Fakzynja (defactinib) / Verastem - LARVOL DELTA

The combination of avutometinib and defactinib in treating recurrent low-grade serous ovarian cancer: a plain language summary of the Phase II clinical trial ENGOT-OV60/GOG-3052/RAMP 201. (PubMed, Future Oncol) - No abstract available

Journal • P2 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Therapeutic targeting of focal adhesion kinase (FAK) modulates oncogenic and immune pathways in myeloid progenitor cells expressing oncogenic Janus kinase 2-V617F. (ASH 2025) - "The JAK2-V617F (JAK2VF) mutation, present in >95% of polycythemiavera (PV) and ~50–60% of essential thrombocythemia (ET) and primary myelofibrosis (PMF), drivesconstitutive JAK/STAT signaling and contributes to inflammation, thrombosis, and disease progression.Although JAK inhibitors (JAKi) such as ruxolitinib (Rux) provide symptom relief and reduce splenomegaly,they have limited disease-modifying activity, and resistance or relapse is frequent...Treatment with theFAK inhibitor defactinib (Def) significantly reduced viability in a dose-dependent manner (1–3µM, 10–55%, p<0.01)... Our findings establish FAK as a functional collaborator of JAK2VF kinase, promoting both cellsurvival and immune evasion in MPNs. We demonstrate that JAK2VF physically interacts with andactivates FAK, revealing a previously unrecognised signalling axis. Targeting FAK with Def synergises withRux, enhancing cytotoxicity and disrupting key survival pathways, including the p53-MDM2..."

IO biomarker • Essential Thrombocythemia • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • Thrombosis • ANXA5 • HAVCR2 • JAK2 • MCL1 • MYC

Co-targeting the PI3K-Akt pathway improves response to MEK inhibition in low-grade serous ovarian cancer cell lines. (PubMed, Gynecol Oncol) - "LGSOC responds to MEK inhibition by upregulating PI3K-Akt signaling, thereby promoting cell survival and proliferation. Our research identified significant upregulation of the PI3K-Akt pathway in response to MEK inhibition. While targeted inhibition of AKT had minimal impact alone, combination with MEK inhibitors produced strong synergistic suppression of proliferation in LGSOC cells. This combination strategy could potentially be used to prevent or reverse the emergence of MEK inhibitor resistance in LGSOC patients."

Journal • Preclinical • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

Final results of the FAK-PD1 phase I/IIA study of FAK (defactinib) and PD-1 (pembrolizumab) inhibition in advanced solid tumours (ESMO-IO 2025) - P1/2 | "Table: 251P *Response evaluable population: received at least 1 dose of each drug and had at least 1 on-treatment scan Conclusions Addition of defactinib (400mg bid) to pembrolizumab was well tolerated, with expected pharmacodynamic effect. Indications of improved activity were limited to pancreatic cancer.Clinical trial identification NCT02758587.Legal entity responsible for the study University of Glasgow & NHS Greater Glasgow and Clyde."

Clinical • Metastases • P1/2 data • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Dual inhibition of RAF/MEK and FAK signaling improves survival in intracranial meningioma models (SNO 2025) - "Mice were randomized into four groups: vehicle, VS-4718 (murine formulation of defactinib, 50 mg/kg, BID), avutometinib (0.3 mg/kg, QD), or combination therapy. Dual RAF/MEK and FAK inhibitor therapy blocks MAPK activation and enhances survival in orthotopic meningioma models, supporting further clinical evaluation for aggressive meningiomas."

Brain Cancer • Meningioma • Solid Tumor • NF2

Focal Adhesion Kinase (FAK) Inhibitor Synergizes with RAF/MEK inhibitor in Malignant Peripheral Nerve Sheath Tumors with Chromosome 8 Gain (WFNOS 2025) - P1 | " We evaluated the efficacy of PTK2 shRNA knockdown or a FAK inhibitor (FAKi), alone or combined with the RAF/MEK inhibitor avutometinib (RAF/MEKi), in MPNST cells using IncuCyte Live-Cell proliferation and cell death assays...Pharmacological inhibition of FAK by defactinib decreased cell proliferation and increased cell death in three MPNST cell-lines, with concurrent suppression of FAK, STAT3, and AKT phosphorylation... These findings support the co-targeting of FAK and RAF/MEK as a promising therapeutic approach for Chr8-gain tumors in MPNST."

