Royal Marsden Hospital, London, United Kingdom.
J Clin Oncol. 2009 Nov 20;27(33):5538-46. doi: 10.1200/JCO.2009.23.3734. Epub 2009 Sep 28.
Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC).
Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.
This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.
人类表皮生长因子受体与激素受体通路的相互作用可能导致乳腺癌内分泌耐药。本试验评估了在芳香化酶抑制剂来曲唑一线治疗激素受体（HR）阳性转移性乳腺癌（MBC）中加入双重酪氨酸激酶抑制剂拉帕替尼（阻断表皮生长因子受体和人表皮生长因子受体 2 [HER2]）对其的影响。
绝经后 HR 阳性 MBC 患者随机分配至每日来曲唑（2.5 mg 口服）联合拉帕替尼（1500 mg 口服）或来曲唑联合安慰剂组。主要终点是 HER2 阳性人群的无进展生存期（PFS）。结果：在 HR 阳性、HER2 阳性患者（n = 219）中，与来曲唑-安慰剂相比，拉帕替尼联合来曲唑显著降低疾病进展风险（风险比[HR] = 0.71；95%CI，0.53 至 0.96；P =.019）；中位 PFS 分别为 8.2 个月和 3.0 个月。拉帕替尼-来曲唑组与来曲唑-安慰剂组相比，临床获益（反应或稳定疾病≥6 个月）显著更高（分别为 48%和 29%；比值比[OR] = 0.4；95%CI，0.2 至 0.8；P =.003）。经中心确认 HR 阳性、HER2 阴性肿瘤的患者（n = 952）无 PFS 改善。一项预先计划的 Cox 回归分析确定既往抗雌激素治疗是 HER2 阴性人群的一个显著因素；在既往他莫昔芬停药后 6 个月内复发的患者中，拉帕替尼-来曲唑组有延长 PFS 的趋势（HR = 0.78；95%CI，0.57 至 1.07；P =.117）。拉帕替尼-来曲唑组与来曲唑-安慰剂组相比，3 级或 4 级不良事件更常见（腹泻，10%比 1%；皮疹，1%比 0%），但可管理。
本试验表明，来曲唑联合拉帕替尼的联合靶向策略可显著提高 HR 和 HER2 共表达 MBC 患者的 PFS 和临床获益率。
