Massachusetts General Hospital, Boston, MA 02114, USA.
Lancet Oncol. 2013 Jan;14(1):88-96. doi: 10.1016/S1470-2045(12)70508-9. Epub 2012 Dec 10.
Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab-the standard adjuvant treatment. We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis.
This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 405 [corrected] centres in 33 countries [corrected] with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00374322.
Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4-60·0) in the lapatinib group and 48·3 (0·7-61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70-1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67-1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3-4 diarrhoea (97 [6%] vs nine [<1%]), rash (72 [5%] vs three [<1%]), and hepatobiliary disorders (36 [2%] vs one [<1%]).
Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population. However, exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival. Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or cannot receive adjuvant trastuzumab.
GlaxoSmithKline.
在全球范围内，许多人患有 HER2 阳性早期乳腺癌并未接受曲妥珠单抗-标准辅助治疗。我们研究了曲妥珠单抗-naive 的 HER2 阳性早期乳腺癌患者的辅助拉帕替尼的疗效和安全性，从诊断后开始的任何时间开始。
这是一项安慰剂对照、多中心、随机 3 期试验。来自 33 个国家/地区的 405 个中心的患有 HER2 阳性早期乳腺癌、以前接受过辅助化疗但未接受曲妥珠单抗的女性门诊患者被随机分配（1:1）接受每日拉帕替尼（1500 mg）或每日安慰剂治疗 12 个月。随机化采用计算机生成的序列进行，按诊断后时间、诊断时淋巴结受累情况和肿瘤激素受体状态分层。研究人员、现场工作人员和患者对治疗分配均不知情。主要终点是意向治疗人群中的无病生存。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00374322。
2006 年 8 月至 2008 年 5 月，共纳入 3161 名女性，3147 名被分配至拉帕替尼（n=1571）或安慰剂（n=1576）组。在拉帕替尼组中位随访 47.4 个月（范围 0.4-60.0）和安慰剂组中位随访 48.3 个月（范围 0.7-61.3）后，拉帕替尼组发生 210 例（13%）无病生存事件，安慰剂组发生 264 例（17%）（风险比 [HR] 0.83，95%CI 0.70-1.00；p=0.053）。HER2 状态的中心审查显示，只有 2490 名（79%）随机女性为 HER2 阳性。在拉帕替尼组的 1230 例经确认的 HER2 阳性患者中，有 157 例（13%）和安慰剂组的 1260 例中有 208 例（17%）发生无病生存事件（HR 0.82，95%CI 0.67-1.00；p=0.04）。1573 名接受拉帕替尼治疗的患者中有 99 名（6%）和 1574 名接受安慰剂治疗的患者中有 77 名（5%）发生严重不良事件，腹泻（97 [6%] 与 9 [<1%]）、皮疹（72 [5%] 与 3 [<1%]）和肝胆疾病（36 [2%] 与 1 [<1%]）发生率较高。
我们的数据显示，在意向治疗人群中分析时，无病生存率在两组之间没有显著差异。然而，对通过中心荧光原位杂交检查确认的 HER2 阳性疾病患者进行的探索性分析表明，拉帕替尼在无病生存率方面有一定的获益。因此，拉帕替尼可能是不能或不能接受曲妥珠单抗辅助治疗的 HER2 阳性乳腺癌患者的一种选择。
葛兰素史克公司。
