Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
Pulmonary and Critical Care Medicine Department, Huizhou Central People's Hospital, Guangdong Medical University, Huizhou, People's Republic of China.
Cancer. 2022 Nov 1;128(21):3804-3814. doi: 10.1002/cncr.34451. Epub 2022 Sep 7.
Afatinib is the only currently approved EGFR-tyrosine kinase inhibitors for advanced non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I. However, there are limited real-world data concerning the benefits and resistance mechanisms of afatinib in patients with these nonclassical mutations. To fill this gap, the present study was conducted.
All NSCLC patients treated with afatinib were screened, and patients with EGFR G719X/L861Q/S768I were enrolled into the analysis. Either tumor tissue or blood specimens were detected by the commercial next-generation sequencing (NGS) panels or amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) to figure out the mutation genotype.
A total of 106 advanced NSCLC patients with EGFR G719X/L861Q/S768I received afatinib treatment. The benefits of afatinib exhibited heterogeneity in different mutation genotypes. Notably, at baseline, NGS testing was performed in 59 patients, and TP53 was the most frequently coexisting mutation. Patients with TP53 mutations obtained fewer survival benefits than those with TP53 wild-type. A total of 68 patients ultimately experienced progression, and 27 patients received NGS testing to clarify the potential resistance mechanisms. EGFR-T790M, CDK4 amplification, FGFR1 amplification, PIK3CA, MET amplification, RET fusions, HER2, and BRAF mutations were identified in three (11.1%), three (11.1%), three (11.1%), three (11.1%), three (11.1%), one (3.7%), one (3.7%), and one (3.7%) of the cases, respectively. Five patients underwent ARMS-PCR testing for detecting EGFR-T790M mutation, and only one patient was T790M-positive.
The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.
阿法替尼是唯一获批用于治疗 EGFR G719X/L861Q/S768I 非小细胞肺癌（NSCLC）患者的 EGFR 酪氨酸激酶抑制剂。然而，对于这些非经典突变患者，阿法替尼的获益和耐药机制的真实世界数据有限。为填补这一空白，开展了本研究。
筛选所有接受阿法替尼治疗的 NSCLC 患者，入组 EGFR G719X/L861Q/S768I 患者。采用商业性下一代测序（NGS）或扩增受阻突变系统（ARMS）-聚合酶链反应（PCR）检测肿瘤组织或血液标本，明确突变基因型。
共 106 例 EGFR G719X/L861Q/S768I 晚期 NSCLC 患者接受阿法替尼治疗。不同突变基因型的阿法替尼获益存在异质性。值得注意的是，基线时 59 例患者进行了 NGS 检测，TP53 是最常见的共存突变。TP53 突变患者的生存获益少于 TP53 野生型患者。共 68 例患者最终出现进展，27 例患者接受 NGS 检测以明确潜在耐药机制。3 例（11.1%）、3 例（11.1%）、3 例（11.1%）、3 例（11.1%）、3 例（11.1%）患者分别出现 EGFR-T790M、CDK4 扩增、FGFR1 扩增、PIK3CA、MET 扩增、RET 融合、HER2 和 BRAF 突变，1 例（3.7%）患者出现 EGFR-T790M 突变，仅 1 例 ARMS-PCR 检测为 T790M 阳性。
本研究阐明了不同突变基因型中阿法替尼的获益差异，并首次揭示了 EGFR G719X/L861Q/S768I 患者潜在耐药机制的范围。本研究结果可为该人群的最佳治疗提供实用的临床信息。
