With the FDA approval, avutometinib/defactinib is now the first and only FDA-approved treatment for patients with recurrent low-grade serous ovarian cancer (LGSOC).
The FDA has approved the combination therapy avutometinib/defactinib (Avmapki/Fakzynja; Verastem Oncology) for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who received prior systemic therapy. With this approval, avutometinib/defactinib has become the first and only FDA-approved medication for this disease.1
Trial Name: A Study of Avutometinib (VS-6766) V. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer with and Without a KRAS Mutation (RAMP 201)
ClinicalTrials.gov ID: NCT04625270
Sponsor: Verastem, Inc.
Completion Date (Estimated): December 2026
“Today’s approval of [avutometinib/defactinib] for patients with KRAS-mutated recurrent LGSOC represents not only the first-ever FDA-approved treatment specifically for this rare cancer but also a new day for people with this disease who have been in desperate need of new treatment options,” Dan Paterson, president and CEO of Verastem Oncology, said in a news release.1
Current standard of care for LGSOC involves hormone therapy and chemotherapy. LGSOC is a rare ovarian cancer that is insidious and persistent. The disease is highly recurrent and less sensitive to chemotherapy than high-grade serous ovarian cancer is. It is estimated that 6000 to 8000 women in the US and 80,000 women worldwide have LGSOC. Additionally, the disease disproportionately affects younger women, with bimodal peaks of diagnosis at ages between 20 and 30 years as well as 50 and 60 years, with a median survival of approximately 10 years.1,2
Avutometinib inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway. By blocking RAF and/or MEK, FAK, which is a key mediator of drug resistance, is activated. Additionally, defactinib is an FAK inhibitor, and when used with avutometinib, it can provide a more complete blockade of the signaling that drives the growth and drug resistance of RAS/MAPK pathway-dependent tumors.1
The approval of avutometinib/defactinib comes before its Prescription Drug User Fee Act action date of June 30, 2025. The FDA granted breakthrough therapy designation for the treatment of patients with recurrent LGSOC after 1 or more prior lines of therapy, including platinum-based chemotherapy, in May 2021. Avutometinib alone or in combination with defactinib was also granted orphan drug designation by the FDA for the treatment of LGSOC.1
“LGSOC is a rare and highly recurrent cancer with limited effective treatment options. This first-ever FDA approval in this disease was based on the primary analysis of the phase 2 RAMP 201 trial, in which the combination of avutometinib and defactinib resulted in a significant overall response rate (ORR) for patients with a KRAS mutation while being generally well tolerated,” said Rachel Grisham, MD, the global lead principal investigator of the GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 trial and section head of ovarian cancer at Memorial Sloan Kettering Cancer Center in New York, New York.1
RAMP 201 (NCT04625270)3 was a multicenter, randomized, open-label phase 2 study designed to evaluate the safety, tolerability, and preliminary efficacy of avutometinib compared with avutometinib/defactinib in patients with molecularly profiled recurrent LGSOC. Patients had received 3.2 mg of avutometinib orally twice weekly for the first 3 weeks of a 4-week cycle and 200 mg of defactinib orally twice daily for the first 3 weeks of a 4-week cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was ORR, and an additional efficacy outcome measure was duration of response (DOR). Additionally, tumor response assessments occurred every 8 weeks for the first 72 weeks, and following this duration, every 12 weeks.1,3
The combination presented an ORR of approximately 44% (n = 25; 95% CI, 31%-58%) with a median DOR ranging from 3.3 to 31.1 months in the study population. Additionally, possible serious adverse events (AEs) of avutometinib/defactinib include ocular disorders, skin toxicities (eg, rash), hepatotoxicity, rhabdomyolysis, and fetal harm when administered during pregnancy. The most common AEs—including laboratory changes—were increased levels of an enzyme in the blood (CPK), nausea, fatigue, abnormal liver test, and rash.1,3
Currently, avutometinib with or without defactinib is undergoing evaluation in other clinical trials, including the phase 3 RAMP 301 study (NCT06072781) for recurrent LGSOC, the phase 1/2 RAMP 203 study (NCT05074810) for KRAS G12C mutant non–small cell lung cancer, and the phase 1b/2 study RAMP 205 (NCT05669482) for frontline metastatic pancreatic cancer.1
“The approval of avutometinib plus defactinib brings a much-needed therapeutic option to patients and establishes this combination as the new standard of care for women with recurrent low-grade serous ovarian cancer harboring a KRAS mutation. I look forward to progressing the confirmatory phase 3 trial, RAMP 301, where we look to continue to support the ongoing body of research of this combination in women with and without a KRAS mutation,” Grisham said in the news release.1
