Abstract CT023: A phase 0/1 ‘trigger’ trial of BDTX-1535 in recurrent glioblastoma (GBM) patients with EGFR alterations or fusions

Abstract Background: Alterations in the epidermal growth factor receptor (EGFR) are common in glioblastoma (GBM) and play a key role in its pathogenesis. This Phase 0/1 study assesses the pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes of BDTX-1535, an ATP-competitive, irreversible 4th generation brain penetrant EGFR inhibitor, in recurrent GBM patients with EGFR alterations. Materials/Methods: Recurrent GBM patients with EGFR alterations received BDTX-1535 for 5 days at 200 mg daily (cohort 1) or 400 mg every other day x 3 doses (cohort 2) prior to planned resection 2-4 hours after the final dose. In the Phase 0 study component, total and unbound drug concentrations were measured in tumor tissue (gadolinium (Gd)-enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK threshold, defined as unbound drug concentrations above 1 nM or 4.1 nM in Gd non-enhancing tumor for patients with EGFR mutations or amplification, respectively, determined eligibility for Phase 1 therapeutic dosing. PD response was evaluated by comparing the percentage of pEGFR, pERK, and MIB-1 positive cells in surgical tumor tissue to baseline pre-treatment tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for Phase 1 therapeutic dosing (200 mg QD) of BDTX-1535 until progression. Results: A total of 22 recurrent GBM patients were enrolled across cohorts 1 and 2 in the Phase 0 component of the study. 4 patients were excluded from PK analysis due to pseudoprogression. Mean unbound concentrations of BDTX-1535 in Gd non-enhancing tumor regions were 18.8 nM and 16.7 nM in cohorts 1 and 2, respectively. Seventeen of eighteen (94.4%) evaluable patients exceeded the PK threshold and qualified for Phase 1. Suppression of pEGFR and MIB1 was observed in 65% and 47% of patients, respectively. No serious adverse events related to BDTX-1535 were observed in any patient; 26.7% (4/15) patients experienced grade ≤3 toxicities resulting in dose interruptions. At data cutoff, the median survival was 4.9 months. Conclusions: For recurrent GBM patients, BDTX-1535 achieves pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue and is associated with suppression of EGFR phosphorylation. Study expansion into MGMT-unmethylated, newly-diagnosed GBM patients is planned. Citation Format: Nader Sanai, Yoshie Umemura, Vahuni Karapetyan, Tigran Margaryan, Dylan Huttenlocher, Brian Pham, Jocelyn Harmon, Amy Hong, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta. A phase 0/1 ‘trigger’ trial of BDTX-1535 in recurrent glioblastoma (GBM) patients with EGFR alterations or fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT023.