Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis
Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis
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DOI：
10.1016/j.annonc.2021.12.005
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发表时间：
2022-02-09
影响因子：
50.5
通讯作者：
Winer, E.
中科院分区：
文献类型：
--
作者：
Curigliano, G.;Mueller, V;Winer, E.
背景：在HER2CLIMB试验的初步分析中，图卡替尼联合曲妥珠单抗和卡培他滨显著改善了人类表皮生长因子受体2阳性(HER2+)转移性乳腺癌患者的总存活率(OS)和无进展存活率(PFS)。我们报告了HER2CLIMB的有效性和安全性结果，包括HER2CLIMB的最终OS和安全结果。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，包括脑转移患者。患者随机接受图卡替尼或安慰剂与曲妥珠单抗和卡培他滨的联合治疗。在初步分析(平均14个月的随访期)后，对方案进行了修改，以允许从安慰剂组合到图卡替尼组合的治疗分配和交叉。从上一位随机抽取的患者开始，在两年内对OS、PFS(由调查者评估)和安全性进行预先指定的描述性分析。结果：612名患者参加了HER2CLIMB试验。Tucatinib联合组的OS中位持续时间为24.7个月，安慰剂联合组为19.2个月[死亡风险比(HR)：0.73，95%可信区间(CI)：0.59-0.9，P=0.004]，2年OS分别为51%和40%。在预先指定的亚组中，OS的HR与整个研究人群的HR是一致的。图卡替尼联合组的中位PFS持续时间为7.6月，安慰剂联合组为4.9个月(进展或死亡的HR：0.57，95%CI：0.47-0.70，P<；0.00001)，1年PFS的中位持续时间分别为29%和14%。Tucatinib联合用药耐受性好，不良反应发生率低。结论：通过额外的随访，Tucatinib联合用药为HER2+转移性乳腺癌患者提供了有临床意义的生存益处。
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 similar to 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.