Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
EBioMedicine. 2024 Jul;105:105186. doi: 10.1016/j.ebiom.2024.105186. Epub 2024 Jun 10.
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC.
This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135.
Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001).
The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments.
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细胞周期蛋白依赖性激酶 4/6（CDK4/6）抑制剂与传统内分泌治疗（ET）联合应用，现已成为激素受体（HR）阳性、HER2 阴性转移性乳腺癌（MBC）的一线治疗推荐方案。然而，在 HER2 低表达和 HER2 阴性亚组中，添加 CDK4/6 抑制剂联合 ET 的获益仍不明确。我们旨在评估 CDK4/6 抑制剂联合 ET 治疗 HR 阳性、HER2 低表达和 HER2 阴性 MBC 患者的疗效。
本二次分析评估了 PALOMA-2 和 PALOMA-3 两项双盲、安慰剂对照的随机临床试验中 HER2 低表达和 HER2 阴性患者的无进展生存期（PFS）。研究纳入了来自 17 个国家的 1186 名 HR 阳性、HER2 阴性女性患者，这些患者在 2013 年 2 月至 2014 年 8 月期间接受了免疫组化（IHC）和/或原位杂交（ISH）检测。HER2 低表达定义为 IHC 1+或 2+且 ISH 阴性，HER2 阴性定义为 IHC 0。数据分析于 2023 年 3 月至 5 月进行。在 PALOMA-2 试验中，患者被随机分配接受 palbociclib 或安慰剂联合来曲唑治疗 HR 阳性 MBC。PALOMA-3 研究中的患者在之前的 ET 中进展或复发，被随机分配接受 palbociclib 联合氟维司群或安慰剂联合氟维司群治疗。主要终点为研究者评估的 PFS。Kaplan-Meier 方法和 Cox 比例风险模型用于估计治疗策略与 HER2 阴性和 HER2 低表达人群 PFS 的相关性。这两项试验均在 ClinicalTrials.gov 注册，编号分别为 NCT01740427 和 NCT01942135。
在 PALOMA-2 研究的 666 例 MBC 患者中，有 153 例 HER2 阴性和 513 例 HER2 低表达患者。在 HER2 阴性患者中，palbociclib-来曲唑组与安慰剂-来曲唑组的 PFS 无显著差异（风险比=0.79，95%置信区间 [CI] 0.48-1.30，p=0.34）。在 HER2 低表达患者中，palbociclib-来曲唑组的 PFS 风险显著低于安慰剂-来曲唑组（风险比=0.52，95%CI 0.41-0.66，p<0.0001）。PALOMA-3 研究分析了 520 例 MBC 患者。在 153 例 HER2 阴性患者中，palbociclib-氟维司群组的 PFS 显著长于安慰剂-氟维司群组（风险比=0.54，95%CI 0.30-0.95，p=0.034）。在 367 例 HER2 低表达患者中，palbociclib-氟维司群组改善了 PFS（风险比=0.39，95%CI 0.28-0.54，p<0.0001）。
CDK4/6 抑制剂联合 ET 显著改善了 HER2 低表达患者的 PFS，而对于 HER2 阴性患者，主要在先前 ET 进展的患者中观察到获益。此外，HER2 阴性患者可能从一线 CDK4/6 抑制剂治疗中获益有限。需要进一步的工作来验证这些发现，并确定最有可能从 CDK4/6 抑制剂联合 ET 作为一线治疗获益的患者亚组。
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