CTNI-14. INTEGRATED PHARMACOKINETICS, PHARMACODYNAMICS, AND CLINICAL DATA UPDATE FROM PHASE 0/1 TRIAL FOR BDTX-1535 IN NEWLY-DIAGNOSED AND RECURRENT GLIOBLASTOMA PATIENTS WITH EGFR ALTERATIONS

Abstract BACKGROUND EGFR alterations are common in glioblastoma (GBM). This Phase 0/1 trial evaluates BDTX-1535, a fourth-generation, brain-penetrant EGFR inhibitor with irreversible and ATP-competitive binding, assessing pharmacokinetics (PK), and pharmacodynamics (PD), and preliminary efficacy in recurrent and newly diagnosed GBM patients harboring EGFR aberrations. MATERIALS/METHODS Recurrent GBM patients with EGFR amplifications/mutations (Arm A) received BDTX-1535 for 5 days at 200 mg daily (cohort 1) or 400 mg every other day (cohort 2) followed by tumor resection 2-4 hours after the final dose. Newly diagnosed, MGMT-unmethylated patients with EGFR alterations (Arm C) will receive either 200 mg QD or 150 mg QD. In Phase 0, total and unbound drug concentrations were measured in gadolinium enhancing and non-enhancing tumor tissue, CSF, and plasma using LC-MS/MS. A PK threshold is defined as unbound drug >1 nM (EGFR mutation) or >4.1 nM (EGFR amplification) in non-enhancing tumor. The PD response was assessed by comparing post-treatment tumor pEGFR and MIB-1 levels to pre-treatment tissue. RESULTS Twenty-seven recurrent GBM patients were enrolled in Arm A; two newly-diagnosed patients were screened for Arm C as of 6/6/2025. Five were excluded from PK analysis due to pseudoprogression. Mean unbound concentrations in non-enhancing tumor regions were 18.8 nM (cohort 1) and 13.7 nM (cohort 2). Twenty of twenty-two (90.9%) patients exceeded the PK threshold and were eligible for therapeutic dosing. pEGFR and MIB1 suppression was seen in 70% and 50% of cases, respectively. No BDTX-1535-related serious adverse events were observed; 20% (4/20) patients experienced grade ≤3 toxicities (i.e., diarrhea, rash) requiring dose interruptions. At cutoff, median follow-up was 5.6 months, overall survival ranged from 2.7-18.4 months with a median of 5.8 months. CONCLUSIONS BDTX-1535 reaches therapeutic levels in infiltrative GBM tissue, with associated biomarker suppression. Safety signals were expected and manageable. Arm C enrollment is ongoing.