ZIIHERA Powder for solution for injection Ref.[113521] Active ingredients: Ζanidatamab

Zanidatamab‑hrii is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab‑hrii with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab‑hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.

Zanidatamab‑hrii exposure-response relationships and the time course of the pharmacodynamic response are unknown.

Cardiac Electrophysiology

A mean increase in the QTc interval >20 ms was not observed at the recommended approved dosage.

Zanidatamab‑hrii PK parameters are presented as means (percent coefficient of variation) following administration of ZIIHERA 20 mg/kg every 2 weeks after the 7^th or later dose unless otherwise indicated.

Zanidatamab‑hrii maximum concentration (C_max) is 600 (22.2) µg/mL, the lowest measured concentration (C_trough) is 178 (29.6) µg/mL, and total systemic exposure (AUC_0-336h) is 3,976 (22.5) days*µg/mL following administration of ZIIHERA. The C_max of zanidatamab‑hrii is dose proportional and the total systemic exposure (AUC_0-inf) of zanidatamab‑hrii is greater than dose proportional with increasing doses. The mean C_trough accumulation ratio of zanidatamab‑hrii is approximately 2.4.

Distribution

The volume of distribution of zanidatamab‑hrii is approximately 7.5 (33) L based on the population pharmacokinetic analysis.

Elimination

The estimated half-life (t_1/2) of zanidatamab‑hrii is approximately 21 days with an associated clearance (CL) of 0.012 L/h (27.9) based on the population pharmacokinetic analysis.

Metabolism

Zanidatamab‑hrii is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of zanidatamab-hrii were observed based on age (24 to 88 years), sex, race (White and Asian), mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD‑EPI), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or body weight (35 kg to 128 kg).

The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min) with or without hemodialysis, and moderate (total bilirubin >1.5 to ≤3 ULN and any AST) or severe (total bilirubin >3 ULN and any AST) hepatic impairment on the pharmacokinetics of zanidatamab‑hrii is unknown.

Studies have not been conducted to evaluate the carcinogenic or mutagenic potential of zanidatamab‑hrii.

Fertility studies with zanidatamab‑hrii have not been conducted.

HER2-positive (IHC 3+) Biliary Tract Cancer (BTC)

The efficacy of ZIIHERA was evaluated in 62 patients with HER2-positive (IHC 3+ by central assessment) BTC in Cohort 1 of HERIZON‑BTC‑01 (NCT04466891), an open-label, multicenter, single arm trial in patients with unresectable or metastatic disease. Patients were required to have received at least one prior gemcitabine-containing systemic chemotherapy regimen in the advanced disease setting and adequate cardiac function (defined as LVEF ≥50%).

Patients received ZIIHERA 20 mg/kg intravenously every 2 weeks. ZIIHERA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as determined by an independent central review (ICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The median age was 64 years (range: 38 to 79 years), 47% of patients were age 65 or older; 55% were female; 61% were Asian, 31% were White, 2% were American Indian or Alaskan Native and for 6% race was unknown or not reported; 89% were Non-Hispanic or Latino, 8% Hispanic/Latino, and for 3% ethnicity was unknown or not reported. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%). Fifty-three percent of patients had gallbladder cancer, 27% had intrahepatic cholangiocarcinoma, and 19% had extrahepatic cholangiocarcinoma. All patients received at least 1 prior line of gemcitabine-based therapy, 31% had 2 prior lines of therapy, and 10% had 3 or more prior lines of therapy for unresectable or metastatic disease.

Efficacy results are summarized in Table 5.

Table 5. Efficacy Results in HERIZON-BTC-01:

^* Assessed by independent central review
^† Based on Kaplan-Meier estimate
^‡ Based on observed duration of response
NE = not estimable