Verastem Oncology has completed its New Drug Application (NDA) to the U.S. FDA for a combination therapy targeting recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC). This investigational treatment combines avutometinib, an oral RAF/MEK clamp, and defactinib, an oral selective FAK inhibitor, and is intended for adults who have undergone at least one prior systemic therapy. Currently, no FDA-approved treatments exist specifically for LGSOC, a rare ovarian cancer distinct from its high-grade counterpart.
Verastem seeks Accelerated Approval and Priority Review for its NDA, given the significant unmet medical need in recurrent LGSOC. If granted Priority Review, the FDA aims to complete its evaluation within six months following a 60-day filing period. A potential FDA approval decision is anticipated by mid-2025. This approval would mark the first FDA-approved therapy for adult patients with recurrent KRAS mutant LGSOC in the United States.
The NDA submission follows preliminary data review with the FDA and is supported by updated Phase 2 RAMP 201 study results. These results, presented at the International Gynecologic Cancer Society 2024 Annual Meeting, demonstrated a 44% overall response rate, median progression-free survival of 22 months, and a 70% disease control rate at six months in patients with KRAS mutant LGSOC. The combination therapy was generally well-tolerated, with a 10% discontinuation rate due to adverse events across all patients. Supportive data from the FRAME Phase 1 trial, the initial study of this combination in recurrent LGSOC, is also included in the NDA.
Avutometinib plus defactinib previously received a Breakthrough Therapy Designation from the FDA for treating recurrent LGSOC after one or more prior therapies, including platinum-based chemotherapy. Both drugs, individually and in combination, were also granted Orphan Drug Designation for LGSOC treatment. Currently, Verastem is enrolling patients in RAMP 301, an international Phase 3 trial. This confirmatory study will investigate the combination therapy in recurrent LGSOC regardless of KRAS mutation status and could potentially support an expanded indication.
LGSOC is a persistent and ultimately fatal disease, impacting an estimated 6,000-8,000 women in the U.S. and 80,000 globally. It differs significantly from high-grade serous ovarian cancer, exhibiting higher recurrence rates and lower chemotherapy sensitivity. LGSOC typically affects younger women, with peak diagnoses between 20-30 and 50-60 years of age, and a median survival of around ten years. Current standard care includes hormone therapy and chemotherapy, but no FDA-approved treatments exist specifically for LGSOC.
Avutometinib is designed to create a more comprehensive and lasting anti-tumor response by forming inactive complexes of MEK with ARAF, BRAF, and CRAF. This unique mechanism maximally inhibits the RAS/MAPK pathway, preventing the compensatory MEK activation that can limit the effectiveness of MEK-only inhibitors. Verastem is exploring the potential of avutometinib combined with various therapies in RAMP trials as part of their Raf And Mek Program.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.