Kalinsky Kevin, Bianchini Giampaolo, Hamilton Erika, Graff Stephanie L, Park Kyong Hwa, Jeselsohn Rinath, Demirci Umut, Martin Miguel, Layman Rachel M, Hurvitz Sara A, Sammons Sarah, Kaufman Peter A, Muñoz Montserrat, Lai Jiun-I, Knoderer Holly, Sandoval Cynthia, Chawla Aarti R, Nguyen Bastien, Zhou Yanhong, Ravenberg Elizabeth, Litchfield Lacey M, Smyth Lillian, Wander Seth A
Winship Cancer Institute at Emory University, Atlanta, GA.
IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy.
J Clin Oncol. 2025 Mar 20;43(9):1101-1112. doi: 10.1200/JCO-24-02086. Epub 2024 Dec 18.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein, we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.
This double-blind, randomized phase III study enrolled patients with disease progression on previous CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i + ET. Patients were randomly assigned (1:1) to abemaciclib + fulvestrant or placebo + fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review, objective response rate (ORR), and safety.
This study randomly assigned 368 patients (abemaciclib + fulvestrant, n = 182 placebo + fulvestrant, n = 186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57 to 0.95; nominal = .017), with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib + fulvestrant and placebo + fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55 [95% CI, 0.39 to 0.77]; nominal < .001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without or mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib + fulvestrant versus placebo + fulvestrant (17% 7%; nominal = .015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib.
Abemaciclib + fulvestrant significantly improved PFS after disease progression on previous CDK4/6i + ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.
细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）联合内分泌治疗（ET）是激素受体阳性（HR+）、人表皮生长因子受体2阴性（HER2-）晚期乳腺癌（ABC）的标准一线治疗方案；然而，几乎所有患者都会出现疾病进展，因此需要更多的治疗选择。在此，我们报告了MONARCH试验之后的研究结果，该研究在CDK4/6i治疗疾病进展后，调查了阿贝西利联合/不联合CDK4/6抑制的内分泌治疗方案转换情况。
这项双盲、随机III期研究纳入了先前接受CDK4/6i加芳香化酶抑制剂作为晚期疾病初始治疗或辅助CDK4/6i+ET后疾病进展或复发的患者。患者被随机分配（1:1）接受阿贝西利+氟维司群或安慰剂+氟维司群。主要终点是研究者评估的无进展生存期（PFS）。次要终点包括盲态独立中央审查评估的PFS、客观缓解率（ORR）和安全性。
本研究随机分配了368例患者（阿贝西利+氟维司群组，n = 182；安慰剂+氟维司群组，n = 186）。在初步分析（258个事件）时，风险比（HR）为0.73（95%CI，0.57至0.95；名义P值 = 0.017），阿贝西利+氟维司群组的中位PFS为6.0（95%CI，5.6至8.6）个月，安慰剂+氟维司群组为5.3（95%CI，3.7至5.6）个月，阿贝西利+氟维司群组和安慰剂+氟维司群组的6个月PFS率分别为50%和37%。这些结果得到了BICR评估的PFS的支持（HR，0.55 [95%CI，0.39至0.77]；名义P值<0.001）。在包括有无 或 突变在内的主要临床和基因组亚组中均观察到一致的治疗效果。在可测量疾病的患者中，研究者评估的阿贝西利+氟维司群组的ORR高于安慰剂+氟维司群组（17%对7%；名义P值 = 0.015）。未观察到新的安全信号，研究结果与阿贝西利已知的安全性特征一致。
对于HR+、HER2-的ABC患者，在先前的CDK4/6i+ET治疗疾病进展后，阿贝西利+氟维司群显著改善了PFS，为这些患者提供了另一种靶向治疗选择。
