Dalpiciclib and chidamide in patients with HR+/HER2- advanced breast cancer and resistance to CDK4/6 inhibitors: A phase Ib trial.

e13072 Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) as first or second-line therapy could improve PFS and OS for patients with HR-positive/HER2-negative breast cancer. However, the standard treatment for patients who have failed CDK4/6 inhibitors has not been established. Histone deacetylase inhibitors (HDACi) inhibit the proliferation of tumor cells through a variety of ways, such as improving the expression level of p21 and other genes. In China, dalpiciclib (a CDK4/6 inhibitor) in combination with ET has been approved for patients with metastatic HR-positive/HER2-negative breast cancer. Chidamide (an HDAC inhibitor) has been approved for the treatment of metastatic HR-positive/HER2-negative breast cancer. The investigator's previous retrospective study has shown that chidamide combined with ET may be an optional sequential strategy for patients who have progressed on CDK4/6 Inhibitor. The aim of this study was to explore the efficacy and safety of dalpiciclib in combination with chidamide in locally advanced or metastatic HR+/HER2- breast cancer patients who have failed CDK4/6 inhibitors (NCT 05586841). Methods: This study is a single-arm, open-label, prospective, phase Ib, dose escalation clinical trial. Before entering this trial, all patients with HR-positive/HER2-negative locally recurrent or metastatic breast cancer (MBC) must have received ≤1 previous line of chemotherapy for MBC, and have failed CDK4/6 inhibitor therapy. The primary endpoint is maximum tolerated dose (MTD) of dalpiciclib in combination with chidamide. Patients were assigned to four groups to receive dalpiciclib and chidamide (Group A: dalpiciclib 125mg/d and chidamide 25mg/BIW; Group B: dalpiciclib 125mg/d and chidamide 20mg/BIW; Group C: dalpiciclib 100 mg/d and chidamide 25mg/BIW; Group D: dalpiciclib 100 mg/d and chidamide 20mg/BIW). Results: Fourteen patients were enrolled between 19/1/2023 and 30/1/2024 (Group A, N=4; Group B, N=3; Group C, N=4; Group D, N=3). All the patients were received ≥ 1 line CDK4/6 inhibitors and 11 patients (78.6%) received chemotherapy in advanced breast cancer. Two patients experienced dose-limiting toxicities (DLT, Group A, n=1; Group B, n=1). The incidence of adverse events of any grade was 100%. The most frequent grade 3-4 adverse events were neutropenia (100%) and thrombocytopenia (35.7%). The median follow-up was 251 days (range, 188.486-313.514), and median PFS was 201 days (95%CI: 158.49-243.51). 2 of 14 patients achieved partial response (PR; Group C, n=2), 10 of 14 patients achieved stable disease (SD) and 2 of 14 had progressive disease (PD; Group A, n=2). In this study, dose group C was identified as recommended phase II dose (RP2D). Conclusions: The combination of dalpiciclib and tucidinostat is an alternative treatment strategy in patients who have failed CDK4/6 inhibitors. Clinical trial information: NCT05586841 .