Zongertinib(LuciZonger)

Zongertinib (LuciZonger) is a kinase inhibitor and an oral, irreversible human epidermal growth factor receptor 2 (HER2/ERBB2) tyrosine kinase inhibitor (TKI) that selectively inhibits HER2 without inhibiting wild-type EGFR. It is administered orally once daily, with or without food.

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Dosage and Administration of Zongertinib (LuciZonger)

1. Pre-treatment Screening

Patients should be selected for treatment with Zongertinib (LuciZonger) based on the presence of an activating mutation in the HER2 (ERBB2) tyrosine kinase domain in tumor specimens or plasma specimens.

If the mutation is not detected in a plasma specimen, tumor tissue should be tested.

2. Patient Monitoring

Monitor liver function tests, including ALT, AST, and total bilirubin, at baseline before dosing, every 2 weeks during the first 12 weeks, and monthly thereafter (or as clinically indicated); patients with transaminase elevations should be tested more frequently.

LVEF should be assessed before initiating treatment, monitored periodically during treatment, and monitored as clinically indicated.

Monitor for new or worsening symptoms suggestive of interstitial lung disease (ILD)/pneumonitis, such as dyspnea, cough, and fever.

3. Method of Administration

Zongertinib (LuciZonger) is administered orally once daily, with or without food. Tablets should be swallowed whole with water and must not be split, crushed, or chewed. Continue treatment until disease progression or unacceptable toxicity.

4. Recommended Dosage

The recommended dosage of Zongertinib (LuciZonger) is determined by body weight and must be strictly differentiated by weight category; categories must not be combined:

Patients weighing less than 90 kg: 120 mg once daily, i.e., 2 × 60 mg tablets per dose.

Patients weighing 90 kg or more: 180 mg once daily, i.e., 3 × 60 mg tablets per dose.

5. Missed Dose

If a missed dose is recognized within 12 hours, take the missed dose as soon as possible.

If more than 12 hours have elapsed since the missed dose, skip the missed dose and take the next dose at the originally scheduled time.

6. Vomiting After Dosing

If vomiting occurs after taking a dose, do not take an additional dose; take the next dose at the originally scheduled time.

Use in Specific Populations of Zongertinib (LuciZonger)

1. Pregnancy

Zongertinib (LuciZonger) may cause fetal harm when administered to pregnant women. Inform pregnant women and women of reproductive potential of the potential risk to the fetus. Verify pregnancy status in women of reproductive potential before initiating Zongertinib (LuciZonger) treatment.

2. Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Zongertinib (LuciZonger) and for 2 weeks after the last dose.

3. Females and Males of Reproductive Potential

Contraception (females): Advise women of reproductive potential to use effective contraception during treatment with Zongertinib (LuciZonger) and for 2 weeks after the last dose.

Fertility (females): Based on animal study results, Zongertinib (LuciZonger) may impair female fertility; the effect in female animals was reversible.

Fertility (males): Based on animal study results, Zongertinib (LuciZonger) may impair fertility in males of reproductive potential; testicular effects in male animals were irreversible within the 4-week recovery period.

4. Pediatric Use

The safety and efficacy of Zongertinib (LuciZonger) in pediatric patients have not been established.

5. Geriatric Use

Among 292 patients with HER2 (ERBB2)-mutated non-squamous non-small cell lung cancer who received Zongertinib (LuciZonger) in clinical studies, 47% were 65 years of age and older and 13% were 75 years of age and older. No overall differences in the safety or efficacy of Zongertinib (LuciZonger) were observed between geriatric patients and younger adult patients.

6. Hepatic Impairment

No clinically significant differences in the pharmacokinetics of Zongertinib (LuciZonger) were observed in patients with mild hepatic impairment (AST > ULN and total bilirubin ≤ ULN; or total bilirubin > 1 to 1.5 times ULN with any AST).

The effect of moderate hepatic impairment (total bilirubin > 1.5 to 3 times ULN with any AST) or severe hepatic impairment (total bilirubin > 3 times ULN with any AST) on the pharmacokinetics of Zongertinib (LuciZonger) has not been studied.

7. Renal Impairment

No clinically significant differences in the pharmacokinetics of Zongertinib (LuciZonger) were observed in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60 to < 90 mL/min).

The effect of moderate renal impairment (eGFR 30 to < 60 mL/min), severe renal impairment (eGFR 15 to < 30 mL/min), or end-stage renal disease (eGFR < 15 mL/min) on the pharmacokinetics of Zongertinib (LuciZonger) has not been studied.

