FDA Grants Priority Review to Verastem's Avutometinib and Defactinib for KRAS Mutant Ovarian Cancer

In December 2024, Verastem Oncology, a biopharmaceutical company based in Boston, announced a significant step forward in cancer treatment. The U.S. Food and Drug Administration (FDA) has accepted the company's New Drug Application (NDA) under the accelerated approval pathway for a new drug combination aimed at treating recurrent low-grade serous ovarian cancer (LGSOC) with a KRAS mutation. This new treatment involves the use of avutometinib, an oral RAF/MEK clamp, in combination with defactinib, an oral FAK inhibitor. The FDA has granted this application Priority Review, with a Prescription Drug User Fee Act (PDUFA) target action date set for June 30, 2025. Notably, the FDA does not plan to conduct an advisory committee meeting to discuss the application.

Verastem's president and CEO, Dan Paterson, expressed optimism about the potential approval, highlighting the lack of FDA-approved treatments specifically for LGSOC. Paterson emphasized the critical need for new therapies for this rare form of ovarian cancer, which presents differently from the more common high-grade serous ovarian cancer and has shown resistance to traditional treatments.

The NDA submission was primarily based on promising results from the Phase 2 RAMP 201 clinical trial. This trial evaluated the efficacy and safety of the combination of avutometinib and defactinib in patients with recurrent LGSOC. The findings, presented at the International Gynecologic Cancer Society Annual Global Meeting in October 2024, demonstrated a substantial overall response rate. The responses were typically durable, and the combination treatment was generally well-tolerated among participants. In addition to the RAMP 201 trial, the NDA included data from the FRAME Phase 1 trial, which initially tested the combination therapy in recurrent LGSOC.

Verastem is also conducting the RAMP 301 international Phase 3 trial to further evaluate the combination's efficacy and safety. Importantly, this study includes patients with recurrent LGSOC regardless of KRAS mutation status, potentially expanding the treatment's indication.

Low-grade serous ovarian cancer is a rare and persistent form of ovarian cancer, affecting around 6,000 to 8,000 women in the U.S. and about 80,000 worldwide. It primarily affects younger women and has a median survival of approximately ten years. The disease significantly impacts patients' mental and physical health, fertility, and overall quality of life. Current treatment options are limited to hormone therapy and chemotherapy, with no FDA-approved treatments specifically for LGSOC.

Avutometinib works by inhibiting MEK1/2 kinase activities and forming inactive complexes with ARAF, BRAF, and CRAF, potentially offering a more effective anti-tumor response compared to existing MEK-only inhibitors. Defactinib targets focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2), which play roles in cell proliferation, survival, and migration. FAK activation is often linked to resistance against various anti-cancer agents, including RAF and MEK inhibitors.

Verastem's commitment to advancing cancer treatment is further demonstrated through various clinical trials, including collaborations with other pharmaceutical companies to explore additional combination therapies. The company remains focused on the development and commercialization of innovative treatments to improve outcomes for cancer patients, with particular emphasis on RAS/MAPK-driven cancers.