Hizuoka Cancer Center, Shizuoka, Japan.
Tokushima University Hospital, Tokushima, Japan.
Cancer Sci. 2018 Sep;109(9):2852-2862. doi: 10.1111/cas.13724. Epub 2018 Aug 9.
Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose-escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25-600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations.
表皮生长因子受体 (EGFR)-激活突变使非小细胞肺癌 (NSCLC) 对酪氨酸激酶抑制剂 (TKI) 治疗敏感。ASP8273 是一种高度特异、不可逆、每日一次、口服的 EGFR TKI，可抑制激活和耐药突变。这项 ASP8273 剂量递增/剂量扩展研究（NCT02192697）分为两个阶段进行。在第 I 阶段，先前接受过≥1 种 EGFR TKI 治疗的≥20 岁日本 NSCLC 患者接受了递增的 ASP8273 剂量（25-600mg），以评估安全性/耐受性，并通过贝叶斯连续评估法确定最大耐受剂量（MTD）和/或推荐的 II 期剂量（RP2D）。在第 II 阶段，日本、韩国和中国台湾的 T790M 阳性 NSCLC 成年患者接受 RP2D 的 ASP8273 治疗，以进一步评估安全性/耐受性，并根据 Simon 的两阶段设计（阈值反应=30%，预期反应=50%，α=0.05，β=0.1）确定抗肿瘤活性。总体而言，121 名（n=45 [33W/12M] 第 I 阶段，n=76 [48W/28M] 第 II 阶段）患者接受了≥1 剂 ASP8273。在第 I 阶段，确定 RP2D 和 MTD 分别为 300 和 400mg。由于接受 ASP8273 300mg 治疗的 63 名患者中有 27 名达到了临床反应，因此确定 ASP8273 具有抗肿瘤活性。所有患者在第 24 周的总体缓解率为 42%（n=32/76；95%置信区间，30.9-54.0）。中位无进展生存期为 8.1 个月（95%置信区间，5.6，上限未达到）。第 II 阶段报告的最常见治疗相关不良事件是腹泻（57%，n=43/76）。ASP8273 300mg 总体耐受性良好，在具有 EGFR 激活和 T790M 突变的亚洲患者中显示出抗肿瘤活性。
