FDA Grants Accelerated Approval to Avutometinib/Defactinib in KRAS+ LGSOC

Findings presented at SGO revealed that among patients who received 3.2 mg of avutometinib twice weekly and 200 mg of defactinib twice daily, the confirmed objective response rate was 31%, with 2% of patients attaining a complete response and 29% of patients attaining a partial response.

The News

The FDA has approved avutometinib in combination with defactinib (Avmapki Fakzynja Co-pack) as a treatment for adult patients with recurrent, KRAS-mutated, low-grade serous ovarian cancer (LGSOC), according to a press release from the agency.1

Supporting Data

The approval for avutometinib/defactinib was supported by findings from the phase 2 RAMP 201 trial (NCT04625270), in which investigators evaluated avutometinib with or without defactinib in patients with recurrent LGSOC previously treated with platinum therapy, measurable disease per RECIST v1.1 criteria, documented KRAS mutations, and prior MEK inhibition or bevacizumab (Avastin) treatment. Investigators previously presented trial findings from a preplanned subgroup analysis at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).2

The findings presented at SGO revealed that among patients who received 3.2 mg of avutometinib twice weekly and 200 mg of defactinib twice daily (n = 109), the confirmed objective response rate (ORR) was 31%, with 2% of patients attaining a complete response (CR) and 29% of patients attaining a partial response (PR). Additionally, among patients with KRAS wild-type disease (n = 52), the confirmed ORR was 17%, which was composed entirely of PRs. Furthermore, among patients with KRAS-mutant disease (n = 57), the confirmed ORR was 44% (95% CI, 31%-58%), with 4% of patients attaining a CR and 40% attaining a PR.

Additionally, the median duration of response (DOR) among all patients was 31.1 months (95% CI, 14.8-31.1; range, 3.1-31.1); among those with KRAS wild-type or KRAS-mutant disease, the median DOR was 9.2 months (95% CI, 5.5-not evaluable [NE]) and 31.1 months (95% CI, 14.8-31.1), respectively. Furthermore, in each respective group, the 6-month response rates were 81% (95% CI, 62%-91%), 63% (95% CI, 23%-86%), and 87% (95% CI, 66%-96%). The 12-month rates were 72% (95% CI, 54%-89%), NE, and 82% (95% CI, 65%-98%).

Among all patients, those with KRAS wild-type disease, and those with KRAS-mutant disease, the median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-20.2), 12.8 months (95% CI, 7.4-18.4), and 22.0 months (95% CI, 11.1-36.6), respectively. The 6-month PFS rates were 79% (95% CI, 70%-86%), 69% (95% CI, 53%-80%), and 88% (95% CI, 76%-95%) in each respective group. The 12-month rates were 58% (95% CI, 47%-68%), 53% (95% CI, 37%-69%), and 62% (95% CI, 48%-77%).

RAMP 201 Trial Design

The trial’s primary end point was blinded independent central review–assessed ORR per RECIST v 1.1 criteria. Specifically, in the prespecified subgroup analysis of the trial, the evaluation of ORR in the combination arm occurred in patients with KRAS-mutant disease and then for all patients, comprising those with KRAS-mutant and wild-type disease.

At a median follow-up of 13.6 months (range, 1.4-39.5), patients were dosed with either 3.2 mg of twice-weekly avutometinib and 200 mg of defactinib twice daily, a lower dose of 1.6 mg of twice-weekly avutometinib plus 200 mg of defactinib twice daily, or 4.0 mg of avutometinib twice weekly. Only patients treated with 3.2 mg of twice-weekly avutometinib and 200 mg of defactinib twice daily were included in the final analysis, and oral dosing occurred 3 consecutive weeks with 1 week off.

Initially starting with a selection phase, treatment continued in an expansion and combination expansion phase once the Go Forward Regimen Selection Criteria were met. The criteria were met if the observed ORR was comparatively greater than another regimen and the observed ORR of the leading regimen was 15% or greater.

Eligible patients had recurrent LGSOC, prior platinum chemotherapy, and measurable disease per RECIST v 1.1 guidelines; they were permitted to have undergone prior MEK inhibition.

Patients evaluated in the subgroup analysis had a median age of 54 years (range, 21-87). Additionally, most patients had an ECOG performance score of 0 (68%) and had a median of 3 prior systemic regimens (range, 1-9). A total of 99% of patients had prior platinum-based chemotherapy, 86% had prior hormonal therapy, 51% had prior bevacizumab treatment, and 22% had prior MEK inhibition therapy. Patients were from either the US (53%) or EU (47%), and 77% of patients identified as White.

Adverse Effects

Common treatment-related adverse effects (TEAEs) included nausea (67%), increased blood creatine phosphokinase (CPK; 60%), diarrhea (58%), edema peripheral (53%), and rash (50%). Additionally, 80% of patients had an AE leading to dose interruption, including 38% due to CPK elevation. Furthermore, 37% had AEs leading to dose reduction, and 10% experienced treatment discontinuation due to AEs. No additional discontinuations for AEs occurred after 3 months of follow-up.

Additionally, 7% of patients experienced serious AEs (SAEs) related to study treatment. Abdominal pain was the only SAE that occurred in more than 1 patient. Furthermore, no additional treatment-related SAEs occurred following 3 months of follow-up.

The most common treatment-related ocular event was blurred vision (41%). The vast majority occurred within the first week with a median onset of 4 days, and all events were grade 1 or 2 in severity. The most common skin and subcutaneous tissue AEs included rash (50%), dermatitis acneiform (34%), and dry skin (26%). Most events were grade 1 or 2, had a median onset of 15 days, and a median duration of 35 days. A total of 6% of patients had a treatment-related skin reaction that resulted in a dose interruption or reduction, and 1 patient experienced treatment discontinuation due to dermatitis acneiform.

The FDA received a rolling new drug application (NDA) for avutometinib/defactinib in KRAS-positive LGSOC in May 2024.3 The rolling NDA was completed in October 2024.4 Avutometinib in combination with defactinib was accepted for FDA priority review in December 2024.5

References

1. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. News release. FDA. May 8, 2025. Accessed May 8, 2025. https://tinyurl.com/ywyd4ps3
2. Grisham RN, Nieuwenhuysen EV, Aghajanian C, et al. Avutometinib + defactinib in recurrent low-grade serous ovarian cancer (ENGOT-ov60/GOG-3052/RAMP 201): dose intensity and subgroup analysis. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO); Seattle, WA, March 14-17, 2025.
3. Verastem Oncology announces the initiation of a rolling submission of NDA to FDA seeking accelerated approval of avutometinib and defactinib combination for the treatment of adult patients with recurrent KRAS mutant low-grade serous ovarian cancer. News release. Verastem Oncology. May 24, 2024. Accessed April 15, 2025. https://tinyurl.com/mfxmuk29
4. 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. News release. Verastem Oncology. October 31, 2024. Accessed April 15, 2025. https://tinyurl.com/2eakc933
5. 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. News release. Verastem Oncology. December 30, 2024. Accessed April 15, 2025. https://tinyurl.com/57brbv3n