Dr Monk on Avutometinib Plus Defactinib in Low-Grade Serous Ovarian Cancer

Bradley Monk, MD, FACS, FACOG, professor, the Division of Gynecologic Oncology the University of Arizona College of Medicine and Creighton University School of Medicine; director, principal investigator, Community Research Development, HonorHealth Research Institute, vice president, member, the Board of Directors, the GOG-Foundation; co-director, GOG-Partners, discusses findings from the phase 2 RAMP 201 trial (NCT04625270) in patients with low-grade serous ovarian cancer and the importance of these results within the context of the larger ovarian cancer treatment paradigm. 

Mature findings from RAMP 201, which were presented at the 2023 ASCO Annual Meeting, included data with 31 evaluable patients with low-grade serous ovarian cancer who received the RAF/MEK inhibitor avutometinib (VS-6766) and 29 evaluable patients with low-grade serous disease who received avutometinib plus the FAK inhibitor defactinib (VS-6063). The patients who received the combination achieved an overall response rate (ORR) of 45%, including ORRs of 60% in those with KRAS-mutant disease and 29% in those with KRAS wild-type disease. In the monotherapy arm, the ORR was 10%, including ORRs of 13% in those with KRAS-mutant disease and 6% in those with KRAS wild-type disease. In addition, the tumor shrinkage rate was 86% with the combination vs 90% with the monotherapy.

In RAMP 201, the median time to response was 5.5 months in the combination arm compared with 7.3 months in the monotherapy arm. The tolerability of avutometinib plus defactinib allowed 83% ± 20% of patients in part A of the trial to maintain the combination dose intensity, Monk says. In the monotherapy arm, 80% ± 20% of patients in part A maintained dose intensity.

The ORR achieved with avutometinib plus defactinib in this population exceeds those seen with other MEK inhibitors in patients with ovarian cancer, Monk explains. Previously, in 2022, the phase 2/3 GOG 281/LOGS trial (NCT02101788) evaluated the efficacy of the MEK inhibitor trametinib (Mekinist) vs standard-of-care (SOC) chemotherapy in patients with recurrent low-grade serous ovarian cancer and found that trametinib elicited an ORR of 26% vs 6% with SOC. Additionally, in 2020, findings from the phase 3 MILO trial (NCT01849874), which investigated the efficacy of the MEK inhibitor binimetinib (Mektovi) vs chemotherapy in patients with recurrent or persistent low-grade ovarian, fallopian tube, or primary peritoneal serous carcinoma, demonstrated an ORR of 16% with binimetinib vs 13% with chemotherapy.

Furthermore, in the phase 1 FRAME trial (NCT03875820), avutometinib plus defactinib produced an ORR of 46% in the 24 evaluable patients treated with the combination. These findings supported the 2021 FDA breakthrough therapy designation for the combination in this population. In the RAMP 201 and FRAME trials combined 53 patients received avutometinib plus defactinib, of whom 45% and 46%, respectively, had clinically meaningful responses with the combination, Monk concludes.