FDA grants accelerated approval to avutometinib, defactinib combination

On May 8, the Food and Drug Administration granted accelerated approval to the combination of avutometinib and defactinib for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer who have received prior systemic therapy. Efficacy was evaluated in RAMP-201, an open-label, multicenter trial that included 57 adult patients 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 3.2 mg orally twice weekly and defactinib 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 RECIST v1.1. An additional efficacy outcome measure was duration of response. Confirmed ORR was 44% and the DOR range was 3.3 months to 31.1 months. The most common adverse reactions, 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 taken orally twice weekly for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. The recommended defactinib dose is 200 mg taken orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Clinical development of avutometinib is being conducted by Verastem (VSTM), and Verastem also manufactures defactinib.