Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial
Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial
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DOI：
10.1016/s1470-2045(11)70034-1
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发表时间：
2011-04-01
期刊：
影响因子：
51.1
通讯作者：
Clement, Paul M. J.
中科院分区：
文献类型：
--
作者：
Machiels, Jean-Pascal;Subramanian, Somasundaram;Clement, Paul M. J.
背景：目前没有治疗方法可以提高铂类化疗失败后复发或转移的头颈部鳞状细胞癌患者的生存率。我们旨在评估zalutumumab（一种靶向表皮生长因子受体的人IgG 1单克隆抗体）对此类患者总生存期的有效性和安全性。方法在我们的开放标签、平行组、3期随机试验中，我们随机分配了头颈部鳞状细胞癌患者，这些患者被认为是标准治疗无法治愈的，WHO体能状态为0-2，在欧洲、巴西和加拿大的医疗中心，以2：1的比例接受zalutumumab+最佳支持治疗（zalutumumab组）或最佳支持治疗+可选的甲氨蝶呤（对照组）。通过集中式交互式语音应答系统进行随机化，按体能状态分层。当随机化代码破盲时，在完成相关数据的累积和清理后，对数据进行分析。独立审查委员会（对治疗分配设盲）根据实体瘤缓解评价标准评估肿瘤缓解和疾病进展。基于皮疹，通过个体剂量滴定每周给予扎鲁木单抗。在预先设定的231例死亡后，我们将所有随机化患者纳入生存分析，并将所有接受至少一次治疗的患者纳入安全性分析。主要终点是总生存期，但也评估了无进展生存期。该试验注册于ClinicalTrials.gov，NCT 00382031。结果我们将286名合格患者中的191名（67%）随机分配到zalutumumab组，95名（33%）分配到对照组。zalutumumab组的中位总生存期为6.7个月（95% CI 5.8-7.0），对照组为5.2个月（4.1-6.4）（按WHO体力状态分层的死亡风险比[HR]为0.77，97.06% CI 0.57-1.05;未校正p=0.0648）。zalutumumab组的无进展生存期长于对照组（按WHO体能状态分层的进展或死亡的HR为0.63，95% CI 0.47-0.84; p=0.0012）。189名给予zalutumumab的患者和94名对照被纳入安全性分析。最常见的3-4级不良事件是皮疹（zalutumumab组39例[21%]患者vs对照组0例），贫血（11例[6%] vs 5例[5%]）和肺炎（9例[5%] vs 2例[2%]）。zalutumumab组有28例（15%）患者发生3/4级感染，而对照组有8例（9%）。最常见的严重不良事件是肿瘤出血（28例[15%] zalutumumab组患者vs 13例[14%]对照组患者），肺炎（13例[7%] vs 3例[3%]）和吞咽困难（11 [6%]对2 [2%]）。解释虽然zalutumumab没有增加总生存率，铂类化疗失败的头颈部复发性鳞状细胞癌患者的无进展生存期延长。根据皮疹进行扎鲁木单抗剂量滴定是安全的。
Background No treatments are presently available to increase survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy. We aimed to assess efficacy and safety of zalutumumab, a human IgG1 monoclonal antibody targeting the epidermal growth factor receptor, for overall survival in such patients.Methods In our open-label, parallel-group, phase 3, randomised trial, we randomly allocated patients with squamous-cell carcinoma of the head and neck who were regarded as incurable with standard therapy, a WHO performance status of 0-2, and progressive disease within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best supportive care (zalutumumab group) or best supportive care with optional methotrexate (control group) at medical centres in Europe, Brazil, and Canada. Randomisation was done via a centralised interactive voice-response system, stratified by performance status. Data were analysed when the randomisation code was broken, after the completion of the accrual and cleaning of the relevant data. An independent review committee, masked to treatment assignment, assessed tumour response and disease progression according to response evaluation criteria in solid tumours. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. After a prespecified 231 deaths, we included all randomised patients in the survival analyses and all patients receiving at least one session of therapy in the safety analysis. The primary endpoint was overall survival, although progression-free survival was also assessed. This trial is registered with ClinicalTrials.gov, NCT00382031.Findings We randomly allocated 191 (67%) of 286 eligible patients to the zalutumumab group and 95 (33%) to the control group. Median overall survival was 6.7 months (95% CI 5.8-7.0) in the zalutumumab group and 5.2 months (4.1-6.4) in the control group (hazard ratio [HR] for death, stratified by WHO performance status, was 0.77, 97.06% CI 0.57-1.05; unadjusted p=0.0648). Progression-free survival was longer in the zalutumumab group than in the control group (HR for progression or death, stratified by WHO performance status, was 0.63, 95% CI 0.47-0.84; p=0.0012). 189 patients given zalutumumab and 94 controls were included in the safety analysis. The most common grade 3-4 adverse events were rash (39 [21%] patients in the zalutumumab group vs none in the control group), anaemia (11 [6%] vs five [5%]), and pneumonia (nine [5%] vs two [2%]). 28 (15%) patients in the zalutumumab group had grade 3/4 infections compared with eight (9%) in the control group. The most common serious adverse events were tumour haemorrhage (28 [15%] patients given zalutumumab vs 13 [14%] controls), pneumonia (13 [7%] vs three [3%]), and dysphagia (11 [6%] vs two [2%]).Interpretation Although zalutumumab did not increase overall survival, progression-free survival was extended in patients with recurrent squamous-cell carcinoma of the head and neck who had failed platinum-based chemotherapy. Zalutumumab dose titration on the basis of rash is safe.