The FDA has accepted an application for review of avutometinib and defactinib in recurrent low-grade serous ovarian cancer (LGSOC) with KRAS mutations. The application was made under the FDA accelerated approval pathway which allows an application to be considered and conditionally approved before all clinical trials are completed. There currently are no FDA-approved treatments specifically for LGSOC.
Avutometinib is a dual RAF/MEK inhibitor and defactinib is a FAK inhibitor. The combination is currently being studied in recurrent low-grade serous ovarian cancer in a multinational phase 3 clinical trial called RAMP 301. In an earlier Phase 2 version of the study (RAMP 201) tumour shrinkage was seen in people with both KRAS mutations, and unmutated KRAS but more people in the KRAS mutated group had tumour shrinkage – which led to the FDA agreeing to accept an application for KRAS mutated LGSOC under the accelerated approval pathway.
The application was also granted Priority Review, which means the FDA plans to act on the application within 6 months versus the standard review of 10 months. Priority Review is granted by the FDA for treatments that offer, if approved, significant improvements over available options or that provide a treatment option where no adequate or approved therapy currently exists.
The results of RAMP 301 clinical trial will be used to confirm the initial KRAS mutant indication, but also have the potential to support a future application to the FDA for extended approval to cover all recurrent LGSOC – regardless of mutation status.
If this initial application to the FDA is successful, the combination could be commercially available off-clinical trial, as early as mid 2025 for women with recurrent KRAS low-grade serous ovarian cancer in the United States of America, with applications to other country regulatory authorities likely to follow.
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About the Avutometinib and Defactinib Combination
Avutometinib is an oral RAF/MEK clamp that 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. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of the MEK-only inhibitors.
Defactinib is an oral, selective inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2), the two members of the focal adhesion kinase family of non-receptor protein tyrosine kinases. FAK and Pyk2 integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion. FAK activation has been shown to mediate resistance to multiple anti-cancer agents, including RAF and MEK inhibitors.
Verastem Oncology is currently conducting clinical trials with avutometinib with and without defactinib in RAS/MAPK-driven tumors as part of its Raf And Mek Program or RAMP. Verastem is currently enrolling patients and activating sites for RAMP 301 (GOG-3097/ENGOT-ov81/NCRI) (NCT06072781), an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC).
Verastem was granted Priority Review and a Prescription Drug User Fee Act (PDUFA) date of June 30, 2025, for its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), for the investigational combination of avutometinib and defactinib in adults with recurrent KRAS mutant LGSOC who received at least one prior systemic therapy. Verastem initiated a rolling NDA in May 2024 to the FDA and completed its NDA submission in October 2024. The FDA granted Breakthrough Therapy Designation for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy, in May 2021. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a late-stage development biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with cancer. Their pipeline is focused on RAS/MAPK-driven cancers, specifically novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition and FAK inhibition. For more information, visit www.verastem.com.
