VS-4718 / Verastem - LARVOL DELTA

THE RAF/MEK INHIBITOR VS-6766 SHOWS EFFICACY IN RAS-MUTANT PEDIATRIC PRECLINICAL XENOGRAFT MODELS- A REPORT FROM THE PEDIATRIC PRECLINICAL IN VIVO TESTING CONSORTIUM (CTOS 2025) - "To evaluate drug combinations, RMS PDXs were treated with VS-6766 in doublet with 14 other drugs targeting additional areas of the MAPK/ERK pathway along with untreated control, VS-6766 alone, and vincristine + irinotecan (standard of care) for a total of 17 treatment groups...In combination testing, survival advantage was most notable when VS-6766 was combined with VS-4718 (FAK), everolimus (mTOR), copanlisib (PI3Kδ/α), capivasertib (AKT), BBP-398 (SHP2) and LY3023414 (PI3K) compared to VS-6766 alone. VS-6766 exhibited antitumor activity across several pediatric cancers... VS-6766 exhibited antitumor activity across several pediatric cancers. As single agent, there was activity in the majority of solid tumor models tested with prolongation of time on study and stabilization of disease. Solid tumor models harboring RAS mutations appear more likely to respond, although limited non-mutant models were tested."

Preclinical • Hematological Malignancies • Leukemia • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HRAS • KRAS • NF1 • NRAS • PIK3CD

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

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

Overcoming carfilzomib resistance in PSMB5 mutated proteasome inhibitor triple-resistant multiple myeloma at moderate toxicity (DGHO 2025) - "Background: The introduction of proteasome inhibitors (PIs) into multiple myeloma (MM) therapy has contributed significantly to making MM a manageable disease for many patients and substantially improved MM patient survival. Overall, these findings suggest that the inhibition of PYK2 using VS-4718 together with low doses of carf could be an effective combination in the majority of MM, including PI resistant relapsed/refractory MM at moderate toxicity."

Hematological Malignancies • Multiple Myeloma • ANXA5 • PSMB5

Focal adhesion kinase plays an essential role in Th17 cell differentiation by stimulating NF-κB signaling. (PubMed, Front Immunol) - "Moreover, pharmacological inhibition of FAK with the specific inhibitor PND1186 prevented Th17 differentiation in vitro, and reduced EAE symptoms in vivo. Thus, FAK plays an essential role in Th17 cell differentiation by stimulating NF-κB signaling."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • CD4 • IL17A

Focal adhesion kinase inhibition promotes critical cytotoxic interactions between CD8 T cells and cancer cells. (CICON 2025) - "Here, we investigated the immunomodulatory and anti -metastatic effects of VS4718, a small -molecule FAK inhibitor, in a murine model of pulmonary metastatic breast cancer and its impact on CD8 T cell–tumor cell dynamics...Further, we highlight the importance of the pattern CD8 T cell and cancer cell interaction for therapy responses. This work identifies a dual mechanism of action for FAK inhibition— immune modulation and ECM remodeling—and provides a compelling rationale for clinical evaluation of FAK."

Breast Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • CD8 • PTPRC

Targeting Focal Adhesion Kinase in Lung Diseases: Current Progress and Future Directions. (PubMed, Biomolecules) - "Some have progressed to clinical trials (Defactinib (Phase II), PF-562271 (Phase I), CEP-37440 (Phase I), PND-1186 (Phase I), GSK-2256098 (Phase II), BI-853520 (Phase I)), offering potential therapeutic targets for lung diseases. Emerging methodologies, such as PROTAC degraders and combination regimens, demonstrate significant potential for future research. Based on a comprehensive analysis of the relevant literature from 2015 to the present, this review briefly introduces the structure and function of FAK and discusses recent research advancements regarding FAK and its inhibitors in the context of pulmonary diseases."

Journal • Review • Acute Lung Injury • Asthma • Colorectal Cancer • Gastric Cancer • Immunology • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation

Preclinical Efficacy of the Estrogen Receptor Degrader Fulvestrant in Combination with RAF/MEK Clamp Avutometinib and FAK Inhibitor in a Low-Grade Serous Ovarian Cancer Animal Model with Acquired Resistance to Chemotherapy and Aromatase Inhibitor. (PubMed, Int J Mol Sci) - "Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors...Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250)...The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC."

Journal • Preclinical • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Transplantation • BRAF • ER • KRAS • NRAS • PRKDC

The role of focal adhesion kinase in bladder cancer: translation from in vitro to ex vivo human urothelial carcinomas. (PubMed, Radiol Oncol) - "To our knowledge, this is the first report demonstrating the role of FAK and its inhibition across both normal and cancerous bladder urothelial models. This study highlights the critical role of FAK in the progression of human bladder cancer and establishes a foundation for exploring FAK inhibition as a potential therapeutic approach in bladder cancer treatment."

