Initial treatment for low-grade serous ovarian carcinoma (LGSOC) consists of surgery followed by chemotherapy and/or hormonal therapy. However, in most patients the disease recurs, after which chemotherapy demonstrates only limited efficacy.
Avutometinib is a RAF/MEK inhibitor that not only inhibits MEK directly but also blocks compensatory reactivation through RAF. However, inhibition of the MAPK pathway results in activation of FAK. Previous studies have shown that adding the FAK inhibitor defactinib to avutometinib enhances therapeutic efficacy.
This study was designed as a four-part randomized open-label trial. Following an initial selection phase in which patients were randomized (1:1) to either avutometinib 4.0 mg monotherapy or avutometinib 3.2 mg combined with defactinib 200 mg, an expansion phase with the same randomization was conducted. Ultimately, the regimen consisting of avutometinib 3.2 mg plus defactinib 200 mg was selected for further development. In the final part of the study, a lower dose of avutometinib (1.6 mg) combined with defactinib 200 mg was also evaluated.
The analysis demonstrated that the combination of avutometinib and defactinib had greater efficacy without increased toxicity. Among patients receiving combination therapy, the overall response rate was higher in patients harboring a KRAS mutation compared with those without a KRAS mutation (44% versus 17%). A similar trend was observed for progression-free survival, with a median of 22.0 months in the KRAS-mutated population versus 12.8 months in the KRASwt patients. This difference may be explained by previous studies showing that KRAS wild-type patients have a poorer prognosis. Despite these differences, 82% of patients experienced a reduction in target lesion size, regardless of KRAS mutation status or prior treatment with a MEK inhibitor.
The safety profile was considered manageable with dose interruptions or dose reductions. In most patients, treatment could be continued until disease progression. In this study, approximately 10% of patients discontinued treatment because of adverse events, which is substantially lower than the 30% previously reported with MEK inhibitors.
In this population of women with recurrent LGSOC and limited treatment options, the combination of avutometinib 3.2 mg and defactinib 200 mg demonstrated clinically meaningful benefits in duration of response and progression-free survival. These findings support the potential role of this combination as a new standard treatment in this population.