first cohort and was escalated to 400mg BID in the
second cohort. The standard dose of paclitaxel 80mg/m2 was
administered on days 1, 8 and 15, every 28 days. Combination therapy was
well tolerated with no dose limiting toxicities observed. There was no
apparent increase in the severity and incidence of paclitaxel related
toxicities and VS-6063 did not alter paclitaxel exposure. Based on these
results, the recommended Phase 2 dose of VS-6063 was determined to be
400mg BID in combination with weekly paclitaxel at 80mg/m2.
Two patients demonstrated significant decreases, or normalization, of
CA-125, a marker that becomes elevated with disease progression in
ovarian cancer. One patient in the VS-6063 200mg BID cohort experienced
an ongoing complete response as confirmed by Response Evaluation
Criteria in Solid Tumors (RECIST) with repeated radiologic scans and a
second patient in the VS-6063 400mg BID cohort continues to experience
prolonged stabilization of her disease. Patient recruitment remains
ongoing in the expansion Phase 1b open-label, multicenter portion of the
study, where
A copy of the poster presentation is available here.
Title:
Abstract
#: 848
Date and Time:
Session ID: Poster Session A; Biomarkers
Location:
Exhibit Hall C-D
Summary: The Neurofibromatosis 2 (NF2)
tumor suppressor gene that encodes the protein merlin is disrupted in
approximately 50% of MPM patients, and low merlin is correlated with
increased sensitivity to the FAK inhibitor, VS-6063. Various methods for
measuring the presence or absence of merlin and NF2 were evaluated using
MPM patient-derived xenograft tumor models. This study utilized
immunohistochemistry (IHC) and Fluorescence In situ Hybridization (FISH)
to correlate the measurement of merlin and NF2, respectively, and
demonstrated that merlin is a predictive biomarker for NF2. These data
support the clinical development of a merlin IHC test for the evaluation
of NF2-mutated MPM, and further support the premise that merlin is a
predictive biomarker for responsiveness to VS-6063.
A copy of the poster presentation is available here.
Title: Defactinib (VS-6063) Targets Cancer Stem Cells Directly
and Through Inhibition of Tumor-Associated Macrophages and Cytokine
Production
Abstract #: 863
Date and Time:
Session: Poster
Session B; Therapeutic Agents: Small Molecule Kinase Inhibitors 2
Location:
Exhibit Hall C-D
Summary: In addition to being a potent FAK
inhibitor, study findings have demonstrated that VS-6063 also inhibits
the activity of PYK2, a closely related protein kinase and only other
member of the FAK kinase family. Several lines of evidence suggest that
dual targeting of FAK and PYK2 should confer greater antitumor efficacy
than inhibition of either target alone. Based on the observation of
reduced macrophage infiltration in PYK2 knockout mice, the effects of
PYK2 inhibition on tumor-associated macrophages (TAMs), which have been
correlated with poor prognosis in multiple cancer types, including
mesothelioma and breast cancer, were investigated.
Study results demonstrated that VS-6063 inhibited production of specific cytokines that are responsible for increasing cancer stem cells in mesothelioma and breast cancer in a dose dependent manner, whereas a FAK-only reference inhibitor had no effect on these cytokines. Results also demonstrated that VS-6063 substantially reduced the number of TAMs in cancer xenograft models. The dual inhibition of FAK and PYK2 by VS-6063 effectively decreases both the presence of TAMs in tumors and the ability of TAMs to release cytokines that stimulate CSC proliferation and survival, and may therefore provide the opportunity for a more durable clinical response than inhibition of FAK alone.
A copy of the poster presentation is available here.
Title: Dual mTORC1/2 and PI3K Inhibitor VS-5584 Preferentially
Targets Cancer Stem Cells
Abstract #: 889
Date and
Time:
Session ID:
Poster Session B; Cancer Stem Cells 2
Location: Exhibit Hall
C-D
Summary: VS-5584 is a highly potent dual inhibitor of
mTORC1/2 and PI3K that preferentially targets cancer stem cells in
vitro and in vivo. VS-5584 has equipotency against all four
human Class I PI3K isoforms and the mTOR kinase. Study data demonstrated
that VS-5584 decreased cancer stem cells across multiple cell lines
including triple negative breast cancer cells (SUM159), while paclitaxel
increased the proportion of cancer stem cells. In small cell lung cancer
models (H69), VS-5584 effectively eliminated the cancer stem cell
population, with a corresponding substantial delay in tumor regrowth
following cisplatin treatment. Similarly, ex vivo treatment with
VS-5584 preferentially reduced cancer stem cells in primary tumor
specimens from patients with breast cancer or ovarian cancer. Further,
oral dosing with VS-5584 was found to substantially reduce cancer stem
cells in vivo in the MDA-MB-231 triple negative and MCF-7 ER+
breast cancer xenograft models.
