Zongertinib — Drug Monograph

Zongertinib (Hernexeos) — HER2-Mutant NSCLC Oral TKI Overview

Zongertinib (Hernexeos) is an oral, covalent, HER2 (ERBB2)-selective tyrosine kinase inhibitor for advanced non-small cell lung cancer (NSCLC) driven by HER2 tyrosine kinase domain (TKD) activating mutations. Its HER2 selectivity spares wild-type EGFR, reducing the rash and diarrhea burden seen with pan-HER inhibitors. A HER2 (ERBB2) TKD activating mutation confirmed by an FDA-authorized test is required before starting. This monograph covers zongertinib oral daily dosing, HER2-mutant NSCLC biomarker selection, selective tyrosine kinase inhibition, and baseline/ongoing hepatotoxicity, LVEF, and ILD monitoring.

Indications (FDA / NCCN)

• Unresectable or metastatic non-squamous NSCLC with HER2 (ERBB2) TKD activating mutations
• Accelerated approval based on ORR and duration of response (Beamion LUNG-1)
• HER2 (ERBB2) TKD mutation confirmed by an FDA-authorized test before starting

Dosing

• Weight-based oral once daily: 120 mg if <90 kg, 180 mg if ≥90 kg
• Take with or without food; swallow tablets whole
• Continue until progression or unacceptable toxicity
• Interrupt, reduce, or discontinue based on toxicity severity

Monitoring

• ALT, AST, total bilirubin at baseline, every 2 weeks × 12 weeks, then monthly
• LVEF at baseline and at regular intervals (left ventricular dysfunction)
• ILD / pneumonitis symptoms (dyspnea, cough, fever)
• HER2 (ERBB2) mutation status confirmation

Brand names: Hernexeos

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Zongertinib is an oral, covalent, HER2 (ERBB2)-selective tyrosine kinase inhibitor that binds the HER2 tyrosine kinase domain and inhibits signaling driven by HER2 TKD-activating mutations, while largely sparing wild-type EGFR — a selectivity that reduces the classic EGFR-mediated rash and diarrhea burden relative to pan-HER inhibitors.

FDA Indications

• Unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) with HER2 (ERBB2) tyrosine kinase domain activating mutations (detected by an FDA-authorized test) — accelerated approval based on ORR and duration of response

Common Side Effects

• Diarrhea
• Rash
• Hepatotoxicity (transaminase elevations)
• Fatigue
• Nausea
• Musculoskeletal pain
• Upper respiratory tract infection
• Decreased lymphocytes
• Decreased potassium
• Decreased neutrophils

Clinical Pearl

Zongertinib is a HER2-selective covalent TKI for HER2 (ERBB2) TKD-mutant non-squamous NSCLC — a distinct target from the EGFR/ALK inhibitors. Its EGFR-sparing selectivity tempers rash/diarrhea, but three axes require structural monitoring: hepatotoxicity (LFTs at baseline, every 2 weeks for 12 weeks, then monthly), left ventricular dysfunction (serial LVEF), and ILD/pneumonitis. Dosing is weight-based (120 mg if =90 kg).

Related Therapies & Mechanisms

• Sevabertinib (Hyrnuo) — Tyrosine Kinase Inhibitor · NSCLC
• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor · NSCLC
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor · NSCLC
• Capmatinib (Tabrecta) — Tyrosine Kinase Inhibitor · NSCLC