Comparative efficacy and safety of first-line EGFR-TKIs for advanced non-small cell lung cancer:a network meta-analysis
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摘要:
目的 比较吉非替尼、厄洛替尼和阿法替尼一线治疗晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)的有效性和安全性。 方法 系统检索2008年12月-2018年12月收录在PubMed、EMBASE和The Cochrane Library中的相关文献进行贝叶斯网状meta分析。 结果 共纳入10篇文献, 包含2 275名患者。就有效性而言, 累积排序概率图下面积(surface under the cumulative ranking, SUCRA)显示厄洛替尼在无进展生存期(progression-free survival, PFS)方面最佳(0.88), 阿法替尼在客观反应率(objective response rate, ORR)(0.82)和疾病控制率(disease control rate, DCR)(0.86)方面最佳, 吉非替尼在PFS(0.45), ORR(0.42)和DCR(0.45)方面均最差。就安全性而言, 仅厄洛替尼与含铂的双重化疗在3~4级不良反应率(OR=0.29, 95% CI:0.08~0.98)和停药率(OR=0.14, 95% CI:0.01~0.86)方面的差异有统计学意义。排序结果也支持厄洛替尼的安全性最好。SUCRA结果提示吉非替尼(0.31)发生3~4级不良反应的可能性比阿法替尼(0.57)小, 其(0.44)发生停药的可能性与阿法替尼(0.41)相似。 结论 厄洛替尼可能是三者中一线治疗晚期NSCLC的首选药物。 Abstract:Objective To compare the efficacy and safety of gefitinib, erlotinib, and afatinib in the first-line treatment of advanced non-small cell lung cancer(NSCLC). Methods PubMed, EMBASE, and The Cochrane Library were searched to identify the relevant literatures published from December 2008 to December 2018. Bayesian network meta-analysis was carried out to rank the three treatments. Results A total of ten eligible studies involving 2275 patients were enrolled. In terms of efficacy, the surface under the cumulative ranking(SUCRA) indicated that erlotinib performed best in progression-free survival(PFS)(0.88), afatinib performed best in objective response rate(ORR)(0.82) and disease control rate(DCR)(0.86), gefitinib performed worst in PFS(0.45), ORR(0.42), and DCR(0.45). For safety, the differences of grade 3 or 4 adverse events rate(OR=0.29, 95%CI:0.08-0.98) and discontinuation rate(OR=0.14, 95%CI:0.01-0.8) between erlotinib and the platinum-based doublet chemotherapy were statistically significant. The ranking results also supported that erlotinib was the safest. SUCRA results suggested that gefitinib(0.31) had a lower grade 3 or 4 adverse events rate than afatinib(0.57), and the possibility of discontinuation in gefitinib(0.44) was similar to that of afatinib(0.41). Conclusion Erlotinib might be the preferred first-line treatment for advanced NSCLC after weighing and balancing the benefits and risks. -
Key words:
- Non-small cell lung cancer /
- Gefitinib /
- Erlotinib /
- Afatinib /
- First-line treatment /
- Network meta-analysis
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图 2 纳入研究的偏倚风险评估结果
Figure 2. The assessment results of the risk of bias for included trials
图 3 网状关系图
注:1=含铂的双重化疗, 2=吉非替尼, 3=厄洛替尼, 4=阿法替尼; A=PFS, B=ORR, C=DCR, D=3~4级不良反应率, E=停药率。
Figure 3. The network diagrams
表 1 纳入研究的基本特征
Table 1. Characteristics of the included trials
纳入研究 种族 治疗措施 例数 中位年龄(岁) 女性占比(%) 非吸烟者占比(%) 腺癌占比(%) IPASS(2009, Ⅲ) 亚洲 吉非替尼 132 - 81.8 93.9 - 卡铂+紫杉醇 129 - 79.8 94.6 - NEJ002(2010, Ⅲ) 亚洲 吉非替尼 114 63.9 63.2 65.8 90.4 卡铂+紫杉醇 114 62.6 64 57.9 96.5 WJTOG3405(2010, Ⅲ) 亚洲 吉非替尼 86 64 68.6 70.9 96.5 顺铂+多烯紫杉醇 86 64 69.8 66.3 97.7 OPTIMAL(2011, Ⅲ) 亚洲 厄洛替尼 82 57 58.5 72 87.8 吉西他滨+卡铂 72 59 59.7 69.4 86.1 First-SIGNAL(2012, Ⅲ) 亚洲 吉非替尼 26 - - 100 100 吉西他滨+顺铂 16 - - 100 100 EURTAC(2012, Ⅲ) 欧洲 厄洛替尼 86 63.4 67.4 66.3 95.3 顺铂+多烯紫杉醇/吉西他滨 87 64.2 78.2 72.4 89.7 LUX-Lung 3(2013, Ⅲ) 全球 阿法替尼 230 61.5 63.9 67.4 100 顺铂+培美曲塞 115 61 67 70.4 100 LUX-Lung 6(2014, Ⅲ) 亚洲 阿法替尼 242 58 64 74.8 100 吉西他滨+顺铂 122 58 68 81.1 100 ENSURE(2015, Ⅲ) 亚洲 厄洛替尼 110 57.5 61.8 71.8 94.5 顺铂+吉西他滨 107 56 60.7 69.2 94.4 LUX-Lung 7(2016, ⅡB) 全球 阿法替尼 160 63 56.9 66.3 99.4 吉非替尼 159 63 66.7 66.7 99.4 注:“-”表示数据缺失。 
