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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
BACKGROUND: None.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
BACKGROUND: None.
摘要：
背景：细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂与传统内分泌疗法（ET）联合使用，现在是激素受体（HR）阳性和HER2阴性转移性乳腺癌（MBC）的推荐一线治疗方法。然而,在HER2低阳性和HER2-0亚组中,对ET添加CDK4/6抑制剂的益处尚不清楚.我们旨在评估CDK4/6抑制剂联合ET在HR阳性患者中的有效性。HER2-低阳性和HER2-0MBC。
方法：这项次要分析评估了HER2低阳性和HER2-0双盲患者的无进展生存期（PFS），安慰剂对照随机临床试验PALOMA-2和PALOMA-3。该研究包括1186例HER2阴性，HR阳性女性患者,有可用的免疫组织化学（IHC）和/或原位杂交（ISH）结果，在2013年2月至2014年8月期间注册的17个国家。HER2低阳性状态由ISH阴性的IHC1+或2+定义，和HER2-零通过IHC0。数据分析在2023年3月至5月之间进行。在PALOMA-2试验中,患者被随机分配接受palbociclib或安慰剂，与来曲唑联合用于HR阳性MBC的一线治疗。PALOMA-3研究中的患者，在以前的ET期间有进展或复发，被随机分配接受帕博西利布加氟维司群或安慰剂加氟维司群。主要终点是研究者评估的PFS。Kaplan-Meier方法和Cox比例风险模型用于评估HER2-0和HER2低阳性人群中治疗策略与PFS的关联。这两项试验在ClinicalTrials.gov注册，编号NCT01740427和NCT01942135。
结果：在PALOMA-2研究的666例MBC患者中，有153例HER2-0和513例HER2低阳性患者.在HER2-0人群中，帕博西尼-来曲唑组和安慰剂-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低阳性人群中，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%CI0.41-0.66,p<0.0001).PALOMA-3研究分析了520例MBC患者。在153例HER2-0患者中，帕博西尼-氟维司群组的PFS明显长于安慰剂-氟维司群组(风险比=0.54,95%CI0.30-0.95,p=0.034).在367例HER2低阳性患者中，帕博西尼-氟维司群改善PFS(风险比=0.39,95%CI0.28-0.54,p<0.0001)。
结论：CDK4/6抑制剂与ET的组合显着改善了HER2低阳性患者的PFS，而对于HER2-0患者，获益主要在先前ET进展的患者中观察到。此外，HER2-0患者可能从一线CDK4/6抑制剂治疗中获得有限的益处。需要进一步的工作来验证这些发现并描述最有可能从CDK4/6抑制剂和ET的组合作为一线治疗中受益的患者亚群。
背景：无。
方法：这项次要分析评估了HER2低阳性和HER2-0双盲患者的无进展生存期（PFS），安慰剂对照随机临床试验PALOMA-2和PALOMA-3。该研究包括1186例HER2阴性，HR阳性女性患者,有可用的免疫组织化学（IHC）和/或原位杂交（ISH）结果，在2013年2月至2014年8月期间注册的17个国家。HER2低阳性状态由ISH阴性的IHC1+或2+定义，和HER2-零通过IHC0。数据分析在2023年3月至5月之间进行。在PALOMA-2试验中,患者被随机分配接受palbociclib或安慰剂，与来曲唑联合用于HR阳性MBC的一线治疗。PALOMA-3研究中的患者，在以前的ET期间有进展或复发，被随机分配接受帕博西利布加氟维司群或安慰剂加氟维司群。主要终点是研究者评估的PFS。Kaplan-Meier方法和Cox比例风险模型用于评估HER2-0和HER2低阳性人群中治疗策略与PFS的关联。这两项试验在ClinicalTrials.gov注册，编号NCT01740427和NCT01942135。
结果：在PALOMA-2研究的666例MBC患者中，有153例HER2-0和513例HER2低阳性患者.在HER2-0人群中，帕博西尼-来曲唑组和安慰剂-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低阳性人群中，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%CI0.41-0.66,p<0.0001).PALOMA-3研究分析了520例MBC患者。在153例HER2-0患者中，帕博西尼-氟维司群组的PFS明显长于安慰剂-氟维司群组(风险比=0.54,95%CI0.30-0.95,p=0.034).在367例HER2低阳性患者中，帕博西尼-氟维司群改善PFS(风险比=0.39,95%CI0.28-0.54,p<0.0001)。
结论：CDK4/6抑制剂与ET的组合显着改善了HER2低阳性患者的PFS，而对于HER2-0患者，获益主要在先前ET进展的患者中观察到。此外，HER2-0患者可能从一线CDK4/6抑制剂治疗中获得有限的益处。需要进一步的工作来验证这些发现并描述最有可能从CDK4/6抑制剂和ET的组合作为一线治疗中受益的患者亚群。
背景：无。
