The combination of avutometinib (VS-6766) and defactinib (VS-6063) has shown promising results in patients with recurrent low-grade serous ovarian cancer, according to interim data from the phase 2 RAMP-201 trial (NCT04625270). The study, a registration-directed trial, indicates encouraging response rates and a manageable safety profile, potentially offering a new treatment option for this patient population.
Objective Response and Disease Control
The interim analysis revealed that among response-evaluable patients (n = 29) treated with the combination therapy, the confirmed objective response rate (ORR) was 28% per blinded independent central review (BICR). Notably, patients with KRAS-mutated disease (n = 15) achieved a confirmed ORR of 27%, while those with KRAS wild-type disease (n = 14) had a confirmed ORR of 29%. The overall disease control rate (DCR) for patients treated with the combination was 93%, and after a minimum follow-up of 5 months, 62% of evaluable patients remained on the study treatment.
In contrast, patients treated with avutometinib monotherapy (n = 30) showed a confirmed ORR of 7% per BICR, with an overall DCR of 90%.
Regulatory Strategy and Future Plans
Following discussions with the FDA, the combination therapy was selected as the go-forward treatment for analysis in all patients with recurrent low-grade serous ovarian cancer, irrespective of KRAS status. Verastem Oncology intends to leverage mature data from the RAMP-201 trial and the phase 1 FRAME trial (NCT03875820) to potentially support an application for accelerated approval of avutometinib plus defactinib in this patient population.
Expert Commentary
"The interim data from the ongoing phase 2 RAMP 201 trial show that the combination of avutometinib with defactinib yields encouraging response rates with a well-tolerated safety profile in women with heavily pretreated recurrent low-grade serous ovarian cancer," said Susana Banerjee, MBBS, MA, PhD, FRCP, global lead investigator of the study. She also noted the importance of the initial findings, leading to the decision to move forward with the combination regimen.
Trial Design and Patient Population
RAMP-201 is an ongoing, adaptive, 2-part, multicenter, parallel cohort, randomized, open-label trial assessing the safety and efficacy of avutometinib alone and in combination with defactinib in patients with recurrent low-grade serous ovarian cancer. The trial enrolled patients with histologically proven low-grade serous ovarian cancer who had experienced progression or recurrence after at least one prior systemic therapy for metastatic disease. Key inclusion criteria included measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.
Safety Profile
The safety profile of the combination therapy was consistent with previous findings. The most common treatment-related adverse events (AEs) included diarrhea, nausea, increased blood creatine phosphokinase, blurred vision, dermatitis acneiform and rash, fatigue, and peripheral edema, most of which were mild to moderate. Treatment discontinuation due to AEs occurred in 9% of patients.
