Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Lung Cancer. 2021 Aug;158:137-145. doi: 10.1016/j.lungcan.2021.06.014. Epub 2021 Jun 19.
Osimertinib is the main treatment choice for pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) T790M mutations. However, the choice of subsequent therapy when progressive disease has developed after osimertinib treatment remains a major therapeutic challenge. This study evaluated the efficacy of osimertinib-based combination therapies in patients who developed progressive disease after treatment with osimertinib.
We enrolled NSCLC patients harbouring T790M mutations pretreated with first- or second-generation EGFR tyrosine-kinase inhibitors and were receiving osimertinib at two tertiary referral centres between August 2015 and July 2019, and the subsequent treatment efficacy was assessed.
Osimertinib-based combination therapy yielded better overall survival (OS) than chemotherapy alone (not achieved vs. 7.8 months; hazard ratio, 0.39; 95 % confidence interval 0.17-0.89; P = 0.025) according to the Cox proportional hazards model adjusted for possible confounders. Synergism (combination index <1) between AZD9291 and chemotherapy and a higher proportion of apoptosis cells in combination treatment were also demonstrated in the T790M-positive PC9 cell line with acquired resistance to AZD9291.
Our data supported the hypothesis that osimertinib-based combination therapy is associated with improved OS among patients with clinical progression following the use of osimertinib. These findings warrant further validation in a randomised controlled study.
奥希替尼是治疗表皮生长因子受体（EGFR）T790M 突变的晚期非小细胞肺癌（NSCLC）患者的主要治疗选择。然而，奥希替尼治疗后疾病进展时的后续治疗选择仍然是一个主要的治疗挑战。本研究评估了奥希替尼为基础的联合治疗在奥希替尼治疗后进展的患者中的疗效。
我们招募了在 2015 年 8 月至 2019 年 7 月期间在两个三级转诊中心接受过第一代或第二代 EGFR 酪氨酸激酶抑制剂预处理且正在接受奥希替尼治疗的 T790M 突变 NSCLC 患者，并评估了随后的治疗效果。
根据 Cox 比例风险模型调整可能的混杂因素后，奥希替尼为基础的联合治疗的总生存期（OS）优于单独化疗（未达到 vs. 7.8 个月；风险比，0.39；95%置信区间 0.17-0.89；P=0.025）。在对 AZD9291 获得性耐药的 T790M 阳性 PC9 细胞系中，也证明了 AZD9291 与化疗联合具有协同作用（组合指数<1），并且联合治疗中有更高比例的凋亡细胞。
我们的数据支持这样一种假设，即在奥希替尼治疗后疾病进展的患者中，奥希替尼为基础的联合治疗与改善 OS 相关。这些发现需要在随机对照研究中进一步验证。
