Verastem Oncology's New Drug Application (NDA) for the combination of avutometinib and defactinib has been granted Priority Review by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC). This regulatory milestone brings hope to patients with this rare and challenging cancer, as there are currently no FDA-approved treatments specifically for LGSOC. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of June 30, 2025.
Targeting RAF/MEK and FAK Pathways
Avutometinib, an oral RAF/MEK clamp, potentially 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). The combination of these two agents targets critical signaling pathways involved in cancer cell survival and tumor growth.
RAMP 201 Trial Results
The NDA submission is based on data from the Phase 2 RAMP 201 clinical trial (NCT04625270), an adaptive, two-part multicenter, randomized, open-label study. The trial evaluated the efficacy and safety of avutometinib alone and in combination with 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 (ORR) with the combination therapy.
In the primary analysis, the combination of avutometinib plus defactinib resulted in a confirmed ORR of 31% (95% CI, 23%-41%) in all evaluable patients with measurable disease (n = 109). Notably, in patients with KRAS-mutated disease, the confirmed ORR was 44% (n = 25/57; 95% CI, 31%-58%). The median duration of response (DOR) was 31.1 months (95% CI, 14.8-31.1) in all evaluable patients and in patients with KRAS-mutant disease. The combination was generally well-tolerated, with 10% of patients discontinuing treatment due to adverse effects (AEs).
Unmet Need in LGSOC
Low-grade serous ovarian cancer (LGSOC) is a rare and distinct type of ovarian cancer, affecting approximately 6,000-8,000 women in the U.S. and 80,000 worldwide. LGSOC is distinct from high-grade serous ovarian cancer (HGSOC) in its biology and response to treatment. It is highly recurrent and less sensitive to chemotherapy compared to HGSOC. The current standard of care includes hormone therapy and chemotherapy, but there are no FDA-approved treatments specifically for LGSOC.
Ongoing RAMP 301 Trial
Verastem Oncology 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.
Potential Impact
If approved, the combination of avutometinib and defactinib would be the first FDA-approved treatment specifically for adults with recurrent KRAS mutant LGSOC. This would represent a significant advancement in the treatment of this rare and challenging cancer, providing a much-needed targeted therapy option for patients with limited treatment alternatives. The FDA's decision is expected by June 30, 2025.
