Verastem Oncology 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, aimed at treating adult patients with recurrent KRAS-mutant low-grade serous ovarian cancer (LGSOC) who have received at least one prior systemic therapy. This submission seeks accelerated approval and priority review, potentially leading to the first FDA-approved treatment for this specific patient population by mid-2025.
Addressing an Unmet Need in LGSOC
Low-grade serous ovarian cancer (LGSOC) is a rare and distinct form of ovarian cancer, differing significantly from high-grade serous ovarian cancer in its biology and behavior. Affecting approximately 6,000-8,000 women in the U.S. and 80,000 worldwide, LGSOC is characterized by its high recurrence rate and relative resistance to traditional chemotherapy. Currently, there are no FDA-approved treatments specifically for LGSOC, highlighting a critical unmet medical need.
Rationale for Avutometinib and Defactinib Combination
The combination of avutometinib and defactinib targets the RAS/MAPK pathway, which is frequently dysregulated in LGSOC. Avutometinib, a RAF/MEK clamp, inhibits MEK kinase activity and RAF phosphorylation of MEK, potentially leading to a more complete and durable anti-tumor response. Defactinib, a selective FAK inhibitor, complements avutometinib by targeting a different node in cancer cell survival and tumor growth pathways. The FDA has granted Breakthrough Therapy Designation for this combination in recurrent LGSOC, underscoring its potential clinical benefit.
Clinical Data from RAMP 201 Trial
The NDA submission is supported by data from the Phase 2 RAMP 201 (ENGOT-ov60/GOG-3052) trial, an adaptive, multicenter, randomized, open-label study. Updated results presented at the International Gynecologic Cancer Society 2024 Annual Meeting demonstrated promising efficacy in patients with KRAS-mutant LGSOC. The data showed a confirmed overall response rate (ORR) of 44%, a median progression-free survival (PFS) of 22 months, and a disease control rate at 6 months of 70%. These results suggest a significant improvement over existing treatment options, which typically involve hormone therapy and chemotherapy.
Interim data from the study also indicated that patients with KRAS mutations (n = 15) had an ORR of 60%, while those with KRAS wild-type disease (n = 14) had an ORR of 29%. Furthermore, tumor regression was observed in 86% of patients treated with the combination. The combination was generally well-tolerated, with a 10% discontinuation rate due to adverse events (AEs) across all patients.
Ongoing and Future Studies
Verastem Oncology is currently enrolling patients in the Phase 3 RAMP 301 trial (NCT06072781), an international study evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy in recurrent LGSOC. This trial aims to serve as a confirmatory study for the initial indication and potentially support an expanded indication regardless of KRAS mutation status.
Management Commentary
"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. "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."
