P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

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

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

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.

Therefore, despite the pleiotropic mechanisms of Rac1-driven MAPKi resistance, we find that combined inhibition of RAF and MEK with the RAF/MEK clamp avutometinib and FAK with the FAK inhibitor defactinib is a promising approach for suppressing the growth of Rac1-driven melanoma cells. Thus, the avutometinib plus defactinib combination, which is currently being investigated for brain metastatic cutaneous melanoma may also have utility against Rac1-driven MAPKi-resistance in heavily pre-treated, advanced disease.