Zongertinib, a kinase inhibitor of human epidermal growth factor receptor 2 (HER2), is an antineoplastic agent.1, 2, 3
Zongertinib is used for the treatment of unresectable or metastatic, non-squamous non-small cell lung cancer (NSCLC) in adults whose tumors have human epidermal growth factor receptor (HER) 2 (ERBB2) tyrosine kinase domain activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.1
This indication is approved under accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.1
Efficacy and safety of zongertinib were evaluated in a phase 1a-1b, single-arm, open-label, multicenter, multi-cohort trial (Beamion LUNG-1) in patients with unresectable or metastatic non-squamous NSCLC with HER2 (ERBB2) mutations.1, 3 Patients with stable brain metastases were eligible to enroll, while patients with a history of non-infectious interstitial lung disease/pneumonitis were excluded.1 The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by blinded independent central review (BICR).1
A total of 71 patients received zongertinib 120 mg orally once daily until disease progression or unacceptable toxicity.1 Among these patients, the median age was 62 years (range, 30 to 80 years); 70% were female, 55% were Asian, 35% were White; 10% had unknown race data; 1.4% were Hispanic or Latino; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0; and 61% had an ECOG performance status of 1.1 All patients had metastatic disease, with brain metastases present in 37% of patients.1 Additionally, 65% of patients never smoked.1 The median number of prior therapies was 1 (range, 1 to 10); 100% of patients received prior platinum therapy and 78% received prior treatment with anti-PD-1/PD-L1 antibody.1 No patient had received previous treatment with a HER2-targeted tyrosine kinase inhibitor (TKI) or HER2-targeted antibody-drug conjugate (ADC).1 Tumor tissue samples were retrospectively tested using Oncomine Dx Target Test in 52% (37/71) of patients.1 While 84% (31/37) of samples were positive for HER2 (ERBB2) TKD mutations, 2.7% (1/37) did not have HER2 (ERBB2) TKD mutations identified, and 13.5% (5/37) were unevaluable.1
The primary efficacy outcome, ORR, was 75%; 6% of patients had a complete response and 69% had a partial response.1 The proportion of responders with an observed DOR ≥6 months was 58%.1, 2 Five patients had measurable CNS metastases by BICR at baseline and had not received radiation therapy to the brain within 2 months prior to treatment initiation; a response was observed in 3 of these patients.1, 2
Zongertinib was also evaluated in 34 patients with unresectable or metastatic HER2 (ERBB2) TKD mutation-positive non-squamous NSCLC who had received previous treatment with platinum-based chemotherapy and a HER2-targeted antibody drug conjugate.1, 2 Among these patients, the median age was 58 years (range, 31 to 85 years); 65% were female, 35% were Asian, 50% were White, 0% were Black or African American; 15% had unknown race data; 2.9% were of Hispanic or Latino ethnicity; 21% had a baseline ECOG performance status of 0, and 79% or had a baseline ECOG performance status of 1.1 All patients had metastatic disease and 74% had brain metastases.1 Additionally, 65% of patients never smoked.1 The median number of prior therapies received was 3 (range, 1 to 8); 100% of patients had prior platinum therapy and 77% had prior treatment with an anti-PD-1/PD-L1 antibody; 2.9% of patients received previous treatment with a HER2-targeted TKI.1 Confirmed ORR by RECIST v1.1 based on BICR was 44%, with 2.9% of patients achieving a complete response.1, 2 The median DOR was 5.4 months, with 27% of responders having an observed DOR ≥6 months.1, 2
The American Society of Clinical Oncology (ASCO) guidelines on management of stage IV NSCLC with driver alterations addresses treatment decisions based on HER2 overexpression.4 For patients with stage IV NSCLC harboring HER2 mutations, ASCO recommends treatment starting in the second-line setting and beyond.4 Trastuzumab deruxtecan may be considered as a treatment option.4 Zongertinib is not discussed in the guideline since the drug was approved after guideline publication.1, 4
Administer as tablets, with or without food.1
Swallow zongertinib whole with water; do not split, crush, or chew tablets.1
If a dose of zongertinib is missed within 12 hours, take the dose.1 If the next dose is missed by more than 12 hours, skip the missed dose and wait until the next scheduled dose.1
If vomiting occurs after administration of zongertinib, do not take an additional dose, and take the next dose at its scheduled time.1
Store tablets at 20-25°C (excursions permitted to 15-30°C).1 Store in the original container with desiccant to protect from moisture.1
Once opened, use within 3 months.1 Discard any unused tablets 3 months after opening the bottle.1
