Interim safety and antitumor activity data from a phase 1 study of INCB123667, a selective CDK2 inhibitor, in patients with metastatic recurrent endometrial cancer.

5603 Background: Cyclin E1 (CCNE1) overexpression or CCNE1 amplification is a predictive indicator of poor prognosis in some endometrial cancers. Inhibition of cyclin-dependent kinase 2 (CDK2), the binding partner of CCNE1, is a potential therapeutic approach for cancers with increased CCNE1 activity. In an ongoing phase 1 study, INCB123667, a potent and selective CDK2 inhibitor, has shown acceptable safety and preliminary efficacy in patients (pts) with advanced solid tumors (NCT05238922). Here, we present interim safety and efficacy data from enrolled pts with metastatic recurrent endometrial cancer. Methods: Eligible pts had ECOG PS ≤1 and measurable disease (RECIST V1.1). Part 1A (dose escalation) enrolled pts with advanced/metastatic solid tumors; CCNE1 amplification (locally tested) was not mandatory. INCB123667 dosing started at 50 mg and escalated to 150 mg daily. In Part 1B (dose expansion), selected RDEs from Part 1A were expanded in 6 tumor-specific cohorts, including an ongoing cohort of pts with metastatic recurrent endometrial cancer with ≤3 prior lines of systemic treatment; pts were required to have locally tested CCNE1 amplification or centrally confirmed CCNE1 overexpression. Blood samples were collected for ctDNA analysis. Results: As of Dec 19, 2024, 17/30 pts with metastatic recurrent endometrial cancer have been enrolled and received INCB123667: 3 in Part 1A (50 mg bid, n=2; 150 mg qd, n=1) and 14 in Part 1B (RDEs: 50 mg bid, n=9; 125 mg qd, n=5). Histologies included carcinosarcoma (n=5), high grade serous (n=6), endometroid (n=4), clear cell (n=1), and mixed serous and clear cell (n=1). Median number of prior systemic therapies was 3 (1-5), including 11 pts pretreated with anti-PD-1 based therapy. Median duration of treatment was 2.3 months (0.3-19.4) and 4 pts (23.5%) are still on treatment. Overall, 16 pts (94.1%) had treatment-emergent adverse events (TEAEs), predominantly anemia (n=8 [47.1%]), nausea (n=6 [35.3%]); thrombocytopenia, abdominal pain, and asthenia (n=5 [29.4%] each). Seven pts (41.2%) had grade 3-4 TEAEs, including neutropenia and thrombocytopenia (n=2 each). No pts discontinued due to TEAEs. Four out of 17 pts had a partial response and 3 had stable disease. Three responders had prior immunotherapy. Cyclin E1 overexpression was present in 3/4 responders, and 2/4 had CCNE1 amplification and overexpression. Decreases in ctDNA were observed on treatment compared with baseline. Conclusions: In this interim analysis, single-agent INCB123667 at various doses has shown an acceptable safety profile in pretreated pts with metastatic recurrent endometrial cancer, including expected cytopenia. The encouraging antitumor activity including post-PD-1 based therapy failure supports future development of INCB123667 in advanced/metastatic endometrial cancer. Clinical trial information: NCT05238922 .