Verastem Oncology (VSTM) has announced that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for avutometinib, an oral RAF/MEK clamp, in combination with defactinib, an oral FAK inhibitor, for the treatment of adult patients with recurrent low-grade serous ovarian cancer (LGSOC) harboring KRAS mutations. The FDA has granted Priority Review to the application, setting a Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025. This combination, if approved, would be the first FDA-approved treatment specifically for recurrent KRAS mutant LGSOC.
Clinical Trial Data and Regulatory Pathway
The NDA is based on data from the Phase 2 RAMP 201 clinical trial (NCT04625270), which evaluated the efficacy and safety of avutometinib and defactinib in patients with recurrent LGSOC. Results presented at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting in October 2024 demonstrated a substantial overall response rate, confirmed by blinded independent central review, with durable responses and general tolerability in patients with recurrent KRAS mutant LGSOC. The NDA also includes supportive data from the FRAME Phase 1 trial.
Dan Paterson, president and chief executive officer of Verastem Oncology, emphasized the critical unmet need among patients diagnosed with this rare disease. He expressed excitement about the potential to bring the first FDA-approved treatment specifically for recurrent KRAS mutant LGSOC to patients in the U.S.
RAMP 301 and Expanded Indication Potential
Verastem is currently enrolling patients with recurrent LGSOC, regardless of KRAS mutation status, in the international Phase 3 RAMP 301 trial (NCT06072781). This trial will serve as a confirmatory study for the initial indication and has the potential to support an expanded indication regardless of KRAS mutation status.
About LGSOC
LGSOC is a rare and distinct ovarian cancer, differing from high-grade serous ovarian cancer in its biology and response to treatment. It is highly recurrent and less sensitive to chemotherapy. Approximately 6,000-8,000 women in the U.S. and 80,000 worldwide are living with LGSOC. The current standard of care includes hormone therapy and chemotherapy, but no treatments are specifically FDA-approved for LGSOC.
Avutometinib and Defactinib Mechanism of Action
Avutometinib is an oral RAF/MEK clamp that inhibits MEK1/2 kinase activities and induces inactive complexes of MEK with ARAF, BRAF, and CRAF, potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. Defactinib is an oral, selective inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2), which regulate cell proliferation, survival, migration, and invasion. FAK activation has been shown to mediate resistance to RAF and MEK inhibitors.
Licensing of VS-7375
Verastem has also exercised its early option to license VS-7375 from GenFleet Therapeutics, an oral and selective KRAS G12D inhibitor. Preliminary clinical data from a Phase 1 study in China showed both confirmed and unconfirmed partial responses in patients with metastatic pancreatic cancer and advanced non-small cell lung cancer. Verastem plans to file a U.S. investigational new drug application for VS-7375 in the first quarter of 2025 and initiate a Phase 1/2a study in mid-2025.
