Dr Sanai on the Evaluation of BDTX-1535 in EGFR-Mutated High-Grade Glioblastoma

Nader Sanai, MD, chief, Neurosurgical Oncology, director, Ivy Brain Tumor Center, Barrow Neurological Institute, discusses a phase 0/1 trial (NCT06072586) investigating BDTX-1535 in patients with recurrent, EGFR-mutated high-grade glioblastoma.

Investigators have long sought to target EGFR fusions and alterations in the treatment of patients with recurrent and newly diagnosed glioblastoma, Sanai says. Several challenges in this area have arisen, including the difficulty of developing an agent with the ability to penetrate the central nervous system (CNS), Sanai explains. BDTX-1535, a fourth-generation, ATP-competitive, irreversible EGFR inhibitor, has been developed by Black Diamond Therapeutics. This agent is designed to penetrate the CNS, Sanai emphasizes.

This investigation evaluated the pharmacokinetics, pharmacodynamics, and efficacy of BDTX-1535 in patients with high-grade glioblastoma harboring EGFR alterations and/or fusions. In the phase 0 portion, patients in cohort 1 received the agent at 200 mg daily, and patients in cohort 2 received the agent at 400 mg 3 times a week. In the phase 1 portion, patients received the agent at 200 mg daily in 28-day cycles.

The mean respective unbound concentrations of BDTX-1535 on Gd-enhancing and Gd-nonenhancing tumor regions were 11.9 nM and 18.8 nM. Furthermore, among 9 evaluable patients, 8 exceeded the pharmacokinetic threshold and were subsequently enrolled in the adjuvant portion of the study. pEGFR and MIB1 suppression was reported in 55% and 60% of patients, respectively.

In the phase 1 portion, among 8 patients evaluable for safety, 37.5% had any-grade adverse effects (AEs), 25.0% had grade 3 or higher AEs, and 25.0% had serious AEs. No serious AEs were attributed to treatment with BDTX-1535. AEs led to dose interruption in 25.0% of patients. No AEs resulted in dose reduction or study discontinuation.

This phase 1 trial shows first-in-human evidence of CNS penetration and target modulation with an EGFR inhibitor in patients with EGFR-mutant recurrent glioblastoma, Sanai concludes.