Brain Cancer • CNS Tumor • Colorectal Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • NF1 • STAT3

Focal Adhesion Kinase (FAK) Inhibitor Synergizes with RAF/MEK inhibitor in Malignant Peripheral Nerve Sheath Tumors with Chromosome 8 Gain (SNO 2025) - " We evaluated the efficacy of PTK2 shRNA knockdown or a FAK inhibitor (FAKi), alone or combined with the RAF/MEK inhibitor avutometinib (RAF/MEKi), in MPNST cells using IncuCyte Live-Cell proliferation and cell death assays...Pharmacological inhibition of FAK by defactinib decreased cell proliferation and increased cell death in three MPNST cell-lines, with concurrent suppression of FAK, STAT3, and AKT phosphorylation... These findings support the co-targeting of FAK and RAF/MEK as a promising therapeutic approach for Chr8-gain tumors in MPNST."

Brain Cancer • Colorectal Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • NF1 • STAT3

Combined Inhibition of RAF, MEK, and FAK Attenuates Brain Metastases and Prolongs Survival in Melanoma Preclinical Models (SNO 2025) - "Based on these results, we have initiated a clinical trial evaluating the efficacy of the RAF/MEK inhibitor avutometinib in combination with the FAK inhibitor defactinib in patients with brain metastases from cutaneous melanoma. Additionally, we are assessing whether RAF, MEK, and FAK inhibition can be combined with standard of care immunotherapy and brain-targeted radiotherapy to create more durable responses that further improve survival in this disease."

IO biomarker • Preclinical • Cutaneous Melanoma • Melanoma • Solid Tumor • AKT1

Combined Inhibition of RAF, MEK, and FAK Attenuates Brain Metastases and Prolongs Survival in Melanoma Preclinical Models (WFNOS 2025) - "Based on these results, we have initiated a clinical trial evaluating the efficacy of the RAF/MEK inhibitor avutometinib in combination with the FAK inhibitor defactinib in patients with brain metastases from cutaneous melanoma. Additionally, we are assessing whether RAF, MEK, and FAK inhibition can be combined with standard of care immunotherapy and brain-targeted radiotherapy to create more durable responses that further improve survival in this disease."

IO biomarker • Preclinical • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • AKT1

Dual inhibition of RAF/MEK and FAK signaling improves survival in intracranial meningioma models (WFNOS 2025) - "Mice were randomized into four groups: vehicle, VS-4718 (murine formulation of defactinib, 50 mg/kg, BID), avutometinib (0.3 mg/kg, QD), or combination therapy. Dual RAF/MEK and FAK inhibitor therapy blocks MAPK activation and enhances survival in orthotopic meningioma models, supporting further clinical evaluation for aggressive meningiomas."

Brain Cancer • Meningioma • Solid Tumor • NF2

Focal Adhesion Kinase (FAK) Inhibitor Synergizes with RAF/MEK inhibitor in Malignant Peripheral Nerve Sheath Tumors with Chromosome 8 Gain (WFNOS 2025) - " We evaluated the efficacy of PTK2 shRNA knockdown or a FAK inhibitor (FAKi), alone or combined with the RAF/MEK inhibitor avutometinib (RAF/MEKi), in MPNST cells using IncuCyte Live-Cell proliferation and cell death assays...Pharmacological inhibition of FAK by defactinib decreased cell proliferation and increased cell death in three MPNST cell-lines, with concurrent suppression of FAK, STAT3, and AKT phosphorylation... These findings support the co-targeting of FAK and RAF/MEK as a promising therapeutic approach for Chr8-gain tumors in MPNST."

Brain Cancer • Colorectal Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Sarcoma • Solid Tumor • CASP3 • NF1 • STAT3

Focal Adhesion Kinase (FAK) Inhibitor Synergizes with RAF/MEK inhibitor in Malignant Peripheral Nerve Sheath Tumors with Chromosome 8 Gain (SNO 2025) - " We evaluated the efficacy of PTK2 shRNA knockdown or a FAK inhibitor (FAKi), alone or combined with the RAF/MEK inhibitor avutometinib (RAF/MEKi), in MPNST cells using IncuCyte Live-Cell proliferation and cell death assays...Pharmacological inhibition of FAK by defactinib decreased cell proliferation and increased cell death in three MPNST cell-lines, with concurrent suppression of FAK, STAT3, and AKT phosphorylation... These findings support the co-targeting of FAK and RAF/MEK as a promising therapeutic approach for Chr8-gain tumors in MPNST."

