Zhang J, Liu R, Gao S, Chen W, Han X, Wang Z, Zhou H, Wang Y, Chen J, Ma Y, Liu K, Shen Z, Ding L, Li P, Hu X
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, China.
ESMO Open. 2025 May 21;10(6):105121. doi: 10.1016/j.esmoop.2025.105121.
Tibremciclib (BPI-16350) is a novel potent selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6). This phase I, first-in-human study assessed the tibremciclib monotherapy and combined with fulvestrant in advanced breast cancer (ABC).
This open-label, phase I study (NCT03791112) comprised dose escalation (phase Ia) and expansion (phase Ib). In phase Ia, Chinese patients with advanced solid tumors received tibremciclib monotherapy (50-500 mg orally once daily). Based on the tolerability and preliminary antitumor activity from phase Ia, two dose cohorts (300 or 400 mg orally once daily) were selected in phase Ib to combine with fulvestrant in patients with hormone receptor (HR)-positive/human epidermal growth receptor 2 (HER2)-negative ABC who failed endocrine therapy. The primary endpoints were safety and tolerability, and secondary endpoints included pharmacokinetics (PK) and antitumor activity.
In phase Ia, 24 patients with advanced tumors (23 ABC and 1 abdominal liposarcoma) received tibremciclib monotherapy, while in phase Ib, 78 patients with HR-positive/HER2-negative stage IV ABC received tibremciclib plus fulvestrant, with a median age of 56.0 (range 26-66) years and 53.5 (range 33-71) years, respectively. In phase Ia, one dose-limiting toxicity (grade 3 blood creatinine increased) occurred at 500 mg and the maximum tolerated dose was not reached. In phase Ib, the recommended phase II dose (RP2D) was tibremciclib 400 mg plus fulvestrant 500 mg. Frequently reported treatment-emergent adverse events of any grade were grade 1-2 blood creatinine increased, hypertriglyceridemia, and anemia. PK demonstrates dose proportionality, a half-life of ∼35.9-51.1 h, and no drug-drug interaction with fulvestrant. In phase Ia, one patient achieved partial response (PR), with a confirmed objective response rate (ORR) of 4.2% and a disease control rate (DCR) of 70.8%. In phase Ib, 42 patients achieved PR, with an ORR of 53.8% and a DCR of 87.2%.
Tibremciclib monotherapy or combined with fulvestrant was well tolerated with the RP2D set at 400 mg plus fulvestrant 500 mg. PK was consistent with dose proportionality. Both regimens showed preliminary antitumor activity in patients with HR-positive/HER2-negative ABC, supporting further evaluation in a phase III study (NCT05433480).
替瑞麦西利（BPI-16350）是一种新型强效细胞周期蛋白依赖性激酶4和6（CDK4/6）选择性抑制剂。这项I期人体首次研究评估了替瑞麦西利单药疗法以及与氟维司群联合用于晚期乳腺癌（ABC）的疗效。
这项开放标签的I期研究（NCT03791112）包括剂量递增（Ia期）和扩展（Ib期）。在Ia期，中国晚期实体瘤患者接受替瑞麦西利单药治疗（口服50 - 500 mg，每日一次）。基于Ia期的耐受性和初步抗肿瘤活性，在Ib期选择了两个剂量组（口服300或400 mg，每日一次）与氟维司群联合，用于接受过内分泌治疗失败的激素受体（HR）阳性/人表皮生长因子受体2（HER2）阴性ABC患者。主要终点是安全性和耐受性，次要终点包括药代动力学（PK）和抗肿瘤活性。
在Ia期，24例晚期肿瘤患者（23例ABC和1例腹部脂肪肉瘤）接受了替瑞麦西利单药治疗，而在Ib期，78例HR阳性/HER2阴性IV期ABC患者接受了替瑞麦西利加氟维司群治疗，中位年龄分别为56.0（范围26 - 66）岁和53.5（范围33 - 71）岁。在Ia期，500 mg时发生1例剂量限制性毒性（3级血肌酐升高），未达到最大耐受剂量。在Ib期，推荐的II期剂量（RP2D）为替瑞麦西利400 mg加氟维司群500 mg。任何级别常见的治疗中出现的不良事件为1 - 2级血肌酐升高、高甘油三酯血症和贫血。PK显示剂量成正比，半衰期约为35.9 - 51.1小时，与氟维司群无药物相互作用。在Ia期，1例患者达到部分缓解（PR），确认的客观缓解率（ORR）为4.2%，疾病控制率（DCR）为70.8%。在Ib期，42例患者达到PR，ORR为53.8%，DCR为87.2%。
替瑞麦西利单药治疗或与氟维司群联合耐受性良好，RP2D设定为替瑞麦西利400 mg加氟维司群500 mg。PK与剂量成正比。两种方案在HR阳性/HER2阴性ABC患者中均显示出初步抗肿瘤活性。支持在III期研究（NCT05433480）中进行进一步评估。
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