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.

P1, N=14, Active, not recruiting, Emory University | Recruiting --> Active, not recruiting

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

Combining BMS-986158 with the FAK inhibitor Defactinib had synergistic effects, reducing EwS cell proliferation, survival, and invasion in vitro, and significantly inhibited tumor outgrowth in vivo. Our studies identify BET and FAK inhibition as a rational combination therapy worthy of further investigation for EwS, and demonstrate that defining emergent mechanisms of epigenetic drug tolerance can identify new vulnerabilities that can be therapeutically targeted.

P1/2, N=40, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting

Re-expression of DIRAS3 and treatment with defactinib produced tumor regression in xenograft models. Our findings suggest that ECM components in the tumor microenvironment like FN enhance the activities of β1 integrin, FAK, and AKT to inhibit DIRAS3-induced autophagic cell death, thereby promoting ovarian cancer cell survival.

Notably, IRF1 suppression or the treatment with the FAK inhibitor, defactinib, significantly reduced melanoma metastasis in vivo. These findings demonstrate that the reduced expression of SOX10 promotes melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway and highlight FAK inhibition as a potential therapeutic strategy.

In May 2025, avutometinib and defactinib was approved in the USA for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This article summarizes the milestones in the development of avutometinib and defactinib leading to this first approval for KRAS-mutated recurrent LGSOC.

P2, N=13, Terminated, Thomas Jefferson University | Active, not recruiting --> Terminated; Trial enrollment was stopped early by study sponsors (before the anticipated accrual of 18 patients) due to no patients having significant reduction in disease.

The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781).