National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Liverpool Hospital, Sydney, Australia.
National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia; School of Medicine, The University of Notre Dame, Sydney, Australia.
J Thorac Oncol. 2017 Apr;12(4):633-643. doi: 10.1016/j.jtho.2016.11.2236. Epub 2016 Dec 19.
Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment.
We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI.
Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs.
EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.
吉非替尼、厄洛替尼和阿法替尼是用于治疗晚期 EGFR 突变型 NSCLC 的酪氨酸激酶抑制剂 (TKI)。评估这些 EGFR TKI 之间的毒性差异对于个性化治疗很重要。
我们对比较 EGFR TKI 治疗与化疗或安慰剂的随机试验进行了荟萃分析。我们从 EGFR TKI 臂中提取数据进行间接比较，以估计每种 EGFR TKI 的毒性死亡、3 至 4 级（G3/4）不良事件 (AE) 和因 AE 停止治疗的相对风险。
16 项试验纳入了 2535 名 EGFR 突变或野生型患者。毒性死亡很少见（1.7%），以肺炎最为常见，EGFR TKI 之间无显著差异。总体而言，40%的患者发生 G3/4 AE。吉非替尼（29.1%）的 G3/4 AE 风险低于厄洛替尼（54.1%）或阿法替尼（42.1%）（p<0.01）。因 AE 而停止治疗的患者占 7.7%，EGFR TKI 之间无显著差异。腹泻（53.3%）和皮疹（66.5%）是最常见的 AE。皮疹的风险阿法替尼（84.8%）高于厄洛替尼（62.0%）或吉非替尼（62.0%）（p<0.01）。腹泻的风险阿法替尼（91.7%）高于厄洛替尼（42.4%）或吉非替尼（44.4%）（p<0.01）。吉非替尼（61.7%）的肝酶水平升高风险高于厄洛替尼（17.8%）或阿法替尼（20.1%）（p<0.01）。使用风险效益轮廓图评估不同 EGFR TKI 之间疗效和毒性的权衡。
EGFR TKI 耐受性良好，不到 10%的患者因 AE 停止治疗。不同 EGFR TKI 的毒性特征和风险不同，可用于指导治疗选择。
