Novel CDK2 Inhibitor INCB123667 Shows Promise in Ovarian Cancer

The investigational CDK2 inhibitor INCB123667 showed encouraging anti-tumor activity with manageable toxicity in patients with heavily pretreated resistant/refractory ovarian cancer, according to results from a phase 1a/b dose escalation/expansion study.¹

The findings, which were presented at the 2025 ASCO Annual Meeting, showed that at the optimal treatment dose of 100 mg daily, INCB123667 achieved an objective response rate (ORR) of 33.3% (10 of 30 patients), with more than 70% of patients experiencing a decrease in tumor size from baseline. The median time to response was 2.1 months (range, 1.6-7.7) and the median duration of response was 3.6 months (range, 1.9-NE). The median progression-free survival was 5.3 months. Of note, all but 1 responder had cyclin E1 overexpression.

The median duration of treatment was 4.5 months (range, 0.1-18.1). Overall, 8 patients (8.9%) remained on treatment at the March 10, 2025, data cutoff. The other 82 patients (91.1%) had discontinued, most commonly due to disease progression (n = 70; 77.8%). There were 3 patients (3.3%) who stopped treatment because of adverse events.

Regarding safety, adverse events with INCB123667 were considered to be manageable. Treatment-emergent adverse events (TEAEs) were for the most part hematologic and gastrointestinal and predominantly grade ≤2. TEAEs led to discontinuation in only 2.2% of patients.

“These data provide a proof of concept in this difficult to treat population and support the advancement of INCB123667 into pivotal studies in patients with platinum-resistant ovarian cancer,” said presenting author Domenica Lorusso, MD, PhD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome and Humanitas San Pio X, Milan, Italy.

Study Design and Objectives

Eligible patients had platinum-resistant or platinum-refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and had received up to 4 prior lines of systemic therapy. Additional inclusion criteria were documented CCNE1 amplification confirmed by a local laboratory or central cyclin E1 overexpression, as well as an ECOG performance status of 0 or 1.

The primary objectives of the study were to evaluate the safety and tolerability of INCB123667 monotherapy and to determine the maximum tolerated dose and recommended dose expansions. Secondary objectives included ORR, disease control rate, and duration of response. Exploratory objectives focused on identifying biomarkers that may predict pharmacologic activity or correlate with clinical safety or efficacy.

INCB123667 was administered starting at a dose of 50 mg daily, with dose escalation reaching up to 150 mg per day.

Baseline Characteristics

The study included 90 patients with ovarian cancer, with 45 patients each enrolled in parts 1a and 1b. The main efficacy data presented at ASCO 2025 were from the 45 patients from phase 1b, 30 of were treated at the optimal dose of 100 mg/daily.

Across the overall group of 90 patients, the median age was 62.0 years (range, 37.0-80.0), with 34.4% (n = 31) aged 65 years or older. Most patients were White (71.1%; n = 64), followed by Asian (8.9%; n = 8), while race was not reported, unknown, or missing for 20.0% (n = 18). The majority of patients (75.6%; n = 68) had an ECOG performance status of 0.

Most patients had serous histology (80.0%; n = 72), with smaller proportions presenting with clear cell (5.6%; n = 5), endometrioid (1.1%; n = 1), or other histologic subtypes (13.3%; n = 12). Cyclin E1 overexpression was observed in 92.2% of patients (n = 83), and CCNE1 amplification was present in 56.7% (n = 51). Patients had received a median of 4 (range, 1-12) prior systemic therapies, with 68.9% (n = 62) having previously been treated with a PARP inhibitor and 76.7% (n = 69) having received bevacizumab.

Key Takeaway

“The observed safety, tolerability, and encouraging antitumor activity of single agent INCB123667 provides proof of concept and supports the advancement of INCB123667 into pivotal studies in patients with advanced or recurrent ovarian cancer,” said Lorusso in her concluding remarks.

Reference

1. Damian S, Lorusso D, Simonelli M. 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). J Clin Oncol. 2025;43(suppl 17):5514. doi: 10.1200/JCO.2025.43.16_suppl.5514