Selective CDK2 Inhibitor Undergoes Investigation in CCNE1-High Tumors

Preclinical data have demonstrated activity of a novel, small molecule CDK2 inhibitor INCB123667 in CDK2/cyclin E1 (CCNE1) expressing cell lines prompting investigators to initiate a phase 1 study (NCT05238922). The agent may fill an unmet need for patients with cancers with primary or acquired CDK4/6 resistance, according to Saswati Chand, PhD.¹

“Hormone receptor–positive or –negative breast cancer remains a significant cause of cancer-related mortality in women,” Chand, a senior research investigator of oncology discovery at Incyte Corporation said in a presentation during the American Association for Cancer Research Annual Meeting 2023. “CDK4/6 inhibitors in combination with endocrine therapy have become the standard-of-care first-line treatment. However, 15% to 30% of patients on CDK4/6 therapy either present [as] de novo that is primary resistance or acquired resistance, both leading to treatment failure and disease progression.

To identify potential drivers of resistance and develop effective treatment paradigms post CDK4/6 inhibition genomic alterations, gene expression and circulating biomarkers have been extensively studied. Cyclin E amplification and overexpression have been reported to be an oncogenic driver of CDK4/6 resistance and shown to be associated with poor clinical outcomes and ovarian, gastric, endometrial, and breast cancers.”

For example, Chand cited data from a baseline, gene panel analysis of patients with hormone receptor–positive, HER2-negative breast cancer who received palbociclib (Ibrance) plus fulvestrant (Faslodex) or placebo plus fulvestrant in the phase 3 PALOMA-3 trial (NCT01942135).² The findings showed that patients with higher CCNE1 mRNA expression had worse outcomes with palbociclib vs placebo (median progression-free survival [PFS] 7.6 vs 4.0 months; HR, 0.851) than those with low expression (median PFS, 14.1 vs 4.8 months; HR, 0.320).²

“In addition to CCNE1 overexpression and hormone receptor–positive breast cancers, notoriously aggressive triple-negative breast cancers [TNBCs] have also been shown to be associated with cyclin E alterations,” Chand said.

To better understand genomic expression between primary and metastatic triple-negative breast tumors, investigators analyzed data from The Cancer Genome Atlas project and the Molecular Taxonomy of Breast Cancer International Consortium. Using paired analyses, 455 differentially expressed genes were identified with 8 cancer-related genes significantly updated including CCNE1. In TNBCs from both datasets, CCNE1 was increased in 48.7% and 42.1%, respectively, of patients compared with non-TNBCs (7.2% and 3.2%, respectively).³

An analysis of overall survival (OS) showed a significant association of poorer OS outcomes with CCNE1 overexpression (P = .023).³ In findings from another analysis, overexpression of CCNE1 was also associated with TNBC samples and associated with poor OS (P < .05).⁴

“Due to a lack of hormone receptor expression and extensive heterogeneity, TNBCs remain unresponsive to current therapies and present a highly unmet clinical need thus far,” Chand said.¹

To address CCNE1 overexpression, investigators sought to elicit synthetic lethality with CDK2. “Cyclin E is a critical regulator of cell cycle progression in normal cells, cyclin E is bound to its in complex with its partner serine/threonine protein kinase CDK2, which phosphorylates the tumor suppressor [phosphorylation of retinoblastoma] Rb, resulting in E2F target gene activation and cell cycle progression from G1/S phase,” Chand said. “In dysregulated cancer cells, hyper activation of CDK2/cyclin E drives CDK2 dependency. Therefore, patients with high cyclin E expression are synthetically lethal with CDK2 inhibition and may benefit from CDK2-targeted therapy.”

INCB123667 has been assessed a potential candidate to inhibit CDK2 and have limited off-target effects.^1,5 In a preclinical, biochemical analysis, the small molecule showed selectivity for CDK2 with limited to no activity against CDK1, CDK4, CDK6, CDK7, and CDK9. Further, INCB123667 blocks G1/S transition in CCNE1-high cells through inhibition of Rb, which is a key regulator.⁵

In an in vivo validation, investigators evaluated dosing palbociclib (75 mg/kg) vs INCB123667 (30 mg/kg) in HCC1569, a hormone receptor–negative, HER2-positive epithelial breast cancer cell line, which has elevated expression of cyclin E. Over the course of 28 days tumor growth inhibition with palbociclib was 34% compared with 66.5% with INCB123667. “This highlights the efficacy of CDK2 inhibition in a cyclin E–high breast tumor model,” Chand said.

“In addition to cyclin E overexpression, loss of Rb has been implicated by multiple preclinical studies to be a driver of resistance to CDK4/6 inhibition,” Chand explained, adding that another analysis looked at a panel of 50 cyclin E–high cell lines and evaluated the response to palbociclib and abemaciclib (Verzenio). “We validated that Rb-mutant cells do not respond to palbociclib and CDK2 inhibitor is active in both Rb-mutant and RB wild-type cells,” she said.

In the NCI-H526, Rb-mutant in vivo tumor model, INCB123667 inhibited tumor growth vs palbociclib.¹

A phase 1a/b clinical trial (NCT05238922) has been initiated to evaluate INCB123667 as monotherapy for the treatment of patients with CCNE1 high advanced malignancies. The dose-escalation phase will determine the recommended dose for expansion and the maximum-tolerated dose. This will be followed by a dose-expansion phase to explore INCB123667 in tumor-specific cohorts including TNBC; hormone receptor–positive, HER2-negative breast cancer following progression or intolerance of CDK4/6 treatment; ovarian/fallopian/primary peritoneal cancer; endometrial/uterine cancer; gastrointestinal malignancies; and other tumor-agnostic indications.⁶

The primary end points focus on toxicity, including incidence of treatment-emergent adverse events, as well as the dose limitations, reductions, interruptions, and discontinuations associated with them. Secondary end points include pharmacokinetics, objective response rate, disease control response, and duration of response.

Recruitment is ongoing with an estimated enrollment of approximately 155 patients.⁶

Editor’s Note: Saswati Chand, PhD, reports the following financial disclosures: Employee of and stockholder in Incyte Corporation.

References

1. Chand S, Hansbury M, Lo Y, et al. Development of a CDK2-selective small molecule inhibitor INCB123667 for the treatment of CCNE1hi breast cancers. Cancer Res. 2023;83(suppl 7):1143. doi:10.1158/1538-7445.AM2023-1143
2. Turner N, Liu Y, Zhu Z, et al. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2019;37(14):1169-1178. doi:10.1200/JCO.18.00925
3. Zhao ZM, Yost SE, Hutchinson KE, et al. CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer. BMC Cancer. 2019;19(1):96. doi:10.1186/s12885-019-5290-4
4. Yuan Q, Zheng L, Liao Y, Wu G. Overexpression of CCNE1 confers a poorer prognosis in triple-negative breast cancer identified by bioinformatic analysis. World J Surg Oncol. 2021;19(1):86. doi:10.1186/s12957-021-02200-x
5. Wee S, Ye M, Lo Y, et al. Discovery of INCB123667, a potent and selective cyclin-dependent kinase 2 (CDK2) inhibitor for the treatment of cyclin E dysregulated cancers. Eur J Cancer. 2022;174(suppl 1):S79. doi:10.1016/S0959-8049(22)01010-3
6. Study of INCB123667 in subjects with advanced solid tumors. ClinicalTrials.gov. Updated April 11, 2023. Accessed April 16, 2023. https://clinicaltrials.gov/ct2/show/NCT05238922