Avutometinib and Defactinib Granted Accelerated Approval for KRAS-Mutated Low-Grade Serous Ovarian Cancer
Expert Perspectives · Lyn Brook · 2025-05-08
The FDA granted accelerated approval to avutometinib plus defactinib (Avmapki™ Fakzynja™ Co-pack, Verastem, Inc.) for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy.
Why This Approval Matters
The accelerated approval of avutometinib and defactinib offers a new therapeutic option for patients with KRAS-mutated recurrent LGSOC, a population with limited effective treatments. This combination targets a specific genetic mutation, addressing an unmet need and potentially improving outcomes for patients who have already undergone systemic therapy, including platinum-based regimens.
Breaking Down the RAMP-201 Trial
Efficacy for this new combination was evaluated in the RAMP-201 trial (NCT04625270), an open-label, multicenter study that enrolled 57 adult patients with measurable KRAS-mutated recurrent LGSOC. All patients had received at least one prior systemic therapy, including a platinum-based regimen, and KRAS mutation status was confirmed through prospective local testing of tumor tissue. Participants received avutometinib 3.2 mg orally twice weekly (on Day 1 and Day 4) and defactinib 200 mg orally twice daily, both administered for the first three weeks of each four-week cycle. Treatment continued until disease progression or unacceptable toxicity.
The primary efficacy end point was overall response rate (ORR), assessed by a blinded independent review committee using RECIST v1.1 criteria. A secondary end point was duration of response (DOR). The confirmed ORR was 44%, with DOR ranging from 3.3 months to 31.1 months.
Managing Adverse Events
The most common adverse events experienced by ≥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.
Dosing and Administration
The recommended dose of avutometinib is 3.2 mg, given as four 0.8 mg capsules, taken orally twice weekly (Day 1 and Day 4) for the first three weeks of each four-week cycle, continuing until disease progression or unacceptable toxicity. Defactinib is recommended at 200 mg, given as one tablet, taken orally twice daily for the first three weeks of each four-week cycle, also until disease progression or unacceptable toxicity.
Clinical Implications and Future Outlook
The accelerated approval of avutometinib and defactinib for KRAS-mutated recurrent LGSOC provides a new targeted treatment option for a patient population with few alternatives. Ongoing studies and post-marketing data will further clarify the long-term benefits and safety of this regimen, potentially shaping future standards of care for KRAS-mutated ovarian cancer.