An evaluation of avutometinib in combination with defactinib for KRAS -mutated recurrent low-grade serous ovarian cancer

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Introduction Low-grade serous ovarian cancer (LGSOC) is a rare, biologically distinct subtype of epithelial ovarian cancer characterized by relative genomic stability, frequent activation of the mitogen-activated protein kinase (MAPK) pathway, and limited sensitivity to cytotoxic chemotherapy. Activating alterations in KRAS, NRAS, and BRAF mutations occur in 70% of cases, with KRAS being the predominant driver in recurrent disease, for which effective and durable treatment options remain limited.Areas covered This article reviews the mechanistic rationale for combined RAF/MEK and focal adhesion kinase (FAK) inhibition in LGSOC, focusing on avutometinib (a first-in-class RAF/MEK clamp) and defactinib (a selective FAK inhibitor). A structured review of preclinical and clinical evidence was conducted, including key findings from phase I FRAME and phase II RAMP-201 trials. Efficacy outcomes, safety and tolerability profiles, and the current regulatory landscape, including accelerated approval in the United States and ongoing phase III evaluation, are discussed.Expert opinion Avutometinib plus defactinib represents a promising targeted therapeutic strategy for recurrent LGSOC, particularly in patients with KRAS-mutant tumors. If confirmed in phase III trials, this combination may establish a molecularly informed disease-specific treatment paradigm with the potential for more durable disease control than existing therapies.

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