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Verastem Oncology Announces Presentation of Preclinical Data Supporting the Combination of VS-6766 and Defactinib in Metastatic Uveal Melanoma
Data Presented at the
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
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
“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
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
Poster #: 6406/30
Date and Time:
Title: The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ
Poster #: 663/10
Date and Time:
Title: Single cell expression analysis of PIK3 genes to direct solid tumor treatment with the dual PI3K-δ,γ inhibitor duvelisib
Poster #: 1552/3
Date and Time:
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
Poster #: 1588/9
Date and Time:
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
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
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
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
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.
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:
6 Sulzmaier F.J. et al. FAK in cancer: mechanistic findings and clinical applications. Nature
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.
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.
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.
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.
Vice President, Investor Relations & Finance