Background: LGSOC is a RAS/MAPK pathway driven cancer that constitutes ≤10% of ovarian cancer. There are no FDA approved treatments specifically for LGSOC. Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition, and defactinib, a small molecule inhibitor of FAK, has shown synergistic antitumor activity with avutometinib in preclinical models. The combination of avutometinib and defactinib has demonstrated a high rate of confirmed and durable responses (overall response rate [ORR] = 46%) in recurrent LGSOC (Banerjee S, ESMO 2021). Methods: A registration-directed phase 2, adaptive, multicenter, randomized study was initiated to evaluate avutometinib ± defactinib in patients with KRAS mutant (mt) and KRAS wild-type (wt) recurrent LGSOC to identify the optimal regimen based on confirmed ORR by blinded independent central review (Part A) and determine the efficacy of the optimal regimen (Part B) (NCT04625270). Pts were randomized to avutometinib 4 mg orally (PO), twice weekly, 3 weeks on, 1 week off (mono) or avutometinib 3.2 mg PO twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off (combo). Key inclusion criteria include histologically confirmed recurrent LGSOC, known KRAS status and prior systemic therapy with platinum chemotherapy. Unlimited additional prior lines, including prior MEK inhibitor, were permitted. Here we present efficacy results from Part A (evaluable patients, N=59) and safety data from all pts enrolled (N=121). Results: In Part A, the median number of prior systemic regimens was 3 for mono, and 4 for combo. In evaluable patients, a confirmed ORR of 7% (2/30) was observed for mono (13% KRAS mt, 0% KRAS wt), and an ORR of 28% (8/29) was observed for combo (27% KRAS mt, 29% KRAS wt). Two of 4 patients previously treated with a MEK inhibitor showed a confirmed partial response (PR) on the combination arm. A high disease control rate (PR or SD ≥ 8 weeks) was observed for both mono (90%) and combo (93%). The majority of treatment related adverse events (AEs, any grade) for combo (N=57) were mild to moderate. The most common Grade ≥3 AEs for combo were blood CPK increase (15.8%), fatigue (5.3%), diarrhea (3.5%), dermatitis acneiform (1.8%), and rash (1.8%). A similar AE profile was observed for mono (N=64). Most AEs were manageable/reversible. On the combo arm, 90.6% (±20%) of planned doses were given and 9% (n=5) of pts discontinued due to AEs [asymptomatic elevated blood CPK (n=3) and fatigue (n=2)]. Conclusions: The 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, and most AEs were mild to moderate. Enrollment continues in Part B for the combination of avutometinib and defactinib. Clinical trial information: NCT04625270.