A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses
A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses
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DOI：
10.1007/s10549-007-9885-0
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发表时间：
2008-12-01
影响因子：
3.8
通讯作者：
Geyer, Charles E.
中科院分区：
文献类型：
--
作者：
Cameron, David;Casey, Michelle;Geyer, Charles E.
目的拉帕替尼是一种小分子、表皮生长因子受体（EGFR）和人表皮生长因子受体2型（HER 2）的双重酪氨酸激酶抑制剂。一项III期试验的初步结果表明，在既往治疗（包括曲妥珠单抗）后进展的HER 2阳性晚期乳腺癌女性中，拉帕替尼联合卡培他滨治疗优于卡培他滨单药治疗的上级效果。报告了本试验的最新疗效和初始生物标志物结果。方法既往接受过蒽环类、紫杉类和曲妥珠单抗治疗的HER 2阳性、局部晚期或转移性乳腺癌患者随机接受拉帕替尼1，250 mg/d连续联合卡培他滨2，000 mg/m2，第1-14天，21天为1个周期，或卡培他滨2，500 mg/m2，相同方案。主要终点是由独立审查小组确定的疾病进展时间（TTP）。评估无进展生存期（PFS）与肿瘤HER 2表达和血清HER 2胞外结构域（ECD）水平之间的关系。结果399名妇女被随机分组。添加拉帕替尼延长了TTP，风险比（HR）为0.57（95% CI，0.43-0.77; P < 0.001），并提供了改善总生存期的趋势（HR：0.78，95% CI：0.55-1.12，P = 0.177），以及首次进展时CNS受累的病例较少（4 vs. 13，P = 0.045）。基线血清HER 2 ECD不能预测拉帕替尼的获益。结论拉帕替尼联合卡培他滨治疗以蒽环类、紫杉类和曲妥珠单抗为基础的治疗后进展的HER 2阳性晚期乳腺癌患者具有上级疗效。生物标志物研究无法确定在卡培他滨基础上加用拉帕替尼未能获益的患者亚组。
Purpose Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported. Methods Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m(2) days 1-14 of a 21-day cycle or capecitabine 2,500 mg/m(2) on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed. Results 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43-0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55-1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib. Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumabbased therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.