Fakzynja (defactinib) / Verastem - LARVOL DELTA

20P.1113: Defactinib and VS-6766 for the Treatment of Patients With Metastatic Uveal Melanoma (clinicaltrials.gov) - P2 | N=13 | Terminated | Sponsor: Thomas Jefferson University | Active, not recruiting ➔ Terminated; Trial enrollment was stopped early by study sponsors (before the anticipated accrual of 18 patients) due to no patients having significant reduction in disease.

Trial termination • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Avmapki Fakzynja Co-Pack for ovarian cancer. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Oncology • Ovarian Cancer • Solid Tumor

Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma. (PubMed, Int J Mol Sci) - "Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

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) - P3 | "The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781)."

Journal • Fibrosarcoma • Hematological Disorders • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Sarcoma • Solid Tumor • KRAS

Verastem Oncology Announces Publication of the Primary Results from the Phase 2 RAMP 201 Trial of Avutometinib in Combination with Defactinib in Patients with Recurrent Low-Grade Serous Ovarian Cancer in the Journal of Clinical Oncology (Businesswire) - P2 | N=225 | RAMP 201 (NCT04625270) | Sponsor: Verastem | "Robust objective response rates were observed (31% overall, 44% in KRAS-mutant, and 17% in KRAS wild-type) in patients whose cancer had progressed after multiple prior lines of therapy. The majority of patients (82%) had some reduction in target lesions, regardless of KRAS mutation status. Median progression-free survival was 12.9 months overall, 31.0 months in KRAS-mutant, and 12.8 months in KRAS wild-type....The Company will submit the RAMP 201 publication and the recent publication of the FRAME study to the National Comprehensive Cancer Network (NCCN) in support of its consideration of inclusion of the KRAS wild-type population evaluated in these trials in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)."

NCCN guideline • P2 data • Low Grade Serous Ovarian Cancer

Verastem Oncology Announces Nature Medicine Publication of the Results from the First-in-Human Phase 1 FRAME Study of Avutometinib in Combination with Defactinib in Solid Tumors, including Low-Grade Serious Ovarian Cancer (Businesswire) - P1 | N=87 | FRAME (NCT03875820) | "Verastem Oncology...announced that updated results from the Phase 1/2 FRAME study...were published online in Nature Medicine....In 26 patients with LGSOC who were evaluable for efficacy, the overall response rate (ORR) was 42.3% (11/26) and median progression-free survival (mPFS) was 20.1 months. In the 24 patients whose samples could be sequenced for KRAS mutations, ORR and mPFS were 58.3% (7/12) and 30.8 months in the 12 patients with KRAS mutations, and 33.3% (4/12) and 8.9 months in the 12 patients without KRAS mutations. In 11 patients who had previously received a MEK inhibitor, the ORR was 27.3% (3/11). Additionally, in two patients with LGSOC who had brain metastases prior to enrolling, MRI imaging at 30 months post-treatment with the combination showed the metastases had shrunk in both patients."

P1 data • Low Grade Serous Ovarian Cancer

Defactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial. (PubMed, Nat Med) - P1 | "This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820 ."

Journal • P1 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

RAMP205: Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=40 | Recruiting | Sponsor: Verastem, Inc. | Trial completion date: Dec 2025 ➔ Aug 2027 | Trial primary completion date: May 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

The role of FAK signaling in early placental development and trophoblast lineage specification in human pregnancy. (PubMed, Cell Signal) - "Additionally, blocking FAK with the inhibitor Defactinib disrupts EVTs cytoskeletons and impairs migration, invasion, and differentiation potential...Our findings highlight FAK as a pivotal regulator of trophoblast lineage development, linking it to placental function and RSA. This study offers new insights into placental disorders and potential therapeutic targets."

Journal

Blood ctDNA vs tumor tissue screening for the detection of KRAS mutations in low-grade serous ovarian cancer (ESMO-GC 2025) - P2 | "Methods Samples from a phase II study (ENGOT-OV60/GOG-3052; RAMP-201; NCT04625270) evaluating the combination of avutometinib (RAF/MEK clamp) + defactinib (FAK inhibitor) versus avutometinib monotherapy in patients with LGSOC were assessed. Clinical trial identification NCT04625270. Legal entity responsible for the study Verastem Oncology."

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

Avutometinib + defactinib: "Impressive efficacy signals and a manageable safety profile, Dose level 1 selected as the RP2D, 10/12 patients in dose level 1 achieved an objective response"; Pancreatic ductal adenocarcinoma (Verastem) - ASCO 2025

P1/2 data • Gastrointestinal Cancer • Oncology • Pancreatic Ductal Adenocarcinoma

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 | "A/D + GnP have been combined in 5 dose cohorts. The MTD has not been reached. Enrollment and evaluation of mature data are ongoing to identify the recommended phase 2 dose."

Clinical • Metastases • P1/2 data • Alopecia • Anemia • Dermatitis • Dermatology • Fatigue • Febrile Neutropenia • Hematological Disorders • Hepatology • Immunology • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Thrombocytopenia • KRAS

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) and the NCCN Drugs & Biologics Compendium (NCCN Compendium) for Ovarian Cancer, Version 2.2025. (NCCN)

NCCN guideline • Low Grade Serous Ovarian Cancer • Ovarian Cancer

Potential of FAK/PYK2 inhibition in overcoming immune checkpoint inhibitor resistance (SID 2025) - "To determine whether these kinases contribute to IFNγ-driven responses, we stimulated cells with IFNγ in the presence of the FAK/PYK2 inhibitor VS6063...These findings demonstrate that dual blockade of FAK and PYK2 effectively suppresses IFNγ-driven PD-L1 and STAT1 expression, offering a promising strategy to overcome ICI resistance in melanoma. Importantly, similar results were observed in breast cancer and glioblastoma models, suggesting that this approach could have broader applications in cancers with immune checkpoint resistance."

Checkpoint inhibition • IO biomarker • Late-breaking abstract • Brain Cancer • Breast Cancer • Glioblastoma • Melanoma • Oncology • Solid Tumor • CD8 • IFNG • STAT1

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

Verastem Oncology Announces Positive Updated Results from RAMP 205 Evaluating Avutometinib Plus Defactinib in Combination with Standard-of-Care Chemotherapy in Frontline Metastatic Pancreatic Ductal Adenocarcinoma (Businesswire) - P1b/2a | N=40 | RAMP205 (NCT05669482) | Sponsor: Verastem, Inc. |"As of April 25, 2025, 60 patients (12 per cohort) had been treated in one of five dose regimens with the combination of avutometinib and defactinib with gemcitabine and Nab-paclitaxel in frontline metastatic PDAC. In the dose level 1 cohort, 12 patients received 2.4 mg of avutometinib twice a week (BIW), 200 mg of defactinib twice a day (BID) for 3 weeks out of every 4 and 800 mg/m2 of gemcitabine and 125 mg/m2 of Nab-paclitaxel on a schedule of day 1, day 8 and day 15. In dose level 1, 83% (10/12) of patients achieved partial responses (8 confirmed and 2 unconfirmed who remain on treatment)....The Company is now developing plans for a registrational Phase 3 front-line metastatic PDAC trial to begin in 2026....Company will host an R&D investor webcast on Monday, June 2 at 11:00 am CDT to review the updated RAMP 205 data as well as updated data on VS-7375 presented at ASCO."

New P3 trial • P1/2 data • Pancreatic Ductal Adenocarcinoma

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