吉非替尼一线用于晚期非小细胞肺癌精准治疗的Meta分析

Gefitinib in first-line precision treatment for patients with advanced non-small cell lung cancer:a Meta-analysis

目的比较吉非替尼单药与含铂双联化学疗法(化疗)一线精准治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的有效性和安全性,并探讨吉非替尼治疗NSCLC的优势人群。方法在Cochrane Library、Pub Med、Embase、中国知网、维普、中国生物医学文献数据库等数据库中检索关于吉非替尼单药与含铂双联化疗一线治疗晚期NSCLC的随机对照试验文献,检索时间为各数据库建库至2017年11月,进行数据提取和质量评价后,使用Rev Man 5.3软件进行Meta分析。结果共纳入4项随机对照试验,吉非替尼组968例,化疗组968例,受试者绝大多数为晚期肺腺癌患者且均为东亚人种。Meta分析结果显示:在总人群或表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变阳性的人群中,吉非替尼组在无进展生存期(progressionfree survival,PFS)和客观有效率(objective response rate,ORR)方面均优于化疗组[总人群PFS:风险比(hazard ratio,HR)=0.76,95%置信区间(confidence interval,CI)(0.67,0.85),P<0.000 01;总人群ORR:危险比(risk ratio,RR)=1.30,95%CI(1.15,1.47),P<0.000 1;EGFR突变阳性人群PFS:HR=0.42,95%CI(0.35,0.50),P<0.000 01;EGFR突变阳性人群ORR:RR=1.92,95%CI(1.46,2.52),P<0.000 01],但在总生存期(overall survival,OS)方面两组差异无统计学意义(P>0.05);而对于EGFR突变阴性的受试者,吉非替尼组PFS较化疗组更差[HR=2.09,95%CI(1.05,4.13),P=0.03],在ORR和OS方面差异无统计学意义(P>0.05)。亚组分析结果显示:对于女性、PS评分0或1分、无吸烟史的患者,吉非替尼组在PFS方面优于化疗组(P<0.05);但对于各类患者,吉非替尼在延长OS方面较化疗组均无明显差异。不良事件方面:吉非替尼组皮肤黏膜异常、腹泻、转氨酶异常发生率较化疗组更高,而脱发、呕吐、恶心、血液系统紊乱、神经毒性反应等发生率均较化疗组更低,差异有统计学意义(P<0.05)。结论基于目前研究,吉非替尼在东亚裔肺腺癌患者中的优势人群为突变阳性、女性、PS评分0或1、无吸烟史的患者。吉非替尼主要不良反应为皮肤黏膜损害,但对消化系统和血液系统影响较化疗更小。该药在提高晚期NSCLC总生存率方面较化疗并无明显优势。

Objective To evaluate the safety and efficacy of gefitinib in comparison with platinum-based doublets chemotherapy as a first-line precision treatment for advanced non-small cell lung cancer （NSCLC）, and find the benefit population of gefitinib. Methods The Cochrane Library, PubMed, Embase, China National Knowledge Internet, VIP database and China Biology Medicine database were searched to collect the randomized contolled trials （RCTs） of gefitinib vs. platinum-based doublets chemotherapy for advanced NSCLC from inception to November, 2017. The data in the included RCTs were extracted, and the qualities were assessed in accordance with Cochrane Collaboration, and a Meta-analysis was conducted with RevMan 5.3 software. Results Four trials were included, including 968 subjects in the gefitinib group and 968 subjects in the chemotherapy group, and a majority of the subjects were diagnosed advanced adenocarcinoma, and all of the subjects were East Asians. The results of Meta-analysis showed that in all population or patients with epidermal growth factor receptor （EGFR） mutation-positive, gefitinib was better than chemotherapy in progression-free survival （PFS） [in all population： hazard ratio （HR）--0.76, 95% confdence interval （CI） （0.67, 0.85）, P〈0.000 01; in patients with EGFR mutation-positive： HR=0.42, 95%CI （0.35, 0.50）, P〈0.000 01] and objective response rate （ORR） [in all population： risk ratio （RR）=I.30, 95%CI （1.15, 1.47）, P〈0.000 1; in patients with EGFR mutation- positive： RR=1.92, 95%CI （1.46, 2.52）, P〈0.000 01], and there was no significant difference between the two groups in overall survival （OS） （P〉0.05）; but in EGFR mutation-negative, chemotherapy was better than gefitinib in PFS [HR=2.09, 95%CI （1.05, 4.13）, P=0.03]. Subgroup analysis showed that in female patients, for patients with Performance Status （PS） score 0 or 1, and the ones who never smoked, gefitinib was better than chemotherapy in PFS （P〈0.05）; but there was no significant difference between the two groups in OS （P〉0.05）. The incidences of rash, itching, dry skin, paronychia, diarrhea, aminotransferase abnormality were higher in the gefitinib group （P〈0.05）, while the incidences of hair loss, vomiting, nausea, constipation, anorexia, leukopenia, thrombocytopenia, and neutropenia, anemia, fatigue, nerve toxicity reaction were higher in the chemotherapy group （P〈0.05）. Conclutions Based on the current evidence, in patients with adenocarcinoma of East Asians, the benefit population are those with the characteristics of EGFR mutation-positive, female, never smoking, and PS 0 or 1. In the aspect of safety, the common adverse drug events in subjects treated with gefitinib are the damage of skin mucous membrane, but the incidences of digestive system diseases and the blood system diseases are less in patients treated with gefitinib than those with chemotherapy.