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, 

Investigators have long sought to target 

 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 

 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 

-mutant recurrent glioblastoma, Sanai concludes.

Videos

Nader Sanai, MD, discusses a phase 1 trial investigating BDTX-1535 in patients with recurrent, EGFR-mutated high-grade glioblastoma.

A Phase 0/1 ‘trigger’ trial of BDTX-1535 in recurrent high-grade glioma (HGG) patients with EGFR alterations or fusions

Dr. Nader Sanai presents the findings of a phase 0/1 trigger trial (NCT06072586) that evaluates the CNS penetration of BDTX-1535 in patients with recurrent high-grade gliomas and EGFR mutations.

A Phase 0/1 ‘Trigger’ Trial of BDTX-1535 in Recurrent High-Grade Glioma (HGG) Patients With EGFR Alterations or Fusions

Although meningiomas, tumors that arise in the meninges surrounding the brain and spinal cord, are the most common form of primary brain tumors. Grade I tumors are often asymptomatic, and patients can live for years without problems. High-grade meningiomas, however, are rare and aggressive tumors. Nader Sanai, MD, chief scientific officer and chief of neurosurgical oncology with the Ivy Brain Tumor Center at the Barrow Neurological Institute, says about 5% of high-grade tumors represent the malignant grade III form of the disease.

Meningiomas are graded as I, II, or III. Grade 1 tumors are often small, benign, and indolent. In many cases, patients with grade I tumors can do not need immediate treatment and can simply be observed.  When treatment is necessary, surgery with or without radiation can often completely resolve these tumors.

Sanai says that grade II tumors are more aggressive, though not technically considered malignant. However, they have a high incidence of recurrence. Sanai says that symptom onset in grade II/III tumors is much more rapid, but those symptoms can be nonspecific. Sanai said higher-grade tumors can be diagnosed with a CT scan but are more often detected on MRI.

The most common symptoms include headache, focal cranial nerve deficit, and seizure. Depending on the site of the tumor, high-grade meningiomas can also cause focal neurologic deficits including cranial nerve deficits. The patient may experience posterior fossa type syndromes such as nausea, vomiting, balance problems, or double vision if the tumor is closer to the cerebellum. 

High-grade meningiomas can also present with progressive symptoms, such as new onset focal neurological deficits, significant headache, or mass effect symptoms such as fatigue, vision problems, or nausea and vomiting. Sanai noted that the rapid growth of grade II/III tumors causes swelling in the brain, leading to seizures.

Nader Sanai, MD, discusses symptoms associated with high-grade meningiomas, a rare brain tumor.

Nader Sanai, MD

Articles

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

A Phase 0/1 ‘Trigger’ Trial of BDTX-1535 in Recurrent High-Grade Glioma (HGG) Patients With EGFR Alterations or Fusions

Dr. Sadai on Signs and Symptoms of High-Grade Meningiomas