A copy of the poster presentation is available here.
Title: Malignant Mesothelioma Lacking Merlin Shows Enhanced
Sensitivity to the FAK Inhibitor Defactinib (VS-6063): Elucidation of
the Merlin-FAK Relationship
Abstract #: 765
Date and
Time:
Session ID:
Poster Session C; Therapeutic Agents: Small Molecule Kinase Inhibitors 3
Location:
Exhibit Hall C-D
Summary: Approximately 50% of malignant
pleural mesothelioma (MPM) patients exhibit a gene mutation that results
in the lack of expression of functional merlin protein. Merlin loss is a
critical driver of MPM tumorigenesis and is related, at least in part,
to up-regulation of FAK activity. Data from this preclinical study
demonstrated that merlin negative cells were especially vulnerable to
FAK inhibition. Study data also demonstrated that MPM cell lines lacking
expression of merlin were found to be more sensitive to VS-6063 than MPM
cell lines with wild-type merlin expression. Oral dosing of VS-6063
induced significant tumor growth inhibition in a merlin-negative MPM
model. When used in combination with pemetrexed or cisplatin, VS-6063
blocked the enrichment of cancer stem cells by these chemotherapeutic
agents. Taken together, these data support the clinical development of
VS-6063 in MPM patients (stratified by merlin status) with a confirmed
response following first line platinum/pemetrexed therapy.
A copy of the poster presentation is available here.
Title: FAK Inhibitor Defactinib (VS-6063) Enhances the Efficacy
of Paclitaxel and Preferentially Targets Ovarian Cancer Stem Cells
Abstract
#: 899
Date and Time:
Session ID: Poster Session C; Therapeutic Agents:
Small Molecule Kinase Inhibitors 3
Location: Exhibit Hall C-D
Summary:
Amplification and overexpression of FAK has been observed in aggressive
human cancers, including ovarian and breast cancers, and is required for
the proliferation and survival of cancer stem cells. In this in vitro
study, results demonstrated that VS-6063, a potent and orally active FAK
inhibitor, synergistically enhanced the efficacy of paclitaxel in
vitro in models of ovarian cancer. In addition, VS-6063
preferentially reduced cancer stem cells and attenuated the induction of
cancer stem cells by either carboplatin or paclitaxel.
A copy of the poster presentation is available here.
About VS-6063
Defactinib (VS-6063) is an oral compound designed to target cancer stem
cells through the potent inhibition of focal adhesion kinase (FAK).
Cancer stem cells are an underlying cause of tumor resistance to
chemotherapy, recurrence and ultimate disease progression. Research by
About VS-5584
VS-5584 is an orally available compound that has demonstrated potent and
highly selective activity against class 1 PI3K enzymes and dual
inhibitory actions against mTORC1 and mTORC2 pathways. In preclinical
studies, VS-5584 has been shown to reduce the percentage of cancer stem
cells and induce tumor regression in taxane-resistant models.
About
Forward-looking statements:
This press release includes forward-looking statements about the
Company’s strategy, future plans and prospects, including statements
regarding the development of the Company’s compounds, including VS-6063,
or defactinib, and the Company’s FAK program generally, the timeline for
clinical development and regulatory approval of the Company’s compounds,
the expected timing for the reporting of data from ongoing trials, and
the structure of the Company’s planned or pending clinical trials. The
words “anticipate,” “appear,” “believe,” “estimate,” “expect,” “intend,”
“may,” “plan,” “predict,” “project,” “target,” “potential,” “will,”
“would,” “could,” “should,” “continue,” 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 that the preclinical testing of the Company’s compounds and
preliminary data from clinical trials may not be predictive of the
results or success of ongoing or later clinical trials, that data may
not be available when we expect it to be, that the Company will be
unable to successfully complete the clinical development of its
compounds, including VS-6063, that the development of the Company’s
compounds will take longer or cost more than planned, and that the
Company’s compounds will not receive regulatory approval or become
commercially successful products. 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
Source:
Verastem, Inc.
Brian Sullivan, 617-252-9314
bsullivan@verastem.com
