Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study
Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study
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DOI：
10.1016/s1470-2045(11)70385-0
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发表时间：
2012-03-01
期刊：
影响因子：
51.1
通讯作者：
Esteban Gonzalez, Emilio
中科院分区：
文献类型：
--
作者：
Ciuleanu, Tudor;Stelmakh, Lilia;Esteban Gonzalez, Emilio
背景厄洛替尼、多西他赛和培美曲塞已被批准作为非小细胞肺癌（NSCLC）的二线治疗药物，但尚无来自大型临床试验的头对头数据。我们进行了特罗凯在治疗晚期非小细胞肺癌（TITAN）的研究，以评估二线厄洛替尼与化疗的疗效和耐受性，在难治性NSCLC患者。方法TITAN是一个国际性的，随机多中心，开放标签，3期研究，在24个国家的77个网站。未接受过化疗的局部晚期、复发性或转移性NSCLC患者接受了最多4个周期的一线铂双联化疗，之后，在化疗期间或化疗后立即发生疾病进展的患者可入组TITAN。通过最小化方法将入组患者随机分配（1：1），以确保平衡分层，接受厄洛替尼150 mg/天或化疗（标准多西他赛或培美曲塞方案，由治疗研究者决定），直至出现不可接受的毒性、疾病进展或死亡。患者按疾病分期、东部肿瘤协作组体力状态、吸烟史和居住地区分层。主要终点是意向治疗人群的总生存期。泰坦由于招募缓慢而过早停止。该研究在ClinicalTrials.gov注册，编号NCT 00556322。结果2006年4月10日至2010年2月24日期间，2590例未经化疗的患者接受了一线铂双联化疗，其中424例疾病进展并入选TITAN。203例患者被随机分配接受厄洛替尼治疗，221例患者被分配接受化疗。厄洛替尼组的中位随访时间为27.9个月（IQR 11.0-36.0），化疗组为24.8个月（12.1-41.6）。厄洛替尼组的中位总生存期为5.3个月（95% CI 4.0-6.0），化疗组为5.5个月（4.4-7.1）（风险比[HR] 0.96，95% CI 0.78-1.19;对数秩p=0.73）。各组的不良事件特征与既往研究一致。皮疹（厄洛替尼组98/196 [50%] vs化疗组10/213 [5%]，所有级别; 3级或4级9 [5%] vs 0）和腹泻（36 [18%]对所有年级的4 [2%]; 5例[3%] vs 0例3级或4级）是厄洛替尼最常见的治疗相关不良事件，而脱发（所有级别均为0例vs 23例[11%];无vs一[
Background Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC.Methods TITAN was an international, randomised multicentre, open-label, phase 3 study that was done at 77 sites in 24 countries. Chemotherapy-naive patients with locally advanced, recurrent, or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy, after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN. Enrolled patients were randomly assigned (1: 1) by a minimisation method to ensure balanced stratification, to receive erlotinib 150 mg/day or chemotherapy (standard docetaxel or pemetrexed regimens, at the treating investigators' discretion), until unacceptable toxicity, disease progression, or death. Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, smoking history, and region of residence. The primary endpoint was overall survival in the intention-to-treat population. TITAN was halted prematurely because of slow recruitment. This study is registered with ClinicalTrials.gov, number NCT00556322.Findings Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27.9 months (IQR 11.0-36.0) in the erlotinib group and 24.8 months (12.1-41.6) in the chemotherapy group. Median overall survival was 5.3 months (95% CI 4.0-6.0) with erlotinib and 5.5 months (4.4-7.1) with chemotherapy (hazard ratio [HR] 0.96, 95% CI 0.78-1.19; log-rank p=0.73). The adverse-event profile of each group was in line with previous studies. Rash (98/196 [50%] in the erlotinib group vs 10/213 [5%] in the chemotherapy group for all grades; nine [5%] vs none for grade 3 or 4) and diarrhoea (36 [18%] vs four [2%] for all grades; five [3%] vs none for grade 3 or 4) were the most common treatment-related adverse events with erlotinib, whereas alopecia (none vs 23 [11%] for all grades; none vs one [