EXTH-46. A PRECISION MEDICINE APPROACH TO TARGET EGFRvIII IN GBM: OSIMERTINIB (AZD9291) INHIBITS THE GROWTH OF EGFRvIII-POSITIVE GLIOBLASTOMA STEM CELLS AND INCREASES SURVIVAL OF MICE BEARING INTRACRANIAL EGFRvIII-POSITIVE GBM

Abstract

Attempts to target EGFRvIII, which is present in over 20% of GBMs, with EGFR-tyrosine kinase inhibitors (EGFR-TKI) and vaccines have been unsuccessful. This failure appears to be due to two main reasons: 1) the selected EGFR-TKI did not penetrate the brain well; and 2) the heterogeneity of EGFRvIII was not addressed. Here we present data on osimertinib (AZD9291), a third generation irreversible EGFR-TKI, that was developed to specifically block the EGFRT790M mutation that leads to drug resistance in lung cancer patients treated with an earlier generation EGFR-TKI. Our initial studies found that osimertinib also potently inhibits EGFRvIII (IC50<50 nM) and is highly brain-penetrant, with a brain/plasma ratio >10. Therefore, we studied osimertinib’s ability to inhibit EGFRvIII in preclinical models of GBM. For in vitro studies, we examined the effect of osimertinib on EGFRvIII biochemistry using EGFRvIII-positive GBM stem cells (GSCs). For in vivo studies, immunocompromised mice were implanted intracranially with EGFRvIII-positive GSCs. Three days after implantation, the animals were given 25 mg/kg of osimertinib twice a day; this is a clinically relevant dose. Our findings are as follows: 1) osimertinib not only inhibits EGFRvIII tyroinse kinase activity with high affinity but also blocks its downstream signaling in EGFRvIII-positive GSCs; 2) osimertinib increases the survival of mice bearing intracranial EGFRvIII-positive GBM. The median survival of mice treated with vehicle alone was 28.5 days whereas the median survival of mice treated with AZD9291 was 42 days (p<0.001); an increase in survival of 47%. In contrast, treatment with lapatinib, a traditional EGFR-TKI, did not result in increased survival. These results indicate that osimertinib may be effective in increasing the survival of a subset of patients with EGFRvIII-positive GBM. Clinical studies to demonstrate the efficacy of osimertinib in EGFRvIII-positive GBM patients will commence soon.