FDA Approves Avutometinib Plus Defactinib for KRAS-Mutated Recurrent Low-Grade Serous Ovarian Cancer

FDA

The FDA has granted accelerated approval to avutometinib plus defactinib (Avmapki Fakzynja Co-pack) for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have previously received systemic therapy.

The regulatory decision was supported by data from RAMP-201 (NCT04625270), which showed that the doublet elicited a confirmed overall response rate of 44% (95% CI, 31%-58%), which comprised a complete response rate of 3.5% and a partial response rate of 40%.³ The duration of response (DOR) ranged from 3.3 months to 31.1 months.

“Low-grade serous ovarian cancer 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 for patients with a KRAS mutation while being generally well tolerated,” Rachel Grisham, MD, section head of Ovarian Cancer at Memorial Sloan Kettering Cancer Center, in New York, NY, stated in a news release.²

Reviewing RAMP-201: Population, Treatment, Objectives

The open-label, multicenter trial enrolled adult patients with measurable KRAS-mutated recurrent LGSOC (n = 57).³ To participate, patients must have previously received at least 1 systemic therapy, including a platinum-based regimen. If patients were eligible for debulking surgery, were receiving warfarin, had an active skin disorder needing systemic treatment within the past year, or had an ocular disorder, they were excluded.

Patients were administered 3.2 mg of avutometinib twice weekly for the first 3 weeks of a 4-week cycle plus 200 mg of defactinib twice daily for the first 3 weeks of a 4-week cycle. Treatment continued until progressive disease or intolerable toxicity.

The primary end point was ORR by blinded independent review committee and per RECIST 1.1 criteria. They also assessed DOR and safety.

The median patient age was 60 years (range, 29-87). Most patients were White (75%) and had an ECOG performance status of 0 (72%). Local testing revealed the following KRAS mutations: G12V (53%), G12D (35%), Q61H (3.5%), G12C (1.8%), G12R (1.8%), A146V (1.8%), and mutations not otherwise specified at G12x (1.8%) and on codon 12/13 (1.8%).

Additionally, 14% of patients had received 1 prior line of systemic treatment; 25%, 18%, and 40% of patients had received 2, 3, or more than 3 prior lines of treatment, respectively. Most patients had prior hormonal therapy (84%); 40% had prior exposure to bevacizumab (Avastin), and 21% had prior MEK inhibition.

Safety Spotlight

The median duration of treatment with the combination was 12 months (range, 0.03-40). Serious toxicities were reported in 32% of patients. Dose interruptions and reductions due to an adverse effect (AE) were experienced by 84% and 44% of patients, respectively. AEs led to permanent discontinuation of the doublet for 14% of patients.

The most common AEs experienced by at least 10% of patients who received the doublet on the trial included nausea (all grade, 74%; grade 3 or 4, 1.8%), fatigue (72%; 3.5%), rash (72%; 3.5%), diarrhea (68%; 7%), musculoskeletal pain (68%; 1.8%), edema (67%; 1.8%), vomiting (49%; 3.5%), abdominal pain (39%; 1.8%), dyspepsia (37%; 0%), dermatitis acneiform (37%; 5.3%), vitreoretinal disorders (37%; 3.5%), stomatitis (35%; 3.5%), pruritus (35%; 1.8%), visual impairment (35%; 0%), constipation (30%; 0%), dry skin (30%; 0%), dyspnea (26%; 5.3%), urinary tract infection (25%, 3.5%), cough (25%; 0%), alopecia (23%; 0%), dizziness (23%; 1.8%), and hemorrhage (23%; 0%), among others.

Looking Ahead

“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," Grisham, who is also global lead principal investigator of GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 (NCT06072781), added in the news release. "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.”

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. FDA approves the Avmapki Fakzynja combination therapy as the first-ever treatment for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer. News release. Verastem Oncology. May 8, 2025. Accessed May 8, 2025. https://investor.verastem.com/news-releases/news-release-details/fda-approves-avmapkitm-fakzynjatm-combination-therapy-first-everhttps://investor.verastem.com/news-releases/news-release-details/fda-approves-avmapkitm-fakzynjatm-combination-therapy-first-ever
3. Avmapki Fakzynja Co-Pack. Prescribing information. Verastem; 2025. Accessed May 8, 2025. https://www.verastem.com/pdf/avmapki-fakzynja-co-pack-full-prescribing-information.pdfhttps://www.verastem.com/pdf/avmapki-fakzynja-co-pack-full-prescribing-information.pdf