Abstract P2-13-43: Preclinical and early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2 positive metastatic breast cancer
Authors: Zhang Jian , McAndrew Nicholas , Yu Wenlei , Pan Xiaomei , Wang Mei , Hu Xichun 
Published: March 2022

Background: Patients with HER2 positive (HER2+) metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases, which is associated with poor prognosis. DZD1516 is designed as a reversible and selective HER2 kinase inhibitor with full blood-brain barrier (BBB) penetration. This compound is currently in phase 1 clinical development in patients with HER2+ MBC (NCT04509596). Here we report the preclinical and preliminary safety and pharmacokinetics (PK) data from the ongoing clinical study. Methods: The cellular activity of DZD1516, including pHER2 modulation and anti-proliferation, was evaluated in a panel of cell lines expressing HER2 or wild type EGFR. The ability of DZD1516 to cross BBB was assessed in both rat and monkey by measuring unbound brain-to-plasma partition ratio (Kpuu,brain ) and unbound CSF-to-plasma partition ratio (Kpuu,CSF). The in vivo anti-tumor activities of DZD1516 alone or in combination with other anti-cancer agents were evaluated in multiple xenograft mouse models including subcutaneous, brain metastasis (BM) and leptomeningeal metastasis (LM) models. The PK and pharmacodynamics (PD) correlation was also investigated. The phase 1 clinical study included monotherapy dose escalation of DZD1516 and in combination with other anti-cancer agents. Results: DZD1516 inhibited pHER2 with IC50 of 4.4 nM. It showed over 300-fold selectivity between pHER2 in cells expressing HER2 and pEGFR in cells expressing wild type EGFR. DZD1516 potently inhibited HER2+ tumor cell proliferation with GI50 of around 20 nM. In vivo, DZD1516 induced profound tumor regression in BT474 subcutaneous, BM and LM xenograft models. A positive correlation between plasma concentration of DZD1516 and pHER2 inhibition in tumor tissue was detected. The measured Kpuu,CSF in rat and monkey were 0.76 and 1.4, respectively.As of June 15, 2021, DZD1516 was explored at 25 mg, 50 mg and 100 mg twice daily with oral administration in eight HER2+ MBC patients from the USA and China. Patient demographics are summarized in Table 1. All patients had prior anti-HER2 antibody and chemotherapy treatment. Majority of patients (75%) also had prior anti-HER2 small molecule treatment. DZD1516 was well tolerated at the doses tested with no dose limiting toxicities observed. The safety data are summarized in Table 2. Drug exposure of DZD1516 increased in a dose proportional manner, with a half-life of around 14.5-19.5 hours and around 1.68 to 2.46-fold accumulation, respectively for single and repeat dosing. In patients with BM, Kpuu,CSF was around 1.82 and 0.78 for DZD1516 and its active metabolite DZ2678, respectively. Patient enrollment is ongoing. The updated data will be presented at the meeting. Conclusion: Preclinical and preliminary clinical data showed that DZD1516 is a full BBB-penetrant HER2 inhibitor, with excellent safety profile. Further clinical evaluation of its safety and efficacy is ongoing.

Table 1.Summary of patient demographics25 mg(n = 1)50 mg (n = 4)100 mg (n = 3)Total (n = 8)Median age, yr6457.5 (47-63)40 (36-60)57.5 (36-64)Race, no. (%) (Asian/White/Other)1 (100%)/0/03 (75%)/0/1 (25%)2 (66.7%)/1 (33.3%)/06 (75%)/1 (12.5)/1 (12.5)Hormone-receptor status, no. (%) (Either ER or PR positive/Neither ER nor PR positive/Other)1 (100%)/0/02 (50%)/1 (25%)/1 (25%)1 (33.3%)/2 (66.7%)/04 (50%)/3 (37.5%)/1 (12.5%)ECOG score, no. (%) (0/1)0/1 (100%)1 (25%)/3 (75%)0/3 (100%)1 (12.5%)/7 (87.5%)Presence or history of brain metastases, no. (%)04 (100%)3 (100%)7 (87.5%)Previous lines of therapy, median no. (range)79 (3-14)4 (4-7)7 (3-14)Previous lines of therapy for metastatic cancer, median no. (range)67 (1-12)4 (1-4)4.5 (1-12)Previous therapies, no. (%) (Trastuzumab or Pertuzumab/T-DM1/Pyrotinib or Lapatinib/Chemotherapy)1 (100%)/0/0/1 (100%)4 (100%)/1 (25%)/3 (75%)/4 (100%)3 (100%)/0/3 (100%)/3 (100%)8 (100%)/1 (12.5%)/6 (75%)/8 (100%)

Table 2.Summary of safety25 mg(n=1)50 mg (n=4)100 mg (n=3)Total (n=8)Patients with any AE, no. (%)1 (100%)3 (75%)3 (100%)7 (87.5%)Patients with any TEAE, no. (%)1 (100%)3 (75%)3 (100%)7 (87.5%)Anaemia, no. (%) (all grade/≥ Grade 3)0/02 (50%)/01 (33%)/03 (37.5%)/0Platelet count decreased, no. (%) (all grade/≥ Grade 3)0/01 (25%)/01 (33%)/02 (25%)/0Blood bilirubin increased, no. (%) (all grade/≥ Grade 3)1 (100%)/00/00/01 (12.5%)/0ALT/AST increased, no. (%) (all grade/≥ Grade 3)0/01 (25%)/00/01 (12.5%)/0Dose modification due to TEAE, no. (%) (Interruption/Reduction/Discontinuation)0/0/00/0/00/0/00/0/0

Citation Format: Jian Zhang, Nicholas McAndrew, Wenlei Yu, Xiaomei Pan, Mei Wang, Xichun Hu. Preclinical and early clinical safety and pharmacokinetics data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-43.