AZD9291 in EGFR Inhibitor-Resistant Non-Small-Cell Lung Cancer
AZD9291 in EGFR Inhibitor-Resistant Non-Small-Cell Lung Cancer
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DOI：
10.1056/nejmoa1411817
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发表时间：
2015-04-30
影响因子：
158.5
通讯作者：
Ranson, Malcolm
中科院分区：
文献类型：
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作者：
Jaenne, Pasi A.;Yang, James Chih-Hsin;Ranson, Malcolm
EGFR T790 M突变是EGFR突变肺癌患者对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂耐药的最常见机制。在临床前模型中，EGFR抑制剂AZD 9291已被证明是有效的对EGFR酪氨酸激酶敏感和T790 M耐药mutation. METHODS我们管理AZD 9291在剂量为20至240毫克，每天一次在晚期肺癌患者有放射学记录的疾病进展后，以前的治疗与EGFR酪氨酸激酶抑制剂。该研究包括剂量递增队列和剂量扩展队列。在扩展队列中，需要进行研究前肿瘤活检，以集中确定EGFR T790 M状态。对患者的安全性、药代动力学和疗效进行了评估。在入组剂量递增队列的31例患者中，在评价的剂量下未发生剂量限制性毒性作用。另外222例患者在5个扩展队列中接受治疗。最常见的全因不良事件是腹泻、皮疹、恶心和食欲下降。总体客观肿瘤缓解率为51%（95%置信区间[CI]，45 - 58）。在127例中心确认的EGFR T790 M患者中，可评价缓解，缓解率为61%（95% CI，52 - 70）。相比之下，在61例中心检测不到EGFR T790 M的患者中，可以评价缓解，缓解率为21%（95% CI，12 - 34）。中位无进展生存期为9.6个月（95% CI，8.3至未达到），EGFR T790 M阳性患者和2.8个月（95%可信区间，2.1至4.3），EGFR T790 M-结论SAZD 9291在EGFR T790 M突变的肺癌患者中具有高活性，这些患者在既往EGFR酪氨酸激酶治疗期间疾病进展抑制剂的
BACKGROUNDThe EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations.METHODSWe administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy.RESULTSA total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients.CONCLUSIONSAZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.