Fakzynja (defactinib) / Verastem - LARVOL DELTA

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Updated safety and efficacy of a phase 1b/2 study (RAMP 205). (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT05669482 The abstract will be released to the public on May 22, 2025 at 4:00 PM"

Clinical • Metastases • P1/2 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Emory University | Trial completion date: Jun 2026 ➔ Sep 2028 | Trial primary completion date: Aug 2025 ➔ Mar 2028

IO biomarker • Trial completion date • Trial primary completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Onco360 Has Been Selected as a National Specialty Pharmacy Partner for AVMAPKI FAKZYNJA CO-PACK (GlobeNewswire) - "Onco360, the nation’s leading independent specialty pharmacy, has been selected as a national pharmacy partner by Verastem Oncology for AVMAPKI FAKZYNJA CO-PACK (avutometinib capsules; defactinib tablets), for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy."

Commercial • Low Grade Serous Ovarian Cancer

Verastem Oncology Reports First Quarter 2025 Financial Results and Highlights Recent Business Updates (Businesswire) - "Avutometinib and Defactinib Combination in Low-Grade Serous Ovarian Cancer (LGSOC) - Key Milestones Expected for 2025: Primary analysis from both the FRAME and RAMP 201 clinical trials anticipated to be published in H1 2025. Complete enrollment for the international Phase 3 confirmatory RAMP 301 clinical trial for patients with recurrent LGSOC regardless of KRAS mutation status by the end of 2025. Report initial data from the RAMP 201J Phase 2 clinical trial being conducted in Japan with JGOG in H2 2025. Continue to advance the regulatory pathway in Japan and Europe."

Enrollment status • P1 data • P2 data • Regulatory • Ovarian Cancer

FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer (FDA) - "On May 8, 2025, the Food and Drug Administration granted accelerated approval to the combination of avutometinib and defactinib (Avmapki Fakzynja Co-pack, Verastem, Inc.) for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy...Efficacy was evaluated in RAMP-201 (NCT04625270), an open-label, multicenter trial that included 57 adult patients with measurable KRAS-mutated recurrent LGSOC."

Accelerated approval • Low Grade Serous Ovarian Cancer

Verastem Oncology Reports First Quarter 2025 Financial Results and Highlights Recent Business Updates (Businesswire) - "RAMP 205: Avutometinib Plus Defactinib in Combination with Chemotherapy in First-Line Metastatic Pancreatic Cancer - Key Milestones Expected for 2025: Plan to report additional data when ASCO abstracts are live on May 22, 2025. Select the recommended Phase 2 Dose (RP2D) for trial expansion in H1 2025. RAMP 203: Avutometinib Plus Defactinib in Combination with a KRAS G12C Inhibitor in Non-Small Cell Lung Cancer (NSCLC): Completed enrollment in the KRAS G12C inhibitor prior-treated Stage 1 Part B doublet cohort in Q1 2025. Completed enrollment in the planned dose level evaluation cohorts for the triplet combination in Q1 2025. Key Milestones Expected for 2025: Present an interim update of both doublet and triplet data at a medical meeting in H2 2025."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

Stereotactic Body Radiotherapy and Focal Adhesion Kinase Inhibitor in Advanced Pancreas Adenocarcinoma (clinicaltrials.gov) - P2 | N=42 | Active, not recruiting | Sponsor: Washington University School of Medicine | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2028 ➔ Apr 2027 | Trial primary completion date: Jun 2027 ➔ Sep 2025

Enrollment closed • Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

PYK2 promotes cell proliferation and epithelial-mesenchymal transition in endometriosis by phosphorylating Snail1. (PubMed, Mol Med) - "PYK2 is a novel binding partner of Snail1. PYK2 promotes the occurrence and development of endometriosis by up-regulating Snail1, which could be a promising therapeutic target for endometriosis."

Journal • Endometriosis • Gynecology • Infertility • Women's Health • PTK2B • SNAI1 • TYK2

Bimodal genomic approach predicting semaphorin 7A (SEMA7A) as a novel prognostic biomarker in adrenocortical carcinoma [WITHDRAWN] (AACR 2025) - "We also identified high protein expression of SEMA7A in the ACC cell line NCI-H295R and found that Cobimetinib (MEKi) and Defactinib (FAKi) synergize each other and reduce SEMA7A protein expression. Immunohistochemistry (IHC) staining demonstrates the feasibility of evaluating SEMA7A in ACC tissues and shows significant correlation between gene (RNA-seq) and protein expression (IHC) levels. Together, these findings suggest SEMA7A is a promising candidate for further research in ACC biology and its potential as prognosis biomarker in ACC patients."

