The FDA is evaluating a new drug application (NDA) for the combination of avutometinib (VS-6766) and defactinib (VS-6063) as a treatment for adult patients with recurrent low-grade serous ovarian cancer (LGSOC) harboring KRAS mutations, who have received at least one prior line of systemic therapy. This application, submitted by Verastem Oncology, seeks to address a significant unmet need in a rare and persistent form of ovarian cancer.
The NDA is based on data from the phase 2 RAMP 201 trial (NCT04625270). Updated results presented at the 2024 International Gynecologic Cancer Society Annual Meeting demonstrated promising efficacy and tolerability of the combination therapy.
RAMP 201 Trial Results
The RAMP 201 trial, an adaptive, two-part multicenter, randomized, open-label phase 2 study, evaluated the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC with or without a KRAS mutation. The primary endpoint was overall response rate (ORR) per blinded independent central review assessment in the KRAS-mutant population and the overall population. Secondary endpoints included complete response, duration of response, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
In the KRAS-mutant subgroup (n = 57), the combination of avutometinib and defactinib yielded a confirmed ORR of 44%, comprising a 4% complete response (CR) rate and a 40% partial response (PR) rate. Stable disease (SD) was observed in 49% of patients, while 4% experienced progressive disease (PD), and 4% were not evaluable (NE).
Across the overall population (n = 109), which included both KRAS-mutant and wild-type disease, the confirmed ORR was 31%, with a 2% CR rate and a 29% PR rate. SD and PD rates were 57% and 8%, respectively, with 4% of patients being NE. In the KRAS wild-type subgroup, the confirmed ORR was 17%, with all responders experiencing a PR. The SD, PD, and NE rates were 65%, 13%, and 4%, respectively.
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 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.
Safety and Tolerability
Adverse events (AEs) led to treatment discontinuation in 10% of patients, dose interruptions in 80%, and dose reductions in 36.5%. Serious AEs deemed related to study treatment occurred in 7% of patients, with abdominal pain being the only treatment-related serious AE reported in more than one 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%).
Mechanism of Action
Avutometinib is an oral RAF/MEK clamp that induces complexes of MEK with ARAF, BRAF, and CRAF, potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. Defactinib is an oral selective FAK inhibitor. The combination treatment was previously granted an orphan drug designation for treating patients with LGSOC regardless of their KRAS status following one or more prior lines of therapy, including platinum-based chemotherapies.
Addressing Unmet Needs
LGSOC is a rare ovarian cancer that is persistent and ultimately fatal. It is distinct from high-grade serous ovarian cancer and requires different treatments. The disease is highly recurrent and less sensitive to chemotherapy, and it tends to affect younger women who have bimodal peaks of diagnosis between ages 20 to 30 and 50 to 60, with a median overall survival (OS) of about 10 years. The current standard of care includes hormone therapy and chemotherapy, but there are no FDA-approved treatments specifically for LGSOC.
"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," said 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."
Enrollment is ongoing for RAMP 301, an international phase 3 trial that will include patients with recurrent LGSOC regardless of KRAS mutation status. The trial will serve as a confirmatory study for the initial indication and has the potential to support an expanded indication, regardless of KRAS mutation status.
