FDA Grants Orphan Drug Designation for Avutometinib Alone or With Defactinib in Recurrent LGSOC

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The designation is for all patients with low-grade serous ovarian cancer, regardless of their KRAS status and after 1 or more prior lines of therapy.

About the Trial

Trial Name: A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer (RAMP 301)

ClinicalTrials.gov ID: NCT06072781

Sponsor: Verastem, Inc.

Completion Date (Estimated): February 9, 2031.

Ovarian Cancer Diagnosis -- Image credit: tashatuvango | stock.adobe.com

Image credit: tashatuvango | stock.adobe.com

The FDA has granted an orphan drug designation (ODD) to avutometinib (VS-6766; Verastem Oncology) alone, or in combination with defactinib (VS-6063;Verastem Oncology) for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC). This indication is for patients with LGSOC regardless of their KRAS status after one or more prior lines of therapy, including platinum-based chemotherapies.

Avutometinib is a RAF/MEK clamp that induces inactive complexes of BRAF, CRAF, and MEK with ARAF, potentially creating a more durable and complete anti-tumor response through maximal RAS/MAPK pathway inhibition. Unlike other currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK, allowing the inhibitor to block MEK signaling without the activation of MEK that hinders the efficacy of other MEK-only inhibitors. Defactinib is a selective FAK inhibitor, and the combined therapy of avutometinib with defactinib was previously granted a breakthrough therapy designation for the treatment of all patients with LGSOC.

Approximately 70% of LGSOC cases are associated with RAS/MAPK pathway alterations—such as KRAS, NRAS, HRAS, and other non-RAS mutations—and 85% of patients with LGOSC experience disease recurrence. Although chemotherapy is the standard of care of LGSOC, there is currently no treatments that are specifically approved by the FDA to treat this disease.

“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. “We are rapidly advancing the development program for avutometinib and defactinib in LGSOC with our ongoing phase 3 clinical trial to deliver this new combination treatment to patients as quickly as possible.

A phase 2 trial evaluating the avutometinib plus defactinib combination therapy has completed enrollment of dose optimization, expansion, and low-dose evaluation segments. In addition, a phase 3 confirmatory trial (NCT06072781) is currently being conducted to evaluate the combination of avutometinib and defactinib in the treatment of recurrent LGSOC compared with chemotherapy or hormonal therapy.

The investigational, randomized, open-label phase 3 study will compare the progression free-survival (PFS) of the combined avutometinib plus defactinib therapy with the investigator’s choice of treatment. Patients are randomly assigned to receive either 3.2 mg of avutometinib twice weekly plus 200 mg of defactinib twice daily in a 28-day week cycle (21 days on treatment, then 7 days off), or 1 of 5 possible chemotherapy or hormonal therapies, including pegylated liposomal doxorubicin, paclitaxel, topotecan, anastrozole, or letrozole. The primary end point is PFS, and secondary end points include overall survival, objective response rate, duration of response, disease control rate, and adverse events.

“We remain on track to begin submission of an NDA to the FDA for accelerated approval of this combination in the first half of 2024 and preparing for a potential launch in 2025,” said Paterson in the press release.

References
1. Businesswire. 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. March 5, 2024. Accessed March 6, 2024. https://www.businesswire.com/news/home/20240305616374/en
2. A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer (RAMP 301).ClinicalTrials.gov identifier: NCT06072781. Updated March 4, 2024. Accessed March 6, 2024.
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