Investigational Agent May Benefit Non-Small Cell Lung Cancer Patients With Leptomeningeal Disease

Korean researchers are now reporting they may have an important new weapon that can cross the blood-brain barrier and combat leptomeningeal disease. If verified in future studies, this could provide a whole new approach to treating patients with non-small cell lung cancer (NSCLC) with leptomeningeal disease.

The epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) AZD9291 has been found to cross the blood-brain barrier. This experimental agent also showed clinical activity in heavily pretreated NSCLC patients with leptomeningeal disease, according to data from a phase I BLOOM clinical trial presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Study results were also published April 30, 2015, in The New England Journal of Medicine.

Leptomeningeal disease, a disease in which lung cancer cells spread to the membranes surrounding the brain and spinal cord, is rare at initial diagnosis of NSCLC. "However, as their lung cancer progresses, up to 15% of patients will develop this devastating complication. Additionally, an increased risk of central nervous system (CNS) involvement has been reported among patients with EGFR-mutant NSCLC, in particular those treated with a first-generation EGFR-TKI," said Dae Ho Lee, MD, PhD,  who is an associate professor in the Department of Oncology in the University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.

Dr. Lee said patients with EGFR-mutated NSCLC and leptomeningeal disease have an average survival of 7 to 11 months, and currently, there are no established effective treatments for this condition.

Of the 13 heavily pretreated EGFR-mutant NSCLC patients that Dr. Lee and colleagues enrolled in the phase I trial, 10 had received other EGFR-TKIs as prior therapies and seven had received radiotherapy to the brain. Among these patients, four had T790M-positive disease detected in their plasma and two had DNA with the T790M mutation detected in their cerebrospinal fluid (CSF). All patients received 160 mg of AZD9291 once daily until disease progression. Treatment beyond progression was allowed at investigator discretion. 

"There is no standardized way to measure response of leptomeningeal disease to therapy, but a combination of clearing cancer cells from the fluid surrounding the brain (CSF cytology), changes on brain MRI imaging, and improvement in neurologic symptoms is likely to be the best composite endpoint to assess clinical benefit," said Dr. Lee.

There were 11 patients who were evaluable for response as of October 12, 2015. Among these patients, six had improvements in brain imaging and three out of seven patients with abnormal neurological exams at baseline had symptomatic improvement. Dr. Lee said one patient had confirmed clearance and four patients had unconfirmed clearance of cancer cells from the CSF.

Dr. Lee said there were nine patients from whom pre- and post-treatment CSF samples were available.  Among these nine patients, eight had a decrease in EGFR-mutant DNA, with the decrease being more than 50% in five of them.  

"Although preliminary, these results show encouraging activity and a manageable safety profile in a patient population with few treatment options. The results support further investigation of AZD9291 in central nervous system disease," Dr. Lee said.