617MO - Safety and tolerability of INCB123667, a selective CDK2 inhibitor, in patients (pts) with advanced solid tumors: A phase I study

Background

CDK2 inhibitors may provide treatment (tx) options for cancers with increased cyclin E1 (CCNE1) activity. INCB123667, a CDK2 inhibitor with 50-fold selectivity over other CDKs, showed antitumor activity in preclinical models of CCNE1-amplified cancers (Chand S. Cancer Res. 2023;83(7):1143). We report dose escalation data from the global Phase 1 open-label, multicenter, dose escalation (Part 1A)/dose expansion (Part 1B) study evaluating the safety, pharmacokinetics, and tolerability of INCB123667 monotherapy in advanced solid tumors.

Methods

Eligible pts (≥18 y) had advanced/metastatic solid tumors, ECOG PS ≤1, and measurable disease (RECIST V1.1). CCNE1 amplification (local result) was preferred in Part 1A. CCNE1 amplification and Cyclin E overexpression (by IHC) were also tested centrally. INCB123667 dosing began at 50 mg QD and was escalated using a hybrid design, with DLT assessed in the first cycle. Selected dose levels were backfilled.

Results

As of 12 Mar 2024, 69 pts received INCB123667 in Part 1A: 50 mg QD, n=5; 50 mg BID, n=19; 75 mg BID, n= 6; 75 mg QD, n=18; 125 mg QD, n=16; 150 mg QD, n= 5; median age, 60 y [range, 18–77], female, 78%. The most common tumors were ovarian (OC; 49%), and breast cancer (BC; 13%). Overall, 65 pts (94%) had tx-emergent AEs (TEAEs); 29 (42%) had grade ≥3 TEAEs. Tx-related AEs occurred in 53 (77%) pts (50 mg QD, n=4 [80%]; 50 mg BID, n=14 [74%]; 75 mg BID, n=6 [100%]; 75 mg QD, n=10 [56%]; 125 mg QD, n=14 [88%]; 150 mg QD, n=5 [100%]), most commonly thrombocytopenia (n=23 [33%]), nausea (n=20 [29%]), and anemia (n=17 [25%]). Grade ≥3 tx-related AEs occurring in ≥5% of pts were thrombocytopenia (n=9), neutropenia (n=6) and anemia (n=5). Three pts (4.3%) discontinued tx due to TEAEs. Of the 60 pts evaluable for response, 28 had stable disease, and 5 had a partial response ([PR], OC, n=3; endometrial and triple-negative BC, n=1 each); 4/5 pts with PR showed Cyclin E1 overexpression, and 2 had CCNE1 amplification.

Conclusions

INCB123667 was generally well tolerated with promising antitumor activity in pts with cyclin E1 overexpressing or CCNE1 amplified advanced/metastatic solid tumors. Dose expansion is ongoing in 6 tumor-specific cohorts. Evaluation of INCB123667 combination tx has been planned.

Clinical trial identification

NCT05238922.

Editorial acknowledgement

Editorial assistance was provided by Emily Sun, PhD of Envision Pharma Group (Fairfield, CT, USA).

Legal entity responsible for the study

Incyte Corporation, Wilmington, DE.

Funding

Incyte Corporation, Wilmington, DE.

Disclosure

M. Simonelli: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Servier, Sanofi, GSK, Incyte. D. Lorusso: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, PharmaMar, AstraZeneca, GSK, MSD, Clovis Oncology, Immunogen, Sutro, Corcept, Genmab, Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, MSD, Clovis Oncology, Immunogen, Sutro, Corcept, Genmab, Seagen; Financial Interests, Institutional, Research Funding: Clovis, Genmab, MSD, Corcept, Immunogen; Financial Interests, Institutional, Research Grant: Clovis Oncology, GSK, MSD. K. Homicsko: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Bristol Myers Squibb, Roche; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MSD Oncology. F. Seguy, M. Kinder, Q. Liu, E. Croft: Financial Interests, Personal, Full or part-time Employment: Incyte; Financial Interests, Personal, Stocks/Shares: Incyte. S. Kitano: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Ayumi, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, GSK, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Chugai Pharma, Eisai, MSD, Novartis, Ono Pharmaceutical; Financial Interests, Institutional, Research Funding: Astellas Pharma, Astellas Pharma, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Gilead Sciences, Ono Pharmaceutical, Regeneron, Takara Bio.