Avmapki (avutometinib)

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.

P1/2, N=53, Recruiting, University of Chicago | Suspended --> Recruiting

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

Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors...Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250)...The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC.

Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+"RAF-MEK clamp" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes.

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

P1/2, N=53, Suspended, University of Chicago | Trial completion date: Aug 2025 --> Feb 2027 | Trial primary completion date: Aug 2025 --> Feb 2027

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.

Taken together, this study provides the first experimental evidence to demonstrate that all G12 mutation cell lines are sensitive to VS6766 applied either alone or combined with 5-FU or AKT inhibitor.

Treatment of recurrent LGSC with the MEK inhibitor trametinib demonstrated improved clinical outcomes relative to other treatment options (chemotherapy, hormonal therapy) in a phase 3 trial...However, some trials of MEK inhibitors showed more limited benefit (e.g. binimetinib), and RAS pathway mutations do not always correlate with increased efficacy, highlighting the need for further clinical and translational research in RAS-MEK-ERK pathway targeted therapeutics...Novel approaches to targeting the RAS-MEK-ERK pathway include the RAF/MEK clamp avutometinib, which has been evaluated in combination with the FAK inhibitor defactinib, and this combination received United States Food and Drug Administration (FDA) accelerated approval in 2025. Multiple newly developed inhibitors of KRAS, including KRAS G12C or G12D inhibitors, as well as pan-RAS inhibitors, including RAS (ON) inhibitors such as RMC-6236, are being evaluated in solid tumors. These emerging strategies for inhibiting RAS-MEK-ERK pathway activity may offer new treatment options for patients with LGSC.

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.