Liang Wenhua, Wu Xuan, Fang Wenfeng, Zhao Yuanyuan, Yang Yunpeng, Hu Zhihuang, Xue Cong, Zhang Jing, Zhang Jianwei, Ma Yuxiang, Zhou Ting, Yan Yue, Hou Xue, Qin Tao, Dinglin Xiaoxiao, Tian Ying, Huang Peiyu, Huang Yan, Zhao Hongyun, Zhang Li
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
PLoS One. 2014 Feb 12;9(2):e85245. doi: 10.1371/journal.pone.0085245. eCollection 2014.
Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons.
We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments.
Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib.
The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.
几种表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKIs），包括厄洛替尼、吉非替尼、阿法替尼和埃克替尼，目前可用于治疗携带EGFR突变的晚期非小细胞肺癌（NSCLC）患者。然而，尚未有在突变人群中对这些TKIs进行的直接对比试验报道，这为间接和综合比较提供了空间。
我们检索电子数据库以获取符合条件的文献。计算客观缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）的汇总数据。针对不同结局建立适当的网状结构以纳入所有证据。基于贝叶斯网络的多治疗比较（MTCs）整合了所有纳入治疗的疗效和特定毒性。
纳入了12项研究EGFR-TKIs的III期随机对照试验，涉及1821名EGFR突变参与者。对于突变患者，通过直接荟萃分析发现，EGFR-TKIs的加权汇总ORR和1年PFS显著优于标准化疗（ORR：66.6%对30.9%，OR 5.46，95%CI 3.59至8.30，P<0.00001；1年PFS：42.9%对9.7%，OR 7.83，95%CI 4.50至13.61；P<0.00001）。在网状荟萃分析中，就所有结局指标而言，这四种TKIs在疗效上未发现统计学显著差异。秩概率趋势分析显示，作为最有效治疗的累积概率分别为（ORR、1年PFS、1年OS、2年OS）：厄洛替尼（51%、38%、14%、19%）、吉非替尼（1%、6%、5%、16%）、阿法替尼（29%、27%、30%、27%）和埃克替尼（19%、29%、无数据、无数据）。然而，与吉非替尼和埃克替尼相比，阿法替尼和厄洛替尼的皮疹和腹泻更为严重。
当前研究表明，厄洛替尼、吉非替尼、阿法替尼和埃克替尼对EGFR突变患者具有同等疗效，但呈现不同的疗效-毒性模式。与吉非替尼和埃克替尼相比，厄洛替尼和阿法替尼显示出潜在更好的疗效，但毒性显著更高。
