一线与二线CDK4/6抑制在激素受体阳性、HER2阴性转移性乳腺癌中的疗效比较

Comparative efficacy of first- versus second-line CDK4/6 inhibition in hormone receptor-positive, HER2-negative metastatic breast cancer.

作者信息

Ravani Lis Victoria, Bagheri Zahra, Brufsky Adam M, Michellon Isabella, O'Regan Ruth, Lustberg Maryam, Han Hyo, Wang Ming, Wander Seth A

机构信息

Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.

Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.

出版信息

Breast Cancer Res. 2025 Aug 13;27(1):146. doi: 10.1186/s13058-025-02095-6.

DOI:10.1186/s13058-025-02095-6

PMID:40804745

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12351955/

Abstract

PURPOSE

The greater progression-free survival (PFS) improvements observed in first-line (1L) versus second-line (2L) CDK4/6 inhibitor (CDK4/6i) trials underpin current guideline recommendations establishing these agents as standard 1L therapy in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). While earlier CDK4/6i use is associated with increased cumulative toxicity and costs, comparative survival data of earlier versus deferred use remain scarce.

METHODS

We performed a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for observational studies and randomized clinical trials (RCTs) including patients treated with first- and/or 2L CDK4/6i. Patients who received CDK4/6 inhibition as part of 1L therapy were included in the 1 L group, while those who did not receive CDK4/6i in the 1L setting and deferred it until the 2L setting were assigned to the 2 L group. Pooled analysis of Kaplan-Meier-derived individual patient data was conducted for PFS2, defined as time from randomization to progression on 2L therapy, and overall survival (OS). Both outcomes were measured from the start of 1L treatment to progression on 2L treatment for both 1L and 2L groups. Sensitivity analysis by study design was also conducted.

RESULTS

Nine studies (5 RCTs and 4 observational studies) comprising 7,602 patients with mBC were included. Of these, 6,475 (85.1%) received CDK4/6i in 1L, and 1,127 (14.8%) in the 2 L setting. Overall, 1L CDK4/6i therapy was associated with significantly longer PFS2 compared to 2L treatment (HR 2.08; 95%CI 1.90-2.27), a trend not observed in sensitivity analysis of RCTs alone (HR 1.10; 95%CI 0.94-1.30). No significant differences in OS were observed between 1L and 2L CDK4/6i regimens (HR 1.09; 95%CI 1.00-1.18), or in sensitivity analysis of only RCTs (HR 1.03; 95%CI 0.84-1.26).

CONCLUSION

This extensive data pool suggests that deferring CDK4/6is to 2L may be associated with worse PFS2 but comparable OS when compared to early use in 1L, challenging the assumption that shifting therapies from 2L to 1L universally improves outcomes despite increased toxicity and costs.

摘要

目的

在一线（1L）与二线（2L）细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）试验中观察到的无进展生存期（PFS）更大改善，支撑了当前指南推荐将这些药物作为激素受体阳性、人表皮生长因子受体2阴性（HR+/HER2-）转移性乳腺癌（mBC）的标准一线治疗。虽然早期使用CDK4/6i与累积毒性增加和成本上升相关，但早期使用与延迟使用的比较生存数据仍然匮乏。

方法

我们进行了一项系统评价和荟萃分析，在PubMed、Embase、Cochrane以及会议论文集中检索观察性研究和随机临床试验（RCT），纳入接受一线和/或二线CDK4/6i治疗的患者。作为一线治疗一部分接受CDK4/6抑制的患者纳入1L组，而那些在一线治疗中未接受CDK4/6i并推迟至二线治疗的患者被分配到2L组。对PFS2（定义为从随机分组到二线治疗进展的时间）和总生存期（OS）进行基于Kaplan-Meier法的个体患者数据汇总分析。两个结局均从1L和2L组的1L治疗开始至二线治疗进展进行测量。还按研究设计进行了敏感性分析。

结果

纳入了9项研究（5项RCT和4项观察性研究），共7602例mBC患者。其中，6475例（85.1%）在一线接受了CDK4/6i治疗，1127例（14.8%）在二线接受治疗。总体而言，与二线治疗相比，一线CDK4/6i治疗与显著更长的PFS2相关（风险比[HR] 2.08；95%置信区间[CI] 1.90 - 2.27），仅RCT的敏感性分析未观察到这一趋势（HR 1.10；95%CI 0.94 - 1.30）。一线和二线CDK4/6i方案之间在OS方面未观察到显著差异（HR 1.09；95%CI 1.00 - 1.18），仅RCT的敏感性分析中也未观察到差异（HR 1.03；95%CI 0.84 - 1.26）。