Dosage Adjustments

Dose Adjustment for Toxicity

1. Dose Reduction Schedule

For patients whose current dose is 180 mg: first reduce to 120 mg, second reduce to 60 mg, and permanently discontinue thereafter.

For patients whose current dose is 120 mg: first reduce to 60 mg, and the second reduction is permanent discontinuation.

Patients who cannot tolerate 60 mg once daily should permanently discontinue Zongertinib (LuciZonger).

2. Dose Adjustment for Hepatotoxicity

For Grade 3 or 4 ALT and/or AST elevation without total bilirubin elevation, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower or baseline, then resume at a reduced dose level.

For Grade 3 total bilirubin elevation, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower or baseline, then resume at a reduced dose level.

For Grade 4 total bilirubin elevation, permanently discontinue Zongertinib (LuciZonger).

For ALT or AST ≥ 3 times ULN with total bilirubin ≥ 2 times ULN, permanently discontinue Zongertinib (LuciZonger).

3. Dose Adjustment for Left Ventricular Dysfunction

For LVEF 40% to 50% with a 10% to 19% decrease from baseline, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower or within 10% of baseline; if recovery to Grade 1 or lower occurs within 4 weeks, resume at the same dose level; if recovery to Grade 1 or lower does not occur within 4 weeks, permanently discontinue Zongertinib (LuciZonger).

For LVEF 20% to 39%, or a decrease from baseline of ≥ 20%, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower or within 10% of baseline; if recovery to Grade 1 or lower occurs within 4 weeks, resume at a reduced dose level; if recovery to Grade 1 or lower does not occur within 4 weeks, permanently discontinue Zongertinib (LuciZonger); for symptomatic congestive heart failure, permanently discontinue Zongertinib (LuciZonger).

4. Dose Adjustment for Interstitial Lung Disease/Pneumonitis

For Grade 2 ILD/pneumonitis, withhold Zongertinib (LuciZonger) until resolution, then resume at a reduced dose level; if ILD/pneumonitis recurs, permanently discontinue Zongertinib (LuciZonger).

For Grade 3 or 4 ILD/pneumonitis, permanently discontinue Zongertinib (LuciZonger).

5. Dose Adjustment for Diarrhea

For Grade 2 diarrhea, maintain the Zongertinib (LuciZonger) dose and initiate antidiarrheal treatment; for Grade 2 diarrhea that persists for ≥ 2 days despite antidiarrheal treatment, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower, then resume at a reduced dose level.

For Grade 3 or 4 diarrhea, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower, then resume at a reduced dose level; if diarrhea does not resolve to Grade 1 or lower within 14 days despite optimal supportive care (including antidiarrheal treatment) and treatment interruption, permanently discontinue Zongertinib (LuciZonger).

6. Dose Adjustment for Other Adverse Reactions

For Grade 3 adverse reactions, interrupt Zongertinib (LuciZonger) until recovery to Grade 1 or lower or baseline, then resume at a reduced dose level.

For Grade 4 adverse reactions, permanently discontinue Zongertinib (LuciZonger).

Dosage Adjustment for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Avoid concomitant use of Zongertinib (LuciZonger) with strong CYP3A inducers. If concomitant use cannot be avoided, increase the Zongertinib (LuciZonger) dose according to body weight:

Patients weighing less than 90 kg: increase from 120 mg to 240 mg.

Patients weighing 90 kg or more: increase from 180 mg to 360 mg.

After discontinuation of the CYP3A inducer, resume the Zongertinib (LuciZonger) dose that was taken before initiation of the CYP3A inducer 7 to 14 days after discontinuation of the CYP3A inducer.

Adverse Reactions of Zongertinib (LuciZonger)

Most common adverse reactions (≥ 20%): diarrhea, rash, hepatotoxicity, fatigue, nausea, musculoskeletal pain, and upper respiratory tract infection.

Most common laboratory abnormalities (≥ 20%): lymphopenia, alanine aminotransferase increased, hemoglobin decreased, leukopenia, aspartate aminotransferase increased, creatine kinase increased, calcium decreased, albumin decreased, bilirubin increased, lipase increased, triglycerides increased, activated partial thromboplastin time prolonged, sodium decreased, bicarbonate decreased, magnesium decreased, potassium decreased, thrombocytopenia, and alkaline phosphatase increased.

Most common Grade 3 or 4 laboratory abnormalities (≥ 2%): lymphopenia, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, potassium decreased, and neutropenia.

