Dr Grisham on the FDA Approval of Avutometinib/Defactinib for KRAS+ Recurrent Low-Grade Serous Ovarian Cancer

“To have a treatment that was developed specifically for patients with low-grade serous ovarian cancer targeting that MAPK pathway, [which] drives this disease for so many of our patients, it really is a game changer and something that was designed specifically for these patients.”

Rachel Grisham, MD, section head of Ovarian Cancer and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center Westchester, discussed the clinical implications of the FDA’s accelerated approval of avutometinib plus defactinib (Avmapki Fakzynja Co-pack) for the treatment of adult patients with KRAS-mutated, recurrent low-grade serous ovarian cancer who have received prior systemic therapy.

The regulatory decision granted on May 8, 2025, represents the first FDA-approved therapy specifically indicated for patients with LGSOC, marking a pivotal advancement in the treatment of this rare ovarian cancer subtype. Historically, patients with LGSOC have been treated with regimens developed for high-grade serous ovarian cancer (HGSOC), despite substantial differences in molecular biology, histopathology, and clinical behavior. LGSOC is characterized by a lower proliferation index, resistance to standard cytotoxic chemotherapy, and frequent activation of the MAPK pathway—most commonly through KRAS mutations.

The approval was based on data from the phase 2 RAMP-201 trial (NCT04625270), where the confirmed objective response rate (ORR) was 44% (95% CI, 31%-58%) in patients with KRAS-mutated recurrent LGSOC treated with the combination of avutometinib—a RAF/MEK clamp that inhibits the MAPK pathway—and defactinib, a selective FAK inhibitor. The duration of response ranged from 3.3 to 31.1 months.

Grisham emphasized that the introduction of a therapy designed specifically for LGSOC addresses a longstanding gap in care. Although LGSOC accounts for less than 10% of all epithelial ovarian cancers, it disproportionately affects younger women and often demonstrates an indolent but persistent disease course. Given its low response rates to chemotherapy and the absence of effective targeted therapies until now, the availability of a biomarker-driven regimen is clinically meaningful.