BMET-37: PHASE I STUDY OF AZD3759, AN EGFR INHIBITOR WITH BLOOD BRAIN BARRIER (BBB) PENETRATION, FOR THE TREATMENT OF EGFRm+ NON-SMALL CELL LUNG CANCER (NSCLC) WITH BRAIN METASTASIS AND LEPTOMENGINGEAL METASTASIS

BACKGROUND: EGFRm+ NSCLC with central nervous system (CNS) metastases, including BM (brain metastasis) and LM (leptomeningeal metastasis), has high unmet medical need due to lack of effective treatment. We discovered AZD3759, an oral EGFR inhibitor with better BBB penetration than other available EGFR TKIs, which demonstrates profound anti-tumor effect in preclinical BM and LM models. Here we present preliminary data of AZD3759 in an ongoing phase I study. METHODS: This is an open label, multi-center study to assess safety and tolerability of AZD3759 in patients with EGFRm+ NSCLC who progressed with EGFR TKI and chemotherapy. This First Time in Human study aims to determine the maximal tolerated dose (MTD) and/or recommended phase II dose (RP2D) and preliminary efficacy. RESULTS: To date, 17 patients with advanced stage EGFRm+ NSCLC were enrolled into the study (5 in 50mg bid, 7 in 100mg bid and 5 in 200mg bid cohorts, respectively). 11 and 2 out of 17 patients have measurable BM and LM, respectively. Dose-dependent plasma and CSF (cerebral spinal fluid) exposure of AZD3759 was observed. At the dose of 200mg, all patients had CSF C_trough concentration above pEGFR IC₅₀ in EGFRm+ cells. Adverse events were consistent with inhibition of wild type EGFR (5 patients experienced skin rash and/or diarrhea, mainly grade 1). No dose limiting toxicities were observed to date. In 16 the evaluable patients with measurable BM, 4 showed tumor shrinkage in the brain. In 2 evaluable patients with LM, 1 patient showed a 94% reduction of pEGFR in tumor cells in CSF, determined by "H" score using immunohistochemistry assay. CONCLUSION: AZD3759 is an EGFR TKI with good BBB penetration with potential to treat EGFRm+ NSCLC patients with BM and LM. The phase 1 study is ongoing and updated clinical results will be presented in the meeting.