Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18.
Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18.
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DOI：
10.1186/s13058-016-0721-5
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发表时间：
2016-06-28
期刊：
影响因子：
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通讯作者：
Slamon DJ
中科院分区：
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作者：
Finn RS;Crown JP;Ettl J;Schmidt M;Bondarenko IM;Lang I;Pinter T;Boer K;Patel R;Randolph S;Kim ST;Huang X;Schnell P;Nadanaciva S;Bartlett CH;Slamon DJ
Palbociclib是一种口服小分子细胞周期蛋白依赖性激酶4和6抑制剂。在随机、开放标签、II期PALOMA-1/TRIO-18试验中，与来曲唑单药相比，palbociclib联合来曲唑作为雌激素受体（ER）阳性、人表皮生长因子受体2（HER 2）阴性的晚期乳腺癌的一线治疗可改善无进展生存期（PFS）（20.2个月vs 10.2个月;风险比（HR）= 0.488，95%置信区间（CI）0.319-0.748;单侧p = 0.0004）。3-4级中性粒细胞减少症是palbociclib +来曲唑组最常见的不良事件（AE）。我们现在根据几种特定的患者和肿瘤特征进行疗效和安全性分析，并详细介绍在总体安全性人群的palbociclib +来曲唑组中观察到的中性粒细胞减少症的临床模式。ER+、HER 2阴性、晚期乳腺癌的绝经后女性患者（n = 165）未接受任何系统性治疗，以1：1的比例随机接受palbociclib联合来曲唑或来曲唑单药治疗。治疗持续至疾病进展、不可接受的毒性、撤回知情同意或死亡。主要终点为PFS。我们现在使用Kaplan-Meier方法，按亚组分析治疗人群的PFS差异，包括年龄、组织学类型、既往新辅助/辅助全身治疗史和远处转移部位。HR和95% CI来自考克斯比例风险回归模型。在评价的每个亚组中，palbociclib +来曲唑组的中位PFS和临床获益应答（CBR）率均出现具有临床意义的改善。3-4级中性粒细胞减少是所有亚组中palbociclib +来曲唑组最常见的AE。前6个治疗周期内按级别分析的中性粒细胞减少症频率显示，3-4级中性粒细胞减少症随时间呈下降趋势。在发生3-4级中性粒细胞减少症的患者中，71.7%的患者没有任何级别的重叠感染，没有患者发生3-4级重叠感染。在几乎所有分析的亚组中，palbociclib与来曲唑联合治疗在改善中位PFS和CBR率方面的临床获益幅度一致，与总体研究人群中观察到的结果一致。所有亚组中联合治疗的安全性特征也与研究的总体安全性人群相当。本文的在线版本（doi：10.1186/s13058-016-0721-5）包含补充材料，可供授权用户使用。
Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319–0.748; one-sided p = 0.0004). Grade 3–4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3–4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3–4 neutropenia over time. Among those who experienced Grade 3–4 neutropenia, 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3–4 infections. The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study. The online version of this article (doi:10.1186/s13058-016-0721-5) contains supplementary material, which is available to authorized users.