Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial
Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial
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DOI：
10.1016/s1470-2045(15)70124-5
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发表时间：
2015-05-01
期刊：
影响因子：
51.1
通讯作者：
Cohen, Ezra E. W.
中科院分区：
文献类型：
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作者：
Machiels, Jean-Pascal H.;Haddad, Robert I.;Cohen, Ezra E. W.
背景头颈部复发或转移性鳞状细胞癌（HNSCC）患者在接受一线铂治疗后预后较差，治疗选择很少。阿法替尼是一种不可逆的ERBB家族阻滞剂，在这种情况下的2期研究中显示出疗效。我们的目的是评估阿法替尼与甲氨蝶呤作为二线治疗在铂基治疗中或之后进展的复发或转移性HNSCC患者的疗效和安全性。在这项开放标签的3期随机对照试验中，研究人员在19个国家的101个中心进行了研究，招募了年龄在18岁或以上的组织学或细胞学证实的复发性、转移性或两者兼有的HNSCC患者，这些患者在一线铂类药物治疗或治疗后进展，不适合补救性手术或放疗，并且东部肿瘤合作组（ECOG）的表现状态为0或1。在这种情况下，以前接受过一种以上的全身治疗是不允许的；先前允许使用egfr靶向抗体治疗（但不允许使用egfr靶向酪氨酸激酶抑制剂）。我们按2∶1的比例随机分配符合条件的患者接受口服阿法替尼（40 mg/天）或静脉注射甲氨蝶呤（40 mg/m(2) /周），根据ECOG表现状态和既往复发或转移性疾病的egfr靶向抗体治疗进行分层。随机化是通过交互式语音或基于网络的响应系统集中完成的。临床医生和患者不受治疗分配的影响；采用盲法对肿瘤反应进行独立评价。主要终点是由独立的中央影像审查委员会评估的无进展生存期。在意向治疗人群中进行了疗效分析，在接受至少一剂研究药物的患者中进行了安全性分析。这项正在进行的研究已在ClinicalTrials.gov注册，编号NCT01345682。在2012年1月10日至2013年12月12日期间，我们招募了483名患者，随机分配322名阿法替尼组和161名甲氨蝶呤组。中位随访6.7个月（IQR 3.1-9.0）后，阿法替尼组的无进展生存期比甲氨蝶呤组更长（中位阿法替尼组为2.6个月[95% CI 2.0-2.7]，甲氨蝶呤组为1.7个月[1.5-2.4]；风险比[HR] 0.80 [95% CI 0.65-0.98], p=0.030）。最常见的3级或4级药物相关不良事件是皮疹或痤疮（阿法替尼组320例患者中有31例[10%]，甲氨蝶呤组160例患者中无一例）、腹泻（30例[9%]对3例[2%]）、口炎（20例[6%]对13例[8%]）、疲劳（18例[6%]对5例[3%]）和中性粒细胞减少（1例[8%]）。
Background Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy.Methods In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2: 1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682.Findings Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6.7 months (IQR 3.1-9.0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2.6 months [95% CI 2.0-2.7] for the afatinib group vs 1.7 months [1.5-2.4] for the methotrexate group; hazard ratio [HR] 0.80 [95% CI 0.65-0.98], p=0.030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [