FDA Grants Orphan Drug Designation to Avutometinib in Ovarian Cancer

Illustration of ovarian cancer - stock.adobe.com

• Avutometinib (VS-6766), an RAF/MEK clamp, has been granted FDA orphan drug designation for the treatment of patients with recurrent low-grade serous ovarian cancer.
• The designation is for avutometinib alone or in combination with defactinib (VS-6063), a selection focal adhesion kinase (FAK) inhibitor.
• This designation marks an important step for this ovarian cancer subtype that currently has no FDA-approved treatments.

The FDA has granted an orphan drug designation to avutometinib with or without defactinib for the treatment of patients with recurrent low-grade serous ovarian cancer.¹

“The FDA orphan drug designation for avutometinib alone or in combination with defactinib in low-grade serous ovarian cancer is an important step in recognizing this rare cancer as a distinct disease that currently has no FDA-approved treatments,” said Dan Paterson, president and chief executive officer of Verastem Oncology, in a press release.

The orphan drug designation is granted to agents that prevent, diagnose, or treat a rare disease. Drug sponsors are eligible for incentives including tax credits for clinical trials, exemption from user fees, and a potential of 7 years of market exclusivity after approval.²

Verastem remains on track to submit a new drug application for accelerated approval for this combination in the first half of 2024, with a potential launch in 2025.¹

The avutometinib/defactinib combination is being evaluated in the confirmatory phase 3 RAMP 301 trial (NCT06072781) where it is being compared with standard chemotherapy or hormonal therapy. The phase 3 RAMP 201 trial (NCT04625270) is also investigating the drug combination in patients with recurrent low-grade serous ovarian cancer and has completed enrollment in dose-optimization, dose-expansion, and low dose-evaluation cohorts.

About RAMP 301

RAMP 301 is a phase 3, open-label, randomized study of the combination of avutometinib and defactinib vs investigator’s choice of treatment in patients with recurrent low-grade serous ovarian cancer.³ The primary end point is progression-free survival (PFS) per blinded independent central review. Secondary end points include overall survival (OS), PFS per investigator assessment, objective response rate (ORR), duration of response (DOR), disease control rate (DCR), frequency and severity of adverse events (AEs), pharmacokinetics, and health-related qualityof life.

Patients in the experimental arm received avutometinib 3.2 mg twice weekly plus defactinib 200 mg twice daily for 21 days on, 7 days off in a 28-day cycle. In the active comparator arm, patients received pegylated liposomal doxorubicin, paclitaxel, topotecan, anastrozole, or letrozole for 28-day cycles.

To be eligible for participation, patients must have disease progression or recurrence following at least 1 prior systemic therapy, an ECOG performance status of 1 or lower, adequate organ function, adequate recovery from toxicities related to prior treatment, and agreement to use a highly effective form of contraception for patients with reproductive potential. Patients were not eligible to participate in the trial if they had received systemic anticancer treatment within 4 weeks of study initiation, coexisting high-grade ovarian cancer, symptomatic brain metastases or spinal cord compression, history of medically significant rhabdomyolysis, or an active infection requiring systemic therapy.

The study has an estimated enrollment of 270 patients and an estimated completion date of February 2031.

About RAMP 201

RAMP 201 is a phase 2, open-label, randomized study evaluating the combination of avutometinib and defactinib in patients with recurrent low-grade serous ovarian cancer with or without a KRAS mutation.⁴ The primary end point is ORR, and secondary end points include DOR, DCR, PFS, and OS.

Patients were randomized to receive either avutometinib monotherapy or avutometinib plus defactinib.

To be eligible for participation, patients must have disease progression or recurrence following at least 1 prior systemic therapy, an ECOG performance status of 1 or lower, adequate organ function, adequate recovery from toxicities related to prior treatment, and agree to use a highly effective form of contraception for patients with reproductive potential. Patients were not eligible to participate in the trial if they had received systemic anticancer treatment within 4 weeks of study initiation, coexisting high-grade ovarian cancer, symptomatic brain metastases, history of medically significant rhabdomyolysis, or concurrent heart or obstructive pulmonary disease.

The study has an estimated enrollment of 225 patients and an anticipated completion date of December 2026.

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/3mhxpud8

2. Designation an orphan product: drugs and biological products. U.S. Food and Drug Administration. Updated July 8, 2022. Accessed March 6, 2024. https://tinyurl.com/24muw8am

3. A study of avutometinib (VS-6777) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. Updated March 4, 2024. Accessed March 6, 2024. https://clinicaltrials.gov/study/NCT06072781

4. A study of avutometinib (VS-6777) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer with and without a KRAS mutation (RAMP 201). ClinicalTrials.gov. Updated September 15, 2023. Accessed March 6, 2024. https://clinicaltrials.gov/study/NCT04625270