达可替尼在非小细胞肺癌中的应用进展

Research progress of Dacomitinib in the treatment of non-small-cell lung cancer

达可替尼(Dacomitinib)是第二代表皮生长因子受体(Epidermal growth factor receptor,EGFR)/Her-2/Her-4酪氨酸激酶不可逆的抑制剂,可作为EGFR Ex21L858R和(或)Ex19del突变的晚期非小细胞肺癌(Non-small-cell lung cancer,NSCLC)患者的一线治疗药物。临床研究显示达可替尼一线治疗EGFR敏感突变的NSCLC的中位无进展生存期(median progression-free survival,mPFS)及中位生存期(median overall survival,mOS)均高于吉非替尼组,同时在亚裔人群、EGFR Ex21L858R突变患者中的疗效也较吉非替尼更佳。达可替尼在一/二代EGFR酪氨酸激酶抑制剂(EGFR tyrosine inhibitor,EGFR-TKI)之间直接比较中获得PFS显著改善,然而根据ARCHER 1050研究设计,尽管该研究取得了PFS的显著统计学意义,由于客观有效率未达到统计学差异,不应再对OS进行统计检验;但生存曲线显示OS存在获益趋势。临床上,达可替尼治疗相关不良反应的发生率也较高,主要表现为腹泻、皮疹、口腔炎、甲沟炎和皮肤干燥等。临床可通过中断治疗、降低药物剂量和辅助药物治疗来对治疗相关不良反应进行管理。如何对达可替尼治疗的患者进行全程管理已成为当前临床工作中需要注意的问题。本综述回顾了达可替尼从Ⅰ期到Ⅲ期的临床发展历程,同时探讨达可替尼的安全性和耐药机制,为达可替尼的合理临床应用提供依据。

Dacomtinib,a second generation of irreversible tyrosine kinase inhibitor targeting epidermal growth factor receptor(EGFR)/Her-2/Her-4,can be used as first-line treatment drug for advanced non-small-cell lung cancer(NSCLC)patients with EGFR ExL858R and/or ex19del mutations.Clinical studies have shown that median progression-free survival(mPFS)and median overall survival(mOS)in EGFR mutated NSCLC with first-line treatment of Dacomitinib are higher than those in gefitinib treatment group.Furthermore,the clinical effects of Dacomitinib in Asian people and patients with EGFR Ex21L858R mutation are superior to those by gefitinib.Dacomtinib shows significant improvement in PFS in direct comparison between different EGFR tyrosine kinase inhibitors(EGFR-TKIs).However,according to the ARCHER 1,050 study design,although the study shows a statistical significance about PFS,statistical tests should not be performed on OS because the objective effective rate does not reach statistical difference.But the survival curve shows that OS has a trend of benefit for dacomitinib.In clinical practise,the incidence of treatment-related adverse effects of dacomitinib is also higher,and the treatment-related adverse effects mainly include diarrhea,rash,stomatitis,paronychia and dry skin.Clinically,treatment-related adverse reactions can be managed by interrupting treatment,reducing drug doses and symptomatic treatment.This article reviews the clinical development of dacomitinib from phaseⅠto phaseⅢtrials,and discusses the safety and resistance mechanisms of dacomitinib,which can provide a basis for the rational use of Dacomitinib in clinical practice.