达可替尼与厄洛替尼治疗表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌（NSCLC）患者：两项随机试验的汇总亚组分析
Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials.
作者信息
Ramalingam S S, O'Byrne K, Boyer M, Mok T, Jänne P A, Zhang H, Liang J, Taylor I, Sbar E I, Paz-Ares L
机构信息
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, USA
Department of Oncology, Princess Alexandra Hospital, Woolloongabba, Brisbane.
出版信息
Ann Oncol. 2016 Mar;27(3):423-9. doi: 10.1093/annonc/mdv593. Epub 2016 Jan 13.
BACKGROUND
The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases.
METHODS
The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib.
RESULTS
One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0-18.2] with dacomitinib and 9.6 months (95% CI 7.4-12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458-1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6-41.5) with dacomitinib versus 23.2 months (95% CI 16.0-31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431-1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib.
CONCLUSIONS
Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721).
CLINICAL TRIALS NUMBER
ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).
背景
不可逆表皮生长因子受体（EGFR）抑制剂已在具有EGFR激活突变的非小细胞肺癌（NSCLC）患者中显示出疗效，但尚不清楚它们是否优于可逆抑制剂。达可替尼是一种口服的、小分子的、对所有具有酶活性的HER家族酪氨酸激酶的不可逆抑制剂。
方法
ARCHER 1009（NCT01360554）和A7471028（NCT00769067）研究将在接受过一或两种先前化疗方案后病情进展的局部晚期/转移性NSCLC患者随机分为达可替尼组或厄洛替尼组。对存档的肿瘤样本进行集中EGFR突变检测。我们汇总了两项研究中具有外显子19缺失和L858R EGFR突变的患者，以比较达可替尼与厄洛替尼的疗效。
结果
共纳入121例有任何EGFR突变的患者；101例在外显子19或21有激活突变。对于外显子19/21突变的患者，达可替尼组的中位无进展生存期为14.6个月[95%置信区间（CI）9.0 - 18.2]，厄洛替尼组为9.6个月（95% CI 7.4 - 12.7）[未分层风险比（HR）0.717（95% CI 0.458 - 1.124），双侧对数秩检验，P = 0.146]。达可替尼组的中位生存期为26.6个月（95% CI 21.6 - 41.5），厄洛替尼组为23.2个月（95% CI 16.0 - 31.8）[未分层HR 0.737（95% CI 0.431 - 1.259），双侧对数秩检验，P = 0.265]。与厄洛替尼相比，两项研究中达可替尼导致腹泻和粘膜炎的发生率更高。
结论
在EGFR突变患者中，达可替尼是一种活性药物，其疗效与厄洛替尼相当。外显子19缺失亚组使用达可替尼有良好的结果。一项正在进行的III期研究将在携带常见EGFR激活突变的NSCLC患者一线治疗中比较达可替尼与吉非替尼（ARCHER 1050；NCT01774721）。
临床试验编号
ARCHER 1009（NCT01360554）和A7471028（NCT00769067）。
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