OBJECTIVES We aimed to investigate the clinical efficacy of EGFR tyrosine kinase inhibitor (TKI, T) plus bevacizumab (an antiangiogenic therapy, A) in a real-world population and to provide insights into their mechanism of resistance. METHODS This study included 256 NSCLC patients harboring EGFR sensitizing mutations (EGFR 19del and L858R) who underwent nextgeneration sequencing (NGS) with 168-gene panel prior to treatment between Jan 2015 to Aug 2018. Cohort A included 60 patients treated with A + T; while cohort B consisted of 120 patients treated with EGFR-TKI monotherapy with the patients identified using Propensity Score Matching (Ratio of 1:2). Clinical outcomes and potential resistance mechanism were evaluated. RESULTS Baseline clinical characteristics were not significantly different between Cohort A and B. Compared with cohort B, cohort A had significantly better overall response rate (95% vs 74.2%, p = 0.001) and longer median progression-free survival (PFS, 16.5m vs.12.0 m, HR = 0.7, p = 0.001). Until Jan 2019, 31 and 103 patients in cohort A and B, respectively, were evaluated with progressive disease and underwent tissue re-biopsy and NGS profiling with 168-gene panel. In cohort B, T790M was the predominant acquired resistance mechanism, detected in 51.5% (53/103) of progressive tumors, followed by amplifications in EGFR (15.5%, 16/103) and MET (6.8%, 7/103). Contrastingly, cohort A had a significantly lower rate of T790 M mutation (35.5%, 11/31, p = 0.0003), followed by mutations in TP53 (29.0%, 9/31), RB1 (9.7%, 3/31), SMAD4 (3.2%, 1/31) and EGFR V834 L (3.2%, 1/31) and amplifications in EGFR (9.7%, 3/31), and MET(6.5%, 2/31). CONCLUSION Treatment with first-line A + T significantly extends the time to progression and increases the response rate with acceptable safety profile. T790 M was the most common acquired resistance mechanism but it was less common in patients who received A + T.

中文翻译：

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在真实人群中对EGFR敏感突变型非小细胞肺癌患者进行EGFR-TKI加贝伐单抗作为一线治疗的疗效和获得性耐药性的调查。

目的我们旨在研究EGFR酪氨酸激酶抑制剂（TKI，T）和贝伐单抗（抗血管生成疗法，A）在现实世界中的临床疗效，并提供其耐药机制的见解。方法该研究纳入了256名具有EGFR致敏突变（EGFR 19del和L858R）的NSCLC患者，他们在2015年1月至2018年8月之前接受了168基因检测，并进行了下一代测序（NGS）。队列A包括60例接受A + T治疗的患者；而队列B包括120例接受EGFR-TKI单药治疗的患者，并使用倾向得分匹配（比例为1：2）确定了患者。评价临床结果和潜在耐药机制。结果A组和B组的基线临床特征无明显差异。与B组相比，队列A的总体缓解率显着提高（95％vs 74.2％，p = 0.001）和中位无进展生存期更长（PFS，16.5m vs.12.0 m，HR = 0.7，p = 0.001）。直到2019年1月，分别对A和B组的31例和103例患者进行了进展性疾病评估，并使用168个基因组进行了组织再活检和NGS分析。在队列B中，T790M是主要的获得性耐药机制，在51.5％（53/103）的进行性肿瘤中检测到，然后在EGFR（15.5％，16/103）和MET（6.8％，7/103）中扩增。相反，同类群组A的T790 M突变发生率明显较低（35.5％，11/31，p = 0.0003），其次是TP53（29.0％，9/31），RB1（9.7％，3/31）突变， SMAD4（3.2％，1/31）和EGFR V834 L（3.2％，1/31）以及EGFR（9.7％，3/31）和MET（6.5％，2/31）的扩增。结论用一线A + T治疗可显着延长进展时间，并以安全性可接受的情况增加缓解率。T790 M是最常见的获得性耐药机制，但在接受A + T的患者中较少见。