Avutometinib Plus Defactinib Moves One Step Closer to Approval for Treatment of Ovarian Cancer

The FDA has accepted a new drug application (NDA) for avutometinib (VS-6766; Verastem Oncology) in combination with defactinib (VS-6063; Verastem Oncology) for the treatment of recurrent low-grade serous ovarian cancer (LGSOC) among adult individuals who received at least 1 prior systemic therapy and have a KRAS mutation. The combination drug has been granted priority review with a Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025.¹

Image credit: Dr_Microbe | stock.adobe.com

As an oral RAF/MEK clamp, avutometinib potentially inhibits MEK1/2 kinase activities and induces inactive complexes of MEK with ARAF, BRAF, and CRAF. This process could create a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition, according to the study authors.¹

Defactinib is an oral, selective inhibitor for focal adhesion kinase (FAK) and proline-rich kinase-2 (Pyk2) that integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion. The study authors noted that FAK activation has demonstrated mediate resistance to various anti-cancer agents.¹

“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 US,” said Dan Paterson, president and chief executive officer of Verastem Oncology, in a news release.¹

If approved, the combination of avutometinib with defactinib would be the first FDA-approved treatment option for LGSOC, as the current standard of care for the disease includes hormone therapy and chemotherapy. The rare ovarian cancer is persistent and fatal, impacting 6000 to 8000 women in the US and 80,000 women worldwide.¹ Compared with high-grade serous ovarian cancer (HGSOC), LGSOC grows more solely and is more likely to be diagnosed in a younger population, with bimodal peaks of diagnosis between the ages of 20 to 30 years and 50 to 60 years.^1,2

The NDA was accepted based on a primary analysis of the phase 2 RAMP 201 clinical trial that assessed the combination of avutometinib and defactinib among individuals with recurrent LGSOC. Presented at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting in October 2024, the results demonstrated a substantial overall response rate of 31% among individuals whose cancer had progressed despite prior treatment with chemotherapy and/or MEK inhibitors and/or bevacizumab.¹ Additionally, individuals treated with the combination achieved a median progression free survival of 12.9 months, and 22 months in the KRAS-mutant population.³

“The notable response rates and low discontinuation rate seen with the combination of avutometinib and defactinib are significant. These updated results confirm the potential of this new combination therapy to change practice and be the new standard for care for recurrent low-grade serous ovarian cancer, which previously had limited effective treatment options,” said Susana Banerjee, MBBS, MA, PhD, FRCP, global lead investigator of the study, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, and team leader in women’s cancers at The Institute of Cancer Research, London, in a new release.³

The study authors noted that additional data from the FRAME phase 1 trial were included in the NDA because it was the first study conducted using the combination of avutometinib with defactinib.¹ An international phase 3 RAMP 301 trial is currently enrolling individuals with LGSOC regardless of KRAS mutation status, which is intended to serve as a confirmatory study for the initial indications.¹

“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,” said Paterson, in a news release.¹

REFERENCES

1. Verastem Oncology Announces FDA Acceptance and Priority Review of New Drug Application for Avutometinib in Combination with Defactinib for the Treatment of Recurrent KRAS Mutant Low-Grade Serous Ovarian Cancer. Business Wire. News release. December 30, 2024. Accessed January 6, 2024. https://www.businesswire.com/news/home/20241230294719/en/Verastem-Oncology-Announces-FDA-Acceptance-and-Priority-Review-of-New-Drug-Application-for-Avutometinib-in-Combination-with-Defactinib-for-the-Treatment-of-Recurrent-KRAS-Mutant-Low-Grade-Serous-Ovarian-Cancer.

2. Trametinib Is a New Treatment Option for Rare Form of Ovarian Cancer. National Cancer Institute. News release. March 10, 2022. Accessed January 6, 2025. https://www.cancer.gov/news-events/cancer-currents-blog/2022/trametinib-low-grade-serous-ovarian-cancer#:~:text=How%20low%2Dgrade%20serous%20ovarian,Gershenson%20continued.

3. Verastem Oncology Presents Positive Updated RAMP 201 Data for Avutometinib and Defactinib Combination in Recurrent Low-Grade Serous Ovarian Cancer at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting. Verastem Oncology. News release. October 17, 2024. Accessed January 6, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-presents-positive-updated-ramp-201-data.