许多临床研究表明表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）和血管内皮生长因子抑制剂具有协同作用。我们假设阿法替尼加贝伐珠单抗在出现各种奥希替尼耐药机制后发挥临床效力。EGFR 突变非小细胞肺癌患者在奥希替尼耐药后入组。阿法替尼 30-40 毫克/天，贝伐单抗 15 毫克/公斤，每三周一次，直至疾病进展。对奥希替尼失败后的血浆/组织学重新活检样本进行分析，以检查耐药机制：使用深度测序进行癌症个性化分析的基因改变/拷贝数增加。2018年1月至2020年10月期间，入组了28名患者。有效率和疾病控制率分别为 17.9% 和 78.6%。中位缓解持续时间为 9.0（范围，4.2-22.3）个月。中位无进展生存期和总生存期分别为 2.7 个月和 9.3 个月。鉴定出二十八 (100%) 血浆和/或 21 (75%) 组织学再活检：17 (61%) TP53； 15 (54%) T790M； 9 (32%) 罕见 EGFR； 9 (32%) 代谢物； 6 (21%) C797S； 3 (11%) BRAF； 2 (7%) HER2； 2 (7%) KRAS；和 2 个 (7%) PI3K 突变。 6 名 C797S 患者中的 1 名 (17%) 显示出完全缓解。 9 名罕见 EGFR 突变患者中的 3 名 (33%) 取得了放射学缓解。 15 个 T790M 阳性和 6 个 EGFR 下游信号突变均不存在：BRAF；克拉斯；或 PI3K 阳性患者有反应，但 13 名 T790M 阴性患者中有 5 名 (38%) 有反应。不良事件≥3级且发生率≥5%为：高血压（29%）；蛋白尿（7%）；和腹泻（7%）。既没有治疗相关的死亡，也没有间质性肺疾病。根据奥希替尼耐药后的重新活检结果，选定的人群可以从阿法替尼加贝伐单抗中获得临床获益。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Many clinical studies showed a synergy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors. We hypothesized afatinib plus bevacizumab exerts clinical potency after developing various osimertinib resistant mechanisms.EGFR-mutant non-small cell lung cancer patients were enrolled after osimertinib resistance. Afatinib at 30-40 mg/day and bevacizumab at 15 mg/kg tri-weekly were administered until progression. Plasma/histologic rebiopsied samples after osimertinib failure were analyzed to examine resistant mechanisms: gene alterations/copy-number gain using cancer personalized profiling by deep sequencing.Between January 2018 and October 2020, 28 patients were enrolled. Response and disease control rates were 17.9 % and 78.6 %, respectively. Median duration of response was 9.0 (range, 4.2-22.3) months. Median progression-free and overall survivals were 2.7 and 9.3 months, respectively. Twenty-eight (100 %) plasma and/or 21 (75 %) histologic rebiopsies identified: 17 (61 %) TP53; 15 (54 %) T790M; 9 (32 %) uncommon EGFR; 9 (32 %) MET; 6 (21 %) C797S; 3 (11 %) BRAF; 2 (7 %) HER2; 2 (7 %) KRAS; and 2 (7 %) PI3K mutations. One (17 %) of 6 C797S patients showed complete response. Three (33 %) of 9 uncommon EGFR-mutated patients achieved radiographic response. Neither 15 T790M-positive nor 6 EGFR downstream signaling mutations: BRAF; KRAS; or PI3K-positive patients responded, but 5 (38 %) of 13 T790M-negative patients responded. Adverse events ≥ grade 3 and incidence ≥ 5 % were: hypertension (29 %); proteinuria (7 %); and diarrhea (7 %). There were neither treatment-related death nor interstitial lung disease.Selected population could obtain clinical benefit from afatinib plus bevacizumab, based on rebiopsy results after osimertinib resistance.Copyright © 2024 Elsevier B.V. All rights reserved.