Fakzynja (defactinib) / Verastem - LARVOL DELTA

Focal adhesion kinase inhibitor defactinib enhances olaparib-induced suppression of BRCA-proficient breast cancer cell proliferation. (PubMed, Oncol Lett) - "To elucidate the molecular mechanisms underlying the enhanced induction of apoptosis, a Western blot analysis of apoptosis-related proteins indicated the contribution of the downregulated expression of X-linked inhibitor of apoptosis protein. This indicates the efficiency of the combination treatment of the PARP inhibitor olaparib and the FAK inhibitor defactinib for breast cancer cells, which may be useful for BRCA-proficient breast cancer or carcinomas that acquire resistance to PARP inhibitors."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • XIAP

Avutometinib plus defactinib (AvDf) with or without gemcitabine and nab-Paclitaxel (GnP) in previously treated patients with pancreatic ductal adenocarcinoma (PDAC) harboring KRAS mutations (ESMO 2026) - No abstract available

Clinical • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS

Preliminary translational immune and stromal correlates in a randomized phase II trial of pembrolizumab with or without defactinib for resectable pancreatic ductal adenocarcinoma (PDAC). (ASCO 2023) - P2 | "All patients received 2 cycles of gemcitabine+nab-paclitaxel neoadjuvant chemotherapy and underwent a biopsy after completion of chemotherapy. In this analysis, pembrolizumab combined with defactinib was associated with lower fibroblast infiltration, higher anti-tumor M1 macrophage expression and increased CD8+ T-cell infiltration into the TME, versus pembrolizumab alone. The increased expression of CXCR4 across both treatment arms may represent a resistance mechanism and supports CXCR4 as an additional TME target. These preliminary findings warrant continued research into FAK inhibition and immune checkpoint combinatorial strategies."

Clinical • IO biomarker • P2 data • Stroma • Gastrointestinal Cancer • Immune Modulation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD8 • CXCR4

Panc 004: Neoadjuvant Avutometinib/Defactinib and mFOLFIRINOX Combination Therapy in Pancreatic Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=31 | Not yet recruiting | Sponsor: University of Virginia

New P1/2 trial • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

RAMP 202: A phase 2 study of avutometinib (VS-6766) ± defactinib, in patients with advanced KRAS G12V mutant non–small cell lung cancer (NSCLC). (ASCO 2023) - P2 | "Patients received up to 5 lines of prior systemic therapy (median 2), including prior platinum-based chemotherapy, ICIs, and bevacizumab. In this heavily pretreated population of patients with KRAS G12V mt NSCLC, limited clinical activity was observed with combination therapy. While no new safety signals were identified, criteria to proceed to part B were not met, and further evaluation of avutometinib ± defactinib in KRAS G12V mt NSCLC will not be pursued. Additional trials evaluating rational avutometinib combinations (sotorasib, adagrasib, everolimus) are ongoing in patients with KRAS mt NSCLC."

Clinical • IO biomarker • Metastases • P2 data • Anemia • Hematological Disorders • Immune Modulation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

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

Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205). (ASCO 2024) - P1/2 | "Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported."

Clinical • Metastases • P1/2 data • Alopecia • Anemia • Cardiovascular • Fatigue • Febrile Neutropenia • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Immunology • Infectious Disease • Neutropenia • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Pulmonary Embolism • Respiratory Diseases • Septic Shock • CA 19-9 • KRAS

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

Defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment refractory pancreatic cancer: A phase I, dose escalation, and expansion study. (PubMed, Clin Cancer Res) - "The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Late-Breaking Abstract: EFFICACY AND SAFETY OF AVUTOMETINIB ± DEFACTINIB IN RECURRENT LOW GRADE SEROUS OVARIAN CANCER: PRIMARY ANALYSIS OF ENGOT-OV60/GOG-3052/RAMP 201 (IGCS 2024) - "Prior therapies included endocrine (86%), bevacizumab (51%), and MEK inhibitor (22%). Conclusion/Implications A+D was well tolerated allowing prolonged exposure to therapy. ORR and durable responses observed are clinically meaningful in this heavily pretreated population and support the potential of A+D as a new standard of care for recurrent LGSOC."

Clinical • Late-breaking abstract • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

EFFICACY OF AVUTOMETINIB AND DEFACTINIB VS CONVENTIONAL CARE IN LOW-GRADE SEROUS OVARIAN CANCER: AN EXTERNAL CONTROL ARM ANALYSIS (IGCS 2026) - " Data from RAMP 201 (avutometinib 3.2 mg BIW and defactinib 200 mg BID) and GOG 281 (physician's choice CC: letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan) were included. 115 patients from RAMP 201 and 130 from GOG 281 CC were included. KRAS mutation status was captured for all patients in RAMP 201 and in 49% in GOG 281. Effective sample size after propensity score weighting was 64.5 for avutometinib + defactinib and 53.6 f or SOC."

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

Long-Term Efficacy and Safety of Avutometinib + Defactinib in Patients with Recurrent Low-Grade Serous Ovarian Cancer: Results from ENGOT-OV60/GOG-3052/RAMP 201 (SGO 2026) - No abstract available

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

Initial Efficacy And Safety Results From ENGOT-Ov60/GOG-3052/RAMP 201: A Phase 2 Study Of Avutometinib (VS-6766) ± Defactinib In Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) (ESGO 2023) - P2 | "Most treatment-related adverse events (AEs) for combo (n=81) were grade 1-2, with a low proportion of dose reductions (17%) and discontinuations due to AEs (12.3%) in the combo arm.Conclusion Interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status. No new safety signals were observed; most AEs were mild to moderate."

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

Long-term efficacy and safety of avutometinib + defactinib in recurrent low-grade serous ovarian cancer: Results of a 2-year follow-up of ENGOT-OV60/GOG-3052/RAMP 201. (PubMed, Gynecol Oncol) - "With a median follow-up of approximately 2 years (about twice the duration of the primary analysis), the combination of avutometinib and defactinib demonstrated durable efficacy in patients with recurrent LGSOC and no new safety signals."

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

Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). (ASCO 2023) - P2 | "The interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status. No new safety signals were observed, and most AEs were mild to moderate. Enrollment continues in Part B for the combination of avutometinib and defactinib."

Clinical • P2 data • Dermatitis • Dermatology • Fatigue • Immunology • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer. (PubMed, Int J Gynecol Cancer) - P3 | "The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781."

Journal • P3 data • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • KRAS

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

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

Avutometinib plus defactinib in recurrent low-grade serous ovarian cancer: A subgroup analysis of ENGOT-OV60/GOG-3052/RAMP 201 Part A (SGO 2024) - P1, P2 | "In RAMP 201 Part A, avutometinib + defactinib achieved high response rates in heavily pretreated recurrent LGSOC, regardless of previous line of therapy. Notably, tumor regression was observed in the majority of patients, including those with stable disease or progressive disease with last line of therapy including previous MEKi."

Late-breaking abstract • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ARAF • BRAF

ROBOTIC-ASSISTED MODIFIED LATERAL EXTENDED ENDOPELVIC RESECTION (IGCS 2026) - "The minimally invasive approach achieved oncologic resection with minimal morbidity and rapid recovery. The patient is currently enrolled in a phase II trial of avutometinib and defactinib, highlighting the importance of integrating surgical and systemic strategies in rare, aggressive histologies."

Gynecologic Cancers • Oncology

Progress with FAK inhibitors in the patent literature (2020-present). (PubMed, Expert Opin Ther Pat) - "Consequently, the recent U.S. FDA approval of the FAK inhibitor defactinib combined with avutometinib for recurrent KRAS-mutant low‑grade serous ovarian cancer (LGSOC) validates FAK as a clinically actionable anticancer target. The clinical success of defactinib-based combination therapy validates the therapeutic potential of FAK targeting, while emerging approaches offer opportunities to overcome resistance. Future progress will depend on biomarker-guided patient selection, rational combination regimens, and exploration of non-catalytic FAK functions to achieve more effective and durable therapies."

Journal • Review • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

Defactinib inhibits focal adhesion kinase to attenuate pancreatic cancer growth via PI3K/AKT pathway modulation. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Notably, Defactinib also triggered ULK1-mediated compensatory protective autophagy, and co-administration with the autophagy inhibitor chloroquine effectively abrogated this process to substantially amplify the anti-tumor effect. Our findings validate PTK2 as a clinically meaningful prognostic biomarker and promising therapeutic target, providing robust new preclinical evidence to support the clinical translation of PTK2-targeted combination therapies for PC."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • CASP3

CTHRC1 Drives Metastasis in Lung Adenocarcinoma via Integrin av and FAK Mediated Vascular Mimicry (IASLC-WCLC 2026) - "Furthermore, we provide pre-clinical evidence that targeting this pathway with the FAK inhibitor VS-6063 significantly suppresses metastatic progression, highlighting its therapeutic potential in LUAD. Conclusions : Our study elucidates a hypoxia-driven autophagic secretion mechanism of CTHRC1, which promotes vascular mimicry and metastasis in lung adenocarcinoma through activation of the Integrin αV-FAK signaling axis. These findings establish CTHRC1 as a prognostic biomarker and highlight the CTHRC1-Integrin αV-FAK pathway as a promising therapeutic target for anti-metastatic intervention."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CTHRC1

Vitronectin enrichment in prostate cancer liver metastases promotes adhesion and survival. (PubMed, Cancer Res Commun) - "FAK inhibition with defactinib abrogated vitronectin- and serum-mediated adhesion in a cell-specific manner and mitigated VTN-driven depletion of hypodiploid populations. These findings support a model where dense intra-sinusoidal vitronectin deposits might capture metastatic prostate tumor cells in the liver and biochemically activate tumorigenic signaling, promoting tumor aggressiveness."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • VTN

Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer. (ASCO-GI 2025) - P2 | " This investigator-initiated, multicenter phase 2 trial will enroll 27 patients with metastatic/unresectable gastric or gastroesophageal junction carcinoma classified as diffuse, poorly cohesive, signet ring cell, or mixed type with progression on at least one line of therapy including platinum/fluorouracil chemotherapy. The trial was opened for enrollment in August 2024. Clinical trial information: NCT06487221."

Clinical • Combination therapy • Metastases • P2 data • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CDH1 • HER-2 • RHOA