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Investigational Drug

Defactinib

Shows activity

Also known as:

PF-04554878 VS-6063

Cancer types include:

brain tumor cervical cancer colon cancer head and neck cancer melanoma

HealthScout AI Analysis

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Overview

Defactinib (PF-04554878; VS-6063) is an oral small‑molecule inhibitor of focal adhesion kinase (FAK; PTK2) with additional activity against PYK2. It has been studied as monotherapy and in combinations across multiple solid tumors, including mesothelioma, ovarian cancer, and pancreatic cancer. In May 2025, the FDA granted accelerated approval to the combination of avutometinib (RAF/MEK clamp) plus defactinib for adults with KRAS‑mutated, recurrent low‑grade serous ovarian cancer (LGSOC) after prior systemic therapy. Defactinib itself remains investigational outside this co‑packaged combination. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Target: Potent, selective inhibition of FAK and PYK2; recommended phase 2 monotherapy dose from first‑in‑human work was 425 mg twice daily. By blocking FAK signaling, defactinib can reduce tumor cell survival/invasion and modulate the tumor microenvironment. (pubmed.ncbi.nlm.nih.gov)
Tumor microenvironment and immunology: Preclinical studies indicate that FAK signaling supports stromal fibrosis and immunosuppression; FAK inhibition can enhance infiltration/efficacy of T‑cell checkpoint blockade in pancreatic models. (nature.com)

Efficacy

Low‑grade serous ovarian cancer (in combination with avutometinib)
Phase 2 (RAMP 201; ENGOT‑ov60/GOG‑3052): Confirmed ORR 31% overall (44% in KRAS‑mutant; 17% in KRAS‑wild‑type); median PFS 12.9 months overall. These data supported the FDA’s accelerated approval in KRAS‑mutant recurrent LGSOC. (ascopubs.org)
Phase 1/2 (FRAME, first‑in‑human combo): In LGSOC, ORR 42.3% and median PFS 20.1 months; in KRAS‑mutant LGSOC, ORR 58.3% and median PFS 30.8 months. (pubmed.ncbi.nlm.nih.gov)
Malignant pleural mesothelioma (maintenance monotherapy)
COMMAND randomized, double‑blind, phase 2 (post‑platinum maintenance; merlin‑stratified): No improvement versus placebo in PFS (4.1 vs 4.0 months) or OS (12.7 vs 13.6 months); results did not support use as maintenance therapy. (ascopubs.org)
Pancreatic ductal adenocarcinoma (investigator‑initiated combinations)
Phase I dose‑escalation/expansion of defactinib + pembrolizumab + gemcitabine in advanced PDAC: Among refractory patients (n=20), DCR 80% (1 PR, 15 SD); median PFS 3.6 months and OS 7.8 months. Maintenance cohort (post–gemcitabine/nab‑paclitaxel, n=10 evaluable): DCR 70% (1 PR). (pubmed.ncbi.nlm.nih.gov)
Early phase RAMP‑205 (first‑line PDAC; avutometinib + defactinib + gemcitabine/nab‑paclitaxel): Interim press‑release data reported high partial response rates in select dosing cohorts; confirmatory peer‑reviewed results are pending. (verastem.gcs-web.com)

Safety

Monotherapy (phase 1): Common adverse events included nausea (37%), fatigue (33%), vomiting (28%), diarrhea (22%), and headache (22%); dose‑limiting toxicities included headache, fatigue, and unconjugated hyperbilirubinemia. A maximum tolerated dose was not defined; 425 mg twice daily was recommended for phase 2. (pubmed.ncbi.nlm.nih.gov)
Mesothelioma maintenance (COMMAND): Most grade ≥3 events with defactinib were gastrointestinal or constitutional (e.g., nausea, diarrhea, fatigue); no survival benefit versus placebo. (ascopubs.org)
Combination with avutometinib in LGSOC:
RAMP 201: Most common adverse events included nausea, diarrhea, and elevated creatine phosphokinase; discontinuation for AEs occurred in about 10%. (ascopubs.org)
FRAME: Frequent AEs included rash and elevated CPK; discontinuation due to toxicity was uncommon. (pubmed.ncbi.nlm.nih.gov)
FDA label (co‑pack approval, May 8, 2025): For the avutometinib/defactinib co‑pack, common adverse reactions (≥25%) included CPK increased, nausea, fatigue, AST/ALT elevations, rash, diarrhea, edema, and hematologic changes. (fda.gov)

Additional notes

Biomarker development: NF2/merlin‑low status did not predict benefit in the COMMAND study, despite preclinical rationale. (ascopubs.org)
Ongoing trials: A confirmatory phase 3 study (RAMP 301) of avutometinib + defactinib versus investigator’s choice in recurrent LGSOC is in progress. Other early‑phase studies are exploring the combination with chemotherapy and/or immunotherapy in pancreatic and other solid tumors. (verastem.gcs-web.com)

Active trials using Defactinib

Found 8 active trials using this drug:

Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer

Sponsor: M.D. Anderson Cancer Center (other) Phase: 2 Start date: Feb. 24, 2025

HealthScout AI summary: This trial enrolls adults with unresectable or metastatic, anti-EGFR-refractory, KRAS/NRAS/BRAF V600E/EGFR WT advanced colorectal cancer (progressed on EGFR antibody and standard chemotherapy), and treats them with avutometinib (a dual RAF/MEK inhibitor), defactinib (FAK inhibitor), and cetuximab. Prior BRAF/MEK/ERK inhibitor therapy and active CNS metastases are exclusion criteria.

