PMID- 35526510 OWN - NLM STAT- MEDLINE DCOM- 20220711 LR - 20221103 IS - 2059-7029 (Electronic) IS - 2059-7029 (Linking) VI - 7 IP - 3 DP - 2022 Jun TI - Safety, pharmacokinetics, and efficacy of BPI-15086 in patients with EGFR T790M-mutated advanced non-small-cell lung cancer: results from a phase I, single-arm, multicenter study. PG - 100473 LID - S2059-7029(22)00091-6 [pii] LID - 10.1016/j.esmoop.2022.100473 [doi] LID - 100473 AB - BACKGROUND: 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 approximately 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: BPI-15086 is a safe and tolerable third-generation EGFR-TKI with a rationale for further clinical studies. CI - Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Xing, P AU - Xing P AD - 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. FAU - Zheng, X AU - Zheng X AD - 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. FAU - Wang, Y AU - Wang Y AD - 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. FAU - Chu, T AU - Chu T AD - Respiratory Department, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai. FAU - Wang, S AU - Wang S AD - 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. FAU - Jiang, J AU - Jiang J AD - 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. FAU - Qian, J AU - Qian J AD - Respiratory Department, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai. FAU - Han, X AU - Han X AD - 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. FAU - Ding, L AU - Ding L AD - Betta Pharmaceuticals Co., Ltd., Hangzhou, China. FAU - Wang, Y AU - Wang Y AD - Betta Pharmaceuticals Co., Ltd., Hangzhou, China. FAU - Cui, L AU - Cui L AD - Betta Pharmaceuticals Co., Ltd., Hangzhou, China. FAU - Li, H AU - Li H AD - Betta Pharmaceuticals Co., Ltd., Hangzhou, China. FAU - Li, L AU - Li L AD - Betta Pharmaceuticals Co., Ltd., Hangzhou, China. FAU - Chen, X AU - Chen X AD - Betta Pharmaceuticals Co., Ltd., Hangzhou, China. FAU - Han, B AU - Han B AD - Respiratory Department, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai. FAU - Hu, P AU - Hu P AD - 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. Electronic address: Hubei@pumch.cn. FAU - Shi, Y AU - Shi Y AD - 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. Electronic address: syuankai@cicams.ac.cn. LA - eng PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20220506 PL - England TA - ESMO Open JT - ESMO open JID - 101690685 RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adolescent MH - Adult MH - Aged MH - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology MH - ErbB Receptors/genetics MH - Humans MH - *Lung Neoplasms/drug therapy/genetics/pathology MH - Middle Aged MH - Mutation MH - Protein Kinase Inhibitors/adverse effects MH - Young Adult PMC - PMC9271465 OTO - NOTNLM OT - NSCLC OT - epidermal growth factor receptor OT - third generation OT - tyrosine kinase inhibitor COIS- Disclosure LD, YW, LC, HL, LL, and XC are employees of Betta Pharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest. Data sharing Data are available upon reasonable request. EDAT- 2022/05/09 06:00 MHDA- 2022/07/12 06:00 PMCR- 2022/05/06 CRDT- 2022/05/08 18:19 PHST- 2021/10/20 00:00 [received] PHST- 2022/03/13 00:00 [revised] PHST- 2022/03/18 00:00 [accepted] PHST- 2022/05/09 06:00 [pubmed] PHST- 2022/07/12 06:00 [medline] PHST- 2022/05/08 18:19 [entrez] PHST- 2022/05/06 00:00 [pmc-release] AID - S2059-7029(22)00091-6 [pii] AID - 100473 [pii] AID - 10.1016/j.esmoop.2022.100473 [doi] PST - ppublish SO - ESMO Open. 2022 Jun;7(3):100473. doi: 10.1016/j.esmoop.2022.100473. Epub 2022 May 6.