Dr Monk on the FDA Approval of Avutometinib and Defactinib for KRAS-Mutated Recurrent Low-Grade Serous Ovarian Cancer

My advice to practitioners would be [that we have to] educate each other and educate our patients about this new opportunity. In addition to my enthusiasm about the activity [of the combination] I think we have to be familiar with the most common adverse [effects]."

Bradley Monk, MD, FACOG, FACS, gynecologic oncologist with Florida Cancer Specialists & Research Institute, medical director of the Late-Stage Clinical Research Program, discussed the regulatory significance and clinical implications of the FDA’s accelerated approval of avutometinib in combination with defactinib (Avmapki Fakzynja Co-pack) for patients with recurrent low-grade serous ovarian cancer harboring KRAS mutations.

On May 8, 2025, the FDA granted accelerated approval to the avutometinib/defactinib combination based on findings from the phase 2 RAMP-201 trial (NCT04625270). The results from the trial demonstrated a confirmed overall response rate (ORR) of 44% (95% CI, 31%-58%) and a duration of response (DOR) ranging from 3.3 to 31.1 months in patients with KRAS-mutant recurrent low-grade serous ovarian cancer who had received at least one prior systemic therapy, Monk stated.

The use of this dual-targeted approach, which combines RAF/MEK inhibition with FAK inhibition, is based on the hypothesis that disrupting parallel signaling pathways can overcome the limited efficacy seen with MEK inhibitors alone in low-grade serous ovarian cancer, Monk explained. Avutometinib inhibits both RAF and MEK in the MAPK pathway, and defactinib targets FAK-mediated tumor-stromal signaling.

Although the efficacy signal was notable, Monk emphasized the importance of understanding the safety profile. The most commonly reported adverse effects that occurred in at least 25% of patients included elevations in creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, blood bilirubin, triglycerides, and alkaline phosphatase; gastrointestinal events such as nausea, vomiting, diarrhea, abdominal pain, dyspepsia, constipation, and stomatitis; fatigue; rash; dermatitis acneiform; pruritus; dry skin; musculoskeletal pain; edema; visual disturbances including vitreoretinal disorders and visual impairment; respiratory symptoms such as dyspnea and cough; urinary tract infections; and hematologic abnormalities including decreased hemoglobin, lymphocyte count, platelet count, and neutrophil count.

Monk concluded by advising clinicians to proactively monitor for these toxicities and educate patients accordingly to ensure optimal treatment adherence.