非聚乙二醇化脂质体阿霉素联合曲妥珠单抗和紫杉醇治疗HER2阳性转移性乳腺癌的III期试验
Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer.
作者信息
Baselga J, Manikhas A, Cortés J, Llombart A, Roman L, Semiglazov V F, Byakhov M, Lokanatha D, Forenza S, Goldfarb R H, Matera J, Azarnia N, Hudis C A, Rozencweig M
机构信息
Memorial Sloan-Kettering Cancer Center, New York, USA; SOLTI Breast Cancer Research Group, Barcelona, Spain.
City Clinical Oncology Dispensary, St. Petersburg, Russia.
出版信息
Ann Oncol. 2014 Mar;25(3):592-598. doi: 10.1093/annonc/mdt543. Epub 2014 Jan 8.
BACKGROUND
Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer.
PATIENTS AND METHODS
Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS).
RESULTS
One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms.
CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials.
CLINICAL TRIAL NUMBER
NCT00294996.
背景
非聚乙二醇化脂质体阿霉素（Myocet™；加拿大Sopherion Therapeutics公司及欧洲的Cephalon公司）（NPLD；Myocet(®)）联合曲妥珠单抗（赫赛汀(®)）（罗氏公司）已显示出有前景的活性及心脏安全性。我们开展了一项随机III期试验，比较一线使用NPLD联合曲妥珠单抗及紫杉醇（Pharmachemie B.V.公司）（MTP）与曲妥珠单抗联合紫杉醇（TP）治疗人表皮生长因子2受体（HER2）阳性转移性乳腺癌患者的疗效。
患者与方法
患者被随机分配接受NPLD（M，每3周50mg/m²，共6个周期）、曲妥珠单抗（T，负荷剂量4mg/kg，随后每周2mg/kg）及紫杉醇（P，每周80mg/m²），或相同剂量的T + P，直至疾病进展或出现毒性反应。主要疗效指标为无进展生存期（PFS）。
结果
181例患者被分配接受MTP方案，183例接受TP方案。MTP组和TP组的中位PFS分别为16.1个月和14.5个月[风险比（HR）0.84；双侧P = 0.174]。在雌激素受体（ER）和孕激素受体（PR）均为阴性的肿瘤患者中，PFS分别为20.7个月和14.0个月[HR 0.68；95%置信区间（CI）0.47 - 0.99]。MTP组和TP组的中位总生存期（OS）分别为33.6个月和28.9个月（HR 0.79；双侧P = 0.083）。在ER和PR阴性肿瘤患者中，OS分别为38.2个月和27.9个月（HR 0.63；95% CI 0.42 - 0.93）。MTP方案的不良事件发生率更高，但各治疗组间心脏毒性无显著差异。
结论
该试验未能证明在TP方案中添加M能带来显著的临床改善。在ER和PR阴性人群的探索性分析中观察到的临床获益值得进一步临床试验考虑。
临床试验编号
NCT00294996
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