Warnings and Precautions for Zongertinib (LuciZonger)

1. Hepatotoxicity

Zongertinib (LuciZonger) can cause severe and life-threatening hepatotoxicity, including drug-induced liver injury.

Monitor liver function tests, including ALT, AST, and total bilirubin, at baseline before dosing, every 2 weeks during the first 12 weeks, and monthly thereafter (or as clinically indicated); patients with transaminase elevations should be tested more frequently; interrupt, reduce, or permanently discontinue Zongertinib (LuciZonger) based on the severity of adverse reactions.

2. Left Ventricular Dysfunction

Zongertinib (LuciZonger) can cause severe left ventricular dysfunction. Decreased LVEF can occur with anti-HER2 therapy, including Zongertinib (LuciZonger). Zongertinib (LuciZonger) has not been studied in patients with a history of clinically significant cardiac disease or with LVEF below 50% before initiating treatment.

Assess LVEF before initiating Zongertinib (LuciZonger) treatment, monitor periodically during treatment, and monitor as clinically indicated; interrupt, reduce, or permanently discontinue Zongertinib (LuciZonger) based on the severity of adverse reactions.

3. Interstitial Lung Disease/Pneumonitis

Zongertinib (LuciZonger) can cause severe and life-threatening ILD/pneumonitis.

Monitor for new or worsening symptoms suggestive of ILD/pneumonitis, such as dyspnea, cough, and fever; interrupt, reduce, or permanently discontinue Zongertinib (LuciZonger) based on the severity of confirmed ILD/pneumonitis.

4. Embryo-Fetal Toxicity

Zongertinib (LuciZonger) may cause fetal harm when administered to pregnant women. Pregnant women and women of reproductive potential are high-risk populations.

Inform pregnant women and women of reproductive potential of the potential risk to the fetus; advise women of reproductive potential to use effective contraception during treatment with Zongertinib (LuciZonger) and for 2 weeks after the last dose.

Drug Interactions of Zongertinib (LuciZonger)

Effects of Other Drugs on Zongertinib (LuciZonger)

Avoid concomitant use of Zongertinib (LuciZonger) with strong CYP3A inducers. If concomitant use cannot be avoided, increase the Zongertinib (LuciZonger) dose.

Zongertinib (LuciZonger) is a substrate of cytochrome P450 (CYP) 3A. Strong CYP3A4 inducers can decrease Zongertinib (LuciZonger) exposure and may reduce the efficacy of Zongertinib (LuciZonger). The effect of moderate CYP3A inducers on the Cmax and AUC of Zongertinib (LuciZonger) when coadministered with Zongertinib (LuciZonger) is not known.

No clinically significant differences in the pharmacokinetics of Zongertinib (LuciZonger) were observed when coadministered with strong CYP3A inhibitors, P-glycoprotein (P-gp) inhibitors, breast cancer resistance protein (BCRP) inhibitors, or rabeprazole (a proton pump inhibitor, a gastric acid-reducing agent).

Effects of Zongertinib (LuciZonger) on Other Drugs

Zongertinib (LuciZonger) is a BCRP inhibitor. Zongertinib (LuciZonger) can increase exposure to BCRP substrates and may increase the risk of adverse reactions associated with these substrates.

Avoid concomitant use of Zongertinib (LuciZonger) with certain BCRP substrates for which small increases in concentration may lead to serious adverse reactions; use alternative treatments. If concomitant use cannot be avoided, monitor patients closely for adverse reactions.

For other BCRP substrates, monitor for increased adverse reactions and adjust the dose of these substrates as clinically needed.

Mechanism of Action of Zongertinib (LuciZonger)

Target: Zongertinib (LuciZonger) is a human epidermal growth factor receptor 2 (HER2) kinase inhibitor that selectively inhibits HER2 without inhibiting wild-type EGFR.

Binding Mode: Zongertinib (LuciZonger) is an oral, irreversible HER2 tyrosine kinase inhibitor that exerts its effect by binding to the HER2 tyrosine kinase domain and inhibiting its phosphorylation. Zongertinib (LuciZonger) is itself the active drug and not a prodrug; total radioactivity in human plasma is predominantly unchanged Zongertinib (LuciZonger), accounting for 75%.

In vitro, Zongertinib (LuciZonger) inhibits HER2 phosphorylation, inhibits downstream HER2 signaling (phosphorylation of extracellular signal-regulated kinase [ERK]), and inhibits the proliferation of lung cancer cells harboring activating mutations in the HER2 tyrosine kinase domain.