Background: Patients with HER2+ metastatic breast cancer (MBC) are at high risk of developing central nervous system metastases. DZD1516 is a reversible HER2-specific tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Here we report the preliminary safety and PK data from the ongoing phase 1 study (NCT04509596) in patients with HER2+ MBC who relapsed from multiple prior treatments. Methods: Eligible patients received single oral dosing of DZD1516 on C0D1 and then twice daily (BID) oral dosing from C1D1 in a continuous 21-day cycle until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to investigate the safety and PK of DZD1516 as a single agent. Results: As of 17 January 2022, DZD1516 was explored in 21 HER2+ MBC patients from the USA and China. DZD1516 was well tolerated at doses < 300 mg, BID. Two DLT events were reported in the 300 mg cohort. In all cohorts, 20 (95.2%) patients reported treatment-emergent adverse events (TEAEs), and 3 (14.3%) patients reported grade 3 drug-related TEAE. Two patients had dose interruption and one patient had dose reduction due to TEAE, all in the 300 mg cohort. Majority of TEAEs were reversible. The longest treatment duration was > 3 months. In all cohorts, the most common (> 20%) TEAEs included headache (42.9%), vomiting (38.1%), nausea (23.8%) and hemoglobin decreased (23.8%). At doses < 300 mg, there is no diarrhea or rash reported. PK data showed that combined exposure of DZD1516 and its active metabolite DZ2678 increased in a dose-proportional manner across the dose ranges. Elimination half-life was about 15-19 hrs. About 2-fold accumulation of DZD1516 in AUC was observed on multiple doses. In vitro, both DZD1516 and DZ2678 showed good permeability, and were not substrates of P-gp and BCRP. In patients, K_puu,CSF of DZD1516 and DZ2678 was around 2.13 and 0.66, respectively, suggesting good CNS penetration. At the time of data cutoff, 16 patients had at least one post treatment anti-tumor assessment. With a median of 7 lines of prior treatment, the best anti-tumor response was stable disease. Conclusions: Preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 TKI, with good safety profile. Consistent with its high selectivity, no wide type EGFR related AEs have been reported. Further evaluation of its safety and efficacy is ongoing. Clinical trial information: NCT04509596.