PO004LBA/#1515 Efficacy and Safety of Avutometinib + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer Following Prior Systemic Therapy

Introduction Avutometinib is a novel small molecule RAF/MEK clamp. 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 45% ORR and a mild to moderate, manageable/reversible safety profile in heavily pretreated (mLoT=4) recurrent LGSOC (KRAS mt + wt) (ENGOT-ov60/GOG-3052/RAMP 201, NCT04625270). Methods This post-hoc analysis of the phase 2 ENGOT-ov60/GOG-3052/RAMP 201 study in recurrent LGSOC (06Apr2023 data cutoff) was performed to assess efficacy (Part A; confirmed ORR via blinded independent central review) and safety (all treated patients) in the context of 1) lines of prior systemic therapy (1–3 LoT, ≥4 LoT) and 2) best response to most recent prior treatment in the metastatic/recurrent setting (PR/CR, no PR/CR; as assessed by treating investigator). Results In the combination arm, similar ORRs were observed in patients that were treated with 1–3 (5/11, 45.5%) and ≥4 LoT (8/18, 44.4%) (table 1). Prior to enrollment in RAMP 201, only 2/23 (8.7%) patients responded to their last prior treatment, whereas the combination of avutometinib + defactinib yielded an ORR of 43.5% (10/23) in this subgroup (table 2). The safety profiles of avutometinib + defactinib were similar in the less and more heavily pretreated subgroups, and both analyses were consistent with previously reported safety data. The majority of TRAEs were mild to moderate, manageable/reversible. Conclusion/Implications Avutometinib + defactinib demonstrated robust efficacy (ORR) in recurrent LGSOC irrespective of the number of prior therapies, and for most of which, response to previous therapy was poor.