James Chih-Hsin Yang and Chia-Chi Lin, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China; Myung-Ju Ahn, Sungkyunkwan University; Dong-Wan Kim, Seoul National University Hospital; Sang-We Kim, Asan Medical Center, Seoul; Joo-Hang Kim, CHA University, Gyeonggi-do, Republic of Korea; Suresh S. Ramalingam, Emory University School of Medicine, Atlanta, GA; Lecia V. Sequist, Massachusetts General Hospital; Pasi A. Jänne, Dana-Farber Cancer Institute, Boston, MA; David Planchard, Institut Gustave Roussy, Villejuif, France; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Fiona Blackhall, The Christie Hospital; University of Manchester, Manchester; Helen Mann and Serban Ghiorghiu, AstraZeneca, Cambridge; Mireille Cantarini, AstraZeneca, Macclesfield, United Kingdom; Daniel Haggstrom, Carolinas Healthcare System, Charlotte, NC; Kiyotaka Yoh, National Cancer Center Hospital East, Kashiwa, Chiba; Tomonori Hirashima, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan; Silvia Novello, University of Turin, Turin, Italy; and Kathryn Gold, University of California San Diego Moores Cancer Center, San Diego, CA.
J Clin Oncol. 2017 Apr 20;35(12):1288-1296. doi: 10.1200/JCO.2016.70.3223. Epub 2017 Feb 21.
Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.
奥希替尼是一种不可逆的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），对 EGFR-TKI 敏感（EGFRm）和 T790M 耐药突变均具有选择性。AURA（NCT01802632）是一项旨在确定奥希替尼剂量、安全性和疗效的 I/II 期临床试验。本文报道了该试验的 II 期扩展部分的结果。
既往接受过 EGFR-TKI 治疗且存在 EGFRm 和 T790M 阳性的晚期非小细胞肺癌（NSCLC）患者接受每日一次 80mg 的奥希替尼治疗。T790M 状态通过对最近疾病进展后获得的肿瘤样本进行中心检测来确认。允许无症状、稳定的中枢神经系统转移且无需使用皮质类固醇的患者入组。主要终点为独立影像学评估的客观缓解率（ORR）。次要终点包括疾病控制率、缓解持续时间、无进展生存期（PFS）和安全性。患者报告的结果包括一项探索性终点。
共有 201 例患者接受了治疗，截至数据截止日期（2015 年 11 月 1 日），中位治疗时间为 13.2 个月。在可评估患者（n=198）中，ORR 为 62%（95%CI，54%至 68%），疾病控制率为 90%（95%CI，85%至 94%）。122 例应答患者的中位缓解持续时间为 15.2 个月（95%CI，11.3 至无法计算）。中位 PFS 为 12.3 个月（95%CI，9.5 至 13.8）。最常见的可能与治疗相关的不良事件（研究者评估）为腹泻（43%；≥3 级，<1%）和皮疹（分组术语；40%；≥3 级，<1%）。有 8 例患者（4%）报告间质性肺病（分组术语）（1 级，n=2；3 级，n=3；5 级，n=3）。
在 EGFR-TKI 治疗后进展的 EGFRm T790M 晚期 NSCLC 患者中，奥希替尼的 ORR 高、PFS 有改善且缓解持续时间长。
