Zongertinib

Risk Summary

Based on findings from animal studies and its mechanism of action, zongertinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of zongertinib in pregnant women to inform a drug-associated risk. Oral administration of zongertinib to pregnant rats during the period of organogenesis caused structural abnormalities and alterations to growth at maternal exposures ≥19 times the human exposure based on AUC at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no data on the presence of zongertinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with zongertinib and for 2 weeks after the last dose.

Carcinogenesis

Carcinogenicity studies have not been conducted with zongertinib.

Mutagenesis

Zongertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Zongertinib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA breaks in a comet assay in liver or duodenum.

Impairment of Fertility

Dedicated animal fertility studies have not been conducted with zongertinib. In a 13-week repeat-dose toxicity study in rats, oral administration of zongertinib induced dose-dependent vacuolation in the testis at doses ≥10 mg/kg/day (≥5.7 times the human exposure based on AUC at the recommended dose), atrophy in the prostate gland at doses ≥30 mg/kg/day (≥8.4 times the human exposure based on AUC at the recommended dose), and atrophy in the uterus and hyperplasia/hyperkeratosis of the cervix and vagina at a dose of 90 mg/kg/day (approximately 17 times the human exposure based on AUC at the recommended dose). Findings in reproductive organs in female rats and prostate gland atrophy in male rats were reversible following a 4-week recovery period. Vacuolation in the testis of male rats was not reversible within a 4-week recovery period.

Clinical Trials Experience

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 clinical practice.

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to zongertinib in 260 patients with unresectable or metastatic non-squamous NSCLC with HER2 (ERBB2) mutations who received zongertinib as a single agent at 120 mg orally once daily until disease progression or unacceptable toxicity in Beamion LUNG-1. Among 260 patients who received zongertinib, 58% of patients were exposed for 6 months or longer and 13% were exposed for greater than one year. In this pooled safety population, the most common (>20%) adverse reactions were diarrhea (53%), hepatotoxicity (27%), rash (27%), fatigue (22%), and nausea (21%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (9%), increased alanine aminotransferase (5%), increased aspartate aminotransferase (4.3%), decreased potassium (2.7%), and increased gamma glutamyl transferase (2.7%).

Beamion LUNG-1

The safety of zongertinib was evaluated in Beamion LUNG-1 in 105 patients with previously treated unresectable or metastatic non-squamous NSCLC with HER2 tyrosine kinase domain (TKD) mutations; all patients had received prior platinum-based chemotherapy, and 34 patients had received prior treatment with a HER2-directed antibody drug conjugate (ADC). Patients received zongertinib as a single agent at 120 mg once daily until disease progression or unacceptable toxicity. Among patients who received zongertinib, 72% were exposed for 6 months or longer and 30% were exposed for greater than one year. The median age of patients who received zongertinib was 61 years (range 30 to 85), 69% were female, 40% White, 49% Asian, and 0% Black or African American; 11% had unknown race data; 1.9% were of Hispanic or Latino ethnicity; and 33% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 and 67% had an ECOG performance score of 1.

Serious adverse reactions occurred in 34% of patients receiving zongertinib. Serious adverse reactions in ≥2% of patients included dyspnea (4.8%), pulmonary embolism (4.8%), hepatotoxicity (2.9%), and pneumonia (2.9%). Fatal adverse reactions occurred in 1% of patients who received zongertinib, due to pneumonia.

Permanent discontinuation of zongertinib due to an adverse reaction occurred in 2.9% of patients. Adverse reactions which resulted in permanent discontinuation of zongertinib were hepatotoxicity, increased blood alkaline phosphatase, dyspnea, increased gamma-glutamyl transferase, hemoptysis, and pyrexia.

Dosage interruption of zongertinib due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were hepatotoxicity, decreased ejection fraction, and rash.

Dose reductions of zongertinib due to adverse reactions occurred in 7% of patients. Adverse reactions which required dose reductions in ≥1% of patients were hepatotoxicity, decreased ejection fraction, increased blood creatinine phosphokinase, increased gamma-glutamyl transferase, and decreased neutrophil count.

Tables 1 and 2 summarize adverse reactions and laboratory abnormalities observed in Beamion LUNG-1.

Table 1. Adverse Reactions (≥15%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received Zongertinib in Beamion LUNG-1:

Events were graded using NCI CTCAE version 5.0.
¹ No Grade 4 or Grade 5 adverse reactions occurred.
^* Grouped term.

Clinically relevant adverse reactions in <15% of patients who received zongertinib included stomatitis, dry skin, pruritus, and peripheral neuropathy.

Table 2. Select Laboratory Abnormalities (≥20%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received Zongertinib in Beamion LUNG-1:

Events were graded using NCI CTCAE version 5.0.
¹ No Grade 5 adverse reactions occurred.