Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
Jilin Provincial Cancer Hospital, Changchun, China.
Lancet Oncol. 2017 Nov;18(11):1454-1466. doi: 10.1016/S1470-2045(17)30608-3. Epub 2017 Sep 25.
Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC).
In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged ≥18 years or ≥20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1:1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients.
Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22·1 months (95% CI 20·3-23·9). Median progression-free survival according to masked independent review was 14·7 months (95% CI 11·1-16·6) in the dacomitinib group and 9·2 months (9·1-11·0) in the gefitinib group (hazard ratio 0·59, 95% CI 0·47-0·74; p<0·0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia).
Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population.
SFJ Pharmaceuticals Group and Pfizer.
达可替尼是第二代不可逆表皮生长因子受体酪氨酸激酶抑制剂。我们比较了它与可逆表皮生长因子受体酪氨酸激酶抑制剂吉非替尼在一线治疗表皮生长因子受体突变阳性非小细胞肺癌（NSCLC）患者中的疗效和安全性。
在这项国际性、多中心、随机、开放标签、III 期ARCHER 1050 研究中，我们纳入了 71 家学术医疗中心和大学医院的新诊断为晚期 NSCLC 且存在一个 EGFR 突变（外显子 19 缺失或 Leu858Arg）的成年患者（年龄≥18 岁或在日本和韩国≥20 岁）。我们以 1:1 的比例随机分配参与者接受口服达可替尼 45 mg/天（28 天周期）或口服吉非替尼 250 mg/天（28 天周期），直至疾病进展或出现其他停药标准。按种族和 EGFR 突变类型进行分层的随机化是通过中央交互式网络响应系统生成的计算机随机代码进行的。主要终点是通过意向治疗人群中的独立盲法评估的无进展生存期。在至少接受一剂研究治疗的所有患者中评估安全性。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01774721，正在进行中，但不再招募患者。
2013 年 5 月 9 日至 2015 年 3 月 20 日，452 名符合条件的患者被随机分配接受达可替尼（n=227）或吉非替尼（n=225）治疗。无进展生存期的中位随访时间为 22.1 个月（95%CI 20.3-23.9）。根据独立盲法评估，达可替尼组无进展生存期的中位值为 14.7 个月（95%CI 11.1-16.6），吉非替尼组为 9.2 个月（9.1-11.0）（风险比 0.59，95%CI 0.47-0.74；p<0.0001）。最常见的 3-4 级不良事件是痤疮样皮炎（达可替尼组 227 例患者中有 31 例[14%]，吉非替尼组无 1 例）、腹泻（达可替尼组 19 例[8%]，吉非替尼组 2 例[1%]）和丙氨酸氨基转移酶升高（达可替尼组 2 例[1%]，吉非替尼组 19 例[8%]）。达可替尼组有 21 例（9%）患者和吉非替尼组有 10 例（4%）患者发生与治疗相关的严重不良事件。达可替尼组有 2 例治疗相关死亡（1 例与未治疗的腹泻有关，1 例与未治疗的胆石症/肝脏疾病有关），吉非替尼组有 1 例（与乙状结肠憩室炎/破裂伴发肺炎有关）。
达可替尼在表皮生长因子受体突变阳性非小细胞肺癌患者的一线治疗中显著改善了无进展生存期，应被视为该人群的新治疗选择。
珐博进医药开发（中国）有限公司和辉瑞公司。
