Verastem Oncology has announced the completion of its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for the combination of avutometinib and defactinib as a treatment for adult patients with recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC) who have received at least one prior systemic therapy. This submission marks a significant step toward potentially providing the first FDA-approved treatment specifically for this rare and challenging cancer. The FDA is anticipated to make a decision by mid-2025.
Clinical Trial Data and Outcomes
The NDA submission is supported by data from the Phase 2 registration-directed RAMP 201 study (ENGOTov60/GOG3052). Updated results presented at the International Gynecologic Cancer Society 2024 Annual Meeting demonstrated a confirmed overall response rate (ORR) of 44% in patients with KRAS mutant LGSOC. The median progression-free survival (PFS) was 22 months, and the disease control rate at 6 months was 70%. The combination therapy was generally well-tolerated, with a 10% discontinuation rate due to adverse events across all patients.
"We believe that avutometinib in combination with defactinib has the potential to change the treatment paradigm for patients with recurrent KRAS mutant low-grade serous ovarian cancer," said Dan Paterson, president and chief executive officer of Verastem Oncology.
Regulatory Designations and Ongoing Studies
The FDA has previously granted Breakthrough Therapy Designation for avutometinib plus defactinib for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.
Verastem is currently enrolling patients with recurrent LGSOC, regardless of KRAS mutation status, in the RAMP 301 Phase 3 trial (NCT06072781). This international study will serve as a confirmatory trial for the initial indication and has the potential to support an expanded indication regardless of KRAS mutation status.
About Low-Grade Serous Ovarian Cancer
Low-grade serous ovarian cancer (LGSOC) is a rare and distinct type of ovarian cancer, differing from high-grade serous ovarian cancer in its biology and behavior. LGSOC 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 this disease. The current standard of care includes hormone therapy and chemotherapy, but there are no FDA-approved treatments specifically for LGSOC.
Mechanism of Action
Avutometinib is a RAF/MEK clamp that 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 FAK inhibitor. The combination aims to provide a more effective treatment strategy for LGSOC.
