HDAC inhibitor tucidinostat and metronomic capecitabine plus endocrine therapy for patients with HR-positive HER2-negative advanced breast cancer after CDK4/6 inhibitors treatment: clinical findings and exploratory circulating tumor cell and ctDNA biomarker analyses of a multicenter, phase 2 study (SYSUCC-020 trial)

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Median progression-free survival: 5.39 months overall

• Primary Outcome: Objective response rate: 25.8% (17 partial responses)

• Nnt Or Sensitivity: Biomarker associations: TP53 wild-type vs mutated (7.64 vs 3.55 months PFS); CTC-negative vs positive (7.59 vs 3.78 months PFS)

• Confidence Interval: 95% CI: 4.07-7.69 months (overall); Cohort 1: 4.76-12.22 months; Cohort 2: 2.79-7.59 months

Clinical Application

Requires access to tucidinostat (HDAC inhibitor) and expertise in metronomic chemotherapy dosing. Biomarker testing for TP53 and CTC may guide patient selection. Tucidinostat not currently PBS-listed in Australia. Would require special access scheme or clinical trial participation. Capecitabine and endocrine therapies are PBS-available. NCCN and ESMO guidelines support combination approaches post-CDK4/6i progression. Patients with HR-positive, HER2-negative advanced breast cancer who have progressed on CDK4/6 inhibitor therapy

Abstract

Treatment options for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that progresses after CDK4/6 inhibitor (CDK4/6i) continue to evolve, and no single regimen has been established as the preferred standard of care. We conducted a phase 2 trial (SYSUCC-020, NCT05411380) to investigate the efficacy and safety of a novel combination of tucidinostat and metronomic capecitabine (mCAP) with endocrine therapy (ET) in patients following progression on CDK4/6i. This trial adopted a Simon two-stage design: eligible patients received tucidinostat plus metronomic capecitabine together with either an aromatase inhibitor (Cohort 1) or fulvestrant (Cohort 2), selected according to prior ET. Seventy-two female patients were screened and sixty-six patients were included in the efficacy and safety analyses. The median follow-up was 13.88 months (Interquartile range, 8.67-20.67) and the objective response rate was 25.8%, with 17 partial responses. The median progression-free survival (PFS) was 5.39 months (95% CI, 4.07-7.69), namely 6.93 months (95% CI, 4.76-12.22) in Cohort 1 and 3.98 months (95% CI, 2.79-7.59) in Cohort 2. Most patients (93.9%) experienced at least one adverse event. In addition, exploratory analyses of biomarkers indicated that the baseline TP53 mutation status (Wild type vs. mutated, 7.64 months vs. 3.55 months) and circulating tumor cell (CTC) status (CTC-negative vs. CTC-positive, 7.59 months vs. 3.78 months) were associated with the median PFS. Our study demonstrated that tucidinostat combined with mCAP and ET is efficacious and well-tolerated in patients with HR-positive HER2-negative ABC previously treated with CDK4/6i.

References

1. 1.Wu, H. L., Xia, W., Xu, Z., Zhou, H., Chen, L., Lu, Y., Liu, X., Pang, D., Liu, Y., Lu, Q., Xu, F., An, X., Huang, J., Jiang, K., Zhang, J., Cai, Y., Hong, R., Zheng, Q., & Wang, S. (2026). HDAC inhibitor tucidinostat and metronomic capecitabine plus endocrine therapy for patients with HR-positive HER2-negative advanced breast cancer after CDK4/6 inhibitors treatment: Clinical findings and exploratory circulating tumor cell and ctDNA biomarker analyses of a multicenter, phase 2 study (SYSUCC-020 trial). Signal Transduction and Targeted Therapy. https://doi.org/10.1016/j.ejca.2008.10.026