Zongertinib (Monograph)

Brand name: Hernexeos
Drug class: Antineoplastic Agents

Introduction

Zongertinib, a kinase inhibitor, is an antineoplastic agent.

Uses for Zongertinib

Zongertinib has the following uses:

Zongertinib is indicated for the treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Zongertinib Dosage and Administration

General

Zongertinib is available in the following dosage form(s) and strength(s):

Tablets: 60 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Select patients for treatment with zongertinib based on the presence of HER2 (ERBB2) tyrosine kinase domain activating mutations in tumor specimens.

• Take zongertinib orally once daily with or without food until disease progression or unacceptable toxicity.

• The recommended dosage of zongertinib is based on body weight as follows:

  Patients <90 kg: 120 mg once daily.

  Patients ≥90 kg: 180 mg once daily.

• See Full Prescribing Information for dosage modification recommendations for adverse reactions and drug interactions.

Cautions for Zongertinib

Contraindications

None.

Warnings/Precautions

Hepatotoxicity

Zongertinib can cause severe and life-threatening hepatotoxicity, including drug induced liver injury. In a pooled safety population, based on adverse reaction data, hepatotoxicity occurred in 27% of patients treated with zongertinib. Grade 3 drug induced liver injury occurred in 1.5% and Grade 4 in 0.4% of patients treated with zongertinib. Grade 3 hepatic failure occurred in 0.4% of patients treated with zongertinib.

Based on laboratory data, 35% of patients treated with zongertinib experienced increased alanine aminotransferase (ALT), including 4.3% Grade 3 and 1.2% Grade 4. Increased aspartate aminotransferase (AST) occurred in 31% of patients treated with zongertinib, including 3.5% Grade 3 and 0.8% Grade 4. Increased bilirubin occurred in 20% of patients treated with zongertinib, including 0.8% Grade 3 and 0.4% Grade 4.

Zongertinib was interrupted for an adverse reaction of hepatotoxicity in 8% of patients, the dose was reduced in 3.5% and permanently discontinued in 1.5%.

Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration of zongertinib, every 2 weeks during the first 12 weeks, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue zongertinib based on the severity of the adverse reaction.

Left Ventricular Dysfunction

Zongertinib can cause severe left ventricular dysfunction. Left ventricular ejection fractions (LVEF) decrease occurred with anti-HER2 therapies, including zongertinib. Treatment with zongertinib has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.

In the pooled safety population, LVEF decrease occurred in 6% of patients treated with zongertinib, including 1.9% Grade 3. Two patients with Grade 3 LVEF decrease required permanent discontinuation. The median time to onset of decreased LVEF was 9 weeks (range: 2.9 to 63 weeks).

Before initiating zongertinib, evaluate LVEF and monitor at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue zongertinib based on the severity of the adverse reaction.

Interstitial Lung Disease/Pneumonitis

Zongertinib can cause severe and life-threatening interstitial lung disease (ILD)/pneumonitis.

In the pooled safety population ILD/pneumonitis occurred in 1.2% of patients (N=3) treated with zongertinib. The median time to first onset of ILD/pneumonitis was 19 weeks (range: 6 to 65 weeks). One patient was able to resume therapy after resolution of pneumonitis. One patient required permanent discontinuation and one patient died with unresolved pneumonitis >30 days after discontinuing zongertinib.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Interrupt, reduce the dose or permanently discontinue zongertinib based on severity of confirmed ILD/pneumonitis.

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, zongertinib can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, 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. Advise females of reproductive potential to use effective contraception during treatment with zongertinib and for 2 weeks after the last dose.

Specific Populations

Pregnancy

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.

Lactation

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.

Females and Males of Reproductive Potential

Based on findings from animal studies and its mechanism of action, zongertinib can cause embryo-fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to initiating zongertinib.

Advise females of reproductive potential to use effective contraception during treatment with zongertinib and for 2 weeks after the last dose.

Based on findings from animal studies, zongertinib may impair fertility in females. The effects in female animals were reversible.

Based on findings from animal studies, zongertinib may impair fertility in males of reproductive potential. The effect on testes in animals was not reversible within a 4-week recovery period.

Pediatric Use

The safety and effectiveness of zongertinib have not been established in pediatric patients.

Geriatric Use

Of the 260 patients with non-squamous NSCLC with HER2 (ERBB2) mutations who received zongertinib in clinical studies, 46% were 65 years of age and older and 12% were 75 years of age and older. No overall differences in safety or effectiveness of zongertinib were observed between older and younger adult patients.

Common Adverse Effects

Most common adverse reactions (≥ 20%) are diarrhea, hepatotoxicity, rash, fatigue, and nausea.

The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, decreased potassium, and increased gamma glutamyl transferase.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A Inducers: Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase zongertinib dose.

• BCRP Substrates: Avoid concomitant use with certain BCRP substrates where minimal concentration increase may lead to serious adverse reactions and consider alternative therapies. If concomitant use cannot be avoided, monitor patients closely for adverse reactions and follow recommendations provided in the BCRP substrate approved product labeling. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate.

Actions

Mechanism of Action

Zongertinib is a kinase inhibitor of human epidermal growth factor receptor 2 (HER2). In vitro, zongertinib inhibited phosphorylation of HER2, downstream signaling of HER2 (phosphorylation of ERK), and proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations. In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC harboring HER2 tyrosine kinase domain activating mutations.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Inform patients that zongertinib can cause severe and life-threatening hepatotoxicity and that they will need to undergo lab tests to monitor liver enzymes during treatment. Advise patients to immediately contact their healthcare provider for signs and symptoms of hepatotoxicity.

• Inform patients that zongertinib can cause severe left ventricular dysfunction. Advise patients to immediately contact their healthcare provider for new or worsening cardiovascular symptoms.

• Inform patients that zongertinib can cause severe or life-threatening ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms.

• Inform patients that zongertinib can cause diarrhea. Advise patients to immediately contact their healthcare provider for signs and symptoms of diarrhea.

• Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with zongertinib and for 2 weeks after the last dose.

• Advise women not to breastfeed during treatment with zongertinib and for 2 weeks after the last dose.

• Advise females and males of reproductive potential that zongertinib may impair fertility.

• Instruct patients weighing <90 kg to take two 60 mg tablets once daily to achieve a complete 120 mg dose and instruct patients weighing ≥ 90 kg to take three 60 mg tablets once daily to achieve a complete 180 mg dose. Instruct patients to swallow zongertinib tablets whole with water. Do not split, crush, or chew tablets.

• Inform patients that if they miss a dose of zongertinib within 12 hours, they should take it as soon as they remember. If the next dose is missed by more than 12 hours, the patient should skip the missed dose and wait until the next scheduled dose.

• If a dose is vomited, do not take an additional dose. Take the next dose at the regularly scheduled time.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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