Avutometinib Earns FDA Orphan Drug Designation in Recurrent Ovarian Cancer

The FDA previously granted breakthrough therapy designation to avutometinib/defactinib as a treatment for patients with recurrent low-grade serous ovarian cancer of any KRAS status following at least 1 prior line of therapy in May 2021.

Avutometinib was designed as a RAF/MEK clamp that activates inactive MEK complexes with ARAF, BRAF, and CRAF, which may elicit enduring anti-tumor activity by inhibiting the RAS/MAPK pathway. The agent is believed to block both MEK kinase activity and RAF capabilities of phosphorylating MEK, thereby allowing it to block MEK signaling without inducing compensative activation of MEK as observed in other MEK-only inhibitors.

“We are rapidly advancing the development program for avutometinib and defactinib in low-grade serous ovarian cancer with our ongoing phase 3 clinical trial to deliver this new combination treatment to patients as quickly as possible. We remain on track to begin submission of a new drug application [NDA] to the FDA for accelerated approval of this combination in the first half of 2024 and preparing for a potential launch in 2025,” Dan Paterson, president and chief executive officer at Verastem Oncology said in the press release.¹

Treatment with avutometinib and defactinib for patients with recurrent low-grade serous ovarian cancer is currently under assessment as part of the confirmatory phase 3 RAF and MEK Program (RAMP) 301 trial (NCT06072781).

In the open-label RAMP 301 study, an estimated enrollment of 270 patients will be randomly assigned to receive avutometinib at 3.2 mg orally twice a week plus oral defactinib at 200 mg twice a day or investigator’s choice of standard chemotherapy or hormonal therapy.² Treatment options in the comparator arm include pegylated liposomal doxorubicin at 40 mg/m² intravenously (IV) on day 1 of each 28-day cycle; IV paclitaxel at 80 mg/m² on days 1, 8, and 15; IV topotecan (Hycamtin) at 4 mg/m² on days 1, 8, and 15; anastrozole at 1 mg orally once a day; or letrozole (Femara) at 2.5 mg orally once a day.

The trial’s primary end point is progression-free survival per blinded independent central review based on RECIST v1.1 guidelines. Secondary end points include overall survival, objective response rate, duration of response, disease control rate, adverse effects, plasma concentration, and health-related quality of life.

Patients 18 years and older with histologically confirmed low-grade serous ovarian cancer and progressive or recurrent disease following 1 or more prior lines of systemic therapy for metastatic disease are able to enroll on the trial. Additional eligibility criteria include having an ECOG performance status of 0 or 1, adequate organ function, and adequate recovery from toxicities following prior therapy.

Those who receive systemic therapy for cancer within 4 weeks of study entry or have co-existing high-grade ovarian cancer are ineligible to enroll on the study. Patients are also unsuitable for enrollment if they have major surgery within 4 weeks of study entry, symptomatic brain metastases or spinal cord compression, a history of medically significant rhabdomyolysis, concurrent ocular disorders, concurrent heart disease, or severe obstructive pulmonary disease.

The FDA previously granted breakthrough therapy designation to avutometinib/defactinib as a treatment for patients with recurrent low-grade serous ovarian cancer of any KRAS status following at least 1 prior line of therapy in May 2021.³

References

1. Verastem Oncology receives orphan drug designation from FDA for avutometinib alone or in combination with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. March 5, 2024. Accessed March 6, 2024. https://tinyurl.com/2pesac44
2. A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Accessed March 6, 2024. https://tinyurl.com/95564a8y
3. Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2021. Accessed March 6, 2024. https://bit.ly/2QLO5dx