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 harboring KRAS 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-mutant low-grade serous ovarian cancer 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-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-mutant low-grade serous ovarian cancer," 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 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-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-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-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-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-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%).
