Sunnybrook Odette Cancer Centre, Toronto, ON M4N 3M5, Canada.
N Engl J Med. 2012 Nov 8;367(19):1783-91. doi: 10.1056/NEJMoa1209124. Epub 2012 Oct 1.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.
We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted.
Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.
T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).
曲妥珠单抗-美坦新偶联物（T-DM1）是一种抗体-药物偶联物，包含曲妥珠单抗针对人表皮生长因子受体 2（HER2）的抗肿瘤特性和微管抑制剂 DM1 的细胞毒性。抗体和细胞毒剂通过稳定的连接子连接。
我们将先前接受过曲妥珠单抗和紫杉烷治疗的 HER2 阳性晚期乳腺癌患者随机分配接受 T-DM1 或拉帕替尼加卡培他滨治疗。主要终点为无进展生存期（由独立评估）、总生存期和安全性。次要终点包括无进展生存期（研究者评估）、客观缓解率和症状进展时间。对总生存期进行了两次中期分析。
在 991 名随机分配的患者中，独立评估的无进展生存期中位数为 T-DM1 组 9.6 个月，拉帕替尼加卡培他滨组 6.4 个月（任何原因导致进展或死亡的风险比，0.65；95%置信区间[CI]，0.55 至 0.77；P<0.001），第二次中期分析的中位总生存期达到了疗效终点（30.9 个月 vs. 25.1 个月；任何原因导致死亡的风险比，0.68；95%CI，0.55 至 0.85；P<0.001）。T-DM1 组的客观缓解率更高（43.6% vs. 拉帕替尼加卡培他滨组 30.8%；P<0.001）；所有其他次要终点的结果均倾向于 T-DM1。T-DM1 组 3 级或 4 级不良事件发生率高于拉帕替尼加卡培他滨组（57% vs. 41%）。T-DM1 组血小板减少症和血清转氨酶水平升高的发生率较高，而拉帕替尼加卡培他滨组腹泻、恶心、呕吐和掌跖红斑感觉迟钝的发生率较高。
在先前接受过曲妥珠单抗和紫杉烷治疗的 HER2 阳性晚期乳腺癌患者中，与拉帕替尼加卡培他滨相比，T-DM1 显著延长了无进展生存期和总生存期，且毒性更小。（由 F. Hoffmann-La Roche/Genentech 资助；EMILIA 临床试验.gov 编号，NCT00829166。）