Journal • Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CASP3 • PTK2

Focal Adhesion Kinase inhibition induces membrane accumulation of aquaporin-2 in renal epithelial cells by actin depolymerization and endocytosis inhibition. (PubMed, Am J Physiol Renal Physiol) - "We first showed that FAK inhibition using the drug VS-4718 caused membrane accumulation of AQP2 in LLC-AQP2 epithelial cells in culture and PC in situ (kidney slices), by immunofluorescence staining and biotinylation...However, VP stimulation induced a redistribution of phospho-FAK (Tyr397) from basolateral toward the apical region of collecting duct principal cells in tissue slices, concomitant with AQP2 accumulation, but no overall change in the level of FAK phosphorylation was detectable after VP treatment. These data, therefore, identify FAK signaling as a distinct pathway that could provide a novel therapeutic avenue for regulating AQP2 trafficking in water balance disorders."

Journal • Otorhinolaryngology • RHOA

Sensitivity of Pancreatic Cancer Cell Lines to Clinically Approved FAK Inhibitors: Enhanced Cytotoxicity Through Combination with Oncolytic Coxsackievirus B3. (PubMed, Int J Mol Sci) - "In this study, we investigated the cytotoxicity of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines. Considering both oncolytic efficacy and the CI, the greatest enhancement in oncolytic activity was achieved when VS-4718 or CEP-37440 was combined with PD-H. These findings indicate that co-treatment with PD-H can potentiate the therapeutic activity of the selected FAKi and may represent a novel strategy to improve treatment outcomes in PDAC."

Journal • Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma. (PubMed, Pharmaceutics) - "While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying effective drug combinations across the broader GBM population remains a challenge...We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and subsequently discovered that combining FAK inhibitors such as VS4718 with MEK inhibitors, particularly trametinib, demonstrated synergistic effects... In vivo, combination therapy significantly reduced the tumor volume in orthotopic transplantation models. These findings suggest that the combination of FAK and MEK inhibitors represents a promising therapeutic strategy to overcome the challenges of GBM treatment."

Heterogeneity • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • Transplantation

Self-emulsifying Nano-PND oral delivery systems of PND1186: In silico modeling for bioavailability estimation. (PubMed, J Mol Liq) - "NanoPODS-S is the first of its kind, self-nanoemulsifying system containing a polymeric precipitation inhibitor mimicking a "spring-parachute effect". It will be a novel platform technology for rapid and enhanced dissolution of poorly soluble molecules."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Distant Brain Metastases in Cutaneous Melanoma May Be Mitigated With Multiple Pathway Inhibitors (DocWire) - "Results were published in Cell Reports Medicine. The researchers used YUMM3.2 cells that express BRAF, which was the specific cutaneous melanoma variant target. To test the efficacy of FAK inhibition alone, the cells were treated with increasing doses of either a defacitinib surrogate (VS-4718) or avutometinib for 72 hours, and confluence was assayed every 2 hours....The combination of VS-4718 and avutometinib significantly reduced cell viability compared to VS-4718 alone (P≤0.001) or avutometinib alone (P≤0.001), showing comparable efficacy to the combination of VS-4718 and encorafenib. Adding encorafenib to the avutometinib and VS-4718 combination did not enhance its in vitro effectiveness."

Preclinical • Cutaneous Melanoma

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

Carnosol mitigates Ang II-stimulated vascular injury and oxidative stress by directly binding to FAK and inhibiting its activation. (PubMed, Inflammopharmacology) - "Notably, when PND-1186 was administered to inhibit the phosphorylation of FAK, carnosol was no longer able to modulate the PI3K/AKT signaling pathway. In conclusion, we showed that carnosol can inhibit the PI3K/AKT signaling pathway by binding to the FAK protein and reducing its phosphorylation, thereby improving Ang II-stimulated vascular injury."

Journal • Cardiovascular • Hypertension

Combined inhibition of focal adhesion kinase and RAF/MEK elicits synergistic inhibition of melanoma growth and reduces metastases. (PubMed, Cell Rep Med) - "Importantly, the study provides insight into the crosstalk between FAK and mitogen-activated protein kinase (MAPK) pathway signaling and highlights the synergistic effects of combined inhibition of FAK, rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK) in cutaneous melanoma. These findings provide the rationale for clinical evaluation of the efficacy of the FAK inhibitor defactinib and the RAF/MEK inhibitor avutometinib in patients with brain metastases from cutaneous melanoma."

