Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Thoracic Oncology, the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Clin Cancer Res. 2018 Dec 15;24(24):6195-6203. doi: 10.1158/1078-0432.CCR-18-1542. Epub 2018 Sep 18.
Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of -mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described.
Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.
In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, = 0.02).
Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients..
奥希替尼最初被批准用于 T790M 阳性非小细胞肺癌（NSCLC），最近又被批准用于 - 突变型 NSCLC 的一线治疗。然而，奥希替尼的耐药机制尚未完全描述。
我们从德克萨斯大学 MD 安德森癌症中心肺癌登月计划 GEMINI 和莫菲特癌症中心肺癌数据库中收集了接受奥希替尼治疗的患者的临床数据。在一部分患者中，在进展时进行了分子谱分析。
在 118 例接受奥希替尼治疗的患者中，42 例在进展时进行了分子谱分析。T790M 在 21 例（50%）患者中保留，在 21 例（50%）患者中丢失。EGFR C797 和 L792（26%）突变是最常见的耐药机制，仅在 T790M 保留的病例中观察到。MET 扩增是第二常见的改变（14%）。在 22 个基因/通路中观察到复发性改变，包括 PIK3CA、FGFR 和 RET。临床前研究证实 MET、PIK3CA 和上皮-间质转化是潜在的耐药驱动因素。细胞周期基因的改变与较短的中位无进展生存期（PFS，4.4 与 8.8 个月， = 0.01）相关。在 76 例进展患者中，47 例继续接受奥希替尼治疗，中位第二次 PFS（PFS2）为 12.6 个月；21 例患者接受局部巩固放疗，中位 PFS 为 15.5 个月。与停药相比，进展后继续使用奥希替尼与更长的总生存期相关（11.2 与 6.1 个月， = 0.02）。
奥希替尼耐药与多种、主要是 EGFR 独立的基因组改变有关。进展后单独或联合放疗继续使用奥希替尼，可能为部分患者提供更长的临床获益。
