Verastem Oncology Submits NDA for Avutometinib and Defactinib to FDA for KRAS Mutant Ovarian Cancer

Verastem Oncology, a biopharmaceutical firm listed on Nasdaq as VSTM, has completed its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for a novel treatment combination. This treatment pairs avutometinib, an oral RAF/MEK clamp, with defactinib, an oral selective FAK inhibitor, targeted at adults with recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC) who have undergone at least one prior systemic therapy. This combination therapy could be a first-in-class treatment if approved.

Currently, there are no FDA-approved treatments specifically for LGSOC, a unique and comparatively rare form of ovarian cancer that differs significantly from high-grade serous ovarian cancer in both biological behavior and treatment response. Verastem’s NDA submission, which seeks accelerated approval, also includes a request for Priority Review from the FDA due to the significant unmet medical needs among patients with recurrent LGSOC. If Priority Review is granted, the FDA could complete its review within six months following the 60-day filing period. An FDA approval would make avutometinib combined with defactinib the first FDA-sanctioned treatment for adult patients in the U.S. with recurrent KRAS mutant LGSOC.

Dan Paterson, President and CEO of Verastem Oncology, emphasized that this treatment combination has the potential to transform the therapeutic landscape for patients with recurrent KRAS mutant LGSOC. He highlighted the significant milestone achieved by completing the NDA submission and expressed optimism about the potential mid-2025 FDA approval, which could provide the first specific treatment option for this rare ovarian cancer.

The rolling NDA submission was initiated in May 2024 following discussions with the FDA. Phase 2 results from the RAMP 201 study showcased promising outcomes. In patients with KRAS mutant LGSOC, the treatment demonstrated an overall response rate (ORR) of 44%, a median progression-free survival (PFS) of 22 months, and a disease control rate at six months of 70%. These findings were presented at the International Gynecologic Cancer Society 2024 Annual Meeting. Moreover, the treatment combination was generally well-tolerated, with a 10% discontinuation rate due to adverse events.

Additionally, the NDA submission includes supportive data from the FRAME Phase 1 trial, which was the initial study conducted with this combination in recurrent LGSOC. The FDA had previously granted Breakthrough Therapy Designation for the combination of avutometinib and defactinib and has also designated the combination as an Orphan Drug for treating LGSOC.

Verastem is continuing to enroll patients with recurrent LGSOC for the RAMP 301 study, an international Phase 3 trial. This study aims to confirm the initial findings and has the potential to support an expanded indication beyond KRAS mutation status.

RAMP 201, the study linked to the NDA submission, is a two-part, multicenter, adaptive, randomized, open-label trial designed to assess the safety and efficacy of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC. The study's first part determined the optimal regimen to proceed, which was the combination of avutometinib and defactinib. The subsequent parts of the study are evaluating the safety and efficacy of this selected regimen and exploring individualized dose reductions.

Low-grade serous ovarian cancer (LGSOC) is a persistent and ultimately fatal form of ovarian cancer, distinct from the more common high-grade serous ovarian cancer (HGSOC). LGSOC is less responsive to chemotherapy and affects a smaller, younger demographic, with about 6,000-8,000 women in the U.S. and 80,000 worldwide living with the disease. Existing treatments include hormone therapy and chemotherapy, but there are no specific FDA-approved treatments for LGSOC, highlighting the urgency for new therapeutic options.