NDA Filed for Avutometinib Plus Defactinib for Low-Grade Serous Ovarian Cancer

The FDA received a rolling new drug application (NDA) for the approval of avutometinib (VS-6766) plus defactinib (VS-6063) for adults with recurrent low-grade serous ovarian cancer harboring KRAS mutations who have received at least 1 prior line of systemic therapy.¹

The NDA is supported by data from the phase 2 RAMP 201 trial (NCT04625270). Updated data from the trial presented at the 2024 International Gynecologic Cancer Society Annual Meeting showed that avutometinib plus defactinib generated a confirmed overall response rate (ORR) of 44% in patients with KRAS-mutant low-grade serous ovarian cancer (n = 57), which comprised a complete response (CR) rate of 4% and a partial response (PR) rate of 40%.2 Forty-nine percent of patients had stable disease (SD), 4% had progressive disease (PD), and 4% were not evaluable (NE).

In the overall population (n = 109), which included patients with KRAS-mutant or wild-type disease, the confirmed ORR was 31%, including a CR rate of 2% and a PR rate of 29%. The respective SD and PD rates were 57% and 8%, and 4% of patients were NE. In the subgroup of patients with KRAS wild-type disease, the confirmed ORR was 17%, where all responders experienced a PR. The SD, PD, and NE rates were 65%, 13%, and 4%, respectively.

“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,” Dan Paterson, president and chief executive officer of Verastem Oncology, stated in a news release.1 “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.”

RAMP 201 enrolled patients with recurrent low-grade serous ovarian cancer who received prior treatment with chemotherapy and had measurable disease per RECIST 1.1 criteria. Prior treatment with a MEK inhibitor was permitted.

A total of 115 patients with KRAS-mutant or wild-type disease were treated at the recommended phase 2 dose of the combination, which was avutometinib at 3.2 mg twice per week plus defactinib at 200 mg twice per day. Treatment was given via a 3-weeks-on, 1-week-off dosing schedule.

The study’s primary end point was ORR per blinded independent central review assessment in the KRAS-mutant population and the overall population.

In the overall population, the median age was 54 years (range, 21-87), and the majority of patients had an ECOG performance status of 0 (68%). Patients received a median of 3 prior lines of therapy (range, 1-9). Ninety-nine percent of patients received prior platinum-based chemotherapy, 86% had prior hormonal therapy, 51% had prior bevacizumab (Avastin), and 22% received a prior MEK inhibitor.

Additional data showed that 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%), 82% (95% CI, 65%-98%), and NE.

In the overall population, KRAS-mutant subgroup, and KRAS wild-type subgroup, the median DOR was 31.1 months (range, 14.8-31.1), 31.1 months (range, 14.8-31.1), and 9.2 months (range, 5.5-NE), respectively.

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.

Regarding safety, adverse effects (AEs) led to treatment discontinuation, dose interruptions, and dose reductions in 10%, 80%, and 36.5% of patients, respectively. Serious AEs deemed related to study treatment occurred in 7% of patients, and abdominal pain was 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%).

References

1. 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 November 1, 2024. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-completes-rolling-nda-submission-fda

2. Avutometinib and defactinib in recurrent low-grade serous ovarian cancer (LGSOC). Verastem Oncology. October 17, 2024. Accessed November 1, 2024. https://investor.verastem.com/static-files/3a401308-b7d3-4889-af50-b84c6325987b