LAUSR

Background: EGFR mutation in non-small cell lung cancer (NSCLC) presents a viable therapeutic target for which tyrosine kinase inhibitor (TKI) therapy has shown impressive clinical benefit over the past 20 years. Unfortunately, most patients inevitably progress on earlier-generation EGFR TKIs due to various mechanisms after a period of therapy. The most commonly acquired on-target resistance mutations are T790M and C797S, often appearing after progression on 1st-, 2nd-generation, and 3rd-generation EGFR TKIs, respectively. To prevent the emergence of drug-resistant subclones, a next-generation EGFR TKI must have activity against both treatment-emergent and drug-naïve mutants. Further preclinical studies were conducted to evaluate the activity of BBT-207 in delaying tumor regrowth or prolonging survival in NSCLC tumor models driven by the EGFR T790M and C797S mutation. Method: We evaluated the inhibitory potency of BBT-207 against wild-type (WT) and mutated EGFR proteins. In vivo anti-tumor activity was evaluated in Ba/F3 EGFR ex19del/T790M (DT), L858R/T790M (LT), ex19del/C797S (DC), L858R/C797S (LC), ex19del/T790M/C797S (DTC) or L858R/T790M/C797S (LTC), H1975 EGFR LTC cell line-derived xenograft (CDX), and EGFR DTC-patient-derived xenograft (PDX) models. In vivo inhibition of brain metastases (BM) was evaluated in a luciferase-expressing PC-9 EGFR DTC BM model through direct intracranial implantation. Results: BBT-207 is broadly active against activating and acquired resistance EGFR mutants and displayed potent anti-proliferation activity against Ba/F3 EGFR DT, LT, DC, LC, DTC, LTC with 4, 4, 1, 16, 5 and 8nM, respectively while being highly selective against Ba/F3 EGFR WT (184 nM). BBT-207 also showed IC50 values <5 nM against Osimertinib-resistant EGFR L792H triple mutants, DTL and LTL in cell-free in vitro kinase assay. QD administration as a single agent resulted in significant tumor regression in the Ba/F3 EGFR DT, LT, DC, LC, DTC, LTC CDX models and EGFR DTC PDX model. Indeed, BBT-207 showed sustained anti-tumor efficacy in Ba/F3 EGFR DC CDX model. Furthermore, BBT-207 exerted dose-dependent intracranial anti-tumor activity and enhanced survival rate of mice in the PC-9/EGFR DTC_Luc BM model. PK studies revealed CNS penetration with good B/P ratios in animals. Conclusion: BBT-207 is a reversible, mutant-specific, broad-spectrum TKI, active to clinically observed mutations of EGFR and is expected to be compatible with monotherapy of QD schedule in humans. BBT-207 is well-positioned to augment the treatment of EGFR mutated NSCLC, either for acquired drug resistance or in earlier line, with potential to treat or prevent CNS metastasis. PK/TK evaluation justify exploration in humans. First-in-human study in patients harboring EGFRm and previously treated with EGFR TKI, is to begin enrollment in USA 1H 2023. Citation Format: Chulwon Kim, Youn Hee Jung, Naeun Jeon, Yong-Hee Lee, Sang-Yoon Lee, Jimmy Taiguang Jin. BBT-207 is a broad-spectrum, highly potent, 4th generation EGFR TKI with enhanced activity to both sensitizing and treatment-emergent EGFR mutations including T790M and C797S. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4018.