Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Jazz Pharmaceuticals Ireland Ltd, 5 th Floor, Waterloo Exchange, Waterloo Road, Dublin 4, D04 E5W7, Ireland
Pharmacotherapeutic group: Antineoplastic agents, HER2 (Human Epidermal Growth Factor Receptor 2) inhibitors
ATC code: L01FD07
Zanidatamab is a dual HER2-targeted bispecific antibody that simultaneously binds extracellular domains 2 and 4 on separate HER2 monomers (binding in trans). Binding of zanidatamab with HER2 results in internalization leading to a reduction of the receptor on the cell surface. Zanidatamab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumour growth inhibition and tumour cell death.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with incidence of ADA in other studies.
ADA were rarely detected. Zanidatamab is categorised as a low-risk molecule to elicit an immune response on the basis of assessment of the immunogenicity risk factors and the low incidence of ADAs observed to date across the clinical studies (1.6% [3 of 183 evaluable participants] and 1.2% [1 of 85 evaluable participants] in Study 101 and Study 203, respectively). No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.
The relationship between time-matched zanidatamab serum concentrations and ΔQTcF measurements was evaluated based on data obtained during treatment with zanidatamab from participants in Study 101. The C-QT analysis dataset included measurements of QTcF from 179 out of the 192 participants enrolled in Study 101. Zanidatamab has no effect on QTc interval and there was no relationship between zanidatamab exposure and change in QTc interval.
The efficacy of Ziihera was evaluated in Cohort 1 (N=62) of ZWI-ZW25-203 (Study 203), a multicentre open-label single arm trial of patients with locally advanced unresectable or metastatic biliary tract cancer who received at least one prior gemcitabine-containing systemic chemotherapy regimen for advanced disease, and experienced disease progression after or developed intolerance to the most recent prior therapy, and whose tumour tested HER2-positive (IHC 3+).
Patients received Ziihera every 2 weeks at a dose of 20 mg/kg intravenously. It was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were confirmed objective response rate (cORR) and duration of response (DoR) as determined by an independent central review (ICR) according to Response Evaluation Criteria in Solid Tumours (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. 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. Forty percent of patients had received more than one prior line of therapy for metastatic or locally advanced disease. The most commonly received prior treatments, other than gemcitabine, included: cisplatin (76%), oxaliplatin (16%), 5-fluoruracil (39%), and PD-1 or PD-L1 inhibitor (26%). The median overall survival (OS) in the IHC3+ population was 18.1 months (95% CI: 12.2, 22.9). The median duration of study follow-up in the IHC3+ population was 34.0 months.
Efficacy results are summarised in Table 6.
Table 6. Efficacy results in Study 203:
| Efficacy parameter* | N=62 |
| Confirmed objective response rate (cORR) | |
| n % (95% CI) | 32 51.6 (38.6, 64.5) |
| Complete response, n (%) | 3 (4.8) |
| Partial response, n (%) | 29 (46.8) |
| Duration of response (DOR) | N=32 |
| Median†, months (95% CI) | 14.9 (7.4, 24.0) |
* Assessed by independent central review
† Based on Kaplan-Meier estimate
LPLV = Last patient last visit 11 July 2024
The European Medicines Agency has waived the obligation to submit the results of studies with Ziihera in all subsets of the paediatric population in biliary tract cancer (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Zanidatamab PK exhibited non-linear kinetics with more rapid clearance (CL) at low doses ranging from 5 to 30 mg/kg. Following the first dose, the geometric mean zanidatamab Cmax was dose proportional with increasing doses, while total systemic exposure (AUC0-∞) was greater than dose proportional with increasing doses. The geometric mean accumulation indices based on Ctrough at steady state was approximately 2.7 for the 20 mg/kg once every 2 weeks zanidatamab dose level. The observed zanidatamab exposure and PK parameters following the first administration in the first cycle and steady state, based on the available sampling scheme, are described in Table 7.
