背景:酪氨酸激酶抑制剂(TKIs)是表皮生长因子受体(EGFR)突变的非小细胞肺癌(NSCLC)的标准治疗选择。越来越多的临床研究已经探索了EGFR-TKIs加抗血管生成药物作为EGFR突变的NSCLC的一线治疗的价值。方法:我们系统地搜索了PubMed,科克伦图书馆,和EMBASE用于研究EGFR-TKIs联合或不联合抗血管生成药物治疗晚期EGFR突变NSCLC的随机对照试验(RCTs)。在2019年欧洲医学肿瘤学会大会上口头提出的最新RCT是在线获得的。终点包括无进展生存期(PFS),总生存期(OS),客观反应率(ORR),疾病控制率(DCRs),和3级或更高的不良事件(AE)。结果:我们纳入了7篇关于5项试验的文章,涉及1,226名患者。实验组的干预措施是第一代EGFR-TKI埃罗替尼联合贝伐单抗(四项研究)或雷莫西单抗(一项研究),和厄洛替尼单药治疗(4项研究)或厄洛替尼加安慰剂(1项研究)为对照组。所有研究均达到其主要研究终点(即,PFS)。与厄洛替尼单一疗法相比,厄洛替尼联合抗血管生成药显著延长PFS[风险比(HR)=0.59,95%置信区间(CI)=0.51-0.69,P=0.000];ORR,DCR,两组间OS相似。合并组3-5级不良事件总体增加(OR=5.772,95%CI=2.38-13.94,P=0.000),尤其是腹泻的发生率(OR=2.51,95%CI=1.21-5.23,P=0.014),痤疮(OR=1.815,95%CI=1.084-3.037,P=0.023),高血压(OR=6.77,95%CI=3.62~12.66,P=0.000),蛋白尿(OR=13.48,95%CI=4.11~44.22,P=0.000)。此外,亚组分析显示,亚洲患者可从联合治疗中获益(HR=0.59,95%CI=0.50-0.69,P=0.000).外显子19缺失(HR=0.61,95%CI=0.49-0.75,P=0.000)和21Leu858Arg突变(HR=0.59,95%CI=0.47-0.73,P=0.000)的患者在接受双重阻断治疗时具有几乎相等的PFS益处。联合组基线时脑转移患者PFS有改善的趋势(HR=0.55,95%CI=0.30-1.01,P=0.001)。结论:厄洛替尼联合贝伐单抗或雷莫珠单抗在EFGR突变的NSCLC一线治疗中产生了显著的PFS获益;然而,这伴随着较高的AE。表皮生长因子受体-TKI联合抗血管生成药物治疗可能被认为是晚期EGFR突变NSCLC患者的新选择。
Background: Tyrosine kinase inhibitors (TKIs) are standard treatment options for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Increasing clinical investigations have explored the value of EGFR-TKIs plus antiangiogenic drugs as the first-line treatment for EGFR-mutated NSCLC. Methods: We systematically searched PubMed, Cochrane Library, and EMBASE for randomized controlled trials (RCTs) investigating EGFR-TKIs administered with or without antiangiogenic agents for advanced EGFR-mutated NSCLC. The latest RCT that was presented orally at the 2019 European Society for Medical Oncology Congress was obtained online. The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rates (DCRs), and grade 3 or higher adverse events (AEs). Results: We included seven articles on five trials with 1,226 patients. The interventions for the experimental group were the first-generation EGFR-TKI erlotinib combined with bevacizumab (four studies) or ramucirumab (one study), and erlotinib monotherapy (four studies) or erlotinib plus placebo (one study) for the control group. All studies reached their primary study endpoints (i.e., PFS). Compared to erlotinib monotherapy, erlotinib plus antiangiogenic agents remarkably prolonged PFS [hazard ratio (HR) = 0.59, 95% confidence interval (CI) = 0.51-0.69, P = 0.000]; however, ORR, DCR, and OS were similar between the two groups. The overall grade 3-5 AEs increased in combination group (OR = 5.772, 95% CI = 2.38-13.94, P = 0.000), particularly the incidence of diarrhea (OR = 2.51, 95% CI = 1.21-5.23, P = 0.014), acneiform (OR = 1.815, 95% CI = 1.084-3.037, P = 0.023), hypertension (OR = 6.77, 95% CI = 3.62-12.66, P = 0.000), and proteinuria (OR = 13.48, 95% CI = 4.11-44.22, P = 0.000). Additionally, subgroup analysis demonstrated that Asian patients could significantly benefit from combination therapy (HR = 0.59, 95% CI = 0.50-0.69, P = 0.000). Patients with exon 19 deletions (HR = 0.61, 95% CI = 0.49-0.75, P = 0.000) and 21 Leu858Arg mutations (HR = 0.59, 95% CI = 0.47-0.73, P = 0.000) had almost equivalent PFS benefits when treated with double-blocking therapy. Patients with brain metastases at baseline in the combination group had a trend toward better PFS (HR = 0.55, 95% CI = 0.30-1.01, P = 0.001). Conclusions: Erlotinib plus bevacizumab or ramucirumab in EFGR-mutated NSCLC first-line setting yielded remarkable PFS benefits; however, this was accompanied by higher AEs. Epidermal growth factor receptor-TKI plus antiangiogenic agent therapy may be considered a new option for advanced EGFR-mutated NSCLC patients.