ClinicalTrials.gov ID: NCT06369259

A Phase II Trial of Avutometinib in Combination With Defactinib in Metastatic Diffuse Gastric Cancer

Sponsor: Ryan H. Moy, MD, PhD (other) Phase: 2 Start date: Oct. 28, 2024

HealthScout AI summary: Adults with unresectable/metastatic diffuse-type gastric or GEJ cancer (including poorly cohesive/signet ring or CDH1/RHOA-mutant tumors) after at least one prior platinum/fluoropyrimidine regimen, ECOG 0–1, and tumor amenable to fresh biopsy. Treatment is oral avutometinib (dual RAF/MEK “clamp”) plus defactinib (FAK/PYK2 inhibitor) on a 3-weeks-on/1-week-off schedule; prior MEK/RAF/FAK inhibitor exposure excluded.

ClinicalTrials.gov ID: NCT06487221

A Phase 2 Study of Defactinib and Avutometinib, in Combination With Nivolumab for Patients With Anti-PD1 Refractory LKB1-Mutant Advanced Lung Adenocarcinoma

Sponsor: Emory University (other) Phase: 2 Start date: July 31, 2024

HealthScout AI summary: This trial is enrolling adults with advanced, LKB1-mutant, anti-PD1-refractory lung adenocarcinoma (including KRAS-mutant subset), testing the combination of oral defactinib (FAK/Pyk2 inhibitor), oral avutometinib (dual RAF/MEK inhibitor), and intravenous nivolumab. Eligible patients must have progressed on prior anti-PD1 therapy and first line chemotherapy, and have ECOG 0-1.

ClinicalTrials.gov ID: NCT06495125

Combination Targeted and Hormonal treAtMEnt of Low-gradE Serous Ovarian Cancer in the upfroNt Setting

Sponsor: Memorial Sloan Kettering Cancer Center (other) Phase: 2 Start date: April 29, 2024

HealthScout AI summary: Upfront therapy for adult women with measurable low-grade serous ovarian or primary peritoneal carcinoma who are not candidates for primary cytoreduction or have residual disease after suboptimal debulking. Patients receive avutometinib (dual RAF/MEK clamp) plus defactinib (FAK inhibitor) on a 3-weeks-on/1-week-off schedule with continuous letrozole (and ovarian suppression if pre/perimenopausal).

ClinicalTrials.gov ID: NCT06394804

A Phase 3, Randomized, Open-Label Study of Combination Therapy With Avutometinib Plus Defactinib Versus Investigator's Choice of Treatment in Patients With Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) (RAMP 301)

Sponsor: Verastem, Inc. (industry) Phase: 3 Start date: March 18, 2024

HealthScout AI summary: Adults with recurrent low-grade serous ovarian, fallopian tube, or primary peritoneal cancer after prior systemic therapy are randomized to avutometinib (a dual RAF/MEK “clamp”) plus defactinib (FAK/Pyk2 inhibitor) versus investigator’s choice of pegylated liposomal doxorubicin, weekly paclitaxel, letrozole, or anastrozole. Requires measurable disease, ECOG 0–1, and known KRAS status; crossover to the combo is allowed at progression.

ClinicalTrials.gov ID: NCT06072781

Phase 1b/2 Trial of Defactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases From Cutaneous Melanoma

Sponsor: University of Utah (other) Phase: 1/2 Start date: March 7, 2024

HealthScout AI summary: Adults with cutaneous melanoma and measurable brain metastases after immune checkpoint inhibitors, including BRAF V600E/K–mutant and non‑BRAF cohorts; requires at least one untreated 0.5–4 cm parenchymal lesion, ECOG 0–1, and known RAS/BRAF/NF1 status. Treatment is avutometinib (dual RAF/MEK “clamp”) plus defactinib (FAK/Pyk2 inhibitor), with an added encorafenib (BRAF inhibitor) dose‑finding and expansion for BRAF V600E/K disease.

ClinicalTrials.gov ID: NCT06194929

Phase II of Avutometinib (VS-6766) and Defactinib In RAF Dimer-Driven RAI-Refractory Differentiated and Anaplastic Thyroid Cancer Patients

Sponsor: Memorial Sloan Kettering Cancer Center (other) Phase: 2 Start date: Aug. 16, 2023

HealthScout AI summary: Adults with RAF dimer–driven thyroid cancers: RAIR differentiated (papillary/follicular/Hürthle cell/poorly differentiated) with recent progression or anaplastic, harboring RAS or NF1 mutations, RET/NTRK/ALK fusions, or non‑V600E/K/class 2–3 BRAF alterations; ECOG 0–1, measurable disease, any prior lines, but no prior MEK/class II–III BRAF/FAK inhibitors. Treatment is oral avutometinib (dual RAF/MEK clamp) plus defactinib (FAK/Pyk2 inhibitor) on a 3-weeks-on/1-week-off schedule, with ORR as the primary endpoint.

ClinicalTrials.gov ID: NCT06007924

ROCKIF Trial: Re-sensitization of Carboplatin-resistant Ovarian Cancer With Kinase Inhibition of FAK

Sponsor: Michael McHale (other) Phase: 1/2 Start date: Feb. 6, 2018

HealthScout AI summary: Adults with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (relapse ≤6 months after last platinum; ≤2 prior cytotoxic lines) receive carboplatin/paclitaxel plus oral defactinib, a reversible ATP-competitive FAK/Pyk2 inhibitor aimed at re-sensitizing to platinum. Primary aims are safety/tolerability and objective response by RECIST 1.1.

ClinicalTrials.gov ID: NCT03287271