Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing.
Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing.
ESMO Open. 2022 Jun;7(3):100473. doi: 10.1016/j.esmoop.2022.100473. Epub 2022 May 6.
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance frequently occurs in patients with non-small-cell lung cancer (NSCLC). EGFR Thr790Met mutation (T790M+) is seen in ∼50% of patients. We assessed the safety, tolerability, and pharmacokinetics (PK) of BPI-15086, a novel, ATP-competitive, irreversible, third-generation, mutation-selective EGFR-TKI in patients with EGFR T790M-mutated NSCLC.
This two-center, phase I, dose-escalation study included patients who were 18-65 years old, with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically or cytologically confirmed locally advanced or metastatic T790M+ NSCLC who were not surgical or radiotherapy candidates, and had imaging-identified disease progression after prior EGFR-TKIs. This dose-escalation study enrolled patients using a 3 + 3 study design. Patients received 25, 50, 100, 200, and 300 mg/day orally in 21-day cycles. The primary endpoints were safety, tolerability, and PK. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). The dose-expansion study was not conducted.
We enrolled 17 patients from 29 December 2016 to 16 May 2018, in the safety and full analysis sets. All patients completed a single dosing trial, and no adverse events (AEs) causing drug discontinuation were seen. Grade 1-2 nausea, hypoalbuminemia, and decreased appetite were the most common treatment-related AEs. Grade 3 hyperglycemia was seen in one patient dosed at 300 mg/day. The ORR and DCR were 17.7% [95% confidence interval (CI) 3.8% to 43.4%] and 47.1% (95% CI 23.0% to 72.2%), respectively.
BPI-15086 is a safe and tolerable third-generation EGFR-TKI with a rationale for further clinical studies.
表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）耐药经常发生在非小细胞肺癌（NSCLC）患者中。约 50%的患者存在 EGFR Thr790Met 突变（T790M+）。我们评估了新型 ATP 竞争性、不可逆、第三代、突变选择性 EGFR-TKI 药物 BPI-15086 在 EGFR T790M 突变型 NSCLC 患者中的安全性、耐受性和药代动力学（PK）。
这是一项两中心、I 期、剂量递增研究，纳入了年龄在 18-65 岁之间、东部肿瘤协作组体能状态为 0-2 分、经组织学或细胞学证实的局部晚期或转移性 T790M+ NSCLC 患者，这些患者不适宜手术或放疗，并且在接受 EGFR-TKI 治疗后影像学显示疾病进展。这项剂量递增研究采用 3+3 设计方案入组患者。患者每日口服 25、50、100、200 和 300 mg，21 天为一个周期。主要终点是安全性、耐受性和 PK。次要终点是客观缓解率（ORR）和疾病控制率（DCR）。未进行剂量扩展研究。
我们于 2016 年 12 月 29 日至 2018 年 5 月 16 日期间纳入了 17 例患者进入安全性和全分析集。所有患者均完成了单次给药试验，未观察到因不良事件（AE）而停药的情况。最常见的治疗相关 AE 是 1-2 级恶心、低白蛋白血症和食欲下降。1 例 300 mg 剂量组患者出现 3 级高血糖。ORR 和 DCR 分别为 17.7%（95%置信区间 [CI]：3.8%至 43.4%）和 47.1%（95% CI：23.0%至 72.2%）。
BPI-15086 是一种安全且耐受良好的第三代 EGFR-TKI，具有进一步开展临床研究的潜力。
