Wander Seth A, Han Hyo S, Zangardi Mark L, Niemierko Andrzej, Mariotti Veronica, Kim Leslie S L, Xi Jing, Pandey Apurva, Dunne Siobhan, Nasrazadani Azadeh, Kambadakone Avinash, Stein Casey, Lloyd Maxwell R, Yuen Megan, Spring Laura M, Juric Dejan, Kuter Irene, Sanidas Ioannis, Moy Beverly, Mulvey Therese, Vidula Neelima, Dyson Nicholas J, Ellisen Leif W, Isakoff Steven, Wagle Nikhil, Brufsky Adam, Kalinsky Kevin, Ma Cynthia X, O'Shaughnessy Joyce, Bardia Aditya
1Massachusetts General Hospital Cancer Center, and.
2Harvard Medical School, Boston, Massachusetts.
J Natl Compr Canc Netw. 2021 Mar 24:1-8. doi: 10.6004/jnccn.2020.7662.
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i.
We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers.
In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib.
A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.
细胞周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）被广泛用作激素受体阳性转移性乳腺癌（HR+MBC）的一线治疗药物。虽然阿贝西利单药疗法也被美国食品药品监督管理局批准用于治疗内分泌治疗后疾病进展的情况，但对于阿贝西利在先前接受CDK4/6i治疗后疾病进展的临床活性了解有限。
我们从美国6个癌症中心识别出HR+MBC患者，这些患者在先前接受CDK4/6i治疗疾病进展后接受了阿贝西利治疗，并提取了临床特征、结局、毒性和预测性生物标志物。
在多中心队列中，阿贝西利在先前基于CDK4/6i（哌柏西利）的治疗疗程后耐受性良好；少数患者因毒性而非疾病进展停用阿贝西利（9.2%）。在哌柏西利治疗进展后，大多数患者（71.3%）接受了与阿贝西利的非序贯治疗（使用≥1种中间的非CDK4/6i方案），大多数患者接受阿贝西利联合抗雌激素药物（氟维司群，47.1%；芳香化酶抑制剂，27.6%），其余患者接受阿贝西利单药治疗（19.5%）。该人群中阿贝西利的中位无进展生存期为5.3个月，中位总生存期为17.2个月，显著类似于在MONARCH-1研究中阿贝西利单药治疗高度预处理的HR+/HER2阴性且未接受过CDK4/6i治疗患者所获得的结果。共有36.8%的患者接受阿贝西利治疗≥6个月。在接受哌柏西利治疗时的临床获益持续时间与随后接受阿贝西利治疗的持续时间之间没有关联。在阿贝西利治疗进展迅速的患者中发现了RB1、ERBB2和CCNE1改变。
一部分HR+MBC患者在先前接受哌柏西利治疗疾病进展后继续从阿贝西利中获得临床获益。这些结果凸显了未来研究的必要性，以确认对CDK4/6i治疗交叉耐药的分子预测指标，并更好地描述阿贝西利在先前接受CDK4/6i治疗疾病进展后的应用价值。
