Today, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the combination of the dual RAF/MEK inhibitor avutometinib and the FAK inhibitor defactinib (Avmapki Fakzynja Co-pack) for adults with KRAS-mutated, recurrent, low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy.
RAMP 201 Trial
Efficacy was evaluated in RAMP 201 (ClinicalTrials.gov identifier NCT04625270), an open-label, multicenter trial that included 57 adults with measurable KRAS-mutated recurrent LGSOC. Patients were required to have received at least one prior systemic therapy, including a platinum-based regimen. KRAS mutation status was determined by prospective local testing of tumor tissue. Patients received avutometinib at 3.2 mg orally twice weekly (day 1 and day 4) and defactinib at 200 mg orally twice daily, both taken for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.
The major efficacy outcome measure was overall response rate assessed by blinded independent review committee according to Response Evaluation Criteria in Solid Tumors version 1.1. An additional efficacy outcome measure was duration of response. Confirmed overall response rate was 44% (95% confidence interval = 31%–58%), and the duration of response ranged from 3.3 months to 31.1 months.
The most common adverse reactions (occurring in ≥ 25% of patients), including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infection, and decreased neutrophil count.
The recommended avutometinib dose is 3.2 mg (four 0.8-mg capsules) taken orally twice weekly (day 1 and day 4) for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. The recommended defactinib dose is 200 mg (one tablet) taken orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity.
This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review. Avutometinib in combination with defactinib was granted Breakthrough Therapy designation and Orphan Drug designation.
