Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM).

9003 Background: AZD3759 was the first EGFR inhibitor primarily designed to effectively across the blood brain barrier to tackle central nervous system (CNS) metastases in patients with EGFRm+ NSCLC. Here we report safety, pharmacokinetic (PK), efficacy and biomarker data from a Phase I, open-label, multicentre study of AZD3759 in patients with advanced stage EGFRm+ NSCLC (NCT02228369; sponsor AstraZeneca). Methods: Patients with EGFRm+ NSCLC who progressed from at least one line of EGFR TKI and one line chemotherapy were enrolled into the study. The primary objective was safety and tolerability, and secondary objectives include but not limited to PK and anti-tumor efficacy. There were 5 dose cohorts (dose ranging from 50mg bid to 500mg bid), with at least 2 BM and 1 LM in each cohort. Results: As of30 Dec, 2015,29 patients were recruited, 21 with measurable BM, 5 with LM and 3 with non-measurable/non BM & LM. All patients had received at least one line of EGFR TKI and chemotherapy. 17 out of 29 had prior brain radiation therapy. AZD3759 was well-tolerated up to 300mg bid, with the longest duration on treatment >40 weeks. Most common AEs included skin rash (total 45% with 17% ≥G3) and diarrhea (total 59% with 3% ≥G3). The Ctrough free plasma and CSF exposure were above pEGFR IC50 and IC90 at the doses ≥ 100 and 200 mg bid, respectively. Among 20 patients with measurable BM evaluable for RECIST assessment, 8 had tumor shrinkage in the brain, with 3 confirmed PR and 3 un-confirmed PR. Among 5 LM patients, 3 out of 4 had > 50% pEGFR inhibition in CSF tumor cells after one week treatment, and 4 out of 5 LM patients had > 50% tumor cell number decrease in CSF. 1 LM patient at 300mg bid had CSF clearance of tumor cells, and improvement of brain MRI imaging as well as CNS symptoms. 2 LM patients at the doses of 200mg and 300mg bid, respectively, are still on AZD3759 treatment after 19 and 29 weeks, respectively. Conclusions: AZD3759 was well tolerated, achieved sufficient CNS exposure and demonstrated promising anti-tumor activity in dose escalation phase. Phase II studies have been initiated in patients with LM and BM, respectively. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.