Abstract C022: Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results
Authors: Yu Helena , Johnson Melissa , Henry Jason T. , Spira Alex , Han Ji-Youn , Barve Minal , Battiste James , Alnahhas Iyad , Nam DoHyun , Edenfield Jeffrey , Halmos Balazs , Yoon Shinkyo , Kim Tae Min , Eathiraj Sudharshan , Hajdenberg Julio , Yurasov Sergey , Ahluwalia Manmeet , Wen Patrick 
Published: December 2023

Abstract
Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (r/rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver (L858R, Ex19del), intrinsic (atypical) driver (L718Q, L861Q, S768I), and acquired resistance mutation (C797X). BDTX-1535 is an oral, highly potent, brain penetrant, selective, irreversible 4th generation tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preliminary results from the Phase 1 dose escalation study (NCT05256290) are presented. Methods: BDTX-1535-101 is a first-in-human study enrolling patients with locally advanced or metastatic NSCLC harboring EGFR mutations, with or without CNS disease, following standard of care EGFR inhibitor therapy, or patients with r/rGBM expressing EGFR alterations. The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Using an adaptive Bayesian optimal interval design, eligible patients are enrolled and dosed daily for 21-day cycles until treatment discontinuation. Results: As of 20 May 2023, 51 patients (24 NSCLC, 27 r/rGBM) were enrolled and treated across 7 dose cohorts (15mg – 400mg QD). For NSCLC, mean age was 65 years (range 47-81), patients had a median of 2 prior lines of treatment (1-9), and 79% received prior osimertinib. For r/rGBM, the mean age was 58 years (41-85) with a median of 2 prior lines of treatment (range 1-4). The most common all-grade treatment-related AEs (TRAE) were rash (76%), diarrhea (51%), stomatitis (29%), paronychia (20%) and nausea (20%), vast majority Gr 1 to Gr 2. Gr 3 TRAEs greater than or equal 10% were diarrhea (12%) and rash (10%). Plasma exposure of BDTX-1535 increased dose proportionally with a half-life of ~15h supporting once daily dosing. The maximum tolerated dose is 300mg QD. Circulating tumor DNA (ctDNA) assessment in NSCLC patients with classical and intrinsic drivers as well as acquired resistance mutations revealed significant ctDNA reductions across all EGFR mutation types. Five of 12 patients with either intrinsic driver (eg, L718Q) or acquired resistance (C797S) mutations in a subgroup of NSCLC efficacy evaluable patients at doses at or above 100mg had a confirmed partial response (PR) by RECIST1.1; 1 patient had unconfirmed PR, while the remaining 6 patients had stable disease. Additional GBM data will be shared separately.Conclusions:BDTX-1535 was well-tolerated at a daily dose up to 300mg and promising preliminary clinical activity was observed in NSCLC patients harboring either intrinsic driver or acquired resistance EGFR mutations post-progression with an EGFR inhibitor. A preliminary RP2D dose is being explored in NSCLC patients in dose expansion cohorts. :
Citation Format: Helena Yu, Melissa Johnson, Jason T. Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. Phase 1 study of BDTX-1535, an oral 4th generation inhibitor, in patients with Non-Small Cell Lung Cancer and Glioblastoma: Preliminary dose escalation results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C022.