Gefitinib or Erlotinib as Maintenance Therapy in Patients with Advanced Stage Non-Small Cell Lung Cancer: A Systematic Review

Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), gefitinib and erlotinib have been tested as maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC). The studies are quite heterogenous regarding study size and populations, and a synopsis of these data could give some more insight in the role of maintenance therapy with TKI.
Methods
In September 2012 we performed a search in the pubmed, EMBASE and Cochrane library databases for randomized phase III trials exploring the role of gefitinib or erlotinib in advanced non-small cell lung cancer. Through a rigorous selection process with specific criteria, five trials (n = 2436 patients) were included for analysis. Standard statistical methods for meta-analysis were applied.
Results
TKIs (gefitinib and erlotinib) significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50–0.76, I2 = 78.1%] and overall survival (HR 0.84, 95% CI 0.76–0.93, I2 = 0.0%) compared with placebo or observation. The PFS benefit was consistent in all subgroups including stage, sex, ethnicity, performance status, smoking status, histology, EGFR mutation status, and previous response to chemotherapy. Patients with clinical features such as female, never smoker, adenocarcinoma, Asian ethnicity and EGFR mutation positive had more pronounced PFS benefit. Overall survival benefit was observed in patients with clinical features such as female, non-smoker, smoker, adenocarcinoma, and previous stable to induction chemotherapy. Severe adverse events were not frequent. Main limitations of this analysis are that it is not based on individual patient data, and not all studies provided detailed subgroups analysis.
Conclusions
The results show that maintenance therapy with erlotinib or gefitinib produces a significant PFS and OS benefit for unselected patients with advanced NSCLC compared with placebo or observation. Given the less toxicity of TKIs than chemotherapy and simple oral administration, this treatment strategy seems to be of important clinical value.

背景：表皮生长因子受体（Epidermal growth factor receptor, EGFR）酪氨酸激酶抑制剂（Tyrosine kinase inhibitors, TKI）吉非替尼与厄洛替尼，已被作为晚期非小细胞肺癌（Non-small-cell lung cancer, NSCLC）患者的维持治疗方案开展相关研究。既往相关研究在样本量与研究人群方面存在较强异质性，对这些数据进行综合分析，或可进一步阐明TKI维持治疗的临床价值。
方法：2012年9月，我们在PubMed、EMBASE及Cochrane图书馆数据库中，检索探索吉非替尼或厄洛替尼治疗晚期非小细胞肺癌的随机Ⅲ期临床试验。经严格的纳入筛选标准遴选后，最终纳入5项临床试验（共2436例患者）进行荟萃分析，并采用标准的荟萃分析统计方法。
结果：相较于安慰剂组或观察组，酪氨酸激酶抑制剂（TKI，吉非替尼与厄洛替尼）可显著延长患者的无进展生存期（Progression-free survival, PFS）[风险比（Hazard ratio, HR）=0.63，95%置信区间（Confidence interval, CI）：0.50~0.76，I²=78.1%]，同时改善总生存期[风险比（HR）=0.84，95%置信区间（CI）：0.76~0.93，I²=0.0%]。该无进展生存期获益在所有亚组中均保持一致，包括临床分期、性别、种族、体能状态、吸烟状态、组织学类型、EGFR突变状态及既往化疗应答情况。其中，女性、从不吸烟者、腺癌患者、亚裔人群及EGFR突变阳性患者的无进展生存期获益更为显著。总生存期获益则见于女性、非吸烟者、吸烟者、腺癌患者及诱导化疗后病情稳定的患者。严重不良事件发生率较低。本分析的主要局限性在于未采用患者个体水平数据，且并非所有纳入研究均提供了详细的亚组分析结果。
结论：研究结果显示，相较于安慰剂组或观察组，厄洛替尼或吉非替尼的维持治疗可显著改善晚期非小细胞肺癌未筛选患者的无进展生存期与总生存期。鉴于TKI的毒性低于化疗且给药方式为简便的口服给药，该治疗策略具有重要的临床应用价值。