On December 30, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) under the accelerated approval pathway for avutometinib, an oral RAF/MEK clamp, in combination with defactinib, an oral FAK inhibitor, for the treatment of adult patients with recurrent low-grade serous ovarian cancer (LGSOC), who received at least one prior systemic therapy and have a KRAS mutation (Press release, Verastem, DEC 30, 2024, View Source [SID1234649359]). The NDA, which was completed in October 2024, has been granted Priority Review with a Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025. In addition, the FDA has stated that it is not currently planning to hold an advisory committee meeting to discuss the application.
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"The FDA filing acceptance and Priority Review for the combination of avutometinib and defactinib underscores the critical unmet need among patients diagnosed with this rare and insidious disease. We are excited by today’s news and to potentially bring the first ever FDA-approved treatment specifically for recurrent KRAS mutant LGSOC to patients in the U.S.," said Dan Paterson, president and chief executive officer of Verastem Oncology. "With the acceptance of this NDA, we’re taking an important step forward in addressing a condition that has long been overlooked, and we look forward to working with the FDA during its review process and preparing for a commercial launch in mid-2025."
There are currently no FDA-approved treatments specifically for LGSOC, a rare and distinct ovarian cancer that differs from high-grade serous ovarian cancer in both its biology and how it responds to treatment. 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 filing was based on a primary analysis of the Phase 2 RAMP 201 clinical trial that evaluated the combination of avutometinib and defactinib in patients with recurrent LGSOC. The results were presented in an oral presentation at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting in October 2024 and demonstrated that the combination of avutometinib plus defactinib resulted in a substantial overall response rate confirmed by blinded independent central review, with responses that were typically durable, and that the combination was generally well-tolerated in patients with recurrent KRAS mutant LGSOC. The NDA also includes supportive data from the FRAME Phase 1 trial, the first study conducted with the combination therapy in recurrent LGSOC.
The Company is currently enrolling patients with recurrent LGSOC regardless of KRAS mutation status for RAMP 301, an international Phase 3 trial, which will serve as a confirmatory study for the initial indication and has the potential to support an expanded indication regardless of KRAS mutation status.
About RAMP 201
RAMP 201 (ENGOTov60/GOG3052) (NCT04625270) is an adaptive, two-part multicenter, parallel cohort, randomized, open-label Phase 2 registration-directed trial evaluating the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent low-grade serous ovarian cancer (LGSOC). The first part of the study (Part A) determined the selection of the go-forward regimen, which was the combination of avutometinib and defactinib versus avutometinib alone, based on overall response rates. The expansion phases of the trial (Parts B and C) are evaluating the safety and efficacy of the go-forward regimen of avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily. The Part D portion of the trial is evaluating a low dose of avutometinib in combination with defactinib to inform individualized dose reduction.
About Low-Grade Serous Ovarian Cancer (LGSOC)
LGSOC is a rare ovarian cancer that is insidious, persistent, and ultimately fatal. LGSOC is distinct and different from high-grade serous ovarian cancer (HGSOC) and requires different treatment. LGSOC is highly recurrent and less sensitive to chemotherapy compared to HGSOC. Approximately 6,000-8,000 women in the U.S. and 80,000 worldwide are living with this disease. LGSOC affects younger women with bimodal peaks of diagnosis at ages between 20-30 and 50-60 and has a median survival of approximately ten years. The majority of patients report a negative impact of LGSOC on their mental and physical health, fertility, and long-term quality of life. The current standard of care for this disease includes hormone therapy and chemotherapy, but there are no treatments specifically approved by the U.S. Food and Drug Administration to treat LGSOC.
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.
Verastem Oncology has established a clinical collaboration with Amgen to evaluate LUMAKRAS (sotorasib) in combination with avutometinib and defactinib in both treatment-naïve patients and in patients whose KRAS G12C mutant non-small cell lung cancer progressed on a G12C inhibitor as part of the RAMP 203 trial (NCT05074810). Verastem has received Fast Track Designation from the FDA for the triplet combination in April 2024. RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. FDA granted Orphan Drug Designation to the avutometinib and defactinib combination for the treatment of pancreatic cancer.