Abstract BACKGROUND Epidermal growth factor receptor (EGFR) alterations are common in glioblastoma (GBM) and play a key role in its pathogenesis. This Phase 0/1 study evaluates 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 AND 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 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 24 recurrent GBM patients were enrolled across cohorts 1 and 2 in the Phase 0 component of the study. 5 patients were excluded from PK analysis due to histopathological confirmation of pseudoprogression. Mean unbound concentrations of BDTX-1535 in Gd non-enhancing tumor regions were 18.8 nM and 11.7 nM in cohorts 1 and 2, respectively. Seventeen of nineteen (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; 25% (4/16) patients experienced grade ≤3 toxicities resulting in dose interruptions. At data cutoff, the median follow-up duration, overall survival range and median survival were 4.7 months, 2.7-16.8 months and 5.8 months, respectively. CONCLUSION For recurrent GBM patients, BDTX-1535 achieves pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue and is associated with suppression of EGFR phosphorylation. Expected safety signals were observed but manageable. Based on these encouraging findings, the trial is being expanded to enroll newly-diagnosed EGFR-positive GBM patients.
Sanai et al. (Wed,) studied this question.