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表 2 点分法分析结果
Table 2. The results of node-splitting analysis
直接比较结果 间接比较结果 合并结果 P值 PFS 2 vs.1 -0.84(-1.40, -0.27) -0.59(-1.90, 0.75) -0.80(-1.30, -0.33) 0.664 4 vs.1 -0.90(-1.70, -0.13) -1.20(-2.40, 0.08) -0.97(-1.60, -0.39) 0.664 4 vs.2 -0.31(-1.40, 0.76) -0.06(-1.00, 0.87) -0.17(-0.82, 0.46) 0.673 ORR 2 vs.1 4.40(2.30, 9.20) 3.00(0.66, 14.00) 4.00(2.40, 7.30) 0.561 4 vs.1 5.60(2.30, 14.00) 8.10(2.10, 35.00) 6.10(3.20, 12.00) 0.563 4 vs.2 1.80(0.53, 6.50) 1.30(0.38, 3.70) 1.50(0.72, 3.00) 0.572 DCR 2 vs.1 2.20(1.10~4.90) 1.90(0.44~8.40) 2.10(1.20~3.90) 0.829 4 vs.1 2.90(1.30, 6.60) 3.40(0.84, 15.00) 3.00(1.60, 5.60) 0.830 4 vs.2 1.50(0.45, 5.10) 1.30(0.41, 4.00) 1.40(0.68, 2.80) 0.829 3~4级不良反应率 2 vs.1 0.27(0.02, 3.00) 0.52(0.03, 9.90) 0.36(0.07, 1.80) 0.658 4 vs.1 0.62(0.11, 3.50) 0.33(0.01, 10.00) 0.55(0.15, 2.10) 0.659 4 vs.2 1.20(0.11, 14.00) 2.30(0.11, 44.00) 1.50(0.30, 8.10) 0.671 注:对PFS, 表中所示为合并的HR的自然对数值及其95%CI; 对其他结局指标, 表中所示为合并的OR值及其95%CI。1=含铂的双重化疗, 2=吉非替尼, 4=阿法替尼; HR=风险比, OR=优势比, CI=置信区间。
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表 3 各结局指标中不同治疗措施的相对治疗效果
Table 3. The relative treatment effects of different treatments for each outcome measure[4]
A PFS 阿法替尼 1.30(0.56~2.90) 厄洛替尼 0.84(0.44~1.60) 0.66(0.31~1.40) 吉非替尼 0.38(0.21~0.67) 0.30(0.16~0.53) 0.45(0.28~0.72) 含铂的双重化疗 B ORR 阿法替尼 1.00(0.40~2.60) 厄洛替尼 1.50(0.72~3.00) 1.50(0.60~3.40) 吉非替尼 6.10(3.20~12.00) 5.90(3.10~12.00) 4.00(2.40~7.30) 含铂的双重化疗 C DCR 阿法替尼 1.10(0.62~2.10) 厄洛替尼 1.40(0.87~2.30) 1.20(0.66~2.30) 吉非替尼 3.00(2.00~4.40) 2.60(1.60~4.20) 2.10(1.40~3.20) 含铂的双重化疗 D 3~4级不良反应率 阿法替尼 1.90(0.31~12.00) 厄洛替尼 1.50(0.30~8.00) 0.81(0.10~6.30) 吉非替尼 0.55(0.14~2.10) 0.29(0.08~0.98) 0.36(0.07~1.80) 含铂的双重化疗 E停药率 阿法替尼 1.70(0.11~44.00) 厄洛替尼 0.99(0.05~22.00) 0.58(0.01~34.00) 吉非替尼 0.24(0.03~2.10) 0.14(0.01~0.86) 0.24(0.01~11.00) 含铂的双重化疗 注:结果以合并的HR/OR及其95% CI表示(列治疗措施vs.行治疗措施)。对于A, HR < 1支持列治疗措施。对于B和C, OR > 1支持列治疗措施。对于D和E, OR < 1支持列治疗措施。HR=风险比; OR=优势比。
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表 4 各结局指标中不同治疗措施的排序概率和SUCRA值
Table 4. The rank probabilities and SUCRAs of different treatments for each outcome measure
治疗措施 排序第一 排序第二 排序第三 排序第四 SUCRA值 A PFS 含铂的双重化疗 0.00 0.00 0.01 0.99 0.00 吉非替尼 0.05 0.26 0.68 0.00 0.45 厄洛替尼 0.72 0.20 0.08 0.00 0.88 阿法替尼 0.23 0.54 0.23 0.00 0.66 B ORR 含铂的双重化疗 0.00 0.00 0.00 1.00 0.00 吉非替尼 0.04 0.19 0.77 0.00 0.42 厄洛替尼 0.44 0.41 0.15 0.00 0.76 阿法替尼 0.53 0.40 0.08 0.00 0.82 C DCR 含铂的双重化疗 0.00 0.00 0.00 1.00 0.00 吉非替尼 0.05 0.25 0.71 0.00 0.45 厄洛替尼 0.32 0.44 0.24 0.00 0.69 阿法替尼 0.64 0.32 0.05 0.00 0.86 D 3~4级不良反应率 含铂的双重化疗 0.80 0.16 0.04 0.00 0.92 吉非替尼 0.06 0.17 0.42 0.35 0.31 厄洛替尼 0.02 0.14 0.28 0.56 0.20 阿法替尼 0.12 0.54 0.26 0.08 0.57 E停药率 含铂的双重化疗 0.77 0.18 0.05 0.00 0.91 吉非替尼 0.18 0.27 0.25 0.31 0.44 厄洛替尼 0.01 0.22 0.24 0.53 0.24 阿法替尼 0.04 0.33 0.46 0.17 0.41 注:SUCRA=累积排序概率图下面积。
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