Abstract

Background

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups.

Methods

We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I²statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP).

Results

Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I² = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I² = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I² = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I² = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I² = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I² = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I² = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I² = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I² = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I² = 0.0%).

Conclusions

CDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.

中文翻译：

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转移性乳腺癌临床相关亚组中基于 CDK4/6 抑制剂的治疗的总生存期：系统评价和荟萃分析。

摘要

背景

细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 抑制剂 + 内分泌治疗 (ET) 作为激素受体阳性 (HR+)/HER2 阴性转移性乳腺癌预后的一线或二线治疗延长了无进展生存期。鉴于最近公布的 3 种 CDK4/6 抑制剂的总生存期 (OS) 数据，我们进行了一项荟萃分析，以确定特定临床亚组中此类治疗的更精确和可靠的益处。

方法

我们进行了系统的文献检索，以选择 CDK4/6 抑制剂 + ET 报告 OS 数据在 HR+/HER2 阴性绝经前或绝经后转移性乳腺癌一线或二线治疗中所有可用的 II 期或 III 期随机临床试验。应用随机效应模型进行分析。用I ²统计量评估异质性。进行亚组分析以探索研究水平因素的影响。该项目已在开放科学框架数据库（doi：10.17605/OSF.IO/TNZQP）中注册。

结果

我们的分析包括六项研究（3421 名患者）。在没有（风险比 [HR] = 0.68，95% 置信区间 [CI] = 0.54 至 0.85，I ² = 0.0%）和有内脏受累（HR = 0.76，95% CI = 0.65）的患者中观察到明显的 OS 获益至 0.89，I ² = 0.0%），至少有 3 个转移部位（HR = 0.75，95% CI = 0.60 至 0.94，I ² = 11.6%），在内分泌耐药（HR = 0.79，95% CI = 0.67 至 0.93，I ² = 0.0%）和敏感子集（HR = 0.73，95% CI = 0.61 至 0.88，I ² = 0.0%），年龄小于 65 岁（HR = 0.80，95% CI = 0.67 至 0.95） , I ² = 0.0%) 和 65 岁或以上 (HR = 0.71, 95% CI = 0.53 to 0.95, I ²= 44.4%），绝经后（HR = 0.76，95% CI = 0.67 至 0.86，I ² = 0.0%）和绝经前或围绝经期（HR = 0.76，95% CI = 0.60 至 0.96，I ² = 0） ）以及未接受化疗的患者（HR = 0.72，95% CI = 0.55 至 0.93，I ² = 0.0%）。

结论

与单独使用 ET 相比，CDK4/6 抑制剂 + ET 组合可改善 OS，与年龄、绝经状态、内分泌敏感性和内脏受累无关，应首选作为前期治疗而不是内分泌单药治疗。