defactinib (VS-6063)

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | N=20 --> 40

P2, N=15, Recruiting, Verastem, Inc.

Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

P1/2, N=182, Recruiting, Institute of Cancer Research, United Kingdom

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781.

Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

Overexpression of CTHRC1 in secreted exosomes promotes the metastatic ability of EC cells in mouse models and may be eliminated by Defactinib, an inhibitor of FAK Tyr397 phosphorylation. Moreover, overexpression of CTHRC1 was increased in EC patients, elevating with cancer progression, and correlated with negative tumor prognosis. Our results revealed that CAF mediated endometrial cancer progression is related to high levels of CTHRC1 and exosomal CTHRC1 derived from CAF may be a promising therapeutic strategy for metastatic endometrial cancer.

P1, N=12, Recruiting, Emory University | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=50, Recruiting, Emory University | Not yet recruiting --> Recruiting

P2, N=42, Recruiting, Washington University School of Medicine | Trial completion date: Dec 2026 --> Jun 2028 | Trial primary completion date: Dec 2025 --> Jun 2027

P2, N=50, Not yet recruiting, Emory University

P2, N=27, Recruiting, Ryan H. Moy, MD, PhD

With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.

These results demonstrate that the epithelial-mesenchymal transition status may be a promising biomarker for the efficacy of combination therapy with avutometinib and defactinib in KRAS-mutated NSCLC.

Finally, therapeutic effects targeted to PTK2 in lung cancer in response to EGF and TLR agonists were verified by using its inhibitor (Defactinib). In summary, we identified that up-regulated PTK2 might be a reliable marker for EGFR- or TLRs-induced lung cancer progression in NSCLC patients via the regulation of the cross-talk between EGFR- and TLRs-mediated signaling. This study provides a theoretical basis for the therapeutic intervention of PTK2 targeting EGFR- or TLRs-induced lung cancer progression.

Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible PDAC patients for treatment with defactinib.

P2, N=42, Recruiting, Washington University School of Medicine | Trial primary completion date: Dec 2026 --> Dec 2025

The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

P2, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=33, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).

P2, N=225, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1/2, N=33, Recruiting, University of Utah | Not yet recruiting --> Recruiting

This study unveils CBG's ability to enhance MME expression, deactivate FAK/STAT3 signaling, and inhibit TNBC metastasis by suppressing M2-skewed macrophages.

P1/2, N=153, Recruiting, Verastem, Inc. | N=53 --> 153 | Trial completion date: Sep 2025 --> Apr 2027

P2, N=42, Recruiting, Washington University School of Medicine | Trial completion date: Jun 2026 --> Dec 2026 | Trial primary completion date: Jun 2026 --> Dec 2026

Focal adhesion kinase (FAK) inhibitor defactinib was used to further explore the molecular mechanism of ITGB4...In addition, ITGB4 could interact with FAK in lung adenocarcinoma cells. ITGB4 may promote cell migration of lung adenocarcinoma through FAK signaling pathway and has the potential to be a biomarker for lung adenocarcinoma.

P2, N=36, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=90, Completed, Verastem, Inc. | Recruiting --> Completed | Trial completion date: Dec 2025 --> Dec 2023 | Trial primary completion date: Mar 2023 --> Aug 2023

Mechanistically, VS-6063 overcomes the physical barriers in tumors and promotes the migration and infiltration of CD8 T cells primed by RT into distant tumors. Our findings highlight that molecular imaging of ICAM-1 levels provides a dynamic readout of the proliferation and effector function of tumor-infiltrating CD8 T cells, which facilitates the high-throughput exploitation of new combinational drugs to maximize the systemic antitumor effect of RT.

P1/2, N=33, Not yet recruiting, University of Utah

P2, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

P3, N=270, Recruiting, Verastem, Inc. | Not yet recruiting --> Recruiting

P2, N=55, Recruiting, University of Oklahoma

P1/2, N=40, Recruiting, Verastem, Inc. | Phase classification: P1b/2a --> P1/2

In vitro, cell viability and proliferation assays were used to test abemaciclib (CDK4/6 inhibitor), defactinib (FAK inhibitor) and VS-6766 (RAF/MEK inhibitor) as monotherapy and in combination...The efficacy of VS-4718 (in vivo formulation of defactinib) and abemaciclib were evaluated in a subcutaneous IOMM-lee meningioma model (having CDKN2A loss) in nude mice... Abemaciclib showed promising efficacy in preclinical meningioma xenografts with CDKN2A loss. Studies to evaluate these therapies in other orthotopic models are underway.

Our current findings provided valuable insights into the role of FTO-mediated mA demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. Video Abstract.

P2, N=13, Active, not recruiting, Thomas Jefferson University | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Jan 2025 | Trial primary completion date: Oct 2023 --> Apr 2024

P3, N=270, Not yet recruiting, Verastem, Inc.

Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable-prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL.