Treatment duration with avutometinib/defactinib in recurrent low-grade serous ovarian carcinoma by KRAS mutation status.

Abstract

5561 Background: Low grade serous ovarian carcinoma (LGSOC) is characterized by MAPK pathway alterations (most commonly KRAS , which occurs in 1/3 of tumors) and poor chemosensitivity. Avutometinib (MEK/RAF clamp) in combination with defactinib (FAK inhibitor) has shown durable responses in patients with recurrent LGSOC harboring a KRAS mutation and was recently FDA approved for this indication. However, data is lacking regarding the activity of avutometinib + defactinib (A+D) vs single agent MEK inhibitors for treatment of women with recurrent LGSOC. Here we examine patients who were treated with A+D. We also examine the duration of treatment in patients who received a single agent MEK inhibitor followed by A+D. Methods: In this single-institution retrospective cohort study, patients with recurrent LGSOC treated with A+D between 2021 – 2025 were included and stratified by tumor KRAS mutation status. The primary outcome was median duration of treatment on A+D, compared using Wilcoxon-Rank sum test. Pair-wise comparison of treatment duration in patients who were treated with single agent MEK inhibitors and A+D was performed. Results: 26 patients were included in the final analysis. Median age at diagnosis was 49 years (range 20-85). Patients had a median of 4 (range 1-9) prior lines of therapy, including hormonal (92%, n=24), bevacizumab (38%, n=10), and MEK inhibitors trametinib and binimetinib (35%, n=8). Eight (31%) patients harbored a tumor KRAS mutation. Among these 26 patients, median duration of treatment with A+D was 16.8 months in the KRAS -mutant and 5.5 months in the KRAS -wild type cohorts, respectively (p=0.037). Nine patients were treated with both A+D and a MEK inhibitor, three of whom had KRAS -mutant tumors. All nine patients received the single agent MEK inhibitor prior to treatment with A+D, with a median of 7 (range 4-8) prior lines of therapy before treatment with A+D. Among the three patients with KRAS -mutant tumors, median duration of treatment with single agent MEK inhibitor was 4.4 months (range 0.4-24.2) while with A+D, it was 17.6 months (range 6.1-23.4). Conclusions: In this single-institution retrospective cohort, treatment with A+D was associated with a significantly longer median duration of therapy in patients with KRAS -mutant recurrent LGSOC compared with KRAS -wild type disease. Among patients who received both regimens, A+D appeared to provide longer treatment duration than prior single agent MEK inhibitors in the KRAS -mutant subset, though this is limited by small sample size. These findings support improved activity of A+D in KRAS -mutant LGSOC and warrant confirmation in larger prospective studies.