A new drug application (NDA) has been accepted by the Food and Drug Administration (FDA) under the accelerated approval pathway for the combination of avutometinib and defactinib in adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who received at least one prior systemic therapy, according to a news release from Verastem Oncology.
The company noted in the release that, if approved, the combination would stand to be the first FDA-approved treatment specifically for adults with recurrent KRAS mutant low-grade serous ovarian cancer. The NDA was initially completed in October 2024 and has a Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025.
In the news release, Dan Paterson, president and chief executive officer of Verastem Oncology, stated, “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 United States.”
Low-grade serous ovarian cancer is highly recurrent and less sensitive to chemotherapy compared with high-grade serous ovarian cancer and approximately 6,000 to 8,000 women in the United States — as well as 80,000 worldwide — are living with the disease, which affects younger women with bimodal peaks of diagnosis at ages between 20 to 30 and 50 to 60. Moreover, the disease has a median survival of approximately 10 years.
Because there are no currently approved treatments for this disease, rare and distinct ovarian cancer which differs from high-grade serous ovarian cancer in both its biology and how it responds to treatment, this potential treatment combination provides a new option where no adequate or approved therapy currently exists.
Glossary
NDA: A request to approve a new drug for sale and marketing in the United States.
The Food and Drug Administration (FDA): a federal agency that protects the public's health.
Prescription Drug User Fee Act (PDUFA): a law that allows the FDA to collect fees from companies that submit certain human drug applications for review.
FAK inhibitor: a drug that specifically targets and blocks the activity of a protein called Focal Adhesion Kinase.
RAF/MEK clamp: a type of drug that simultaneously inhibits both RAF and MEK proteins.
KRAS Mutation: a gene mutation that occurs in the Kirsten rat sarcoma (KRAS) gene, which is involved in cell growth and death.
Furthermore, the NDA filing was based data from the phase 2 RAMP 201 clinical which evaluated the combination of avutometinib and defactinib in patients with this recurrent disease. Results from the trial were shared in an oral presentation at the International Gynecologic Cancer Society Annual Global Meeting in October 2024 and showed preferable responses with the investigative combination.
Additional data from the phase 1 FRAME trial, the first study conducted with the combination therapy in recurrent low-grade serous ovarian cancer, was also included as supportive data in the NDA.
More on the RAMP 201 Clinical Trial
Data from the phase 2 RAMP 201 study showed that the combination of avutometinib plus defactinib had a substantial overall response rate confirmed by blinded independent central review, and that responses were typically durable, as well as that the combination was generally well-tolerated in patients with recurrent KRASmutant low-grade serous ovarian cancer.
Avutometinib is an oral RAF/MEK clamp which inhibits MEK1/2 kinase activities and induces inactive complexes of MEK with ARAF, BRAF, and CRAF. In turn, this creates a more durable anti-tumor response. Comparatively, defactinib is an oral, selective inhibitor of FAK and proline-rich tyrosine kinase-2.
The adaptive, two-part multicenter, parallel cohort, randomized, open-label registration-directed RAMP 201 trial evaluated efficacy and safety of avutometinib alone and in combination with defactinib for patients with recurrent low-grade serous ovarian cancer. In part A of the study, investigators evaluated and determined that the combination of avutometinib and defactinib would be the go-forward regimen versus avutometinib alone, based on overall response rates. Parts B and C of the study evaluated the safety and efficacy of this regimen, including avutometinib at a 3.2 milligram (mg) twice weekly dose and defactinib at a 200 mg twice daily dose. Part D of the study is currently evaluating a low dose of the combination in order to inform individualized dose reduction.
Future Directions with the Combination
Notably, Verastem Oncology shared that patients with recurrent disease are currently being enrolled — regardless of KRAS mutation status — for the international, phase 3 RAMP 301 clinical trial, which will serve as a confirmatory study for the initial indication. Notably, the company shared that results from this trial has the potential to support an expanded indication regardless of KRAS mutation status.
“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,” Paterson concluded in the news release.
