Medical Oncology Unit A.O. Papardo, Department of Human Pathology, University of Messina, 98158 Messina, Italy.
Int J Mol Sci. 2019 Mar 21;20(6):1431. doi: 10.3390/ijms20061431.
Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.
非典型表皮生长因子受体（EGFR）突变代表了非小细胞肺癌（NSCLC）中一个独特且高度异质的亚组，约占所有 EGFR 突变患者的 10%。由于下一代测序（NGS）在诊断中的广泛应用，罕见变体得以被识别，而非典型 EGFR 突变的发生率正在增加，这些罕见变体通常会被现有的商业试剂盒所遗漏，因为这些试剂盒仅能检测有限数量的 EGFR 突变。然而，与经典突变（即外显子 19 缺失和外显子 21 L858R 点突变）相比，罕见 EGFR 突变对第一代和第二代 EGFR 酪氨酸激酶抑制剂（TKI）的敏感性差异较大，且不太为人所知，因为大多数针对一线 EGFR TKI 的关键性研究都排除了罕见和/或复杂变体的患者，只有少数例外。最近，第三代 EGFR TKI 奥希替尼进一步改变了 EGFR 突变 NSCLC 的治疗方案，但它在除外显子 19 缺失和/或 L858R 以外的 EGFR 突变患者中的作用还知之甚少。因此，更好地了解罕见突变对目前可用的 EGFR TKI 的敏感性对于指导临床实践中的治疗决策至关重要。本文的目的是全面概述目前批准的治疗方案对携带非典型 EGFR 突变的 NSCLC 患者的治疗，并讨论这一特殊亚组患者中新兴的治疗机会，包括化疗免疫联合治疗、下一代 EGFR TKI 和新型靶向药物。