The pharmacokinetics of zanidatamab following intravenous infusion in participants with HER2 expressing cancers was evaluated in a population pharmacokinetic model analysis from 279 participants. From the PopPK analysis, participants with BTC were predicted to have a typical CL of 0.0115 L/h, a typical Vc of 3.51 L, a typical Vp of 3.95 L, and an estimated t1/2 of approximately 21 days. Based on the estimated t1/2, it would take approximately 3.5 months (i.e., 5 half-lives) to reach steady state following multiple dose administration of zanidatamab.
Table 7. Study 203: Pharmacokinetic parameters (geometric mean [percent coefficient of variation]) of zanidatamab following the first administration of zanidatamab at 20 mg/kg Q2W in cycle 1 and steady-state in BTC patients:
| Cycle | Cmax (μg/mL) | Ctrough (μg/mL) | AUC0-tau (days*μg/mL) |
|---|---|---|---|
| Cycle 1 N=19 | 455 (16.3) | 68.3 (42.9) | 2280 (22.7) |
| Cycle 4 or later (steady-state) N=8 | 600 (22.2) | 178 (29.6) | 3980 (22.5) |
Abbreviations: AUC0-tau = area under the curve during the dosing interval; Cmax = maximum concentration; Ctrough = trough concentration; Q2W = once every 2 weeks
Note: Cycle 1 and Cycle 4 are referred to as "first dose" and "steady-state", respectively; these terms are interchangeable.
Ziihera is administered as an intravenous infusion.
Following intravenous dosing, zanidatamab undergoes biphasic elimination from the circulation. Based on population pharmacokinetic analysis, participants with HER2 amplified BTC were predicted to have a typical Vc of 3.51 L and a typical Vp of 3.95 L.
Based on population pharmacokinetic analysis, participants with BTC were predicted to have a typical CL of 0.0115 L/h and an estimated t½ of approximately 21 days for zanidatamab administered at 20 mg/kg every 2 weeks at steady-state.
Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on age (24 to 88 years), sex, race (White, Black, Asian), and body weight (35.4 kg to 128 kg).
Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD-EPI). The pharmacokinetics of zanidatamab in patients with severe renal impairment and end-stage renal disease with or without hemodialysis is unknown. However, as IgG monoclonal antibodies are not primarily cleared via renal pathways, a change in renal function is not expected to influence zanidatamab exposure.
Based on population pharmacokinetics analysis, no clinically significant differences in the pharmacokinetics of zanidatamab were observed based on 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). The pharmacokinetics of zanidatamab in patients with moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe hepatic impairment (total bilirubin > 3 ULN and any AST) is unknown. However, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence zanidatamab exposure.
Studies have not been conducted to evaluate the carcinogenic potential of zanidatamab.
Studies have not been conducted to evaluate the mutagenic potential of zanidatamab.
Zanidatamab was generally well tolerated in a 13-week repeat dose toxicity study in cynomolgus monkeys dosed once weekly (intravenous) at dose levels resulting in exposure margins up to at least 10 times the exposure in human patients. Non-severe, transient, non-dose dependent treatment-related soft or watery faeces was observed at clinically relevant exposure. In some, but not all animals, soft or watery faeces correlated with non-severe changes in blood urea nitrogen and blood albumin levels. From day 22, BUN was generally increased (up to 45%) and albumin levels tended to be decreased (up to 12%) throughout the dosing phase. However, these values were not dosed-related and remained within historical control ranges.
Reproductive and developmental toxicity studies have not been conducted with zanidatamab. However, antibodies that bind to HER2 have been observed to cause severe embryo-foetal toxicity. Fertility studies have not been performed with zanidatamab. In a 13-week repeat-dose toxicity study in cynomolgus monkeys dosed once weekly (intravenous) at dose levels resulting in exposure margins up to at least 10-times the exposure in human patients, zanidatamab had no effect on male and female reproductive organs when evaluated by organ weights and histopathology.
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