表皮生长因子受体酪氨酸激酶抑制剂联合化疗一线治疗表皮生长因子受体突变晚期非小细胞肺癌疗效及安全性的Meta分析
Efficacy and Safety of EGFR-TKI Combined with Chemotherapy for the First-line Treatment of EGFR-mutated Advanced Non-small Cell Lung Cancer：a Meta-analysis
背景 表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的靶向治疗已成为表皮生长因子受体（EGFR）突变晚期非小细胞肺癌（NSCLC）的规范治疗方案，但临床发现不可避免的原发性或继发性耐药最终导致了疾病进展。为此，寻找早期预测有效人群的标志物和探索延长或逆转继发性耐药的优化治疗方案成为国内外研究重点，EGFR-TKI的靶向联合治疗成为探索的模式之一。目的 依据国内外文献数据系统评价EGFR-TKI联合化疗一线治疗EGFR突变晚期NSCLC的疗效及安全性。方法 计算机检索PubMed、Embase、CochraneLibrary数据库发布的有关EGFRTKI联合化疗对比单药EGFR-TKI一线治疗EGFR突变晚期NSCLC患者疗效及安全性的随机对照试验，检索时间为建库至2023年11月。由2名研究者独立筛选文献、提取数据并评价纳入研究的偏倚风险，对无进展生存期（PFS）、总生存期（OS）、客观缓解率（ORR）、疾病控制率（DCR）以及≥3级不良反应等数据收集和分析。基于基线临床特征进行亚组分析，使用RevMan5.4.1版本进行数据统计分析。结果 纳入符合条件的10项研究，共2029例患者，其中EGFR-TKI联合化疗组1049例患者，单纯EGFR-TKI组980例患者。Meta分析结果显示，与单纯EGFR-TKI组相比，EGFR-TKI联合化疗组可延长EGFR突变晚期NSCLC患者的PFS（HR=0.54，95%CI=0.49~0.60，P<0.00001）和OS（HR=0.69，95%CI=0.59~0.79，P<0.00001）。与单纯EGFR-TKI组相比，EGFR-TKI联合化疗组可提高EGFR突变晚期NSCLC患者的ORR（OR=1.95，95%CI=1.57~2.42，P<0.00001）和DCR（OR=1.76，95%CI=1.13~2.74，P=0.01）。在伴随脑转移的患者中，与单纯EGFR-TKI治疗相比，EGFR-TKI联合化疗延长EGFR突变晚期NSCLC患者的PFS（HR=0.42，95%CI=0.34~0.52，P<0.00001）和OS（HR=0.69，95%CI=0.51~0.94，P=0.02）。在基线无脑转移的患者中，与单纯EGFR-TKI治疗相比，EGFR-TKI联合化疗延长EGFR突变晚期NSCLC患者的PFS（HR=0.62，95%CI=0.53~0.72，P<0.00001）。EGFR-TKI联合化疗治疗EGFR突变晚期NSCLC患者的≥3级不良反应发生率高于单纯EGFR-TKI治疗（OR=4.25，95%CI=2.74~6.61，P<0.00001）。结论 EGFR-TKI联合化疗可显著延长EGFR突变晚期NSCLC患者的一线PFS及OS，尤其是基线脑转移患者；但不良反应发生率增加，尤其是≥3级血液学毒性发生率，整体是安全可控的。
Background Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitorsEGFR-TKIs has become a standardized treatment option for epidermal growth factor receptorEGFR mutation-positive advanced non-small cell lung cancerNSCLCbut clinical findings of unavoidable primary or secondary resistance ultimately lead to disease progression. For this reasonfinding markers for early prediction of effective populations and exploring optimized therapeutic regimens to prolong or reverse secondary resistance have become the focus of research at home and abroadand targeted combination therapy with EGFR-TKI has become one of the modes explored. Objective To systematically evaluate the efficacy and safety of EGFR-TKI combined with chemotherapy for the first-line treatment of EGFR-mutated advanced non small cell lung cancer based on data from domestic and international literature. Methods Three professionally recognized databasesPubMedEMBASEand the Cochrane Librarywere searched for randomized controlled trials eligible for the efficacy and safety of EGFR-TKI combination chemotherapy versus single-agent EGFR-TKI for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer published from the time of construction to November 2023. Data on progression-free survivalPFSoverall survivalOSobjective remission rateORRdisease control rateDCRand grade 3 adverse events were collected and analyzed by two investigators who independently screened the literatureextracted the dataand evaluated the risk of bias of the included studies. Subgroup analyses were performed based on baseline clinical characteristicsand data were statistically analyzed using RevMan 5.4.1. Results Ten eligible studies with a total of 2 029 patients were includedincluding 1 049 patients in the experimental group of EGFR-TKI combined with standard chemotherapyand 980 patients in the control group of EGFR-TKI alone. Meta-analysis showed that compared with EGFR-TKI monotherapyEGFR-TKI combination chemotherapy prolonged PFSHR=0.5495%CI=0.49-0.60P<0.000 01and OSHR=0.6995%CI=0.59-0.79P<0.000 01. Compared with EGFR-TKI monotherapyEGFR-TKI combination chemotherapy improved ORROR=1.9595%CI=1.57-2.42P<0.000 01 and DCROR=1.7695%CI=1.13-2.74P=0.01 in patients with advanced NSCLC with EGFR mutations.In patients with concomitant brain metastasesEGFR-TKI combination chemotherapy prolonged PFSHR=0.4295%CI=0.34-0.52P<0.000 01 and OSHR=0.6995%CI=0.51-0.94P=0.02 in patients with EGFR-mutated advanced NSCLC compared with single-agent EGFR-TKI treatment.In patients without brain metastases at baselineEGFR-TKI combination chemotherapy prolonged PFS compared with single-agent EGFR TKI treatment in patients with advanced NSCLC with EGFR mutationsHR=0.6295%CI=0.53-0.72P<0.000 01. The incidence of grade 3 adverse reactions was higher with EGFR-TKI combination chemotherapy than with single-agent EGFRTKI treatment in patients with advanced NSCLC with EGFR mutationsOR=4.2595%CI=2.74-6.61P<0.000 01. The incidence of grade 3 adverse reactions was higher in the combination therapy group than in the monotherapy group. Conclusion EGFR-TKI combination chemotherapy significantly prolongs first-line PFS and OS in EGFR-mutated advanced non-small cell lung cancerespecially in patients with baseline brain metastases. The incidence of adverse events was increased in the combination therapy groupparticularly the incidence of grade 3 hematologic toxicitybut was overall safe and manageable.
史健、王亚静、侯冉、黄娅婕、段晓阳
医药卫生
非小细胞肺癌表皮生长因子受体突变表皮生长因子受体酪氨酸激酶抑制剂联合治疗Meta 分析
史健,王亚静,侯冉,黄娅婕,段晓阳.表皮生长因子受体酪氨酸激酶抑制剂联合化疗一线治疗表皮生长因子受体突变晚期非小细胞肺癌疗效及安全性的Meta分析[EB/OL].(2024-11-26)[2024-12-12].https://chinaxiv.org/abs/202411.00250.点此复制
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