From the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston (P.A.J.); National Taiwan University and National Taiwan University Hospital (J.C.-H.Y.) and Cheng Kung University Hospital (W.-C.S.) - both in Taipei, Taiwan; Seoul National University Hospital (D.-W.K.), Samsung Medical Center (M.-J.A.), Asan Medical Center (S.-W.K.), and Yonsei Cancer Center, Yonsei University Health System (J.-H.K.) - all in Seoul, South Korea; Institut Gustave Roussy, Villejuif, France (D.P.); National Cancer Center Hospital, Tokyo (Y.O.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Vanderbilt Ingram Cancer Center, Nashville (L.H.); Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC (D.H.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (E.F.); and AstraZeneca, Macclesfield (P.F., M.C., K.H.B., P.A.D., S.G.), and University of Manchester, Christie Hospital, Manchester (M.R.) - both in the United Kingdom.
N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.
The 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.
We 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.
A 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.
AZD9291 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. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）耐药的最常见机制是 EGFR 突变，此类患者患有 EGFR 突变型肺癌（EGFR-mutated lung cancer）。在临床前模型中，EGFR 抑制剂 AZD9291 对 EGFR TKI 敏感和 T790M 耐药突变均有效。
在先前接受 EGFR TKI 治疗后疾病进展的晚期肺癌患者中，我们给予 AZD9291 剂量为 20 至 240mg 每日一次，每日一次。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进行中央 EGFR T790M 状态检测。评估患者的安全性、药代动力学和疗效。
共治疗了 253 例患者。在接受剂量递增队列的 31 例患者中，未发生剂量限制毒性。另外 222 例患者在五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%可信区间[CI]，45 至 58）。在可评估反应的 127 例经中心确认为 EGFR T790M 的患者中，缓解率为 61%（95%CI，52 至 70）。相比之下，在可评估反应的 61 例无中心检测到 EGFR T790M 的患者中，缓解率为 21%（95%CI，12 至 34）。EGFR T790M 阳性患者的中位无进展生存期为 9.6 个月（95%CI，8.3 至未达到），而 EGFR T790M 阴性患者的中位无进展生存期为 2.8 个月（95%CI，2.1 至 4.3）。
AZD9291 对先前接受 EGFR TKI 治疗期间疾病进展的 EGFR T790M 突变型肺癌患者具有高度活性。（由阿斯利康公司资助；ClinicalTrials.gov 编号，NCT01802632。）
