Ζanidatamab

Risk Summary

Based on mechanism of action, zanidatamab can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of zanidatamab in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Use of zanidatamab is not recommended during pregnancy. Advise patients of potential risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor women who received zanidatamab during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care.

There are no data on the presence of zanidatamab in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for zanidatamab treatment and any potential adverse effects on the breastfed child from zanidatamab or from the underlying maternal condition. This consideration should also take into account the zanidatamab half-life of approximately 21 days and a washout period of 4 months.

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

Fertility studies with zanidatamab have not been conducted.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population of zanidatamab described in WARNINGS AND PRECAUTIONS reflect exposure in 233 patients administered zanidatamab 20 mg/kg intravenously as a single agent in two single-arm, open-label studies (ZWI‑ZW25‑101 and HERIZON‑BTC‑01), which enrolled 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received zanidatamab, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year.

Biliary Tract Cancer

The safety of zanidatamab was evaluated in 80 patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer who received at least one prior gemcitabine-containing chemotherapy regimen in HERIZON‑BTC‑01. Patients received zanidatamab 20 mg/kg by IV infusion once every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to zanidatamab was 5.6 months (range: 0.5 to 27.2 months).

Serious adverse reactions occurred in 53% of patients who received zanidatamab. Serious adverse reactions in >2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received zanidatamab.

Permanent discontinuation due to an adverse reaction occurred in 2.5% of patients who received zanidatamab. Adverse reactions which resulted in permanent discontinuation in ≥1% of patients who received zanidatamab included decreased ejection fraction and pneumonitis.

Dosage interruptions due to an adverse reaction, excluding temporary interruptions of zanidatamab infusions due to infusion-related reactions, occurred in 41% of patients who received zanidatamab. The most frequent adverse reactions (>2% of patients) that required dosage interruption were diarrhea, increased alanine aminotransferase, increased aspartate aminotransferase, decreased ejection fraction, pneumonia, cholangitis, fatigue, biliary obstruction, abdominal pain, increased blood creatinine, and decreased potassium.

Dosage reductions due to an adverse reaction occurred in 4% of patients who received zanidatamab. Adverse reactions requiring dosage reductions in >1% of patients were diarrhea, nausea, and decreased weight.

The most common adverse reactions in patients receiving zanidatamab (≥20%) were diarrhea, infusion-related reaction, abdominal pain, and fatigue.

Table 1 summarizes the adverse reactions that occurred in HERIZON‑BTC‑01.

Table 1. Adverse Reactions (≥15%) in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving Ζanidatamab in HERIZON-BTC-01:

^* Graded per CTCAE version 5.
^a Diarrhea includes diarrhea and enteritis
^b Abdominal pain includes abdominal pain and abdominal pain upper
^c Fatigue includes asthenia and fatigue
^d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, rash, rash maculo-papular, and rash pustular

Table 2 summarizes the laboratory abnormalities in HERIZON‑BTC‑01.

Table 2. Laboratory Abnormalities (≥30%) that Worsened from Baseline in Patients with Unresectable or Metastatic HER2-Positive BTC Receiving Ζanidatamab in HERIZON-BTC-01:

^* The denominator used to calculate the rate varied from 78 to 80 based on the number of patients with a baseline value and at least one post-treatment value.