FDA Approves Avutometinib and Defactinib for KRAS-Mutated Ovarian Cancer

On May 8, 2025, the Food and Drug Administration (FDA) granted accelerated approval for a novel treatment regimen combining avutometinib and defactinib, marketed as Avmapki Fakzynja Co-pack by Verastem, Inc. This approval is specifically for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have undergone prior systemic therapy. More detailed prescribing information for this treatment will be available on the Drugs@FDA website.

The basis for this approval stemmed from the RAMP-201 trial (NCT04625270), an open-label and multicenter study. In this trial, 57 adult patients with measurable KRAS-mutated recurrent LGSOC participated. The participants were required to have previously received at least one systemic therapy, inclusive of a platinum-based regimen. The KRAS mutation status of these patients was confirmed through prospective local testing of tumor tissue.

In the administered treatment protocol, patients received avutometinib at a dosage of 3.2 mg orally twice a week (on Day 1 and Day 4) and defactinib at a dosage of 200 mg orally twice daily. These medications were taken for the first three weeks of each four-week cycle and continued until patients experienced disease progression or intolerable toxicity.

The major measure of efficacy for this treatment was the overall response rate (ORR), which was evaluated by a blinded independent review committee following RECIST version 1.1 guidelines. Additionally, the duration of response (DOR) was also observed. In this study, the confirmed ORR was 44%, with a 95% confidence interval ranging from 31% to 58%. The DOR varied significantly among participants, ranging from 3.3 months to 31.1 months.

The treatment was associated with several common adverse reactions, occurring in 25% or more of patients. These included increased levels of creatine phosphokinase, nausea, fatigue, and increased aspartate aminotransferase. Other frequently noted side effects were rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, and increased blood bilirubin levels. There were also instances of increased alanine aminotransferase, vomiting, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, and vitreoretinal disorders. Further adverse effects included increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infections, and decreased neutrophil count.

For optimal administration, the recommended dose for avutometinib consists of 3.2 mg (four 0.8 mg capsules) taken orally twice a week (on Day 1 and Day 4) during the initial three weeks of a four-week cycle. This routine continues until there is either disease progression or unacceptable toxicity. Similarly, the recommended dosage for defactinib is 200 mg (one tablet) taken orally twice daily for the first three weeks of each cycle, following the same conditions for continuation.

The review of this application was conducted using the Real-Time Oncology Review (RTOR) pilot program, which facilitated data submission before the entire clinical application was filed. Additionally, the Assessment Aid, a voluntary submission from the applicant, was used to aid the FDA's evaluation process. This application received priority review status. Moreover, the combined treatment of avutometinib and defactinib was granted designations of both breakthrough therapy and orphan drug. These designations are part of the FDA's expedited programs, which are detailed in the Guidance for Industry document on expedited programs for serious conditions.