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Verastem Oncology Initiates Phase 2 Registration-Directed Trial of VS-6766 and Defactinib in Previously Treated KRAS Mutant Non-Small Cell Lung Cancer
Phase 2 Adaptive Trial Design to Evaluate VS-6766 Alone and in Combination with Defactinib With a Focus on KRAS-G12V Mutations
Trial Designed to Address Significant Unmet Medical Need in These Treatment-Resistant Tumors
Verastem Oncology to Seek FDA Accelerated Approval, Pending Trial Outcome
“Currently available options for patients with KRAS mutant NSCLC are associated with minimal efficacy, as well as resistance and toxicity issues. Our study will further elucidate the impact of VS-6766, alone or in combination with defactinib, in overcoming these challenges to improve outcomes,” said
The RAMP 202 (Raf And Mek Program) study is a Phase 2, adaptive two-part multicenter, parallel cohort, randomized, open-label trial to evaluate the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with KRAS mutant NSCLC, following treatment with a platinum-based regimen and immune checkpoint inhibitor.1 The first part of the study will determine the optimal regimen of either VS-6766 monotherapy or in combination with defactinib in patients with KRAS-G12V mutant NSCLC randomized 1:1 in each treatment arm. An exploratory arm of the initial phase of the study will evaluate other KRAS mutations. The determination of which regimen to take forward into the expansion phase of the trial will be made based on data from KRAS-G12V mutant patients. The second phase of the study will examine efficacy and safety parameters of the most effective regimen. Additional information about this study can be found here on ClinicalTrials.gov (NCT04620330).
“In this study, we hope to advance our understanding of a potential new option for patients with KRAS mutant NSCLC by targeting the RAF/MEK and FAK pathways,” said
“NSCLC, which constitutes over 80% of lung cancers,2 is the single leading cause of cancer deaths worldwide2 and approximately 25% of NSCLCs contain activating mutations in the RAS signaling pathway,”3 said
Verastem Oncology recently announced the initiation of its RAMP 201 Phase 2 registration-directed clinical trial of VS-6766 and defactinib, in patients with recurrent low-grade serous ovarian cancer.
About KRAS Mutant Non-Small Cell
Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC),2 which are the single leading cause of cancer deaths worldwide.2 KRAS mutation occurs in approximately 25% of NSCLC adenocarcinoma patients.3 Two of the most common types of KRAS mutations are G12V, which are present in approximately 7% of NSCLC and G12C,4 which occur in approximately 13% of NSCLCs.5 There are several agents in development for KRAS-G12C mutations, but this study represents the first time that an agent will be studied specifically for KRAS-G12V. Studies suggest that these types of KRAS mutations differ in clinical characteristics and response to traditional treatments such as chemotherapy.6
VS-6766 is an oral small molecule 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.
Defactinib (VS-6063) is an oral small molecule inhibitor of the FAK and PYK2 signaling pathways that is currently being evaluated as a potential combination therapy for various solid tumors. Verastem Oncology has received Orphan Drug Designation for defactinib in ovarian cancer in the
About the VS-6766/Defactinib Combination
RAS mutant tumors are present in about 30% of all human cancers, have historically presented a difficult treatment challenge and are often associated with significantly worse prognosis.9 Challenges associated with identifying new treatment options for these types of cancers include resistance to single agents,9 identifying tolerable combination regimens with MEK inhibitors and new RAS inhibitors in development addressing only a minority of all RAS mutated cancers.
The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors. In an ongoing investigator-initiated Phase 1/2 FRAME study, the combination of VS-6766 and defactinib is being evaluated in patients with recurrent low-grade serous ovarian cancer (LGSOC), KRAS mutant NSCLC and colorectal cancer. Updated data from this study presented at the 2nd Annual RAS-Targeted Drug Development Summit in
About Verastem Oncology
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 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 our Quarterly Report on Form 10-Q for the quarter ended
1 Clinicaltrials.gov. A Study of VS-6766 v. VS-6766 + Defactinib in Recurrent G12V or Other KRAS-Mutant Non-Small Cell
2 Molina, Julian R., Non–Small Cell
3 Roman, Marta, et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Molecular Cancer (2018) 17:33.
4 TCGA PanCancer Atlas (cBioPortal analysis)
6 Garassino, M. C. et al. Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Annals of Oncology. 2011 Jan;22(1):235-237. doi: 10.1093/annonc/mdq680. PMID: 21169473.
7 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.
8 ClinicalTrials.gov. Phase I Trial of VS-6063 and RO5126766. (FRAME). Available at: https://clinicaltrials.gov/ct2/show/NCT03875820. Accessed
9 Baines, A. T., Xu, D., & Der, C. J. (2011). Inhibition of Ras for cancer treatment: the search continues. Future medicinal chemistry, 3(14), 1787–1808. https://doi.org/10.4155/fmc.11.121
10 Verastem Oncology Press Release. Verastem Oncology Announces Presentation of Updated Phase 1/2 FRAME Study Data at the 2nd Annual RAS-Targeted Drug Development Summit.
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