Avmapki (avutometinib) / Verastem, Roche - LARVOL DELTA

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

Pyk2 and MEK/Erk signaling regulate extracellular vesicle biogenesis and cargo in glioblastoma (WFNOS 2025) - "EVs were analyzed by flow cytometry, western blotting, and PCR, and MEK/Erk signaling was inhibited using Avutometinib (1 µM)...These pathways influence EV size, membrane origin, and immune-regulatory cargo. This study reveals the role of Pyk2 and MEK/Erk in EV biogenesis in GBM."

IO biomarker • Brain Cancer • Glioblastoma • Solid Tumor • CCL2 • TYK2

A Study of VS-6766 and Cetuximab in Patients With Advanced Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=53 | Recruiting | Sponsor: University of Chicago | Suspended ➔ Recruiting

Enrollment open • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • KRAS • MSI • PD-L1

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

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

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 • Solid Tumor • AKT1

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

Small Molecule Modulation of Inactive-to-Active State Transitions of RAS:RAF-Family Complexes (AACR-NCI-EORTC 2025) - "AGLUE-1 notably increased MEK:ARAF interaction without affecting other RAF isoforms and led to elevated MEK phosphorylation without a corresponding increase in ERK phosphorylation, suggesting a distinct mode of action compared to known MEK inhibitors such as Avutometinib and Trametinib. Moreover, AGLUE1 exhibited synergistic anti-proliferative effects with the RAF inhibitor belvarafenib in cancer cell lines. Our data demonstrate that AGLUE1 enhances endogenous ARAF-MEK interactions and selectively increases MEK phosphorylation, with minimal impact on ERK activity... Our data demonstrate that AGLUE1 enhances endogenous ARAF-MEK interactions and selectively increases MEK phosphorylation, with minimal impact on ERK activity. These findings suggest a unique mode of action and potential for AGLUE1 to synergize with existing RAF inhibitors. This work supports the development of ARAF-targeted chemical tools to explore its pharmacological role in cancer and highlights the..."

Oncology • ARAF • BRAF • KRAS

RAS-GTP inhibition enhances antitumor efficacy of the RAF/MEK clamp avutometinib in NF1-associated Malignant Peripheral Nerve Sheath Tumors (AACR-NCI-EORTC 2025) - "As compared to MEK-only inhibitors trametinib or selumetinib, avutometinib inhibited RAF-mediated MEK phosphorylation in NF1-MPNST cells. Furthermore, the combination of avutometinib with a pan-RAS inhibitor induced strong ERK1/2 signaling inhibition in NF1-MPNST cells and induced significant anti-tumor responses relative to the single agents in 3 xenograft models. We conclude that avutometinib in combination with a pan-RAS inhibitor could have clinical implications for patients with NF1-MPNST."

Clinical • Brain Cancer • Neurofibrosarcoma • Oncology • MAP2K1 • NF1

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

A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition. (PubMed, Oncogene) - "Therefore, despite the pleiotropic mechanisms of Rac1-driven MAPKi resistance, we find that combined inhibition of RAF and MEK with the RAF/MEK clamp avutometinib and FAK with the FAK inhibitor defactinib is a promising approach for suppressing the growth of Rac1-driven melanoma cells. Thus, the avutometinib plus defactinib combination, which is currently being investigated for brain metastatic cutaneous melanoma may also have utility against Rac1-driven MAPKi-resistance in heavily pre-treated, advanced disease."

Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF • RAC1

Identification of Treatment Concentrations of Defactinib or VS-6766 for the Treatment of Patients With Glioblastoma (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Emory University | Recruiting ➔ Active, not recruiting

Enrollment closed • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Erratum: Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201. (PubMed, J Clin Oncol) - No abstract available

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

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

Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma. (PubMed, J Biol Chem) - "Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+"RAF-MEK clamp" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes."

IO biomarker • Journal • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BCL2 • GNA11 • GNAQ

Avutometinib and Defactinib: First Approval. (PubMed, Drugs) - "In May 2025, avutometinib and defactinib was approved in the USA for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This article summarizes the milestones in the development of avutometinib and defactinib leading to this first approval for KRAS-mutated recurrent LGSOC."

Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS • TYK2

RAMP205: Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=40 | Active, not recruiting | Sponsor: Verastem, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Verastem Oncology Reports Second Quarter 2025 Financial Results and Highlights Recent Business Updates (Businesswire) - "Achieved net product revenue of $2.1 million in the first six weeks of launch. AVMAPKI FAKZYNJA CO-PACK was launched in the U.S. within one week of FDA Approval. AVMAPKI FAKZYNJA CO-PACK is now available through a distribution network in the U.S. that includes specialty pharmacies, specialty distributors, and group purchasing agreements that are in place. Prescriptions for patients are being received from both academic and community centers, including both repeat prescriptions from physicians prescribing to multiple patients and refills for individual patients and there has been broad payer coverage and reimbursement. A support program for patients prescribed AVMAPKI FAKZYNJA CO-PACK, called Verastem Cares, went operational immediately following launch."

Launch US • Sales • US reimbursement • Low Grade Serous Ovarian Cancer