FDA Sets Goal Date for Ovarian Cancer Combination

The FDA has accepted Verastem Oncology’s new drug application (NDA) under the accelerated approval pathway for avutometinib in combination with defactinib to treat adult patients with recurrent low-grade serous ovarian cancer (LGSOC), who received at least one prior systemic therapy and have a KRAS mutation. The NDA has been granted priority review with a Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025.

Serous ovarian cancer is the largest group of ovarian cancers in the epithelial lining, which covers the outside of the ovary. Low grade serous ovarian cancer is rare subtype and is less sensitive to chemotherapy than high grade serous ovarian cancer. Patients with ovarian cancer who have KRAS mutations have been found to have poor outcomes. Between 6,000 and 8,000 women in the United States and 80,000 worldwide are living with this disease. Currently, there are no FDA-approved treatments specifically for recurrent LGSOC.

Avutometinib is a RAF/MEK clamp that may overcome resistance and block tumor growth. Defactinib is a selective FAK inhibitor that has demonstrated synergy with avutometinib.

The NDA is based on the primary analysis of the phase 2 RAMP 201 clinical trial. Results were presented in an oral presentation at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting in October 2024.

At a data cutoff of June 30, 2024, the confirmed overall response rate for the combination of avutometinib plus defactinib was 31% in all evaluable patients with measurable disease with 12 months of follow up. Among patients with KRAS mutant disease, the overall response rate was 44%. The median duration of response (DOR) was 31.1 months in all evaluable patients, as well for patients with the KRAS mutations.

In the trial, there was a 10% discontinuation rate due to adverse events (AEs). The most common treatment-related adverse events were nausea, diarrhea and increased blood creatine phosphokinase levels.

Verastem Oncology had begun a rolling submission of the new drug application in May 2024 and completed the submission in October 2024.

The company is currently enrolling patients with recurrent LGSOC regardless of KRAS mutation status for RAMP 301, an international phase 3 trial, which will serve as a confirmatory study for the initial indication and has the potential to support an expanded indication regardless of KRAS mutation status.

Verastem is also conducting a phase 1b/2 trial of avutometinib in combination with defactinib and Amgen’s sotorasib. Sotorasib is approved as Lumakras to treat patients with non-small cell lung cancer who have a KRAS G12C mutation. The drug received an accelerated approval in May 2021. Verastem has a research collaboration with Amgen.