Istituto Europeo di Oncologia, Milan, IRCCS and University of Milano, Milan, Italy.
Universitaetsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Ann Oncol. 2022 Mar;33(3):321-329. doi: 10.1016/j.annonc.2021.12.005. Epub 2021 Dec 23.
BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.
背景：在 HER2CLIMB 试验的初步分析中，与曲妥珠单抗和卡培他滨联合使用，tucatinib 显著改善了人表皮生长因子受体 2 阳性（HER2+）转移性乳腺癌患者的总生存期（OS）和无进展生存期（PFS）。我们报告了疗效和安全性结果，包括 HER2CLIMB 的最终 OS 和随访安全性结果。
患者和方法：HER2CLIMB 是一项针对局部晚期或转移性 HER2+乳腺癌患者的随机、双盲、安慰剂对照试验，包括有脑转移的患者。患者按 2:1 随机接受 tucatinib 或安慰剂，联合曲妥珠单抗和卡培他滨治疗。在主要分析（中位随访 14 个月）后，方案修订允许对研究地点进行揭盲，并允许从安慰剂联合治疗组交叉到 tucatinib 联合治疗组。根据方案预先指定的描述性分析，在最后一位随机患者入组后约 2 年进行 OS、PFS（研究者评估）和安全性分析。
结果：共有 612 名患者入组 HER2CLIMB 试验。在中位随访 29.6 个月时，tucatinib 联合组的中位 OS 为 24.7 个月，安慰剂联合组为 19.2 个月[死亡风险比（HR）：0.73，95%置信区间（CI）：0.59-0.90，P=0.004]，2 年 OS 分别为 51%和 40%。各亚组的 OS 风险比与总体研究人群的 HR 一致。tucatinib 联合组的中位 PFS 为 7.6 个月，安慰剂联合组为 4.9 个月[进展或死亡风险比（HR）：0.57，95%CI：0.47-0.70，P<0.00001]，1 年 PFS 分别为 29%和 14%。tucatinib 联合治疗耐受性良好，因不良反应导致停药的发生率低。
结论：随着随访时间的延长，tucatinib 联合治疗为 HER2+转移性乳腺癌患者带来了具有临床意义的生存获益。
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