根据PALOMA-1、2、3研究结果，已经证实细胞周期蛋白依赖型激酶（CDK）4/6抑制剂哌柏西利可以可以显著延长激素受体阳性HER2阴性晚期乳腺癌内分泌治疗的无进展生存。不过，哌柏西利对于早期乳腺癌术后内分泌辅助治疗的效果尚不明确。
6月28日，欧洲肿瘤内科学会《肿瘤学报》在线发表美国哈佛大学医学院达纳法伯癌症研究所、贝斯以色列和新英格兰女执事医疗中心、麻省总医院癌症中心、宾夕法尼亚大学艾布拉姆森癌症中心、加利福尼亚大学旧金山分校迪勒家族综合癌症中心、印第安纳大学医学院西蒙癌症中心、辉瑞纽约总部的研究报告，探讨了激素受体阳性HER2阴性早期乳腺癌术后哌柏西利＋内分泌辅助治疗的可行性。
NCT02040857: A Study of Palbociclib in Combination With Adjuvant Endocrine Therapy for Hormone Receptor Positive, HER2 Negative Invasive Breast Cancer (A Phase 2 Pilot Feasibility Study of Palbociclib in Combination With Adjuvant Endocrine Therapy for Hormone Receptor Positive Invasive Breast Carcinoma)
该多中心II期单组非盲可行性临床研究于1月～12月入组符合条件的激素受体阳性HER2阴性II～III期乳腺癌术后患者162例（其中III期占52%、已经接受化疗占80%）接受2年哌柏西利（每天125毫克，每3周停1周）联合内分泌辅助治疗。主要终点为由于毒性反应、不依从性或耐受性相关事件停用哌柏西利。预设停用率≥48%表明持续治疗2年不可行，并且通过二项式检验单侧α=0.025进行评估。
结果，完成2年哌柏西利患者共计102例（63%）；由于治疗方案相关原因提前停药患者50例（31%，95%置信区间：24%～39%，P=0.001），由于治疗方案无关原因停药患者10例。治疗开始12个月时，治疗方案相关停药发生率累计21%（95%置信区间：14%～27%）。
早期乳腺癌哌柏西利相关毒性反应发生率与晚期乳腺癌经验一致，并且无发热性中性粒细胞减少病例。需要至少一次剂量减少患者91例（56%）。
因此，该研究结果表明，早期乳腺癌术后哌柏西利辅助治疗可行，大多数患者能够完成2年治疗。早期乳腺癌术后辅助治疗安全性特征符合了晚期乳腺癌所见，大约一半患者需要剂量调整。由于延长哌柏西利辅助治疗持续时间对于大多数患者似乎可行并且可耐受，III期随机对照研究正在评估该人群的临床获益。
NCT02513394: PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer (PALLAS)
NCT01864746: A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery (PENELOPE-B)
Ann Oncol. Jun 28. [Epub ahead of print]
A Phase II Feasibility Study of Palbociclib in Combination with Adjuvant Endocrine Therapy for Hormone Receptor Positive Invasive Breast Carcinoma.
Mayer EL, DeMichele A, Rugo HS, Miller K, Waks AG, Come SE, Mulvey T, Jeselsohn R, Overmoyer B, Guo H, Barry WT, Bartlett CH, Koehler M, Winer EP, Burstein HJ.
Dana-Farber Cancer Institute, Boston, USA; Beth Israel Deaconess Medical Center, Boston, USA; Massachusetts General Hospital Cancer Center, Boston, USA; University of Pennsylvania Abramson Cancer Center, Philadelphia, USA; University of California San Francisco Diller Comprehensive Cancer Center, San Francisco, USA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, USA; Pfizer, Inc., New York, USA.
BACKGROUND: The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer.
PATIENTS AND METHODS: Eligible patients with HR+/HER2- stage II-III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary endpoint was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of two years was not feasible, and was evaluated under a binomial test using a one-sided alpha=0.025.
RESULTS: Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95%CI 24-39%, p = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95%CI 14-27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction.
CONCLUSION: Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population.
CLINICALTRIALS.GOV REGISTRATION: NCT02040857
KEYWORDS: breast cancer, palbociclib, adjuvant endocrine therapy, CDK4/6 inhibitor, feasibility, hormone receptor positive
PMID: 31250880
DOI: 10.1093/annonc/mdz198
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