Journal • Cutaneous Melanoma • Developmental Disorders • Fibrosarcoma • Melanoma • Oncology • Sarcoma • Solid Tumor

MFAP2 upregulation promotes ESCC metastasis via FAK-AKT signaling pathway. (PubMed, FASEB J) - "Treatment of ESCC cells with the FAK inhibitor PND-1186 reduced MFAP2, induced the activation of the FAK-AKT pathway in vitro, and suppressed lung metastasis in a mouse model of ESCC. These findings support a major role for MFAP2 in promoting ESCC metastasis, in part via the activation of FAK-AKT signaling, and highlight the potential of MFAP2 as a promising therapeutic target for ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • ITGB4

Combination treatment with RAF/MEK and FAK inhibition enhances tumor growth inhibition in meningioma (SNO 2024) - "The cells were plated in Matrigel-coated wells, treated with defactinib (FAK inhibitor), VS-6766 (RAF/MEK inhibitor, avutometinib) and the combination over a 7-day period and assessed for cell viability using the CellTiter-Glo 3D assay. In vivo, we tested the efficacy of the FAK inhibitor VS-4718 (possessing favorable pharmacokinetic properties in mice) and RAF/MEK inhibitor VS-6766, both given daily via oral gavage, in athymic nude mice bearing IOMM-Lee or CH157-MN tumors... Treatment with FAK and RAF/MEK inhibitors showed synergistic or combination effects in the NF2 mutant CH157-MN model in vitro and in vivo. RAF/MEK inhibitor monotherapy was effective for the IOMM-Lee model (NF2 wild-type), without clear benefit of combining with the FAK inhibitor. Investigations in intracranial tumor models are underway."

Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • CDKN2A • NF2

Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy. (PubMed, Sci Transl Med) - "Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies."

Journal • Stroma • Fibrosarcoma • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Sarcoma • Solid Tumor • CAFs • KRAS • MYC

Leveraging novel imaging techniques to investigate the bottlenecks of immunotherapy for metastatic breast cancer (CRI-ENCI-AACR ICIC 2024) - "Upon anti-PD1 therapy alone, extravasation of CD8 T cells is only slightly increased but in combination with VS-4718 – a focal adhesion kinase inhibitor, targeting the lung microenvironment – we observe a significant increase in extravasation and prolonged interaction of adoptively transferred labelled CD8 T cells with cancer cells... This research will provide a new platform to study limitations of immunotherapies and help to elucidate the role of therapy on the metastatic foci. It will provide the first insights into the benefit and limitations of the dynamics of this therapy on secondary site immune responses."

Metastases • Breast Cancer • Oncology • Solid Tumor • CD8

Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer. (PubMed, Cancer Med) - "Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients."

Journal • Preclinical • Endometrial Cancer • Oncology • Solid Tumor • ARID1A • BRAF • KRAS • PIK3CA • PTEN

Preclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas. (PubMed, Gynecol Oncol) - "The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts."

Combination therapy • Journal • Preclinical • Oncology • Sarcoma • Solid Tumor • BRAF • KRAS • MAP2K1

Combined inhibition of RAF, MEK and FAK increases PDAC responsiveness to cytotoxic- and immune therapy (AACR 2024) - P1/2 | "Concomitant inhibition of both FAK (VS-4718) and RAF/MEK (avutometinib) signaling dramatically suppressed tumor growth, leading to increased survival across multiple PDAC mouse models...These findings led to testing of FAK (defactinib) plus RAF/MEK (avutometinib) inhibition in combination with gemcitabine and nab-paclitaxel in advanced front-line pancreatic cancer patients (RAMP 205; NCT05669482). Finally, we tested whether addition of immunotherapy could enhance the efficacy of FAKi + RAF/MEKi + chemotherapy and found that addition of either PD-1 or CTLA4/PD-1 blockade led to long term disease control in PDAC animal models. Together, these studies identified FAK inhibition as a novel approach to overcome both tumor intrinsic and stromal-derived resistance to RAS/MAPK inhibition and showed that this combination can be exploited to increase the efficacy of cytotoxic and immunotherapy approaches."

IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • KRAS • MYC

Pre-clinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition for low-grade serous ovarian cancer (SGO 2024) - P2 | "Avutometinib (VS-6766) is a dual RAF/MEK inhibitor, while defactinib and VS-4718 are focal-adhesion-kinase inhibitors (FAKi). Avutometinib and, to a larger extent, its combination with FAK inhibition demonstrated promising in vivo activity against KRAS wild-type LGSOC PDX. These data support the ongoing registration-directed study with avutometinib + the FAK inhibitor defactinib for patients with recurrent LGSOC (NCT04625270)."

Combination therapy • Preclinical • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ADRB2 • BRAF • KRAS • NRAS • PRKDC • PTK2B