Brain Cancer • Colorectal Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • NF1 • STAT3

CELESTIAL-MDS: Combined Evaluation of Epigenetic and Sensitising Therapy in AML and MDS (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Clinical Hub for Interventional Research (CHOIR) | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Jun 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

RhoE down-regulation leads to enhanced cholesterol biosynthesis and sorafenib resistance in hepatocellular carcinoma. (PubMed, J Biol Chem) - "Genetic knockout of FAK or pharmacological inhibition using defactinib or PF-573228 effectively suppressed the sorafenib-induced upregulation of AKT and HMGCR...Importantly, another RAF-targeting multikinase inhibitor, regorafenib, also triggered a similar adaptive FAK-cholesterol response, suggesting that this may be a common resistance mechanism shared among RAF inhibitors...Collectively, this study systematically uncovers a new mechanism of sorafenib resistance in HCC: downregulation of RhoE drives cholesterol biosynthesis through activation of the FAK/AKT axis, thereby activating the SHH pathway and upregulating GLI1. These findings provide a strong theoretical rationale for the use of FAK inhibitors to overcome resistance and highlight the dual clinical relevance of the cholesterol biosynthesis gene signature-both as a molecular marker for predicting resistance and as a potential guide for personalized treatment strategies in HCC."

Journal • Brain Cancer • Glioma • Hepatocellular Cancer • Oncology • Solid Tumor • GLI1 • RHOA

Unmet needs and emerging therapeutics in low-grade serous ovarian carcinoma: from chemoresistance to precision medicine. (PubMed, Future Oncol) - "Notably, the recent US Food and Drug Administration approval of the avutometinib/defactinib combination for KRAS-mutated recurrent LGSOC marks a significant milestone in targeted therapy for this disease. Despite these advances, challenges remain in optimizing sequencing strategies and overcoming acquired resistance. This review addresses the importance of understanding the distinct pathophysiology of LGSOC, diagnostic challenges, limitations of conventional treatments, and evolving therapeutic approaches in LGSOC."

Journal • Review • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

Focal Adhesion Kinase (FAK) Inhibitor Synergizes with RAF/MEK inhibitor in Malignant Peripheral Nerve Sheath Tumors with Chromosome 8 Gain (WFNOS 2025) - " We evaluated the efficacy of PTK2 shRNA knockdown or a FAK inhibitor (FAKi), alone or combined with the RAF/MEK inhibitor avutometinib (RAF/MEKi), in MPNST cells using IncuCyte Live-Cell proliferation and cell death assays...Pharmacological inhibition of FAK by defactinib decreased cell proliferation and increased cell death in three MPNST cell-lines, with concurrent suppression of FAK, STAT3, and AKT phosphorylation... These findings support the co-targeting of FAK and RAF/MEK as a promising therapeutic approach for Chr8-gain tumors in MPNST."

Brain Cancer • Colorectal Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • NF1 • STAT3

AVMAPKI FAKZYNJA CO-PACK (avutometinib in combination with defactinib) U.S. Launch (Businesswire) - "Achieved net product revenue of $11.2 million in the first full quarter of the launch."

Sales • Low Grade Serous Ovarian Cancer

RAMP 203: Avutometinib Plus Defactinib in Combination with a KRAS G12C Inhibitor in NSCLC (Businesswire) - "Patients continue to be evaluated in both the doublet and triplet combination cohorts of the study...Key Milestone: Report an interim update on the safety and efficacy results in RAMP 203 from both the doublet and triplet combinations in Q4 2025."

Enrollment status • P1/2 data • Non Small Cell Lung Cancer

RAMP 205: Avutometinib Plus Defactinib in Combination with Chemotherapy in First-Line Metastatic PDAC (Businesswire) - "Completed enrollment in the RAMP 205 expansion cohort in Q3 2025...Key Milestone: Expect to report an update on the safety and efficacy of the RAMP 205 expansion cohort with 29 patients at the RP2D in 1H26."

