Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC.
Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC.
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DOI：
10.1158/1078-0432.ccr-18-1542
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发表时间：
2018-12-15
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影响因子：
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通讯作者：
Heymach JV
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作者：
Le X;Puri S;Negrao MV;Nilsson MB;Robichaux J;Boyle T;Hicks JK;Lovinger KL;Roarty E;Rinsurongkawong W;Tang M;Sun H;Elamin Y;Lacerda LC;Lewis J;Roth JA;Swisher SG;Lee JJ;William WN Jr;Glisson BS;Zhang J;Papadimitrakopoulou VA;Gray JE;Heymach JV
奥希替尼最初被批准用于T790 M阳性NSCLC，最近被批准用于EGFR突变型NSCLC的一线治疗。然而，对奥希替尼的耐药机制尚未完全描述。使用MD安德森肺癌Moonshot GEMINI和莫菲特癌症中心肺癌数据库中的队列，我们收集了接受奥希替尼治疗的患者的临床数据。在一个患者亚组的进展时进行分子谱分析。在118例接受奥希替尼治疗的患者中，42例在进展时具有分子谱。T790 M保留21例（50%），丢失21例（50%）。EGFR C797和L792（26%）突变是最常见的耐药机制，仅在T790 M保留病例中观察到。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PIK 3CA、FGFR和RET。临床前研究证实MET、PIK 3CA和上皮-间充质转化（EMT）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PFS相关（4.4 vs 8.8个月，p=0.01）。在76例进展患者中，47例继续使用奥希替尼，中位第二次无进展生存期（PFS 2）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，在进展后继续使用奥希替尼与更长的总生存期相关（OS 11.2 vs 6.1个月，p=0.02）。奥希替尼耐药与多种主要为EGFR非依赖性基因组改变相关。疾病进展后继续使用奥希替尼，单独或联合放疗，可为选定患者提供长期临床获益。
Osimertinib was initially approved for T790M positive NSCLC and, more recently, for first-line treatment of EGFR-mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described. Using cohorts from 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 (EMT) as potential resistance drivers. Alterations of cell cycle genes were associated with shorter median PFS (4.4 vs 8.8 months, p=0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second progression-free survival (PFS2) was of 12.6 months; 21 patients received local consolidation radiation with median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared to discontinuation (OS 11.2 vs 6.1 months, p=0.02). Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib post-progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.