Zanidatamab

Zanidatamab has not been evaluated in patients with severe renal impairment and patients with end-stage renal disease with or without dialysis. However, due to minor involvement of renal processes in the clearance of zanidatamab, no dose adjustment is recommended for patients with renal impairment as no difference in exposure is expected.

Zanidatamab has not been evaluated in patients with moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) to severe (total bilirubin > 3 ULN and any AST) hepatic impairment. However, due to minor involvement of hepatic processes in the clearance of zanidatamab, no dose adjustment is recommended for patients with hepatic impairment as no difference in exposure is expected.

Based on the mechanism of action, zanidatamab may cause foetal harm when administered to a pregnant woman. There are no human or animal data on the use of zanidatamab in pregnancy. In post-marketing reports of other HER2-directed antibodies, use during pregnancy resulted in cases of oligohydramnios manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Zanidatamab is not recommended for use during pregnancy or in women of childbearing potential not using contraception. Patients should be advised on potential risks to the foetus.

Women who received zanidatamab during pregnancy or within 4 months prior to conception should be monitored for oligohydramnios. If oligohydramnios occurs, foetal testing that is appropriate for gestational age and consistent with local standard of care should be performed.

It is not known whether zanidatamab is excreted in human milk, or what effect it has on a breast-fed child or milk production.

A decision should be made whether to discontinue breast-feeding or to discontinue treatment, taking into account the benefit of breast-feeding for the child and the benefit of zanidatamab therapy for the woman. This consideration should also take into account the washout period of 4 months.

Women of childbearing potential/Contraception in females

To exclude pregnancy, women of childbearing potential should undergo pregnancy testing before initiation of zanidatamab.

Based on the mechanism of action, zanidatamab may cause embryo-foetal harm when administered during pregnancy. Female patients should use effective contraception during treatment with zanidatamab and for 4 months following the last dose.

Fertility

Fertility studies have not been performed with zanidatamab.

Zanidatamab has minor influence on the ability to drive and use machines. Fatigue has been reported with the use of zanidatamab. Therefore, patients should be advised to use caution when driving or operating machines.

Summary of the safety profile

The pooled safety population of zanidatamab reflects exposure in 233 patients who were administered zanidatamab 20 mg/kg intravenously as a single agent in two single-arm trials. Among 233 patients who received zanidatamab, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year.

From the pooled data, serious adverse reactions were observed in 8.2% of patients. The most frequent serious adverse reactions were diarrhoea (1.7%) and fatigue (1.3%).

The most common adverse reactions observed in the pooled data were diarrhoea (48.5%), infusion related reaction (30.5%), fatigue (26.2%), anaemia (21.9%) and rash (21.5%).

The safety of zanidatamab in adult patients with BTC (N=87) was evaluated in Study 203, an open-label, multi-cohort, multicenter trial.

In Study 203 (N=87), serious adverse reactions occurred in 16.1% of patients. The most frequent serious adverse reactions were diarrhoea (2.3%), fatigue (2.3%), and alanine aminotransferase increased (2.3%).

The most common adverse reactions in Study 203 (N=87) were diarrhoea (46%), infusion related reaction (33.3%), abdominal pain (26.4%), anaemia (25.3%) and fatigue (24.1%).

Tabulated list of adverse reactions

Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 233 patients exposed to zanidatamab at 20 mg/kg administered intravenously as a single agent in two single-arm trials.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions in patients receiving zanidatamab as monotherapy reported in the pooled safety population (N=233):

^a Abdominal pain includes abdominal pain and abdominal pain upper
^b Rash includes dermatitis acneiform, rash, rash maculo-papular, rash pruritic, and urticaria.
^c Fatigue includes asthenia, fatigue, and malaise.
^* See “Description of selected adverse reactions” below

Description of selected adverse reactions in the pooled safety population (N=233)

Diarrhoea

Diarrhoea was reported in 48.5% of patients who received zanidatamab. Grade 3 reported event incidence in patients was 5.2%, Grade 4 and Grade 5 events were not observed. Median time to first onset was 10 days and median time to resolution was 3 days. The dose of zanidatamab was reduced due to diarrhoea in 1.3% of patients and was held or delayed in 2.6% of patients. There were no discontinuations of treatment due to diarrhoea.

Infusion related reactions

Infusion related reactions (IRRs) were reported in 30.5% of patients who received zanidatamab. Grade 3 reported event incidence in patients was 0.4%, Grade 4 and Grade 5 events were not observed. Median time to first onset was 1 day and median time to resolution was 1 day. Zanidatamab infusion was interrupted in 25.3% of patients and discontinued in 0.4% of patients due to IRRs.

Anaemia

Anaemia was reported in 21.9% of patients who received zanidatamab. Grade 3 reported event incidence in patients was 9.9%, Grade 4 was 0.4% and no Grade 5 events were observed. Median time to first onset was 42 days and median time to resolution was 14 days. Zanidatamab infusion was held or delayed in 0.4% of patients and there were no other actions taken with zanidatamab due to anaemia.

ALT increased

ALT increased was reported in 12.4% of patients who received zanidatamab. Grade 3 reported event incidence in patients was 1.7%, Grade 4 was 0.4% and no Grade 5 events were observed. Median time to first onset was 78 days and median time to resolution was 16 days. Zanidatamab infusion was held or delayed in 7 patients (3%) and there were no other actions taken with zanidatamab due to ALT increased.

AST increased

AST increased was reported in 11.6% of patients who received zanidatamab. Grade 3 reported event incidence in patients was 1.3%, Grade 4 was 0.9% and no Grade 5 events were observed. Median time to first onset was 87 days and median time to resolution was 15 days. Dose of zanidatamab was held or delayed in 6 patients (2.6%) and there were no other actions taken with zanidatamab due to AST increased.

Left ventricular dysfunction

Decreases in LVEF have been reported with medicinal products that block HER2 activity, including zanidatamab. Twelve events of LVEF decreased were observed in 10 patients (4.3%) and one of these events was considered serious. Grade 3 reported event incidence in patients was 1.3%, Grade 4 and Grade 5 events were not observed. Median time to first onset was 171 days and median time to resolution was 27 days. The dose of zanidatamab was reduced in 1 patient (0.4%), was held or delayed in 5 patients (2.1%) and was discontinued in 2 patients (0.9%).