Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy.

2069 Background: AZD3759 is the first EGFR inhibitor primarily designed to effectively cross the blood brain barrier (BBB) to treat central nervous system (CNS) metastases. A phase I study is ongoing to assess AZD3759 in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other treatment (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Two dose levels of AZD3759, 200 mg and 300 mg BID, were assessed. Results: As of24 September, 2016,38 patients were recruited into the expansion cohorts of this phase I study. Of those, 18 were TKI pre-treated EGFRm NSCLC patients with LM. 10 and 8 patients were in the 300 and 200 mg BID cohorts, respectively. No DLTs were observed at either dose, while AZD3759 was better-tolerated at 200 than 300 mg BID during > 2 month treatment. The longest duration on treatment was > 9 months. Most common AEs included skin rash and diarrhea. 67% (12 out of 18) patients had drug-related dose interruption and/or reduction, however, there were no drug-related discontinuations.The C trough free plasma and CSF exposure were above pEGFR IC 90 at the two doses. 40% of patients (4 out of 10) had > 50% inhibition of pEGFR in CSF tumor cells at C1D8, and 70% of patients (7 out of 10) had reduced EGFR copy numbers in CSF at C3D1. 53% of evaluable patients (9 out of 17) had confirmed improved/stable LM MRI imaging. 2 out of 3 patients with concomitant measurable BM lesions achieved confirmed/unconfirmed partial CNS response. Among 18 patients with measurable extracranial lesions, 6 (33%) had confirmed stable extracranial disease as best response. 3 patients achieved clearance of tumor cells in CSF by two consecutive assessments. After 6 months follow-up, 29% patients (5 out of 17 evaluable) were still surviving, plus 5 surviving patients with less than 6 months follow-up. Conclusions: AZD3759 was well-tolerated, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor activity in patients with LM who progressed after multiple lines of treatment. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.