Avutometinib/Defactinib Earns FDA Accelerated Approval for KRAS+ LGSOC

The accelerated approval is based on overall response and duration of response data from the RAMP-201 trial.

The FDA has granted accelerated approval to avutometinib (VS-6766) plus defactinib (VS-6063) for the treatment of adult patients with KRAS-mutated recurrent, low-grade serous ovarian cancer (LGSOC) following previous systemic therapy.¹

This decision is based on data from the open-label, multicenter phase 2 RAMP-201 trial (NCT04625270), which evaluated the efficacy of the drug combination in 57 adult patients with KRAS-mutated recurrent LGSOC.

Diving Into Approval Data

Confirmed overall response rate (ORR), the primary end point of the trial, of patients who received the experimental drug combination was 44% (95% CI, 31-58). The duration of response (DOR), a secondary end point, was 3.3 months to 31.1 months with the combination. Data was evaluated based on RECIST v1.1 criteria by a blinded independent review committee.

The most frequent adverse events (AEs), which occurred in at least 25% of patients, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, emesis, hyperbilirubinemia, hypertriglyceridemia, lymphocytopenia, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, thrombocytopenia, constipation, dry skin, dyspnea, cough, urinary tract infection, and neutropenia. This list included the occurrence of laboratory abnormalities.

Patients evaluated on the RAMP-201 trial had received at least 1 line of systemic therapy previously, which was required to include a platinum-based regimen; prospective local testing of tumor tissue was used to determine patients’ KRAS mutation.

The recommended dosage of avutometinib is 3.2 mg via 4 0.8 mg capsules taken twice weekly on day 1 and day 4 of the first 3 weeks of every 4-week cycle. Defactinib is to be taken in combination with 200 mg oral tablets taken twice daily in the first 3 weeks of every 4-week cycle. Patients are to continue treatment until experiencing disease progression or unacceptable toxicity.

History of Avutometinib and Defactinib

Verastem Oncology, the developer of the drug combination, announced its submission of a new drug application (NDA) for the therapy on October 31, 2024.² Prior to this, according to the announcement, no treatment was approved for LGSOC specifically.

On December 30, 2024, the FDA accepted this NDA application and granted it priority review.³ The combination, along with avutometinib monotherapy, was granted orphan drug designation for use in patients with LGSOC in March 2024.⁴

“The FDA filing acceptance and priority review for the combination of avutometinib and defactinib underscores the critical unmet need among patients diagnosed with this rare and insidious disease,” said Dan Paterson, the president and chief executive officer of Verastem Oncology, at the time of the NDA’s acceptance.

“With the acceptance of this NDA, we’re taking an important step forward in addressing a condition that has long been overlooked, and we look forward to working with the FDA during its review process and preparing for a commercial launch in mid-2025,” said Paterson.

Future of the Combination

The phase 3 RAMP-301 is actively recruiting patients for evaluation of the combination therapy in recurrent LGSOC regardless of mutational status.⁵ The study will compare progression-free survival (PFS) of the combination vs investigator’s choice of 1 of 4 standard-of-care (SOC) therapies in patients who have progressed on platinum-based therapy.

The trial will enroll an estimated 270 patients and has a planned completion data of February 9, 2031. Patients who progress on a SOC treatment may be eligible to switch to experimental treatment.

References

1. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. FDA. May 8, 2025. Accessed May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low
2. Verastem oncology completes rolling NDA submission to the FDA for avutometinib plus defactinib as a treatment for recurrent KRAS mutant low-grade serous ovarian cancer. Verastem Oncology. October 31, 2024. Accessed May 8, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-completes-rolling-nda-submission-fda
3. Verastem oncology announces FDA acceptance and priority review of new drug application for avutometinib in combination with defactinib for the treatment of recurrent KRAS mutant low-grade serous ovarian cancer. December 30, 2024. Accessed May 8, 2025. https://www.businesswire.com/news/home/20241230294719/en/Verastem-Oncology-Announces-FDA-Acceptance-and-Priority-Review-of-New-Drug-Application-for-Avutometinib-in-Combination-with-Defactinib-for-the-Treatment-of-Recurrent-KRAS-Mutant-Low-Grade-Serous-Ovarian-Cancer
4. Verastem Oncology receives orphan drug designation from FDA for avutometinib alone or in combination with defactinib in recurrent low-drade serous ovarian cancer. March 5, 2024. Accessed May 8, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-orphan-drug-designation-fda
5. A study of avutometinib (VS-6766) + defactinib (VS-6063) in recurrent low-grade serous ovarian cancer (RAMP 301). ClinicalTrials.gov. October 2, 2023. Updated April 29, 2024. Accessed May 8, 2025. https://www.clinicaltrials.gov/study/NCT06072781?term=RAMP%20301&cond=ovarian&rank=1#study-record-dates