Verastem Oncology has announced the completion of its New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for the combination of avutometinib and defactinib for the treatment of 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 expected to make a decision by mid-2025.
Addressing Unmet Needs in LGSOC
LGSOC is a distinct form of ovarian cancer, differing significantly from high-grade serous ovarian cancer (HGSOC) in its biology and behavior. Affecting approximately 6,000-8,000 women in the US and 80,000 worldwide, LGSOC is characterized by its insidious nature, high recurrence rate, and relative resistance to traditional chemotherapy. The current standard of care includes hormone therapy and chemotherapy, but no treatments are specifically approved by the FDA for LGSOC.
Dan Paterson, president and chief executive officer of Verastem Oncology, stated, "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. Completing our NDA submission is a significant milestone not only for Verastem as we plan for potential FDA approval in mid-2025, but also for patients as there are no FDA-approved treatments specifically for this rare ovarian cancer."
Clinical Trial Data and Outcomes
The NDA submission is supported by data from the Phase 2 RAMP 201 study (ENGOTov60/GOG3052), an adaptive, two-part multicenter, randomized, open-label trial. 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 was generally well-tolerated, with a 10% discontinuation rate due to adverse events (AEs) across all patients.
The RAMP 201 trial evaluated the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC. The expansion phases of the trial evaluated the combination of avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily.
Regulatory Designations and Ongoing Studies
The FDA 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. These designations may expedite the review and approval process.
Verastem is currently enrolling patients in RAMP 301 (NCT06072781), an international Phase 3 trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for recurrent LGSOC, regardless of KRAS mutation status. This trial will serve as a confirmatory study and has the potential to support an expanded indication.
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-tumour response through maximal RAS/MAPK pathway inhibition. Defactinib is an oral selective FAK inhibitor. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors.
