Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Lancet Oncol. 2015 May;16(5):583-94. doi: 10.1016/S1470-2045(15)70124-5. Epub 2015 Apr 16.
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.
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.
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 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients.
Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC.
Boehringer Ingelheim.
对于接受过一线铂类治疗后进展的复发性或转移性头颈部鳞状细胞癌（HNSCC）患者，预后较差，治疗选择有限。阿法替尼是一种不可逆的 ERBB 家族阻滞剂，在该治疗环境下的 2 期研究中显示出疗效。我们旨在评估阿法替尼与甲氨蝶呤作为复发性或转移性 HNSCC 患者的二线治疗方案，这些患者在铂类治疗后或之后出现进展，无法进行挽救性手术或放疗，且东部肿瘤协作组（ECOG）体能状态为 0 或 1。在此情况下，不允许之前接受过多种全身治疗方案；允许之前接受过针对 EGFR 的靶向抗体治疗（但不包括针对 EGFR 的酪氨酸激酶抑制剂）。在 19 个国家的 101 个中心进行的这项开放标签、3 期、随机对照试验中，我们招募了年龄在 18 岁及以上、组织学或细胞学证实的 HNSCC 复发、转移或两者均有的患者，这些患者在接受一线铂类治疗后或之后出现进展，无法进行挽救性手术或放疗，且 ECOG 体能状态为 0 或 1。在此情况下，不允许之前接受过多种全身治疗方案；允许之前接受过针对 EGFR 的靶向抗体治疗（但不包括针对 EGFR 的酪氨酸激酶抑制剂）。我们按照 ECOG 体能状态和针对复发性或转移性疾病的之前的 EGFR 靶向抗体治疗，将符合条件的患者以 2:1 的比例随机分配接受口服阿法替尼（每天 40mg）或静脉注射甲氨蝶呤（每周 40mg/m2）。随机分配在中央进行，采用交互式语音或基于网络的应答系统。临床医生和患者对治疗分配不知情；肿瘤反应的独立评估以盲法进行。主要终点是独立中心影像学评估委员会评估的无进展生存期。疗效分析基于意向治疗人群，安全性分析基于至少接受过一剂研究药物的患者。这项正在进行的研究在 ClinicalTrials.gov 注册，编号为 NCT01345682。
在 2012 年 1 月 10 日至 2013 年 12 月 12 日期间，我们共纳入 483 名患者，并将 322 名患者随机分配至阿法替尼组，161 名患者分配至甲氨蝶呤组。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长于甲氨蝶呤组（阿法替尼组的中位无进展生存期为 2.6 个月[95%CI，2.0-2.7]，而甲氨蝶呤组为 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 名患者中有 31 名[10%]，而甲氨蝶呤组 160 名患者中无 1 名）、腹泻（阿法替尼组 30 名[9%] vs 甲氨蝶呤组 3 名[2%]）、口腔炎（阿法替尼组 20 名[6%] vs 甲氨蝶呤组 13 名[8%]）、疲劳（阿法替尼组 18 名[6%] vs 甲氨蝶呤组 5 名[3%]）和中性粒细胞减少症（阿法替尼组 1 名[<1%] vs 甲氨蝶呤组 11 名[7%]）；阿法替尼治疗组 44 名（14%）和甲氨蝶呤治疗组 18 名（11%）患者发生严重不良事件。
阿法替尼治疗与无进展生存期的显著改善相关，且具有可管理的安全性特征。这些发现为该患者人群的治疗提供了重要的新见解，并支持进一步研究 HNSCC 中不可逆的 ERBB 家族阻滞剂。
勃林格殷格翰。
