Investigational Drug
Defactinib
TrialFetch AI Analysis
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Overview
Defactinib (PF-04554878; VS-6063) is an oral small-molecule kinase inhibitor developed primarily for cancer treatment. Although still investigational in many tumor types, it is no longer wholly investigational in the United States: on May 8, 2025, the FDA granted accelerated approval to defactinib combined with avutometinib for adults with previously treated, KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC). Defactinib monotherapy is not FDA-approved. (fda.gov)
Mechanism of action
Defactinib inhibits focal adhesion kinase (FAK/PTK2) and the related kinase PYK2/PTK2B. These non-receptor tyrosine kinases transmit signals from integrins and growth-factor receptors that can promote tumor-cell survival, proliferation, migration and invasion. FAK inhibition may also affect cancer stem-like cells and the tumor microenvironment. In combination with avutometinib, defactinib is intended to suppress adaptive FAK signaling that may limit responses to RAF–MEK pathway inhibition. (pubmed.ncbi.nlm.nih.gov)
Efficacy
- KRAS-mutated recurrent LGSOC: In the phase II RAMP-201 trial, 57 previously treated patients receiving avutometinib plus defactinib had a blinded independent-review objective response rate (ORR) of 44% (95% CI 31%–58%). Response duration ranged from 3.3 to 31.1 months. These results supported accelerated FDA approval; confirmatory evidence remains required. (fda.gov)
- Earlier LGSOC evidence: In the phase I FRAME trial, the combination produced an ORR of 42.3% (11/26) and median progression-free survival (PFS) of 20.1 months. Outcomes appeared stronger in KRAS-mutated disease, although subgroup numbers were small. (pmc.ncbi.nlm.nih.gov)
- NF2-altered tumors, monotherapy: NCI-MATCH Subprotocol U reported one partial response among 30 evaluable patients (ORR 3.3%), stable disease in 40%, and median PFS of approximately 1.9 months, indicating limited activity across an unselected group of NF2-altered tumors. (pmc.ncbi.nlm.nih.gov)
- Pleural mesothelioma, monotherapy: In the randomized phase II COMMAND trial, maintenance defactinib did not improve median PFS versus placebo (4.1 vs 4.0 months) or median overall survival (12.7 vs 13.6 months), including in the proposed merlin-low subgroup. (ascopubs.org)
- Early solid-tumor study: No radiographic responses occurred in the initial 46-patient phase I monotherapy trial; 6 of 37 patients receiving at least 100 mg twice daily had disease stabilization at approximately 12 weeks. (pubmed.ncbi.nlm.nih.gov)
Overall, meaningful clinical efficacy has been demonstrated principally when defactinib is combined with avutometinib in KRAS-mutated LGSOC; single-agent activity has generally been limited.
Safety
In the initial monotherapy phase I trial, common adverse events included nausea (37%), fatigue (33%), vomiting (28%), diarrhea (22%) and headache (22%). Reversible dose-limiting toxicities included headache, fatigue and unconjugated hyperbilirubinemia. (pubmed.ncbi.nlm.nih.gov)
For avutometinib plus defactinib, frequent adverse reactions and laboratory abnormalities included increased creatine phosphokinase, gastrointestinal symptoms, fatigue, rash, edema, musculoskeletal pain, elevated liver enzymes or bilirubin, cytopenias and ocular effects including vitreoretinal disorders and visual impairment. Because these data concern combination treatment, individual events cannot necessarily be attributed to defactinib alone. (fda.gov)
Further reading
- FDA accelerated-approval summary for avutometinib plus defactinib
- RAMP-201 phase II primary analysis
- FRAME phase I combination trial
- Initial phase I defactinib monotherapy study
- NCI-MATCH NF2-altered tumor study
- COMMAND randomized mesothelioma trial
Last updated: Sep 2026
Active trials using Defactinib
Found 8 active trials using this drug:
TrialFetch AI summary: Adults with unresectable or metastatic colorectal adenocarcinoma that progressed after an initial response to cetuximab or panitumumab, following prior chemotherapy, receive cetuximab plus avutometinib, a RAF/MEK clamp, and defactinib, a FAK/PYK2 inhibitor. Patients must have had KRAS, NRAS, EGFR ectodomain, and BRAF V600E wild-type disease before anti-EGFR therapy.
ClinicalTrials.gov ID: NCT06369259
TrialFetch AI summary: Adults with previously treated unresectable or metastatic diffuse-type, poorly cohesive, signet ring cell, or mixed gastric or gastroesophageal junction cancer are eligible; patients with pathogenic CDH1 or RHOA mutations are eligible regardless of histology. All participants receive oral avutometinib, a RAF–MEK pathway inhibitor, plus defactinib, a focal adhesion kinase inhibitor.
ClinicalTrials.gov ID: NCT06487221
TrialFetch AI summary: Adults with unresectable, LKB1-mutant advanced lung adenocarcinoma that has progressed after checkpoint inhibition and first-line chemotherapy receive defactinib (FAK/PYK2 inhibitor), avutometinib (RAF–MEK pathway inhibitor), and nivolumab (anti-PD-1). One cohort also requires a KRAS mutation.
ClinicalTrials.gov ID: NCT06495125
TrialFetch AI summary: Adults with measurable, previously untreated low-grade serous ovarian or peritoneal cancer who are not candidates for primary debulking or have measurable disease after attempted debulking receive upfront avutometinib (RAF–MEK pathway inhibitor), defactinib (FAK inhibitor), and letrozole. Premenopausal or perimenopausal patients with an ovary in situ also receive leuprolide for ovarian suppression.
ClinicalTrials.gov ID: NCT06394804
TrialFetch AI summary: Patients with measurable recurrent low-grade serous ovarian, fallopian tube, or peritoneal cancer after prior systemic therapy, including platinum, are randomized to oral avutometinib (a RAF–MEK signaling inhibitor) plus defactinib (a FAK inhibitor) or investigator’s choice of pegylated liposomal doxorubicin, paclitaxel, letrozole, or anastrozole. Documented KRAS status and ECOG performance status 0–1 are required.
ClinicalTrials.gov ID: NCT06072781
TrialFetch AI summary: Adults with cutaneous melanoma brain metastases progressing after immunotherapy and at least one untreated, measurable brain lesion receive defactinib (a FAK/PYK2 inhibitor) plus avutometinib (a RAF/MEK clamp). Patients with BRAF V600E/K-mutant disease also receive encorafenib, a BRAF inhibitor.
ClinicalTrials.gov ID: NCT06194929
TrialFetch AI summary: Adults with a qualifying RAS, NF1, RET, NTRK, ALK, or class 2/3 BRAF alteration and either progressive, radioiodine-refractory recurrent/metastatic differentiated thyroid cancer or anaplastic thyroid cancer receive avutometinib plus defactinib. Avutometinib is a RAF/MEK clamp that suppresses ERK signaling; defactinib inhibits FAK/PYK2.
ClinicalTrials.gov ID: NCT06007924
TrialFetch AI summary: For patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months of platinum chemotherapy, this single-arm study combines carboplatin and paclitaxel with defactinib, an oral FAK/PYK2 inhibitor. Platinum-refractory disease is excluded.
ClinicalTrials.gov ID: NCT03287271
