Verastem Unveils Critical FDA Review of Avutometinib-Defactinib for Ovarian Cancer
Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company dedicated to advancing new cancer treatments, has announced that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for the investigational combination of avutometinib and defactinib. This application seeks accelerated approval for the treatment of adult patients with recurrent low-grade serous ovarian cancer (LGSOC), specifically those with KRAS mutations who have received at least one prior systemic therapy. This submission, completed in October 2024, has been granted Priority Review by the FDA, with a Prescription Drug User Fee Act (PDUFA) action date set for June 30, 2025. Additionally, the FDA has indicated it does not plan to hold an advisory committee meeting to discuss the application.
Verastem’s President and CEO, Dan Paterson, expressed excitement about the FDA’s acceptance, emphasizing the urgent need for effective treatments in this patient population. “We are thrilled to receive FDA filing acceptance and Priority Review for our combination therapy, as it highlights the significant unmet need in treating recurrent KRAS mutant LGSOC,” Paterson stated. “We are committed to bringing the first-ever FDA-approved treatment specifically for this rare disease to patients in the U.S. and are preparing for a commercial launch in mid-2025.”
LGSOC is a rare form of ovarian cancer that differs significantly from high-grade serous ovarian cancer (HGSOC) in its biological behavior and response to treatments. It is highly recurrent, less sensitive to chemotherapy, and often lacks targeted therapies. Despite these challenges, there are currently no FDA-approved treatments specifically for LGSOC. The FDA’s Priority Review designation was granted to treatments that offer significant improvements over available options or provide a novel approach where no adequate therapy exists.
The NDA for the combination of avutometinib and defactinib was supported by data from the Phase 2 RAMP 201 clinical trial. This study evaluated the efficacy and safety of the two drugs in patients with recurrent KRAS mutant LGSOC.
The primary analysis, presented at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting in October 2024, showed that the combination therapy resulted in a substantial overall response rate, with durable responses confirmed by blinded independent central review. Moreover, the therapy was generally well-tolerated by patients. The NDA also includes data from the FRAME Phase 1 trial, which was the first to evaluate the combination in patients with recurrent LGSOC.
Key Details from the NDA Submission:
| Topic | Details |
|---|---|
| FDA Review | FDA accepted the NDA for avutometinib and defactinib under the accelerated approval pathway. |
| Indication | Treatment of recurrent low-grade serous ovarian cancer (LGSOC) in patients with KRAS mutations. |
| Filing Completion Date | October 2024 |
| Priority Review Status | Granted Priority Review with a PDUFA action date of June 30, 2025. |
| Phase 2 Trial (RAMP 201) | Demonstrated a substantial overall response rate with durable results and good tolerability in recurrent KRAS mutant LGSOC. |
| FDA Designations | Breakthrough Therapy Designation, Orphan Drug Designation. |
| RAMP 301 | Ongoing Phase 3 trial, enrolling patients regardless of KRAS mutation status. |
| Combination Therapy | Avutometinib (RAF/MEK clamp) and defactinib (FAK inhibitor). |
| Target Population | Adults with recurrent KRAS mutant LGSOC, who received at least one prior systemic therapy. |
In addition to the RAMP 201 data, Verastem is enrolling patients in the RAMP 301 trial, an international Phase 3 study that aims to confirm the efficacy of the combination and potentially support an expanded indication for LGSOC, regardless of KRAS mutation status. This ongoing trial will help establish the therapy’s potential as a new standard of care for recurrent LGSOC.
LGSOC, which affects approximately 6,000 to 8,000 women in the U.S. and 80,000 women globally, is particularly prevalent in younger women, with diagnoses occurring most frequently in the 20-30 and 50-60 age ranges. Despite its chronic and persistent nature, LGSOC is less responsive to chemotherapy compared to other ovarian cancer types. As a result, the disease presents a significant challenge to both patients and healthcare providers, with existing treatments offering limited benefit. The approval of the combination of avutometinib and defactinib could offer a groundbreaking new approach to manage this difficult-to-treat cancer.
Avutometinib is an oral RAF/MEK clamp that works by inhibiting MEK1/2 kinase activities, potentially inducing durable anti-tumor responses through maximal RAS/MAPK pathway inhibition. This mechanism of action differs from traditional MEK inhibitors, as avutometinib also blocks RAF phosphorylation of MEK, preventing compensatory activation of MEK that can limit the efficacy of other MEK inhibitors. Defactinib, an oral selective inhibitor of focal adhesion kinase (FAK), works by disrupting cell signaling pathways that contribute to tumor cell survival, migration, and resistance to anti-cancer therapies.
The combination of these two agents represents a novel approach to treating cancers driven by RAS/MAPK signaling, such as LGSOC, and Verastem is also exploring the use of this combination in other cancers. The company is conducting additional trials evaluating avutometinib and defactinib in various RAS-driven cancers, including non-small cell lung cancer and pancreatic cancer.
Verastem’s commitment to developing new therapies for difficult-to-treat cancers is also evident in its partnership with Amgen to evaluate the combination of LUMAKRAS™ (sotorasib), avutometinib, and defactinib in patients with KRAS G12C mutant non-small cell lung cancer. This trial, known as RAMP 203, has received Fast Track Designation from the FDA. Additionally, Verastem’s investigational treatment for pancreatic cancer is supported by the PanCAN Therapeutic Accelerator Award.
Verastem Oncology remains focused on advancing its RAS/MAPK-driven cancer therapies and is eager to work with the FDA in bringing the combination of avutometinib and defactinib to market. With the Priority Review and a PDUFA action date in June 2025, Verastem is one step closer to addressing the critical needs of patients with recurrent KRAS mutant LGSOC.ne 2025, the Verastem company is one step closer to addressing the critical needs of patients with recurrent KRAS mutant LGSOC.
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