FDA Grants First-Ever Approval for Treatment of KRAS-Mutated Recurrent LGSOC

Verastem Oncology announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for the AVMAPKI FAKZYNJA CO-PACK, which includes avutometinib capsules and defactinib tablets, for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have previously received systemic therapy. This marks the first and only FDA-approved treatment specifically for this condition. The approval is based on tumor response rate and duration of response, with continued approval dependent on confirmation of clinical benefit in a subsequent trial. In the U.S., the treatment is available exclusively as an oral combination co-pack containing both prescription products.

Efficacy of CO-PACK Evaluated in RAMP-201 Trial with KRAS-Mutated Recurrent LGSOC Patients

The RAMP-201 trial (NCT04625270), an open-label, multicenter study, evaluated the efficacy of the AVMAPKI FAKZYNJA CO-PACK in 57 adult patients with measurable KRAS-mutated recurrent LGSOC. All participants had previously received at least one systemic therapy, including a platinum-based regimen. Researchers confirmed KRAS mutation status through prospective local testing of tumor tissue. They treated patients with avutometinib at 3.2 mg orally twice weekly (on Days 1 and 4) and defactinib at 200 mg orally twice daily. The study administered both drugs for the first three weeks of each four-week cycle until disease progression or unacceptable toxicity developed.

The study assessed the primary efficacy endpoint, overall response rate (ORR), through a blinded independent review committee using RECIST version 1.1. An additional endpoint was duration of response (DOR). The confirmed ORR reached 44%, with DOR ranging from 3.3 months to 31.1 months, demonstrating meaningful clinical activity in this patient population.

The study also assessed treatment-related safety. Researchers observed the most common adverse reactions (occurring in 25% or more of patients), including increased creatine phosphokinase, nausea, fatigue, elevated aspartate aminotransferase, rash, and diarrhea. Other common events included musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, elevated blood bilirubin, increased triglycerides, and decreased lymphocyte count.

“Today’s approval of AVMAPKI FAKZYNJA CO-PACK for patients with KRAS-mutated recurrent low-grade serous ovarian cancer represents not only the first-ever FDA-approved treatment specifically for this rare cancer but also a new day for people living with this disease who have been in desperate need of new treatment options,” said Dan Paterson, president and chief executive officer of Verastem Oncology. 

LGSOC Affects 6,000-8,000 Women in the U.S. and 80,000 Worldwide

LGSOC is a rare and persistent form of ovarian cancer that differs significantly from high-grade serous ovarian cancer (HGSOC) in both its biology and treatment response. This disease is less responsive to chemotherapy, has a high recurrence rate, and often requires distinct treatment approaches. It primarily affects younger women, with diagnosis commonly occurring between the ages of 20–30 and 50–60, and has a median survival of around ten years. Approximately 6,000–8,000 women in the U.S. and 80,000 globally are living with this disease. The majority of LGSOC cases involve RAS pathway-related mutations, with about 30% showing a specific KRAS mutation.

The disease has a profound impact on patients’ physical and mental well-being, including their fertility and long-term quality of life. Until now, hormone therapy and chemotherapy were the only treatment options, with no therapies approved specifically for KRAS-mutated recurrent LGSOC. The recent FDA approval of a targeted treatment marks a significant advancement for this underserved patient population.

Verastem Oncology began a rolling submission of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in May 2024 and completed the process in October 2024. The application received Priority Review status, and the FDA granted approval ahead of the scheduled Prescription Drug User Fee Act (PDUFA) action date of June 30, 2025. 

Previously, in May 2021, the FDA had granted Breakthrough Therapy Designation to avutometinib in combination with defactinib for the treatment of recurrent LGSOC following at least one prior line of therapy, including platinum-based chemotherapy. In addition, avutometinib, both alone and in combination with defactinib, received Orphan Drug Designation for the treatment of LGSOC. The CO-PACK will become available in the United States within one week for adult patients diagnosed with KRAS-mutated recurrent LGSOC.

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Denisse Sandoval