New Drug Gets Through Blood-Brain Barrier to Shrink NSCLC Brain Metastases

Non-small cell lung cancer (NSCLC) tumors can have mutations in the epidermal growth factor receptor (EGFR) protein that makes them sensitive to EGFR inhibitors.  Anti-EGFR therapy (typically gefitinib or erlotinib) is often an effective treatment option against these tumors until the cancer spreads (metastasizes) from the lung to the brain where it forms metastatic brain tumors. 

There is no effective long-term treatment or cure for metastatic NSCLC.  One major issue is that it is difficult to get anti-EGFR therapies across the blood-brain barrier (BBB) in high enough concentrations that shrink brain metastases without reaching toxic levels in the rest of the body.

Authors of a recent paper in Science Translational Medicine have discovered a new EGFR inhibitor, AZD3759, which can successfully cross the BBB resulting in equal concentrations of drug in the bloodstream and brain of NSCLC patients.  

Excitingly, AZD3759 was able to effectively treat NCLC brain metastases in a range of four different mouse models designed to mimic different disease settings in the clinic.  The results of these preclinical experiments demonstrated that AZD3759 could both prevent the growth of metastases in the brain and effectively shrink existing metastases.

AZD3759 is now being tested in an ongoing clinical trial (BLOOM study) for efficacy against metastatic tumors in NSCLC patients. One patient examined with brain metastases in this trial experienced a 46% reduction in metastatic tumor size after 6 weeks of AZD3759 treatment.  This patient had already progressed after multiple lines of treatment, including anti-EGFR therapy with gefitinib.

Gefitinib was effective in treating tumors growing outside of the brain, but it did not limit metastatic brain tumor growth.  The fact that AZD3759 did shrink multiple brain metastases in the same patient underscores the importance of BBB penetration for treating brain metastases.  The hope is that AZD3759 will continue to perform well in ongoing clinical trials and become a new option for NSCLC patients with metastases in the central nervous system. 

Source article for this story: 
Yang Z, Guo Q, Wang Y, et al. AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Science Translational Medicine. December 7, 2016. 8(368):368ra172.