Verastem Oncology has completed a rolling new drug application (NDA) submission to the FDA, seeking accelerated approval for avutometinib in combination with defactinib 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. The FDA has granted priority review, with a decision anticipated before the end of 2024. If approved, this regimen would be the first commercially available therapy specifically for adults with KRAS-mutated LGSOC, addressing a significant unmet need in this patient population.
RAMP 201 Trial Results
The NDA submission is supported by data from the phase 2 RAMP 201 trial (NCT04625270). Updated findings were presented at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting. The confirmed overall response rate (ORR) with avutometinib/defactinib was 31% (95% CI, 23%-41%) across all evaluable patients (n = 109) per blinded independent central review. In the KRAS-mutated disease subgroup (n = 57), the confirmed ORR was 44% (95% CI, 31%-58%). For those with KRAS wild-type disease (n = 52), the ORR was 17% (95% CI, 8%-30%).
The median progression-free survival (PFS) with avutometinib/defactinib was 12.9 months (95% CI, 10.9-20.2) across all evaluable patients. Specifically, the median PFS was 22.0 months (95% CI, 11.1-36.6) in patients with KRAS mutations and 12.8 months (95% CI, 7.4-18.4) in those with KRAS wild-type disease.
Safety Profile
Data from the RAMP 201 trial indicated that 10% of patients discontinued study therapy due to adverse effects (AEs). Common treatment-related AEs of any grade included nausea (67.0%), diarrhea (58.3%), and blood creatine phosphokinase level elevations (60.0%). Grade 3 or higher treatment-related AEs included blood creatine phosphokinase level elevations (24.3%) and diarrhea (7.8%).
Investigator Commentary
Lead trial investigator Susana Banerjee, MBBS, MA, PhD, FRCP, emphasized the potential impact of the avutometinib and defactinib combination: "The notable response rates and low discontinuation rate seen with the combination of avutometinib and defactinib are significant. These updated results confirm the potential of this new combination therapy to change practice and be the new standard for care for recurrent low-grade serous ovarian cancer, which previously had limited effective treatment options."
Trial Design and Further Investigation
The RAMP 201 trial is a two-part, multicenter, open-label study assessing the safety and efficacy of avutometinib as monotherapy and in combination with defactinib in patients with recurrent LGSOC. Parts B and C of the trial involve a go-forward regimen of avutometinib at 3.2 mg twice weekly plus defactinib at 200 mg twice daily. Part D will assess a lower dose of avutometinib plus defactinib to determine individualized dose reduction strategies.
An international phase 3 RAMP 301 trial (NCT06072781) is currently enrolling patients with recurrent LGSOC of any KRAS mutation status. This confirmatory trial will further evaluate the avutometinib combination and potentially support expanded indications regardless of KRAS mutation status.
