On December 15, 2020 Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to advancing new medicines for patients battling cancer, reported the initiation of a Phase 2 registration-directed clinical trial of VS-6766, its RAF/MEK inhibitor, alone and in combination with defactinib, its FAK inhibitor, in patients with KRAS mutant non-small cell lung cancer (NSCLC) (Press release, Verastem, DEC 15, 2020, View Source [SID1234572878]).
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"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 Brian Stuglik, Chief Executive Officer of Verastem Oncology. "Our VS-6766 and defactinib NSCLC development program’s specific focus on G12V mutations is unique and represents a potentially significant step forward in understanding how we can deliver a better treatment option for these patients."
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 D. Ross Camidge, M.D., Ph.D., Director of Thoracic Oncology at the University of Colorado School of Medicine and University of Colorado Cancer Center member and the study’s U.S. principal investigator. "Some key advances have come from looking at specific KRAS mutations and by also focusing on G12V mutations, allowing us to build upon the areas that have shown particular promise and determine an optimal path forward."
"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 Silvia Novello, M.D., Ph.D., Professor of Respiratory Medicine at the Department of Clinical and Biological Sciences of the University of Turin, Italy and EU principal investigator of the study. "Making progress with these mutated tumors is critical as they have proven extremely difficult to target with an effective and well-tolerated option and have, therefore, left patients with limited options and minimal results."
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 Lung Cancer (NSCLC)
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
About VS-6766
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.
About Defactinib
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 U.S., EU and Australia. Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions have 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.7,8
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 September 2020 demonstrated a 56% overall response rate and long duration of therapy among patients with KRAS-G12 mutant LGSOC.10 Based on an observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study, Verastem Oncology is also exploring the role of VS-6766 and defactinib in KRAS-G12V mutant NSCLC in its Phase 2 RAMP 202 (Raf And Mek Program) study. The FRAME study was expanded in August 2020 to include new cohorts in pancreatic cancer, KRAS mutant endometrial cancer and KRAS-G12V mutant NSCLC.