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CDK4/6 抑制剂联合芳香化酶抑制剂对比联合氟维司群一线治疗 HR+/HER2- 晚期乳腺癌的疗效和安全性研究

Efficacy and safety of CDK4/6i combined with AI versus Fulvestrant as first-line therapy in patients with HR+/HER2- metastatic breast cancer

    摘要
  • 摘要:
    背景　在激素受体阳性(hormone receptor positive，HR+)/HER2阴性(HER2-)乳腺癌晚期一线解救治疗中，细胞周期依赖性激酶4/6(cyclin-dependent kinase 4/6，CDK4/6)抑制剂最佳内分泌药物配伍方案尚不明确。目的　对比CDK4/6抑制剂联合芳香化酶抑制剂(aromatase inhibitors，AI)或联合氟维司群作为一线解救治疗方案，在HR+/ HER2- 晚期乳腺癌患者中的疗效及安全性。方法　纳入2018年10月— 2024年6月于解放军总医院第五医学中心确诊为HR+/HER2-晚期乳腺癌患者，根据其一线解救治疗方案，分为AI联合组(CDK4/6抑制剂联合AI)和氟维司群联合组(CDK4/6抑制剂联合氟维司群)。主要研究终点为无进展生存期(progression free survival，PFS)，次要研究终点包括客观缓解率(objective response rate，ORR)、临床获益率(clinical benefit rate，CBR)和安全性。结果 202例HR+/HER2- 晚期乳腺癌患者(AI联合组102例，中位年龄51岁；氟维司群联合组100例，中位年龄53岁)纳入分析。AI联合组与氟维司群联合组的ORR(32.4% vs 28.0%，P=0.500)、CBR (83.3% vs 81.0%，P=0.665)及中位PFS (18.0 vs 13.0)个月(HR=0.75，95% CI：0.54 ~ 1.03，P=0.067)差异均无统计学意义。亚组分析提示，无病间隔期(disease-free interval，DFI)≥24个月的患者中，AI联合组中位PFS优于氟维司群联合组(19.0 vs 13.0)个月(HR=0.64，95% CI：0.44 ~ 0.94，P=0.019)，组间比较差异有统计学意义。AI联合组与氟维司群两组中，最常见的不良反应为中性粒细胞减少(72.5% vs 70.0%)、白细胞减少(70.6% vs 69.0%)和贫血(38.2% vs 29.0%)，最常见的3/4级不良事件为中性粒细胞减少(35.3% vs 38.0%)。25例患者(12.4%)因不良反应在治疗过程中下调了CDK4/6抑制剂或内分泌药物的剂量，AI 联合组与氟维司群联合组剂量下调率(6.9% vs 18.0%)，组间比较差异有统计学意义(P=0.016)。结论　在 HR+/HER2-晚期乳腺癌一线解救治疗时，AI或氟维司群均为CDK4/6抑制剂可选择的内分泌配伍方案，且安全性良好。对于DFI≥24 个月的患者，CDK4/6 抑制剂联合 AI 可能获得更好的疗效，且这种联合治疗方案能维持 CDK4/6 抑制剂靶向治疗的剂量。

     

    Abstract:
    Abstract: Background In the first-line salvage treatment of advanced hormone receptor positive (HR+)/HER2 negative (HER2-) breast cancer, the optimal endocrine combination regimen for CDK4/6 inhibitors (CDK4/6i) remains unclear. Objective To compare the efficacy and safety of CDK4/6i combined with aromatase inhibitors (AI) or Fulvestrant as first-line salvage therapy in patients with HR+ /HER2- advanced breast cancer.Methods Patients diagnosed with HR+/HER2- advanced breast cancer at the Fifth Medical Center of Chinese PLA General Hospital from October 2018 to June 2024 were enrolled. Based on the first-linesalvage therapy regimen, patients were divided into AI combination group (CDK4/6i combined with AI) and Fulvestrant combination group (CDK4/6i combined with Fulvestrant). The primary endpoint was progression-free survival (PFS), and secondary 
    endpoints included objective response rate (ORR), clinical benefit rate (CBR), and safety. Results Totally 202 patients were enrolled, with 102 cases in the AI combination group and 100 cases in the Fulvestrant combination group. There were no statistically significant differences in ORR (32.4% vs 28.0%, P=0.500), CBR (83.3% vs 81.0%, P=0.665) and the median PFS (18.0 vs 13.0 months, HR=0.75, 95% CI: 0.54-1.03, P=0.067) between the AI combination group and the Fulvestrant combination group. In patients whose DFI≥24 months, the median PFS was 19 months in the AI combination group, which was superior to 13 months in the Fulvestrant combination group (HR=0.64, 95% CI: 0.44-0.94, P=0.019). The most common adverse events in the AI and Fulvestrant combination groups were neutropenia (72.5% vs 70.0%), leukopenia (70.6% vs 69.0%), and anemia (38.2% vs 29.0%). The most common grade 3/4 adverse events were neutropenia (35.3% vs 38.0%). There were 25 patients (12.4%) showing a dose reduction of CDK4/6i or endocrine drugs due to adverse events, and the dose reduction rate was 6.9% in the AI combination group and 18.0% in the Fulvestrant combination group, with statistically significant difference (P=0.016). Conclusion In first-line salvage therapy for HR+/HER2- advanced breast cancer, both AI and Fulvestrant are viable endocrine combination options with CDK4/6 inhibitors, exhibiting good safety profiles. For patients whose DFI≥24 months, the combination of CDK4/6i and AI may achieve better efficacy, and this combined regimen can maintain the targeted therapy dose of CDK4/6i.

     

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