Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in patients with TKI-naïve, EGFRm NSCLC with CNS metastases.

Abstract

2006 Background: The dose escalation phase is complete forAZD3759, the first EGFR inhibitor primarily designed to cross the blood brain barrier (BBB) to treat patients with EGFRm NSCLC with CNS metastases. AZD3759 is being further evaluated in patients with brain (BM) and leptomeningeal metastases (LM) in TKI-naïve and TKI pre-treated cohorts (data presented separately) (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Dose levels of 200 and 300 mg BID AZD3759 were assessed based on safety and efficacy data in dose escalation cohorts. Results: As of24 September, 2016,38 patients with EGFRm NSCLC were recruited into the expansion cohorts of this study: 16 patients with TKI naïve BM and 4 patients with TKI naïve LM. 15 and 5 patients were treated with 200 and 300 mg BID of AZD3759, respectively. No DLTs were observed at either dose, while 200 mg BID AZD3759 was better tolerated than 300 mg BID during > 2 month treatment. The longest duration on treatment was > 9 months. Drug-related adverse events (AEs) seen are typically observed for EGFR TKIs. In BM cohort, 56% and 13% of patients had dose interruptions and reductions respectively due to drug-related AEs. The Ctrough free plasma and CSF exposure at both doses were above pEGFR IC90. By investigators’ assessment, the intracranial objective response rate (ORR) was 63% (12 out of 19 evaluable patients) and achieved confirmed/unconfirmed partial/complete response [PR/CR]), extracranial ORR was 50% (10 out of 20 evaluable patients), and the overall ORR was 60% (12 out of 20 evaluable patients). 4 patients have not reached the 6-week RECIST assessment at the data cut-off. 18 of 20 patients are still ongoing (median 4-month follow up). 2 patients have withdrawn, one due to disease progression (de novo T790M mutation in both plasma and CSF), and another due to a non-drug related SAE. Conclusions: AZD3759 was well tolerated at the selected doses, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor efficacy in both intracranial and extracranial tumors in TKI-naïve patients with CNS metastases. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.