Biomarker • Adrenal Cortex Carcinoma • Endocrine Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CYP17A1 • SEMA7A

Correlative preclinical studies to elucidate mechanisms of synergy of the combination of the RAF/MEK clamp avutometinib and the FAK inhibitor defactinib in low grade serous ovarian cancer (AACR 2025) - P1, P2, P3 | "This organoid model was used in in-vivo experiments with vehicle, avutometinib, VS-4718 (FAK inhibitor) and the combination for 2 weeks. The combination of avutometinib with defactinib has shown preclinical and clinical activity in LGSOC greater than avutometinib alone, and is being evaluated in a randomized phase 3 trial in patients with LGSOC (RAMP-301; NCT06072781). These preclinical studies show that avutometinib + FAK inhibitor inhibits MAPK pathway signaling more strongly than avutometinib alone. Further, putative mechanisms of resistance to avutometinib, including MYC and PI3K signaling, were overcome by the combination of avutometinib with a FAK inhibitor in LGSOC models."

Preclinical • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • CCND1 • ETV4 • ETV5 • KRAS

RAF/MEK clamp avutometinib combined with a pan-RAF inhibitor induces nearly complete MAPK pathway inhibition with deep tumor regressions in NRAS or BRAF class III mutant models (AACR 2025) - P3 | "The combination of avutometinib with the focal adhesion kinase (FAK) inhibitor defactinib has shown clinical activity for patients with low-grade serous ovarian cancer and is currently being investigated in a Phase 3 confirmatory study (RAMP 301; NCT06072781)...In contrast to the tumor regressions induced by avutometinib plus exarafenib in this ME9518 model, the combination of the MEK-only inhibitor binimetinib with exarafenib caused substantial body weight loss and failed to show tumor regression. Strong tumor regressions in all mice were also observed with the combination of avutometinib and the pan-RAFi belvarafenib in an NRAS mutant xenograft model (SKMEL2). Mechanistically, the deep tumor regressions observed with the combination of avutometinib plus exarafenib corresponded with virtually complete elimination of MAPK pathway markers such as pMEK, DUSP4 and pS6 in the tumors relative to avutometinib or exarafenib alone which conferred less complete inhibition...."

Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • DUSP4 • KRAS • NRAS

Discovery of potent focal adhesion kinase (FAK) inhibitor A8 with enhanced antitumor activity. (PubMed, Eur J Med Chem) - "Our structure-activity relationship (SAR) studies identified A8 as a potent FAK inhibitor, with an FAK-IC50 value of 0.87 nM, superior to VS6063 (1.49 nM)...Combination therapy with paclitaxel further enhanced A8's antitumor effects in SKOV-3 models...Molecular docking and dynamics simulations substantiated the stable binding of A8 to the FAK protein. Collectively, our findings underscore the potential of compound A8 as a lead candidate for FAK-targeted cancer therapeutics, warranting further preclinical and clinical investigations."

Journal • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells. (PubMed, J Clin Invest) - "Importantly, Defactinib treatment was demonstrated to limit aortic aneurysm development by inhibiting the FAK signal pathway. Thus, HINT1/ITGA6/FAK axis emerges as potential therapeutic strategies in aortic aneurysm."

Journal • Cardiovascular • HINT1 • ITGA6 • NUP98 • TFAP2A

A Study of Avutometinib (VS-6766) and Defactinib in People With Mesonephric Gynecologic Cancer (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Gynecologic Cancers • Oncology

Study of Pembrolizumab With or Without Defactinib Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P2 | N=36 | Active, not recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2024 ➔ Jul 2025 | Trial primary completion date: Dec 2024 ➔ Jul 2025

Enrollment closed • Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Correlative preclinical studies to elucidate mechanisms of synergy of the combination of the RAF/MEK clamp avutometinib and the FAK inhibitor defactinib in low-grade serous ovarian cancer (Businesswire) - "Verastem Oncology announces multiple presentations focused on RAS/MAPK pathway inhibition at AACR Annual Meeting 2025....Abstract #: 6368....In a patient-derived LGSOC xenograft model, addition of a FAK inhibitor with avutometinib augmented tumor regression, more strongly inhibited RAS/MAPK pathway signaling compared to avutometinib alone and suppressed multiple putative mechanisms of resistance to avutometinib monotherapy including PI3K and YAP/TEAD signaling."

