Verastem, Inc. VSTM, focused on discovering and developing drugs to
treat cancer by the targeted killing of cancer stem cells, today announced the
initiation of a Phase 2 trial of defactinib (VS-6063), a potent inhibitor of
focal adhesion kinase (FAK), in KRAS-mutated non-small cell lung cancer
(NSCLC).
“We currently do not have any effective targeted treatment options for
patients with KRAS-mutated non-small cell lung cancer (NSCLC) which represents
about 30% of the NSCLC population,” said Dr. David Gerber, Associate Professor
of Internal Medicine, Lung Cancer Specialist at the University of Texas
Southwestern Medical Center and Study Chairman of the defactinib clinical
trial. “Research by Dr. Scaglioni here at UTSW has demonstrated that
inhibition of Focal Adhesion Kinase in KRAS-mutated NSCLC with a secondary
mutation in either p16 or p53, extends survival in xenograft models of this
disease.”
Dr. Scaglioni's group at UTSW published a paper in 2013 in Cancer Discovery
titled “RHOA-FAK is a Required Signaling Axis for the Maintenance of
KRAS-Driven Lung Adenocarcinoma” that describes the critical role of FAK
signaling in NSCLC that has both a KRAS-mutation and accompanying secondary
mutation in the p16/ARF/INK4a locus (p16) or p53. As reported in the paper,
genetic silencing or deletion of FAK replicated the effects of treatment with
Verastem's first generation small molecule inhibitor of FAK, VS-6062, in both
in vitro and xenograft models of the disease.
"The reported rates vary, but we believe approximately 10-15% of NSCLC tumors
have both the KRAS mutation and an accompanying secondary mutation in p16 or
p53 leading to silencing of those tumor suppressor genes, which appears to be
a prerequisite for the activity of FAK inhibitors in KRAS-mutated NSCLC
models,” said Dr. Joanna Horobin, Verastem Chief Medical Officer. “Patients
with KRAS mutated tumors derive limited benefit from chemotherapy. This study
is designed to elucidate the role of the secondary mutation in response to FAK
inhibitor treatment and hopefully make a meaningful impact on the clinical
response to therapy in a subset of patients with difficult to treat NSCLC.”
The Phase 2 study is designed to assess the effect of defactinib on
Progression Free Survival (PFS), Overall Response Rate (ORR) and Overall
Survival (OS). There will be 4 study arms, including patients with a
KRAS-mutation, or a KRAS-mutation with accompanying secondary mutations in
p16, p53 or both p16 and p53. The trial is being conducted at 8-10 sites in
the US and is expected to enroll up to 44 patients (11 per arm) in the first
stage of the Simon two-stage trial design. A Simon two-stage trial design
incorporates a single, pre-planned interim analysis to determine which
enrollment arms are exhibiting a favorable response to treatment and allows
for enrollment of an additional 12 patients with the same tumor mutation
profile per arm.
“With the initiation of this study we now have a total of five clinical
studies underway,” said Robert Forrester, Verastem President and Chief
Executive Officer. “In addition to the NSCLC trial, we recently initiated the
registration-directed COMMAND study in mesothelioma, a Phase 1 trial of
defactinib in Japan and continue enrollment in the Phase 1b combination study
of defactinib and paclitaxel for patients with ovarian cancer. In parallel to
the development of defactinib, we have an ongoing Phase 1 study of VS-4718 in
advanced solid tumors. We will continue to execute on our development plans
and remain committed to bringing novel therapies targeting cancer stem cells
to patients with few to no adequate treatment options.”
The paper “RHOA-FAK is a Required Signaling Axis for the Maintenance of
KRAS-Driven Lung Adenocarcinoma” by Konstantinidou et. al., Cancer Discovery
2013, can be accessed at http://bit.ly/1bd1Zta
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