Verastem Oncology's avutometinib, in combination with defactinib, has shown promising results in patients with recurrent low-grade serous ovarian cancer (LGSOC), a rare and often chemotherapy-resistant form of ovarian cancer. Updated findings from the phase 2 RAMP 201 trial, presented at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting, indicate a significant overall response rate (ORR) and progression-free survival (PFS) benefit, particularly in patients with KRAS-mutated LGSOC.
The RAMP 201 trial (NCT04625270) evaluated the efficacy and safety of avutometinib and defactinib in patients with recurrent LGSOC who had progressed after at least one prior systemic therapy. The study included both KRAS-mutant and KRAS wild-type LGSOC patient populations. Key findings from the primary analysis, with a data cutoff of June 30, 2024, revealed a confirmed ORR of 31% (95% CI, 23%-41%) in all evaluable patients (n = 109) per blinded independent central review (BICR). In the KRAS-mutant subgroup (n = 57), the ORR was 44% (95% CI, 31%-58%), while in the KRAS wild-type subgroup (n = 52), the ORR was 17% (95% CI, 8%-30%).
Progression-Free Survival and Duration of Response
The median duration of response (DOR) across all evaluable patients was 31.1 months (95% CI, 14.8-31.1). Specifically, the median DOR was 31.1 months (95% CI, 14.8-31.1) in the KRAS-mutant subgroup and 9.2 months (95% CI, 5.5-NE) in the KRAS wild-type subgroup. The median progression-free survival (PFS) was 12.9 months (95% CI, 10.9-20.2) in all evaluable patients, 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. The disease control rate (DCR) at 6 months or longer was 61% in the overall population, 70% in the KRAS-mutant population, and 50% in the KRAS wild-type population.
Safety and Tolerability
The combination of avutometinib and defactinib was generally well-tolerated, with a 10% discontinuation rate due to adverse events (AEs). No new safety signals were identified. Common treatment-related AEs included nausea (67.0%), diarrhea (58.3%), and increased blood creatine phosphokinase levels (60.0%). Grade 3 or higher AEs were relatively infrequent, with nausea at 2.6%, diarrhea at 7.8%, and increased blood creatine phosphokinase levels at 24.3%.
Regulatory Pathway and Future Development
Verastem Oncology is currently on track to complete its New Drug Application (NDA) submission to the FDA in October 2024, seeking accelerated approval for the combination of avutometinib and defactinib in adult patients with recurrent KRAS-mutant LGSOC who have received at least one prior systemic therapy. The FDA previously granted Breakthrough Therapy Designation to this combination for recurrent LGSOC after one or more prior lines of therapy. A phase 3 trial, RAMP 301 (NCT06072781), is underway to confirm these findings and potentially expand the treatment's indication regardless of KRAS mutation status.
"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," said Susana Banerjee, MBBS, MA, PhD, FRCP, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research in London, United Kingdom.
