Safety and preliminary efficacy from a phase 1 study of INCB123667, a selective CDK2 inhibitor, in patients with advanced platinum-resistant and refractory ovarian cancer (OC).

5514 Background: Inhibition of cyclin-dependent kinase 2 (CDK2), the binding partner of cyclin E1 (CCNE1), is a potential therapeutic approach for cancers with increased CCNE1 activity. In an ongoing phase 1 study, the potent and selective CDK2 inhibitor, INCB123667, has shown acceptable safety and preliminary efficacy in patients (pts) with advanced solid tumors (NCT05238922). Here, we present safety and preliminary efficacy data for enrolled pts with OC. Methods: Eligible pts had ECOG PS ≤1 and measurable disease (RECIST V1.1). Part 1A (dose escalation) enrolled pts with advanced/metastatic solid tumors with no maximum prior lines of treatment; CCNE1 amp (locally tested) was not mandatory. INCB123667 dosing started at 50 mg and escalated up to 150 mg daily. In part 1B (dose expansion), selected RDEs from part 1A were expanded in 6 tumor cohorts, including platinum-refractory/resistant (r/r) OC with ≤4 prior lines of systemic treatment; pts must have had locally tested CCNE1 amp or centrally confirmed CCNE1 overexpression. Blood samples were collected for ctDNA analysis. Results: As of Dec 19, 2024, 90 pts with advanced/metastatic platinum-r/r OC received INCB123667: 45 in part 1A (50 mg qd, n=1; 50 mg bid, n=4; 75 mg qd, n=12; 75 mg bid, n=4; 125 mg qd, n=18; 150 mg qd continuous or intermittent, n=6) and 45 in part 1B (RDEs: 50 mg bid, n=16; 100 mg qd, n=14; 125 mg qd, n=15). Sixty one pts (67.8%) had prior PARPi. Median number of prior systemic therapies was 4 (1-12). Median duration of treatment was 4.9 months (0.1-13.6), with 17 pts (18.9%) still on treatment. Overall, 88 pts (97.8%) had treatment-emergent adverse events (TEAEs), predominantly nausea (n=51 [56.7%]), anemia (n=34 [37.8%]), and vomiting (n=33 [36.7%]). Of 38 pts (42.2%) with grade ≥3 TEAEs, most common were intestinal obstruction (n=8 [8.9%]), anemia (n=6 [6.7%]), neutropenia (n=5 [5.6%]), and thrombocytopenia (n=5 [5.6%]). Treatment was discontinued due to TEAEs in 3 pts (3.3%). Overall response rate (ORR) among all pts in parts 1A and 1B was 21.1% (19/90; complete response, n=4; partial response, n=15) and 43 (51.2%) achieved stable disease, with an ORR of 33.3% (10/30) at selected RDEs of 100 mg daily (ie, 50 mg bid and 100 mg qd) in part 1B. All but 1 responder had CCNE1 overexpression (18/19); responses were observed in pts with CCNE1 -amp (6/19) and in pts without CCNE1 -amp but with CCNE1 overexpression (13/19). Consistent decreases in ctDNA were observed on treatment compared with baseline. Conclusions: In this phase 1 study of pts with heavily pretreated advanced/metastatic platinum-r/r OC, single agent INCB123667 at various doses showed an acceptable safety profile including expected cytopenia and nausea. The encouraging antitumor activity in this difficult-to-treat population support the advancement of INCB123667 into pivotal studies in pts with platinum-resistant OC. Clinical trial information: NCT05238922 .