Vidal Óscar Juan
Servicio de Oncología Médica, Hospital Universitari i Politècnic La Fe, Valencia, España.
Med Clin (Barc). 2016 Apr;146 Suppl 1:12-8. doi: 10.1016/S0025-7753(16)30258-5.
The discovery of endothelial growth factor receptor (EGFR) mutations has laid the foundations for personalized medicine in non-small cell lung carcinoma (NSCLC). In phase III trials, the first-generation tyrosine kinase inhibitors (TKI), gefitinib and erlotinib, demonstrated greater efficacy compared with chemotherapy in patients with EGFR mutations, achieving progression-free survival of 8-13.5 months. Afatinib, a second-generation irreversible pan-ErbB inhibitor, is the first TKI that has shown a benefit in overall survival (OS) compared with chemotherapy in EGFR mutation-positive NSCLC when used as first-line treatment. Exon 19 deletion (Del19) and the single-point substitution mutation (L858R) in exon 21, called activating mutations due to their ability to confer sensitivity to TKI, represent approximately 90% of the EGFR mutations in NSCLC. Distinct sensitivity to TKI has been observed depending on the type of mutation, with greater progression-free survival in patients with the Del19 mutation. The analysis of OS in the LUX-Lung 3 and LUX-Lung 6 trials showed a statistically significant increase in survival in afatinib-treated patients with the Del 19 mutation, but no significant increase in that of patients with the L858R mutation. Direct comparison of afatinib and gefitinib as first-line therapy (LUX-Lung 7 trial) showed a statistically-significant increase in progression-free survival (hazard ratio: 0.73; 95% confidence interval, 0.57-0.95; p=0.0165) with afatinib. In the analysis by type of mutation, this benefit was observed for both the Del19 and the L858R mutations.
内皮生长因子受体（EGFR）突变的发现为非小细胞肺癌（NSCLC）的个性化医疗奠定了基础。在III期试验中，第一代酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼，在EGFR突变患者中显示出比化疗更高的疗效，无进展生存期达到8 - 13.5个月。阿法替尼是第二代不可逆泛ErbB抑制剂，是首个在EGFR突变阳性NSCLC患者中作为一线治疗使用时，与化疗相比在总生存期（OS）方面显示出优势的TKI。外显子19缺失（Del19）和外显子21中的单点替代突变（L858R），因其赋予对TKI敏感性的能力而被称为激活突变，约占NSCLC中EGFR突变的90%。根据突变类型观察到对TKI的不同敏感性，Del19突变患者的无进展生存期更长。LUX - Lung 3和LUX - Lung 6试验中的OS分析显示，阿法替尼治疗的Del19突变患者的生存期有统计学显著增加，但L858R突变患者则无显著增加。阿法替尼和吉非替尼作为一线治疗的直接比较（LUX - Lung 7试验）显示，阿法替尼组的无进展生存期有统计学显著增加（风险比：0.73；95%置信区间，0.57 - 0.95；p = 0.0165）。在按突变类型进行的分析中，Del19和L858R突变患者均观察到这一益处。
