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EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins

机译:EGFR外显子20在先进的非小细胞肺癌中插入:新的历史开始

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摘要

Although targeted therapy is standard of care in a large subset of oncogenic addicted non-small cell lung cancers (NSCLC), until recently, this therapeutic approach has not been feasible for all genomic alterations such as for those tumors harboring Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations. Despite being the third most common EGFR mutation, a limited efficacy of firstand second-generation EGFR tyrosine kinase inhibitors (TKI) exists. This is related to the heterogeneity at the molecular level in EGFR ex20ins mutation variants and the finding that this mutation promotes active kinase conformation but does not increase the affinity for EGFR TKI. As a result, the prognosis of this population is diminished. Therefore, chemotherapy remained the most suitable strategy in this subset of EGFR mutant NSCLC patients. Recently, new treatment strategies have been reported in this landscape, either with new EGFR TKI or bispecific antibodies, which may establish a new standard of care in the coming future for these patients. Future research should focus on elu-cidating the oncogenic degree of all EGFR ex20ins variants, the potential role of combination strategies either with chemotherapy or immune checkpoint inhibitors, and the most appropriate first-line treatment strategy in this subgroup. Finally, the knowledge of mechanisms of acquired resistance to these new agents upon progression is a priority for personalising treatment at that time. It is in this framework, that we provide a thorough overview on this subject.
机译:尽管靶向治疗是大多数致癌性上瘾的非小细胞肺癌(NSCLC)的标准治疗方法,但直到最近,这种治疗方法还不适用于所有基因组改变,例如表皮生长因子受体(EGFR)外显子20插入(ex20ins)突变的肿瘤。尽管是第三常见的EGFR突变,但第一代和第二代EGFR酪氨酸激酶抑制剂(TKI)的疗效有限。这与EGFR ex20ins突变变体在分子水平上的异质性以及该突变促进活性激酶构象但不增加EGFR TKI亲和力的发现有关。因此,该人群的预后降低。因此,化疗仍然是这一亚群EGFR突变NSCLC患者最合适的治疗策略。最近,有报道称,在这一领域有新的治疗策略,可以使用新的EGFR TKI或双特异性抗体,这可能在未来为这些患者建立新的护理标准。未来的研究应侧重于阐明所有EGFR ex20ins变体的致癌程度、联合化疗或免疫检查点抑制剂的潜在作用,以及该亚组中最合适的一线治疗策略。最后,了解这些新药物在进展过程中获得性耐药性的机制是当时个性化治疗的重点。正是在这个框架内,我们对这个主题进行了全面的概述。

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