Preliminary results of a randomized phase II trial of chidamide plus fulvestrant with or without sintilimab in HR+/HER2- advanced breast cancer after progression on CDK4/6 inhibitors (CISFORT).

Abstract

e13051 Background: Chidamide is a subtype-selective histone deacetylase (HDAC) inhibitor that has demonstrated clinical activity in hormone receptor–positive (HR+)/HER2-negative (HER2−) advanced breast cancer (aBC). Previous studies suggest that chidamide enhances tumor immunogenicity and synergizes with PD-1 blockade. This study evaluated the efficacy and safety of chidamide plus fulvestrant with or without sintilimab (a PD-1 inhibitor) in patients with HR+/HER2− aBC. Methods: This was a randomized, multi-center, phase II study enrolling patients with HR+/HER2− aBC who experienced disease progression after CDK4/6 inhibitor–based endocrine therapy and had received no more than one prior line of chemotherapy in the advanced setting. Patients were randomized 1:1 to receive either chidamide plus fulvestrant (Arm A) or chidamide plus fulvestrant in combination with sintilimab (Arm B). Treatment consisted of chidamide 30 mg orally twice weekly, fulvestrant 500 mg intramuscularly every 4 weeks (after loading doses), and sintilimab 200 mg intravenously every 3 weeks (Arm B only). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. (www.chictr.org.cn, #ChiCTR2200058570). Results: By July 2025, 17 patients had been enrolled (Arm A, n = 9; Arm B, n = 8). The median age was 52 years; 59% had visceral metastases; 82% had received prior chemotherapy; and the median duration of prior CDK4/6 inhibitor therapy was 12.99 months. At a median follow-up of 40.2 months, 15 patients experienced disease progression (Arm A, n = 8; Arm B, n = 7), and 9 patients died (Arm A, n = 4; Arm B, n = 5). Median PFS was 3.5 months in Arm A and 1.3 months in Arm B (Arm A vs. Arm B, hazard ratio [HR], 0.26; 95% CI, 0.08–0.81; p = 0.014). Median OS was 19.04 months in both arms (Arm A vs. Arm B, HR, 0.59; 95% CI, 0.16–2.12; P = 0.415). No objective responses were observed. DCR was 57.1% in Arm A and 25.0% in Arm B ( p = 0.559). Grade ≥3 adverse events occurred in 33.3% and 37.5% of patients in Arms A and B, respectively. One case of immune-related pneumonitis was reported in Arm B. Conclusions: In this preliminary analysis of patients with HR+/HER2− aBC progressing after CDK4/6 inhibitor therapy, the addition of sintilimab to chidamide plus fulvestrant did not improve progression-free survival. Safety was manageable with no new toxicity signals identified. Further follow-up and enrollment are ongoing. Clinical trial information: ChiCTR2200058570. Clinical trial information: ChiCTR2200058570 .