Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Japan.
Department of Medical Oncology, Takarazuka City Hospital, Japan.
Lung Cancer. 2024 Nov;197:107988. doi: 10.1016/j.lungcan.2024.107988. Epub 2024 Oct 5.
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.
多项临床研究表明，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，在出现各种奥希替尼耐药机制后，阿法替尼联合贝伐珠单抗将发挥临床疗效。
奥希替尼耐药后，招募 EGFR 突变型非小细胞肺癌患者。阿法替尼 30-40mg/天和贝伐珠单抗 15mg/kg 每 3 周给药，直至进展。在奥希替尼耐药后，对血浆/组织学再活检样本进行分析，以检查耐药机制：使用深度测序进行癌症个体化分析检测基因改变/拷贝数增加。
2018 年 1 月至 2020 年 10 月期间，共招募了 28 名患者。客观缓解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 个月（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。28 名患者的（100%）血浆和/或 21 名患者的（75%）组织学再活检中鉴定出：17 名患者（61%）存在 TP53 突变；15 名患者（54%）存在 T790M 突变；9 名患者（32%）存在罕见的 EGFR 突变；9 名患者（32%）存在 MET 扩增；6 名患者（21%）存在 C797S 突变；3 名患者（11%）存在 BRAF 突变；2 名患者（7%）存在 HER2 扩增；2 名患者（7%）存在 KRAS 突变；和 2 名患者（7%）存在 PI3K 突变。在 6 名 C797S 患者中，有 1 名（17%）患者出现完全缓解。在 9 名存在罕见 EGFR 突变的患者中，有 3 名（33%）患者出现影像学缓解。15 名 T790M 阳性和 6 名 EGFR 下游信号通路突变（BRAF；KRAS；或 PI3K）阳性患者均未出现缓解，但在 13 名 T790M 阴性患者中有 5 名（38%）患者出现缓解。发生率≥5%且≥3 级的不良事件有：高血压（29%）；蛋白尿（7%）；腹泻（7%）。没有与治疗相关的死亡或间质性肺病。
根据奥希替尼耐药后再活检的结果，在选定的人群中，阿法替尼联合贝伐珠单抗可能获得临床获益。
