DZD1516 Demonstrates Safety, Early Activity in Heavily Pretreated Metastatic HER2+ Breast Cancer

DZD1516 monotherapy elicited early clinical activity and was found to be well tolerated in patients with HER2-positive metastatic breast cancer with or without brain metastases.

DZD1516 monotherapy elicited early clinical activity and was found to be well tolerated in patients with HER2-positive metastatic breast cancer with or without brain metastases, according to updated findings from the first-in-human phase 1 WEN-JI1 trial (NCT04509596) presented at the 2022 ESMO Congress.1

Among 18 evaluable patients who completed at least 1 post-treatment assessment per RECIST v1.1 criteria, the best antitumor response achieved with the oral HER2-targeted TKI was stable disease in intracranial, extracranial, and overall lesions. Notably, these patients had received a median of 7 prior lines of treatment (range, 3-15).

“DZD1516 is a full BBB-penetrant HER2 TKI with [a] good safety profile,” lead study author Dr Jian Zhang, of the Department of Medical Oncology at Fudan University Shanghai Cancer Center, and colleagues, wrote in a poster featuring the findings. “Consistent with its high selectivity, no wild-type EGFR-related adverse effects [AEs] have been reported at the maximum tolerated dose [MTD] or below doses.”

Patients with HER2-positive metastatic breast cancer carry a high risk of developing central nervous system (CNS) metastases, which are associated with a poor prognosis. DZD1516, an oral, potent, reversible, selective, and full blood-brain barrier penetrable HER2 TKI, has more than 300-fold selectivity for HER2 vs EGFR.

The ongoing WEN-JI1 trial is evaluating DZD1516 as a single agent, in combination with trastuzumab (Herceptin) and capecitabine, and in combination with ado-trastuzumab emtansine (T-DM1; Kadcyla).2 Safety and pharmacokinetic data from part A, which featured patients treated with single-agent DZD1516, were presented at the 2022 ESMO Congress.

The trial is enrolling patients who are at least 18 years of age with histologically confirmed HER2-positive metastatic breast cancer who relapsed on or were intolerant to standard-of-care treatment in the metastatic setting.

Notably, those with CNS metastases are permitted to enroll. Patients without CNS metastases must have at least 1 measurable lesion per RECIST v1.1 criteria, and those with CNS metastases must have at least 1 measurable intracranial lesion per modified RECIST v1.1 criteria.

Other key inclusion criteria include having an ECOG performance status of 0 or 1 for patients without leptomeningeal metastases, or 0 to 2 for those with leptomeningeal metastases; a life expectancy of at least 12 weeks; and adequate bone marrow reserve and organ system functions.

Within 4 weeks of first study treatment, patients are not permitted to have received any investigational agents or study drugs from a previous clinical study; undergone a major surgery procedure; experienced significant traumatic injury; or received radiotherapy with a wide field of radiation. Intrathecal chemotherapy is not allowed within 2 weeks of first study treatment, and radiotherapy with a limited field of radiation for palliation cannot be given within 1 week of study treatment.

Other key exclusion criteria include CNS complications that require urgent neurosurgical intervention or any evidence of severe or uncontrolled systemic diseases.

Patients enrolled to part A received escalating doses of DZD1516 twice daily, including 25 mg (n = 1), 50 mg (n = 4), 100 mg (n = 4), 200 mg (n = 5), 250 mg (n = 4), and 300 mg (n = 4).

The primary end points of the trial include safety, incidence of dose-limiting toxicities (DLTs), finding the MTD, and establishing the recommended phase 2 dose. Secondary end points are pharmacokinetics and preliminary antitumor efficacy.

At a data cutoff of February 20, 2022, a total of 22 patients from the United States and China were enrolled to the trial and received single-agent DZD1516. In these patients, the median age was 57 years (range, 36-66); most patients (n = 17) were Asian. Fifteen patients had CNS metastases. Moreover, 20 patients had an ECOG performance status of 1, and the remaining 2 patients had a status of 0. Prior therapy classes received included HER2-targeted antibodies/antibody-drug conjugates (n = 22), a HER2 TKI (n = 19), chemotherapy (n = 22), and other (n = 14).

At data cutoff, the longest treatment duration with DZD1516 was more than 3 months.

DLTs were reported only at the 300-mg dose level. One patient had grade 3 musculoskeletal pain and the other patient experienced grade 2 AEs that led to dose interruption for 20 days. The MTD of DZD1516 was determined to be 250 mg twice daily.

Overall, 20 of the 22 patients experienced at least 1 treatment-emergent AE (TEAE), and 19 patients had at least 1 treatment-related AE (TRAE). Grade 3 or higher TRAEs were reported in 3 patients; 2 of these patients were in the 300-mg cohort and 1 patient was in the 200-mg cohort. No TRAEs resulting in dose interruption or reduction were observed in the other dosing cohorts.

The most common any-grade TEAEs included increased hemoglobin (n = 10), headache (n = 9), vomiting (n = 8), increased aspartate aminotransferase (n = 5), increased blood bilirubin (n = 5), and nausea (n = 5).

Pharmacokinetics showed that following a single dose of DZD1516, the agent was eliminated, with a terminal half-life of approximately 13.4 to 22.5 hours across the range of doses. Following twice-daily dosing for 15 days, moderate accumulation of DZD1516 systemic exposure was observed at doses of up to 200 mg.

The combined exposure of DZD1516 and its active metabolite, DZ2678, generally increased with higher doses. The mean Kpuu,CSF for DZD1516 and DZ2678 across the dose range were 2.1 and 0.76, respectively. Free trough concentrations of DZD1516 were above pHER2 IC50 in BT474C1 cells at 100 mg or higher dose levels.

Future clinical evaluation of DZD1516 is warranted, the study authors concluded.


  1. Zhang J, McAndrew N, Yu W, et al. Clinical safety and pharmacokinetics (PK) data of DZD1516, an BBB-penetrant selective HER2 inhibitor for the treatment of HER2-positive metastatic breast cancer. Ann Oncol. 2022;33(suppl 7):S646. doi:10.1016/j.annonc.2022.07.277
  2. DZD1516 in combination with trastuzumab and capecitabine, or in combination with T-DM1, in patients with metastatic HER2 positive breast cancer. Updated June 1, 2022. Accessed October 6, 2022.
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