Background:The use of cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) is a first-line standard treatment for hormone receptor-positive (ER+) Human Epidermal Growth factor Receptor-2-negative (HER2-) advanced breast cancer. The data supporting incorporation of CDK 4/6i + ET beyond progression are variable. Here, we report a pooled analysis of this strategy.Methods:A systematic review identified reports of both observational and clinical studies, which evaluated the continuation of CDK4/6i beyond progression. The mean overall response rate (ORR) and progression-free survival (PFS) weighted by the study sample size were calculated. Meta-regression comprising linear regression weighted by the sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and the benefit from continuing CDK4/6i. Quantitative significance was assessed using the Burnand criteria.Results:Thirteen studies comprising 1530 patients were included. The median age was 58 years, 50.8% had visceral metastases, and 48% had ESR1 mutations; the median lines of prior therapies were 1 (range 1–5), and 96.3% received palbociclib as the initial CDK4/6i. Eight studies tested a CDK4/6i switch as the intervention. The median PFS was 5.3 months, and the ORR was 14%. In randomized studies, statistically significant differences were observed between CDK4/6i continuation and control, although it is uncertain whether the magnitude of the effect is clinically meaningful. Increasing age, lack of prior chemotherapy, no visceral metastasis or ESR1 mutations, and a switch to a non-palbociclib CDK4/6i were associated with better outcomes.Conclusion:Continuing a CDK 4/6i + ET beyond progression yields modest benefits. Switching CDK4/6i likely results in improved ORR and PFS. Continuing palbociclib beyond progression is likely ineffectual.
背景：细胞周期蛋白依赖性激酶4/6抑制剂（CDK 4/6i）联合内分泌治疗（ET）是激素受体阳性（ER+）、人表皮生长因子受体2阴性（HER2-）晚期乳腺癌的一线标准治疗方案。关于疾病进展后继续使用CDK 4/6i联合ET的疗效数据存在差异。本研究对该治疗策略进行汇总分析。 方法：通过系统综述筛选出评估CDK4/6抑制剂进展后持续治疗的观察性和临床研究。按研究样本量加权计算平均总缓解率（ORR）和无进展生存期（PFS）。采用以样本量加权的线性回归（混合效应模型）进行元回归分析，探讨疾病与治疗相关因素与持续使用CDK4/6抑制剂获益之间的关联。使用Burnand标准评估定量显著性。 结果：共纳入13项研究，涉及1530例患者。中位年龄58岁，50.8%存在内脏转移，48%携带ESR1突变；既往治疗中位线数为1（范围1-5），96.3%初始使用哌柏西利作为CDK4/6抑制剂。其中8项研究采用更换CDK4/6抑制剂的干预方案。中位PFS为5.3个月，ORR为14%。随机研究显示CDK4/6抑制剂持续治疗组与对照组存在统计学显著差异，但效应幅度是否具有临床意义尚不确定。年龄增长、既往未接受化疗、无内脏转移或ESR1突变、以及换用非哌柏西利CDK4/6抑制剂与更好的预后相关。 结论：疾病进展后继续使用CDK 4/6抑制剂联合内分泌治疗的获益有限。更换CDK4/6抑制剂可能改善ORR和PFS。进展后继续使用哌柏西利可能无效。
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