编者按：哌柏西利（帕柏西利）为首个细胞周期蛋白依赖型激酶4和6（CDK4/6）抑制剂，可以阻止乳腺癌细胞有丝分裂周期由DNA合成前期（G1期）进入DNA合成期（S期）。2015年，根据PALOMA-1研究结果，哌柏西利联合来曲唑一线治疗雌激素受体阳性HER2阴性晚期乳腺癌，可以显著延长患者的无进展生存（20.2比10.2个月，P = 0.0004），哌柏西利首先获得美国加速批准。2016年，根据PALOMA-3研究结果，哌柏西利联合氟维司群二线治疗对内分泌疗法耐药的雌激素受体阳性HER2阴性转移性乳腺癌，可以显著延长患者的无进展生存（9.5比4.6个月，P < 0.0001），哌柏西利再次获得美国补充批准。2018年，辉瑞的哌柏西利（中文商品名：爱博新）或将获得中国有关部门批准，而大量哌柏西利国产仿制药也正蓄势待发。
2018年5月16日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表比利时荷语天主教鲁汶大学医院的研究报告，调查了哌柏西利联合内分泌疗法对于绝经后转移性乳腺癌至少四线治疗失败女性的作用。
该研究于2015年9月28日～2017年3月14日在比利时荷语天主教鲁汶大学医院开展了辉瑞（哌柏西利生产商）免费提供的爱心用药计划（又称特许慈善用药项目），入选至少四线全身治疗失败的绝经后雌激素受体阳性HER2阴性转移性乳腺癌女性82例（中位年龄67.1岁，范围34.8～85.9岁）接受哌柏西利联合内分泌疗法（来曲唑73例、他莫昔芬2例、氟维司群3例、依西美坦1例、阿那曲唑1例、甲地孕酮2例）并且接受至少6个月随访，进行有效性和安全性分析。主要研究终点指标为哌柏西利联合内分泌疗法的临床获益，定义为接受治疗后疾病稳定≥6个月。次要研究终点指标为毒性反应和临床获益的潜在预测因素。
结果，治疗时间平均5.6个月（范围1～19个月），中位无进展生存3.17个月（95%置信区间：2.76～4.70）。数据截止时，10例患者仍在接受哌柏西利治疗。
对于这些至少4种（至多达11种）全身治疗方案失败的患者，其中：
疾病稳定≥ 6个月34例（41.5%）
疾病稳定≥ 9个月17例（20.7%）
疾病稳定≥12个月11例（13.4%）
所调查的预测因素与6个月时临床获益均无显著相关性。治疗推迟或剂量减少的患者占43.9%。
因此，对于多种治疗失败后的雌激素受体阳性HER2阴性转移性乳腺癌患者，哌柏西利联合内分泌疗法的临床获益率高于既往其他治疗方案研究结果，并且安全性良好。
相关阅读
Breast Cancer Res Treat. 2018 May 16.
Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer.
G. Hoste, K. Punie, H. Wildiers, B. Beuselinck, I. Lefever, E. Van Nieuwenhuysen, S. N. Han, P. Berteloot, N. Concin, R. Salihi, I. Vergote, P. Neven.
Multidisciplinary Breast Center, UZ Leuven, Leuven, Belgium.
PURPOSE: We aimed to investigate the role of palbociclib, a first-in-class cyclin-dependent kinase 4 and 6 inhibitor, in postmenopausal women with highly pretreated endocrine therapy-resistant metastatic breast cancer (MBC).
METHODS: Between 28 September 2015 and 14 March 2017, a compassionate use program was established in the University Hospitals Leuven in which 82 postmenopausal women with estrogen receptor-positive, HER2-negative MBC were included after at least four lines of systemic treatment. The efficacy and safety analysis was performed in 82 patients who had received at least one dose of palbociclib and who had at least 6-month follow-up at the data cut-off point. The primary objective was the evaluation of efficacy of the combination of palbociclib and endocrine therapy with clinical benefit as primary endpoint, defined as the absence of progressive disease and being on treatment for at least 6 months. Secondary objectives were the evaluation of toxicity and the identification of potential predictors for clinical benefit.
RESULTS: The median age of the patients was 67.1 years (range 34.8-85.9) at the time of inclusion. The average duration of treatment was 5.6 months (range 1-19), with a median progression-free survival of 3.17 (95% CI 2.76-4.70) months. At the data cut-off point, 10 patients were still on treatment with palbociclib. In this highly pretreated setting, 34 patients experienced no progressive disease within 6 months, resulting in an overall clinical benefit rate (CBR) of 41.5%. 20.7% (17/82) showed stable disease for ≥9 months and 13.4% for ≥12 months. None of the investigated predicting factors were significantly associated with clinical benefit at 6 months. For 43.9% of the patients, treatment delay or dose reduction was indicated.
CONCLUSIONS: Palbociclib in combination with endocrine therapy shows an unexpectedly high CBR and favorable safety profile in heavily pretreated endocrine-resistant estrogen receptor-positive, HER2-negative MBC patients.
KEYWORDS: Palbociclib; Compassionate use program; Highly pretreated metastatic breast cancer
DOI: 10.1007/s10549-018-4827-6
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