Fakzynja (defactinib)

The oral drug combination was well tolerated with no dose-limiting toxicity or need for dose reduction over the 4 year period. The Avutometinib and Defactinib combination may represent a new standard treatment option for platinum-resistant and AI-resistant/recurrent LGSOC who have failed other MEKi.

P1/2, N=153, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2025 --> Jun 2026

To investigate whether FAK plays a role in this checkpoint, we inactivated the protein in normal human oral keratinocytes by specific shRNAs or by the specific inhibitor defactinib...Concomitant inhibition of FAK-downstream Rho-associated kinase (Rock) rescued mitotic progression. The results unveil a rapid Rock-dependent mitosis switch upon inactivation of FAK, inducing terminal differentiation, pointing at a mitotic automatic mechanism of epithelia to suppress suprabasal proliferation of precancerous cells.

P1, N=31, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=36, Not yet recruiting, Washington University School of Medicine

P2, N=42, Active, not recruiting, Washington University School of Medicine | Trial primary completion date: Dec 2025 --> Apr 2026

P2, N=16, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting

MEK inhibitors, especially trametinib and avutometinib in combination with defactinib, have recently demonstrated improved outcomes in recurrent disease, while new combination strategies are under active evaluation to overcome resistance mechanisms. Immunotherapy remains of limited efficacy, though biomarker-driven combinations are explored. Ongoing biomarker-guided trials are expected to refine treatment paradigms.

P1, N=14, Active, not recruiting, Emory University | Trial completion date: Oct 2026 --> Dec 2027 | Trial primary completion date: Oct 2025 --> Dec 2026

Genetic knockout of FAK or pharmacological inhibition using defactinib or PF-573228 effectively suppressed the sorafenib-induced upregulation of AKT and HMGCR...Importantly, another RAF-targeting multikinase inhibitor, regorafenib, also triggered a similar adaptive FAK-cholesterol response, suggesting that this may be a common resistance mechanism shared among RAF inhibitors...Collectively, this study systematically uncovers a new mechanism of sorafenib resistance in HCC: downregulation of RhoE drives cholesterol biosynthesis through activation of the FAK/AKT axis, thereby activating the SHH pathway and upregulating GLI1. These findings provide a strong theoretical rationale for the use of FAK inhibitors to overcome resistance and highlight the dual clinical relevance of the cholesterol biosynthesis gene signature-both as a molecular marker for predicting resistance and as a potential guide for personalized treatment strategies in HCC.

Notably, the recent US Food and Drug Administration approval of the avutometinib/defactinib combination for KRAS-mutated recurrent LGSOC marks a significant milestone in targeted therapy for this disease. Despite these advances, challenges remain in optimizing sequencing strategies and overcoming acquired resistance. This review addresses the importance of understanding the distinct pathophysiology of LGSOC, diagnostic challenges, limitations of conventional treatments, and evolving therapeutic approaches in LGSOC.

FAK inhibition was shown to suppress non-angiogenic vascularization. Defactinib has the potential to serve as a novel treatment for malignant breast cancer which is resistant to conventional therapies.