Preclinical • Ovarian Cancer

Key Milestones Expected for 2025: (Businesswire) - "Plan for FDA decision on NDA submitted for the combination of avutometinib plus defactinib in KRAS mutant recurrent LGSOC, expected by June 30, 2025; Plan to submit for NCCN guideline inclusion upon FDA approval; Primary analysis from both the FRAME and RAMP 201 clinical trials anticipated to be published in H1 2025."

Clinical data • FDA event • Ovarian Cancer

Fourth Quarter 2024 Financial Results (Businesswire) - "Verastem Oncology ended the fourth quarter of 2024 with cash, cash equivalents and investments of $88.8 million...additional sources of capital along with the existing cash, cash equivalents, and investments provide an expected cash runway through a potential launch of avutometinib and defactinib for recurrent LGSOC into Q4 2025."

Commercial • Ovarian Cancer

RAMP 205: Avutometinib Plus Defactinib in Combination with Chemotherapy in First-Line Metastatic Pancreatic Cancer (Businesswire) - P1b/2a | N=40 | RAMP205 (NCT05669482) | Sponsor: Verastem, Inc. | "Verastem announced an interim update on RAMP 205...A new dose level '0' was added to evaluate the doses of avutometinib and defactinib used in LGSOC, 3.2 mg of avutometinib, 200 mg of defactinib, in combination with 800 mg/m2 of gemcitabine and 100 mg/m2 of Nab-paclitaxel on a schedule of day 1, 8, and 15; All dose levels have been expanded to 12 patients each; 59 of 60 patients have been treated and enrollment is on track to be completed in Q1; Based on the initial safety and efficacy data from these cohorts, dose level 1 or 0 is anticipated to be chosen for expansion; Adverse events across all dose cohorts remained generally consistent with the previously announced safety and tolerability profile, and no new safety signals have emerged...Plan to present additional data at a medical meeting mid-year 2025. Select the recommended Phase 2 Dose (RP2D) for trial expansion in H1 2025."

P1/2 data • Trial status • Pancreatic Ductal Adenocarcinoma

Elevated interstitial flow in the cerebrospinal fluid microenvironment accelerates glioblastoma cell migration on a microfluidic chip. (PubMed, Lab Chip) - "Finally, cytoskeleton inhibitors and decreased expressions of focal adhesion proteins, such as cytochalasin D, FAK inhibitors (VS-6063 and PF-573228), and FAK siRNA, were both proved to decrease the cells' response to IF. This work not only demonstrates the effect of IF on glioblastoma cell migration, but also indicates the reliability of microfluidic chips for modeling complex physiological environments, which is expected to be further developed for drug screening."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Avutometinib/Defactinib Combo Drives Responses in Recurrent Low-Grade Serous Ovarian Cancer (OncLive) - P2 | N=225 | RAMP 201 (NCT04625270) | Sponsor: Verastem, Inc. | "Treatment with the combination of avutometinib (VS-6766) and defactinib (VS-6063) led to a clinically meaningful overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer, according to data from the RAMP 201 trial...presented at the 2025 Society of Gynecological Oncology Annual Meeting on Women’s Cancer....Findings showed that evaluable patients treated with avutometinib at 3.2 mg and defactinib at 200 mg (n = 109) experienced a confirmed ORR of 31% comprising a complete response (CR) rate of 2% and a partial response (PR) rate of 29%. The stable disease (SD) and progressive disease (PD) rates were 57% and 8%, respectively, and 4% of patients were not evaluable for response."

P2 data • Ovarian Cancer

(ENCORE) AVUTOMETINIB + DEFACTINIB IN RECURRENT LOW GRADE SEROUS OVARIAN CANCER (ENGOT-OV60/GOG-3052/RAMP 201): DOSE INTENSITY AND SUBGROUP ANALYSIS (SGO 2025) - No abstract available

Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer (clinicaltrials.gov) - P2 | N=33 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Suspended ➔ Recruiting

Enrollment open • Colorectal Cancer • Oncology • Solid Tumor

A PHASE II STUDY OF AVUTOMETINIB AND DEFACTINIB IN ADVANCED OR RECURRENT GYNECOLOGIC MESONEPHRIC CANCER: INTERIM RESULTS (SGO 2025) - No abstract available

Metastases • P2 data • Oncology

Focal adhesion kinase (FAK): emerging target for drug-resistant malignant tumors. (PubMed, Mol Biol Rep) - "While FAK is a compelling anticancer target, challenges such as tissue-specific physiological variability and broad ligand specificity remain. This review provides a detailed analysis of FAK's role in cancer progression and explores emerging molecules targeting FAK as potential treatments for drug-resistant malignant tumors."

Journal • Review • Oncology • Solid Tumor • EZR • RDX