Supplementary file 1_Comparative effectiveness of CDK4/6 inhibitor plus endocrine therapy combinations in HR-positive, HER2-negative metastatic breast cancer: the inspiration 01 study.pdf

BackgroundThe optimal combination of different cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) for HR+/HER2− metastatic breast cancer (MBC) remains undefined due to a lack of head-to-head comparisons. This real-world study aimed to evaluate the effectiveness and safety of three CDK4/6 inhibitors combined with aromatase inhibitors (AI) or fulvestrant in the MBC setting.
MethodsThis study was a retrospective, observational, single-center analysis conducted in Tianjin Medical University Cancer Institute and Hospital, China between 1 January 2019 and 1 November 2023. The eligibility criteria were as follows: age ≥18 years; histologically confirmed hormone receptor-positive, HER2-negative breast cancer; recurrent or metastatic disease; at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and no prior systemic endocrine therapy for advanced disease. However, up to one line of prior chemotherapy in the metastatic setting was allowed. Statistical analyses were conducted using R software. Effective endpoints included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR).
ResultsThis study enrolled 341 patients with HR+/HER2− MBC who received first-line CDK4/6i-based therapy consisting of palbociclib (n = 138), abemaciclib (n = 119), or dalpiciclib (n = 84) in combination with either an AI or fulvestrant. The median follow-up durations for PFS were 15.6 months, 10.9 months, and 18.2 months in the palbociclib, abemaciclib, and dalpiciclib groups, respectively. The maximum follow-up durations were 58.0 months for the palbociclib group, 53.7 months for the abemaciclib group, and 49.3 months for the dalpiciclib group. Regarding clinical benefit rate (CBR), the values for palbociclib, abemaciclib, and dalpiciclib combined with an AI versus fulvestrant were 93.8% (95% CI: 86.2%, 97.3%) versus 93.1% (83.6%, 97.3%), 97.7% (92.1%, 99.4%) versus 96.8% (83.8%, 99.4%), and 93.3% (84.1%, 97.4%) versus 87.5% (69.0%, 95.7%), respectively. For objective response rate (ORR), the corresponding rates were 37.5% (95% CI: 27.7%, 48.5%) versus 60.3% (47.5%, 71.9%), 48.9% (38.7%, 59.1%) versus 67.7% (50.1%, 81.4%), and 45.0% (33.1%, 57.5%) versus 54.2% (35.1%, 72.1%), respectively. Median PFS was 25.3 months for the palbociclib group, not reached (NR) for the abemaciclib group, and 36.0 months for the dalpiciclib group. Statistical analysis showed that both abemaciclib and dalpiciclib combinations were associated with longer PFS compared with palbociclib (both P < 0.05); however, due to the shorter median PFS follow-up duration and the lower number of PFS events in the abemaciclib group, the data for this group remain immature and warrant further follow-up. The PFS following CDK4/6i plus ET treatment was not significantly related to the status of key molecular biomarkers. The type of ET (AIs vs. fulvestrant) did not significantly affect PFS, although a consistent trend toward PFS benefit was observed in the fulvestrant-based combination group, without reaching statistical significance. Liver and bone metastases were associated with shorter PFS. Safety profiles were consistent with known spectra of each CDK4/6i, with no new signals identified.
ConclusionIn this real-world analysis, dalpiciclib was associated with superior PFS compared to palbociclib as first-line CDK4/6i-based therapy for HR+/HER2- MBC. ET partner did not significantly impact effectiveness, supporting tailored CDK4/6i selection based on patient and disease characteristics.

研究背景：由于缺乏头对头比较，不同细胞周期蛋白依赖性激酶4/6抑制剂（cyclin-dependent kinase 4/6 inhibitors, CDK4/6i）联合内分泌治疗（endocrine therapy, ET）用于激素受体阳性、人表皮生长因子受体2阴性（HR+/HER2-）转移性乳腺癌（MBC）的最优联合方案仍未明确。本真实世界研究旨在评估三种CDK4/6抑制剂分别联合芳香化酶抑制剂（aromatase inhibitors, AI）或氟维司群在MBC治疗中的有效性与安全性。
研究方法：本研究为一项回顾性观察性单中心分析，于2019年1月1日至2023年11月1日在中国天津医科大学肿瘤医院开展。入组标准如下：年龄≥18岁；经组织学确认的激素受体阳性、HER2阴性乳腺癌；复发性或转移性疾病；根据实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors, RECIST）1.1版存在至少1个可测量病灶；未接受过针对晚期疾病的系统性内分泌治疗，但允许转移性阶段接受过至多1线化疗。统计分析采用R软件完成。有效性终点包括无进展生存期（progression-free survival, PFS）、客观缓解率（objective response rate, ORR）及临床获益率（clinical benefit rate, CBR）。
研究结果：本研究共纳入341例接受一线CDK4/6抑制剂联合治疗的HR+/HER2- MBC患者，其中哌柏西利（palbociclib）组138例、阿贝西利（abemaciclib）组119例、达尔西利（dalpiciclib）组84例，联合治疗方案为芳香化酶抑制剂或氟维司群。哌柏西利、阿贝西利、达尔西利组的PFS中位随访时间分别为15.6个月、10.9个月及18.2个月；最长随访时间分别为58.0个月、53.7个月及49.3个月。
就临床获益率（CBR）而言，哌柏西利联合芳香化酶抑制剂与联合氟维司群的CBR分别为93.8%（95%置信区间[CI]：86.2%，97.3%）与93.1%（83.6%，97.3%）；阿贝西利联合芳香化酶抑制剂与联合氟维司群分别为97.7%（92.1%，99.4%）与96.8%（83.8%，99.4%）；达尔西利联合芳香化酶抑制剂与联合氟维司群分别为93.3%（84.1%，97.4%）与87.5%（69.0%，95.7%）。
客观缓解率（ORR）方面，对应数值分别为37.5%（95%CI：27.7%，48.5%） vs 60.3%（47.5%，71.9%）、48.9%（38.7%，59.1%） vs 67.7%（50.1%，81.4%）、45.0%（33.1%，57.5%） vs 54.2%（35.1%，72.1%）。
哌柏西利组中位PFS为25.3个月，阿贝西利组中位PFS未达到（NR），达尔西利组为36.0个月。统计分析显示，与哌柏西利组相比，阿贝西利组与达尔西利组的PFS均更长（均P<0.05）；但由于阿贝西利组的中位PFS随访时间更短且PFS事件数更少，该组数据仍不成熟，有待进一步随访。CDK4/6抑制剂联合ET治疗后的PFS与关键分子生物标志物状态无显著相关性。内分泌治疗药物类型（芳香化酶抑制剂 vs 氟维司群）对PFS无显著影响，尽管基于氟维司群的联合治疗组观察到PFS获益的一致趋势，但未达到统计学显著性。肝转移与骨转移与更短的PFS相关。安全性特征与各CDK4/6抑制剂已知的不良反应谱一致，未发现新的安全信号。
研究结论：本真实世界分析显示，在HR+/HER2- MBC的一线CDK4/6抑制剂联合治疗中，达尔西利对比哌柏西利可带来更优的PFS。内分泌治疗搭档对有效性无显著影响，支持根据患者及疾病特征个体化选择CDK4/6抑制剂。