Avutometinib Plus Defactinib NDA Filed for KRAS-Mutant Low-Grade Serous Ovarian Cancer
核心洞察
The FDA has received a rolling NDA for avutometinib plus defactinib to treat recurrent KRAS (搜索)-mutant low-grade serous ovarian cancer (搜索) in adults after one prior systemic therapy.
The NDA is based on phase 2 RAMP 201 trial data, which showed a 44% confirmed overall response rate in patients with KRAS (搜索)-mutant low-grade serous ovarian cancer (搜索).
Verastem Oncology anticipates potential FDA approval in mid-2025, addressing a critical unmet need as there are currently no FDA-approved treatments specifically for this cancer.
Verastem Oncology has announced the FDA acceptance of a rolling New Drug Application (NDA) for the combination of avutometinib (VS-6766) plus defactinib (VS-6063) for adult patients with recurrent low-grade serous ovarian cancer (搜索) harboring KRAS (搜索) mutations, who have previously undergone at least one line of systemic therapy. This submission is based on the promising results from the Phase 2 RAMP 201 trial (NCT04625270).
RAMP 201 Trial Results
Updated findings from the RAMP 201 trial, presented at the 2024 International Gynecologic Cancer Society Annual Meeting, revealed a confirmed overall response rate (ORR) of 44% (n = 57) in patients with KRAS (搜索)-mutant low-grade serous ovarian cancer (搜索) treated with avutometinib plus defactinib. This included a complete response (CR) rate of 4% and a partial response (PR) rate of 40%. Stable disease (SD) was observed in 49% of patients, while 4% experienced progressive disease (PD), and another 4% were not evaluable.
In the overall study population (n = 109), encompassing both KRAS (搜索)-mutant and wild-type disease, the confirmed ORR was 31%, with a CR rate of 2% and a PR rate of 29%. SD and PD rates were 57% and 8%, respectively, with 4% of patients being not evaluable. Specifically, in the KRAS wild-type subgroup, the confirmed ORR was 17%, with all responders achieving a PR. The SD, PD, and NE rates were 65%, 13%, and 4%, respectively.
Management Perspective
"We believe that avutometinib in combination with defactinib has the potential to change the treatment paradigm for patients with recurrent KRAS (搜索)-mutant low-grade serous ovarian cancer (搜索)," stated Dan Paterson, president and chief executive officer of Verastem Oncology. "Completing our NDA submission is a significant milestone not only for Verastem as we plan for potential FDA approval in mid-2025, but also for patients as there are no FDA-approved treatments specifically for this rare ovarian cancer."
Trial Design and Patient Population
The RAMP 201 trial enrolled patients with recurrent low-grade serous ovarian cancer (搜索) who had previously received chemotherapy and exhibited measurable disease according to RECIST 1.1 criteria. Prior treatment with a MEK inhibitor was permitted. A total of 115 patients, with either KRAS (搜索)-mutant or wild-type disease, were administered the recommended Phase 2 dose of avutometinib at 3.2 mg twice per week in combination with defactinib at 200 mg twice per day, following a 3-weeks-on, 1-week-off dosing schedule.
The primary endpoint of the study was ORR, as assessed by blinded independent central review in both the KRAS (搜索)-mutant population and the overall population.
The median age of the overall population was 54 years (range, 21-87), with the majority of patients having an ECOG performance status of 0 (68%). Patients had received a median of 3 prior lines of therapy (range, 1-9). Prior treatments included platinum-based chemotherapy (99%), hormonal therapy (86%), bevacizumab (Avastin) (51%), and a MEK inhibitor (22%).
Additional Efficacy and Safety Data
The median time to response for the overall population was 3.7 months (range, 1.7-19.2). The 6-month duration of response (DOR) rate was 81% (95% CI, 62%-91%) for the overall population, 87% (95% CI, 66%-96%) for the KRAS (搜索)-mutant population, and 63% (95% CI, 23%-86%) for the KRAS wild-type population. The respective 12-month DOR rates were 72% (95% CI, 54%-89%) and 82% (95% CI, 65%-98%).
The median DOR was 31.1 months (range, 14.8-31.1) in the overall population and the KRAS (搜索)-mutant subgroup, and 9.2 months (range, 5.5-NE) in the KRAS wild-type subgroup.
The median progression-free survival was 12.9 months (95% CI, 10.9-20.2) in the overall population, 22 months (95% CI, 11.1-36.6) in the KRAS (搜索)-mutant population, and 12.8 months (95% CI, 7.4-18.4) in the KRAS wild-type population.
Adverse events (AEs) led to treatment discontinuation in 10% of patients, dose interruptions in 80%, and dose reductions in 36.5%. Serious AEs related to study treatment occurred in 7% of patients, with abdominal pain being the only treatment-related serious AE reported in more than 1 patient.
The most common treatment-related AEs included nausea (any-grade, 67.0%; grade ≥3, 2.6%), diarrhea (58.3%; 7.8%), peripheral oedema (53.0%; 0.9%), fatigue (43.5%; 2.6%), vomiting (42.6%; 2.6%), blurred vision (40.9%; 0%), rash (35.7%; 1.7%), acneiform dermatitis (33.9%; 4.3%), dry skin (26.1%; 0%), and anemia (22.6%; 5.2%). Laboratory-related AEs included increased blood creatinine levels (60.0%; 24.3%), increased blood bilirubin levels/hyperbilirubinemia (33.0%; 4.3%), and increased aspartate aminotransferase levels (31.3%; 1.7%).