Abstract
Introduction/Background LGSOC, a RAS/MAPK driven cancer, constitutes ≤10% of ovarian cancer, with no FDA-approved treatments. Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition; defactinib, a small molecule FAK inhibitor, has shown synergistic antitumor activity with avutometinib. Avutometinib + defactinib demonstrated a high confirmed and durable response rate (objective response rate [ORR]=46%) in recurrent LGSOC. Methodology A phase 2, multicenter, randomized study evaluated avutometinib ± defactinib in patients with KRAS mutant (mt) and KRAS wild-type (wt) recurrent LGSOC to identify an optimal regimen based on confirmed ORR by blinded independent central review (Part A) and determine efficacy (Part B) (NCT04625270). Patients were randomized to avutometinib (mono) or avutometinib + defactinib (combo). Key inclusion criteria: histologically-confirmed recurrent LGSOC, known KRAS status, prior platinum chemotherapy. Unlimited prior therapies, including MEK inhibitor, were permitted. Efficacy results from Part A (evaluable patients, N=64) and safety data from all patients (N=151) are presented (April 2023 data cutoff). Results In Part A, median number of prior regimens was 3 for mono, 4 for combo. A 45% confirmed ORR was observed for combo (60% KRAS mt, 29% KRAS wt) and 10% for mono (13% KRAS mt, 6% KRAS wt). Three of 4 patients previously treated with MEK inhibitor showed confirmed partial response on combo arm. Median time to response: 7.3 months (mono) and 5.5 months (combo). Most treatment-related adverse events (AEs) for combo (n=81) were grade 1–2, with a low proportion of dose reductions (17%) and discontinuations due to AEs (12.3%) in the combo arm. Conclusion Interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status. No new safety signals were observed; most AEs were mild to moderate.