Dalpiciclib plus chidamide in HR+/HER2- advanced breast cancer following CDK4/6 inhibitor treatment failure: Final results of a phase Ib trial.

e13071 Background: There is currently no standard treatment for patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (BC) after prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment failure. Histone deacetylase inhibitors (HDACi) can decrease cellular myelocytomatosis oncogene (c-MYC) accumulation due to the inactivation of CDK4/6 and have a synergistic effect with CDK inhibitors to enhance the inhibition of tumor proliferation. Our previous study showed that HDACi combined with endocrine therapy may be an sequential strategy. This study aims to explore the optimal dose of dalpiciclib plus chidamide after CDK4/6i treatment failure in HR+/HER2- BC, and to evaluate the safety and efficacy. Methods: This study is a single-arm, open-label, phase Ib, dose escalation study. All enrolled patients with HR+/HER2- locally recurrent or metastatic BC received ≤1 prior line of chemotherapy in an advanced setting and CDK4/6i therapy failure. Eligible patients were assigned to 4 groups according to the Bayesian optimal interval design (BOIN) to receive dalpiciclib and chidamide (Group A, 125 mg dalpiciclib per day and chidamide 25 mg twice a week [BIW]; Group B, dalpiciclib 125 mg/d, chidamide 20 mg BIW; Group C, dalpiciclib 100 mg/d, 25 mg chidamide BIW; Group D, dalpiciclib 100 mg/d, chidamide 20 mg BIW). The primary endpoint was maximum tolerated dose (MTD). The secondary endpoints were objective response rate (ORR), progression-free survival (PFS), and safety analysis. This study is registered with ClinicalTrials.gov, NCT05586841. Results: A total of 22 patients were enrolled in this study (Group A, n = 4; Group B, n = 3; Group C, n = 12; Group D, n = 3). Dose-limiting toxic reactions were observed in 3 patients (Group A, n = 1; Group C, n = 2), all with Grade 4 thrombocytopenia, and the MTD was established as Group C (dalpiciclib 100 mg/d, chidamide 25 mg BIW). The most common grade 3-4 AEs were neutropenia (100%, 22/22), leukopenia (64%, 14/22) and thrombocytopenia (32%, 7/22). The ORR was 9.1% in all patients and 16.7% in Group C. The median PFS was 5.8 months (95% CI: 2.2-9.99) in all patients and 12.3 months (95% CI: 2-17.15) in Group C. The next-generation sequencing (NGS) results showed that PIK3CA mutation was detected in 8 (57%) of 14 patients, ESR1 mutation in 4 patients (29%) and TP53 mutation in 4 patients (29%). Compared to patients with genetic mutations, a trend toward improved PFS was observed in wild-type patients. Conclusions: Our results revealed that dalpicilib plus chidamide achieved promising efficacy and safety in HR+/HER2- BC. The combination of dalpiciclib and chidamide may serve as an alternative treatment strategy in HR+/HER2- BC patients following CDK4/6i therapy failure. Clinical trial information: NCT05586841 .