Gynecological Cancers: Treatment Updates and Expert Perspectives - Episode 6
Panelists discuss how the recent approval of avutometinib plus defactinib for KRAS-mutated low-grade serous ovarian cancer addresses a significant unmet need in this lethal disease, with the dual FAK/MEK inhibition approach showing impressive response rates despite requiring careful toxicity management.
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Avutometinib plus defactinib represents a significant breakthrough for low-grade serous ovarian cancer, receiving accelerated FDA approval for patients with KRAS-mutation based on unprecedented response rates exceeding 50% in the RAMP-201 study. This combination targets both MEK and focal adhesion kinase pathways, providing dual blockade that appears more effective than the single-agent MEK inhibitors previously studied. The approval addresses a critical unmet need in this lethal disease where patients inevitably recur and die from progressive disease.
Clinical experience with avutometinib plus defactinib shows rapid CA-125 reductions up to 85% within initial treatment cycles, though toxicity management requires expertise. Adverse effects include ocular toxicities affecting both anterior and posterior eye segments, skin rash, diarrhea, and bone marrow suppression. Participation in clinical trials provides valuable experience managing these novel toxicities and optimizing dose modifications, highlighting the importance of clinical trial participation for community oncologists.
The mechanism of dual pathway inhibition appears crucial for efficacy, though questions remain about whether improved MEK inhibition or focal adhesion kinase targeting drives superior outcomes. Ongoing studies will determine benefits in KRAS wild-type patients and optimal treatment duration for sustained responses. The collaboration between GOG and pharmaceutical partners demonstrates successful drug development in rare ovarian cancer subtypes, providing hope for continued therapeutic advances in low-grade serous ovarian cancer management.