Enrollment status • Pancreatic Ductal Adenocarcinoma

Avutometinib and Defactinib Combination in Low-Grade Serous Ovarian Cancer (LGSOC) (Businesswire) - "Preliminary safety and efficacy data from the Phase 2 RAMP 201J trial in Japan was accepted as an E-Poster (EP228/ #371) at the International Gynecologic Cancer Society (IGCS) 2025 Annual Meeting. In the published abstract, with a data extract date of April 11, 2025, no dose limiting toxicities were observed, and avutometinib and defactinib drug exposure levels were comparable to those observed in the global RAMP-201 study. Additional data, including efficacy (response rates) and updated safety will be available on November 5, 2025, when the embargo lifts....Expect to complete patient enrollment of the IDMC recommended increase in Q1 2026."

Enrollment status • P2 data • Low Grade Serous Ovarian Cancer

Targeting focal adhesion kinase inhibits cell migration and non-angiogenic vascularization in malignant breast cancer. (PubMed, Breast Cancer) - "FAK inhibition was shown to suppress non-angiogenic vascularization. Defactinib has the potential to serve as a novel treatment for malignant breast cancer which is resistant to conventional therapies."

Journal • Breast Cancer • Oncology • Solid Tumor • PTK2 • SERPINE2

Seminal Abstract: BLOOD CTDNA VS TUMOR TISSUE SCREENING FOR THE DETECTION OF KRAS MUTATIONS IN LOW-GRADE SEROUS OVARIAN CANCER: RESULTS FROM ENGOT-OV60/GOG-3052/RAMP 201 (IGCS 2025) - " Samples from a phase 2 study evaluating the combination of avutometinib (RAF/MEK clamp) + defactinib (FAK inhibitor) versus avutometinib monotherapy in patients with LGSOC (RAMP 201) were analyzed to determine ctDNA fraction and presence of mutations in 105 cancer-related genes including KRAS using the Tempus xF panel. Only 32% (21/65) showed ctDNA tumor fraction above the limit of detection of 0.25% (range 0.4% to 19%). Among the patients for which KRAS mutations were detectable in tumor tissue, 44% (22/50) showed KRAS mutation by blood-based ctDNA testing, whereas more than half of patients (56%; 28/50) showed a false negative result by blood-based KRAS testing. No correlation between high KRAS VAF in tumor tissue samples and detection rate of KRAS mutation in blood samples was observed."

Circulating tumor DNA • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

AVUTOMETINIB + DEFACTINIB IN RECURRENT LOW-GRADE SEROUS OVARIAN CANCER (LGSOC): A PHASE 2 STUDY IN JAPANESE PATIENTS (IGCS 2025) - "At data extract (April 11, 2025), 9 patients were enrolled; median treatment duration, 3 months (range, 1–5); median age, 47 years (range, 31–70); all ECOG PS=0; 5/9 KRAS mt; 6/9 ≥4 prior therapies. No dose-limiting toxicities occurred amongst 6 patients enrolled and reviewed for safety dose confirmation. The most frequent treatment-related adverse events (n=9) were increased creatine phosphokinase (89%), rash (78%), and peripheral edema (56%)."

Clinical • P2 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

PRIMARY ANALYSIS: PHASE II STUDY OF AVUTOMETINIB AND DEFACTINIB IN WOMEN WITH ADVANCED OR RECURRENT GYNECOLOGIC MESONEPHRIC CANCER (IGCS 2025) - P2 | "From 3/2023-12/2024 the study enrolled 20 patients with GMC (Cervical=6, Endometrial=8, Ovarian=6) with a median of 2 prior therapies (0-7). Based on 4/2025 data cut-off the confirmed response rate was 25%, with confirmed responses seen in women with cervical (2/6), endometrial (2/8) and ovarian (1/6) GMC. Sixty percent of patients remained progression free at 6 months of treatment and 3/5 of the responders remain on treatment."

Clinical • Metastases • P2 data • Cervical Cancer • Oncology • Ovarian Cancer • KRAS

A PHASE 2 STUDY OF AVUTOMETINIB (VS-6766; DUAL RAF/MEK INHIBITOR) PLUS DEFACTINIB (FAK INHIBITOR) IN RECURRENT GYNECOLOGICAL CANCERS (DURAFAK) (IGCS 2025) - "Current Status & Future Directions: There are currently 15 patients that have been enrolled. Based on the literature review of similar patient populations, ORR of at least 40% in endometrioid cancer patients, 25% in MOC patients, 25-30% in HGSOC patients, and 30% solid gynecological cancer patients will warrant future study."

P2 data • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BRAF