Pharmacist's Application to Practice: Zongertinib

FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations

What is the potential role for zongertinib in the treatment of non-squamous non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) tyrosine kinase domain (TKD) activating mutations?

• Human epidermal growth factor 2 (HER2) mutations are observed in approximately 2% to 5% of non-small cell lung carcinoma (NSCLC), predominantly in cases of adenocarcinoma, among non-smokers and females.1,2
• Zongertinib is the first oral HER2-targeted tyrosine kinase inhibitor (TKI) approved for use in HER2-mutant NSCLC. It is FDA-approved as subsequent therapy after progression on first-line systemic treatment.2
• Zongertinib selectively inhibits HER2 while sparing EGFR, reducing the severity of associated toxic effects such as diarrhea and rash. 2
• There are currently no other HER2-directed TKIs approved for the treatment of NSCLC. Current HER2-targeted therapies for NSCLC include fam-trastuzumab deruxtecan-nxki and ado-trastuzumab emtansine.2
  • Zongertinib may be preferred in appropriate patients due to oral administration, patient convenience, and feasibility considerations.
• Zongertinib drug approval was based on the Beamion LUNG-1 trial (NCT04886804), a phase Ia/Ib, single-arm, open-label, multi-center, multi-cohort trial conducted in patients with advanced tumors including HER2-mutated NSCLC.2
• Beamion LUNG-1 enrolled 105 patients as of May 2024, who had progressed on or were not eligible to receive standard therapy.2
• The primary outcome objective response rate (ORR) resulted at 71%. Secondary outcomes included progression-free survival (PFS) and duration of response (DoR). The median PFS was 12.4 months and the median DoR was 14.1 months.2
• Intracranial ORR was noted to be 41%
• Dose reductions due to adverse reactions occurred in 11% of patients. Adverse reactions that required dose reductions included hepatotoxicity, decreased ejection fraction, increased blood creatine phosphokinase, and decreased neutrophil count.2
• The most frequently reported adverse reactions included diarrhea (50%), rash (16%), and anemia (10%)

What role can the pharmacist play in the management of patients on Zongertinib?

• Dosing and Administration3
  • Zongertinib is dosed based on actual body weight:
    • < 90 kg =120 mg daily
    • ³90 kg = 180 mg daily
  • Zongertinib is taken by mouth once daily, with or without food, with water, and is continued until medication intolerance or disease progression.
• Renal Impairment3
  • No dose adjustment mentioned in the package insert
  • eGFR <60 mL/min: has not been studied.
• Hepatic Impairment3
  • No dose adjustment mentioned in the package insert
  • Moderate to severe hepatic impairment: has not been studied.
• Metabolism & Drug Interactions3
  • Zongertinib is a substrate of CYP3A and BCRP.
  • Avoid concurrent administration with strong CYP3A inducers.
  • If co-administration with strong CYP3A inducers is unavoidable, the dosage should be adjusted according to body weight as follows:
    • Less than 90 kg: increase from 120 mg to 240 mg
    • Equal to or greater than 90 kg: increase from 180 mg to 360 mg
  • Avoid concurrent administration with certain BCRP substrates when possible.
• Monitoring3:
  • Prior to initiation:
    • LFTs (AST, ALT, total bilirubin) at baseline and every two weeks x 12 weeks followed by monthly
    • Left ventricular ejection fraction (LVEF) at baseline and then periodically during treatment
  • Advise females of reproductive potential or males with partners of reproductive potential to utilize effective contraception during and 2 weeks after the last dose.
• The package labeling provides dosage modifications for adverse reactions based on severity. Dosage modifications are provided for patients who develop hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and diarrhea.
• If a dose reduction is necessary, Zongertinib should be reduced based on initial dose (according to body weight):
  • 180 mg à 120 mg once daily OR
  • 120 mg à 60 mg once daily for patients commencing treatment at 180 mg, or to 60 mg once daily for those starting at 120 mg
• Zongertinib must be permanently discontinued in patients unable to tolerate 60 mg once daily.
• Refer to the package insert for additional information on holding, dose adjustment, and permanent discontinuation for toxicity.
• Supportive care is essential, particularly management of diarrhea, nausea, and fatigue. Early pharmacist intervention improves adherence and tolerability.

Clinical Pearls

• Zongertinib is supplied as 60 mg tablets. Tablets should be swallowed whole and cannot be split, crushed, or chewed. 3
• Zongertinib should be stored in its original container at room temperature to prevent moisture exposure. Do not remove desiccants from the original container after opening. The bottle must be used within 3 months of opening. Any unused tablets remaining after 3 months of opening should be discarded.3
• If a dose is missed within 12 hours, then it can be taken. If it has been more than 12 hours, then skip that dose and take at the next scheduled dose.3
• If a dose is vomited, do not re-dose.3
• Patient assistance program available through the Boehringer Ingelheim Cares Foundation.4

References

1.Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol. 2021;12(4):217-237. doi:10.5306/wjco.v12.i4.217

2.Heymach JV, Ruiter G, Ahn MJ, et al; Beamion LUNG1 Investigators. Zongertinib in previously treated HER2mutant non–smallcell lung cancer. N Engl J Med. 2025;392(23):23212333. doi:10.1056/NEJMoa2503704

3.HERNEXEOS (zongertinib) [prescribing Information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; August, 2025.

4.Savings & Support. Boehringer Ingelheim Pharmaceuticals. Accessed October 22, 2025. https://patient.boehringer-ingelheim.com/us/products/hernexeos/support-and-saving