Dalpiciclib plus chidamide in HR + /HER2-advanced breast cancer after CDK4/6 inhibitor failure: a phase Ib trial.

The optimal therapy after cyclin‑dependent kinase 4/6 inhibitor (CDK4/6i) failure in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 - ) advanced breast cancer (BC) remains undefined. In this study, we demonstrate that dalpiciclib combined with chidamide exerted synergistic antitumor effects in estrogen receptor-positive (ER + )/HER2 - BC cell lines and patient-derived organoids, providing a rationale for subsequent clinical evaluation. We conducte a single‑arm, phase Ib, Bayesian optimal interval dose‑escalation study (NCT05586841) evaluating dalpiciclib plus chidamide across four groups [A, 125 mg dalpiciclib mg/d and chidamide 25 mg twice a week (BIW); B, dalpiciclib 125 mg/d, chidamide 20 mg BIW; C, dalpiciclib 100 mg/d, 25 mg chidamide BIW; D, dalpiciclib 100 mg/d, chidamide 20 mg BIW]. The primary endpoint is maximum tolerated dose (MTD), and the secondary endpoints are objective response rate (ORR), progression‑free survival (PFS), disease control rate and safety. Among 22 enrolled patients, dose‑limiting toxicities occur in 3 patients, and the MTD is identified as group C. Grade 3-4 adverse events include neutropenia (100%), leukopenia (64%), and thrombocytopenia (36%). The ORR is 9.1% overall and 16.7% at the MTD, with median PFS of 5.8 months overall and 12.3 months at the MTD. Patients with PIK3CA mutations have shorter mPFS [5.04 months; 95% CI: 2.0-not estimable (NE)] compared to those with wild type (9.25 months; 95% CI: 1.97-NE). Here we show that dalpiciclib plus chidamide has manageable safety and preliminary antitumor activity in HR + /HER2- advanced BC following CDK4/6i failure.