defactinib (VS-6063)

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.

P2, N=30, Recruiting, Memorial Sloan Kettering Cancer Center

The pioneering bruton tyrosine kinase (BTK) inhibitor, ibrutinib along with the second-generation inhibitors acalabrutinib and zanubrutinib, have displayed remarkable therapeutic efficacy in patients with CLL. In summary, our findings demonstrate that defactinib, by inhibiting FAK activation, exhibits greater capability as an apoptotic agent compared to BTKi. Moreover, defactinib enhances the cytotoxic effects of BTKi in vitro and counteracts the protective effect of HS5 stromal cells on CLL cell survival. These results highlight FAK as a promising target for developing of novel therapeutic approaches in CLL.

The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients.

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.

P1, N=87, Active, not recruiting, Institute of Cancer Research, United Kingdom | Recruiting --> Active, not recruiting | Trial completion date: Mar 2023 --> Oct 2023 | Trial primary completion date: Sep 2022 --> Apr 2023

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: May 2023 --> May 2024

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.

Further investigations confirmed that the stromal NNMT-aggravated oncogenic activities were attenuated by treatment with inhibitors of either collagen synthesis (e.g. losartan, tranilast, and halofuginone) in fibroblasts, or the focal adhesion kinase (FAK) signal (i.e. defactinib) in cancer cells. Mechanistically, overexpression of NNMT reduced the enrichment of H3K27me3 at the promoter of the gene encoding lysyl oxidase (LOX), a key enzyme that regulates the cross-linking of collagen I. Overall, we propose that the NNMT-LOX-FAK cascade contributes to the crosstalk between cancer cells and fibroblasts during OSCC development, and that NNMT-centric extracellular matrix remodelling is a novel therapeutic target for patients with OSCC.

P2, N=184, Recruiting, Verastem, Inc. | N=100 --> 184

Nuclear p85β represses RB1 expression by stabilizing histone methyltransferase EZH1/EZH2 proteins. Last, the FAK inhibitor defactinib significantly suppresses the tumor growth of ccRCC with high p85β Y464 levels.

Combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviated HCC progression and metastasis mediated by the HMGB1-KLF7 axis. HMGB1-induced KLF7 overexpression facilitated HCC progression and metastasis by upregulating TLR4 and PTK2 expression. Combined administration of TLR4 and PTK2 inhibitors, or genetic ablation of KLF7 via AAV gene therapy represented promising therapy strategies for KLF7-positive HCC patients.

Tumoroids werethen treated with stromal targeting strategies for TGF-beta (galunisertib), the FGF pathway(Dovitinib), FAK inhibitors (defactinib), and cell adhesion modulators (plerixafor) alone or incombination with nivolumab for 72-hours ex vivo. Treatment-mediated changes in the tumor immune microenvironment was furthercorroborated by a multiplex cytokine release assay detecting GM-CSF, sCD137, IFNγ, sFas,sFasL, Granzyme A, Granzyme B, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, MIP-1α, MIP-1β, TNF-α,Perforin in tumoroid culture media and correlated with clinicopathologic findings and PD-L1expression for individual tumnors. Further, this 3D-tumoroid platform provides unique insightinto the microenvironment of both treatment responsive and non-responsive tumors and can aidin the development of patient-centered therapeutic regimens.

VS-4718 is a focal adhesion kinase (FAK) inhibitor that has shown synergistic anti-tumor activity with avutometinib in other cancer models, as it blocks the potential of FAK to function as an adaptive resistance mechanism to RAF/MEK inhibition. Combination of avutometinib with FAK inhibition showed improved in vivo preclinical anti-tumor efficacy relative to either agent alone in an LGSC PDX model with wildtype KRAS and with a RAF1 mutation. These data support an ongoing registration-directed study with avutometinib ± the FAK inhibitor defactinib for patients with recurrent LGSC (NCT04625270).

When combined with inhibitors against mitogen-activated protein kinase kinase (MEK) [trametinib and selumetinib], mammalian target of rapamycin (mTOR) [rapamycin], focal adhesion kinase (FAK) [defactinib and Ascentage’s APG-2449, which targets FAK/ALK/ROS1], and MEK/rapidly accelerated fibrosarcoma [RAF] [VS-6766], alrizomadlin demonstrated enhanced antiproliferative activity. Combining MEK and FAK inhibitors also markedly augmented caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage (apoptosis hallmarks) and enhanced observed antitumor effects. In conclusion, our results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM.

P2, N=55, Recruiting, University of Oklahoma | Not yet recruiting --> Recruiting