Investigation of efficacy and acquired resistance for EGFR-TKI plus bevacizumab as first-line treatment in patients with EGFR sensitive mutant non-small cell lung cancer in a Real world population
Investigation of efficacy and acquired resistance for EGFR-TKI plus bevacizumab as first-line treatment in patients with EGFR sensitive mutant non-small cell lung cancer in a Real world population
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DOI：
10.1016/j.lungcan.2020.01.009
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发表时间：
2020-03-01
期刊：
影响因子：
5.3
通讯作者：
Mansfield, Aaron S.
中科院分区：
文献类型：
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作者：
Zeng, Liang;Xiao, Lili;Mansfield, Aaron S.
目的：研究EGFR酪氨酸激酶抑制剂(TKI，T)联合贝伐单抗(抗血管生成疗法A)在真实人群中的临床疗效，并为其耐药机制提供深入的认识。方法：本研究包括从2015年1月至2018年8月，256例携带EGFR敏化突变(EGFR 19del和L858R)的非小细胞肺癌患者，在治疗前接受了168个基因小组的下一代测序(NGS)。A组包括60名接受A+T治疗的患者；而B组包括120名接受EGFR-TKI单一治疗的患者，这些患者采用倾向评分匹配(比例为1：2)。结果：A组和B组的基线临床特征无显著差异。与B组相比，A组的总有效率(95%vs74.2%，p=0.001)和较长的中位无进展生存期(PFS，16.5m vs.12.0m，HR=0.7p=0.001)显著提高。直到2019年1月，A组和B组分别有31名和103名患者被评估为进展性疾病，并接受了组织再次活检和使用168基因小组进行NGS分析。在B组中，T790M是主要的获得性耐药机制，在进展期肿瘤中有51.5%(53/103)，其次是EGFR扩增(15.5%，16/103)和MET扩增(6.8%，7/103)。与之形成鲜明对比的是，A组的1790M突变率显著低于A组(35.5%，11/31，p=0.0003)，其次是TP53(29.0%，9/31)、RBI(9.7%，3/31)、Smad4(3.2%，1/31)和EGFR V834(3.2%，1/31)，扩增的EGFR(9.7%，3/31)和MET(6.5%)，结论：一线A+T治疗可显著延长病情进展时间，提高有效率，且安全性可接受。T790M是最常见的获得性耐药机制，但在接受A+T治疗的患者中较少见。
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 1790 M mutation (35.5%, 11/31, p = 0.0003), followed by mutations in TP53 (29.0%, 9/31), RBI (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.