Abstract 1365TiP
Background
First- and third-generation epidermal growth factor receptor (EGFR) inhibitors such as gefitinib and osimertinib, respectively, have improved survival outcomes for patients with advanced EGFR-mutant NSCLC. However, acquired resistance invariably emerges, leading to disease progression. The predominant mechanism of acquired resistance is a tertiary mutation at C797 position of EGFR gene added to T790M mutation which is the most well-known resistance mechanism to 1st generation EGFR inhibitors. BBT-176 specifically and non-covalently inhibits triple-mutant EGFR (exon19del/T790M/C797S and L858R/T790M/C797S). Preclinical data including Ba/F3 engineered cells, patient-derived xenografts and cells showed efficacy of BBT-176 in triple-mutant EGFR models. Synergistic efficacy of BBT-176 with Cetuximab was also observed in animal studies. Therefore, the first-in-human (FIH) study of BBT-176 was designed and the enrollment of first cohort began in April, 2021 under the IND of USA and Republic of Korea.
Trial design
The objectives of this study include determination of the maximum tolerated dose (MTD), recommended phase II dose (RP2D) and characterization of dose-limiting toxicities (DLTs). It is composed of a dose-escalation part guided by Bayesian linear regression model and a dose-expansion part. Approximately 90 patients are planned to be enrolled. All patients must have advanced NSCLC with activating EGFR mutation and must have progressed on at least 1 prior EGFR inhibitor. Starting from 20 mg QD continuous dosing, dose levels will be escalated after evaluating dose-DLT relationships and toxicity probabilities after the first 21 days of dosing. Potential ethnic variability in pharmacokinetics will be compared. In order to determine MTD, modified continual reassessment method will be performed. When RP2D is determined in Part 1, then Part 2 will be initiated to evaluate efficacy in molecularly selected target populations. Objective response rate, duration of response and progression-free survival will be measured in addition to safety and tolerability of BBT-176 at RP2D (NCT04820023).
Clinical trial identification
NCT04820023; Release date: March 29, 2021.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
D. Kim: Financial Interests, Institutional, Funding: Alpha Biopharma; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Hanmi; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Merus; Financial Interests, Institutional, Funding: Mirati Therapeutics; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Ono Pharmaceuticals; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Roche/Genentech; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Institutional, Funding: TP Therapeutics; Financial Interests, Institutional, Funding: Xcovery; Financial Interests, Institutional, Funding: Yuhan; Financial Interests, Institutional, Funding: Chong Keun Dang; Financial Interests, Institutional, Funding: Bridge Biotherapeutics; Financial Interests, Institutional, Funding: GSK; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. G. Lee: Other, Personal, Other, Ex-employee: Bridge Biotherapeutics. J. Ryou: Other, Personal, Invited Speaker, Ex-employee: Bridge Biotherapeutics. S. Kang: Financial Interests, Personal, Stocks/Shares, Employee: Bridge Biotherapeutics. Y. Lee: Financial Interests, Personal, Stocks/Shares, Employee: Bridge Biotherapeutics. H. Shin: Financial Interests, Personal, Full or part-time Employment: Bridge Biotherapeutics. S.Y. Yum: Financial Interests, Personal, Stocks/Shares, Employee: Bridge Biotherapeutics. E. Yim: Financial Interests, Personal, Full or part-time Employment: Bridge Biotherapeutics. S. Lee: Financial Interests, Personal, Full or part-time Employment: Bridge Biotherapeutics. All other authors have declared no conflicts of interest.