The recommended dosage of zongertinib for the treatment of unresectable or metastatic, non-squamous non-small cell lung cancer (NSCLC) in adults with tumors harboring activating mutations in the human epidermal growth factor receptor (HER) 2 (ERBB2) tyrosine kinase domain is 120 mg once daily for patients weighing <90 kg, and 180 mg once daily for patients weighing ≥90 kg.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Adverse Reactions
If adverse events occur during therapy, temporary interruption, dosage reduction, and/or discontinuance of zongertinib may be necessary.1 For patients receiving 180 mg once daily, an initial reduction to 120 mg once daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 60 mg once daily.1 For patients receiving 120 mg once daily, a reduction to 60 mg once daily is recommended.1 If a dosage of 60 mg once daily is not tolerated, zongertinib should be permanently discontinued.1
The recommended dosage modifications for adverse reactions are present in Table 1.1
Adverse Reaction | Dosage Modification Based on Severity |
|---|---|
Hepatotoxicity | Grade 3 or 4 ALT and/or AST without increased total bilirubin: Interrupt until recovery to ≤Grade 1 or baseline. Resume at reduced dose level. Grade 3 total bilirubin: Interrupt until recovery to ≤Grade 1 or baseline. Resume at reduced dose level. Grade 4 total bilirubin: Permanently discontinue. ALT or AST ≥3 times ULN with total bilirubin ≥2 times ULN: Permanently discontinue. |
Left Ventricular Dysfunction | LVEF 40 to 50% and decrease from baseline of 10 to 19%: Interrupt until recovery to ≤Grade 1 or within 10% from baseline. If recovery to ≤Grade 1 in ≤4 weeks, resume at same dose level. If not recovered to ≤Grade 1 within 4 weeks, permanently discontinue. LVEF 20 to 39% or ≥20% decrease from baseline: Interrupt until recovery to ≤Grade 1 or within 10% from baseline. If recovery to ≤Grade 1 in ≤4 weeks, resume at reduced dose level. If not recovered to ≤Grade 1 within 4 weeks, permanently discontinue. Symptomatic congestive heart failure: Permanently discontinue. |
Interstitial Lung Disease/Pneumonitis | Grade 2: Withhold until resolution. Resume at reduced dose level. Permanently discontinue for recurrent ILD/pneumonitis. Grade 3 or Grade 4: Permanently discontinue. |
Diarrhea | Grade 2: Maintain dose. Initiate anti-diarrheal treatment. Grade 2 lasting ≥2 days despite anti-diarrheal treatment: Interrupt until recovery to ≤Grade 1. Resume at reduced dose level. Grade 3 or Grade 4: Interrupt until recovery to ≤Grade 1. Resume at reduced dose level. Permanently discontinue if diarrhea does not resolve to ≤Grade 1 within 14 days, despite optimal supportive care (including anti-diarrheal treatment) and treatment interruption. |
Other Adverse Reactions | Grade 3: Interrupt until recovery to ≤Grade 1 or baseline. Resume at reduced dose level. Grade 4: Permanently discontinue. |
Dosage Modifications for Drug Interactions
Concomitant use of strong CYP3A inducers with zongertinib should be avoided.1 If concomitant use cannot be avoided, the zongertinib dose should be increased based on body weight.1 For patients weighing <90 kg, increase the zongertinib dose from 120 mg to 240 mg; for patients weighing ≥90 kg, increase the zongertinib dose from 180 mg to 360 mg.1
Seven to 14 days after discontinuation of a CYP3A inducer, the zongertinib dose that was taken prior to initiating the CYP3A inducer should be resumed.1
The manufacturer makes no specific dosage recommendations for geriatric patients or patients with hepatic or renal impairment.1
Zongertinib may cause severe and life-threatening hepatotoxicity, including drug-induced liver injury.1 In a pooled safety population, hepatotoxicity occurred in 27% of patients treated with zongertinib.1 Grade 3 and 4 drug induced liver injury occurred in 1.5% and 0.4% of patients, respectively, who were treated with zongertinib.1 Grade 3 hepatic failure occurred in 0.4% of patients receiving zongertinib.1
ALT elevations occurred in 35% of patients treated with zongertinib, including 4.3% Grade 3 and 1.2% Grade 4.1 AST elevations occurred in 31% of patients, including 3.5% Grade 3 and 0.8% Grade 4.1 Increased bilirubin occurred in 20% of patients, including 0.8% Grade 3 and 0.4% Grade 4.1 Dose interruption due to an adverse reaction of hepatotoxicity occurred in 8% of patients, dose reduction occurred in 3.5% of patients, and permanent discontinuation was necessary in 1.5% of patients.1
Monitor liver function tests including ALT, AST, and total bilirubin at baseline, every 2 weeks during the first 12 weeks of treatment, and then monthly and as clinically indicated, with more frequent testing in patients who develop transaminase elevations.1 Interrupt, reduce the dose, or permanently discontinue zongertinib based on the severity of the adverse reaction.1
Zongertinib may cause severe left ventricular dysfunction.1 Decreases in left ventricular ejection fraction (LVEF) have been observed with anti-HER2 therapies, including zongertinib.1 Zongertinib has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiating treatment.1
In a pooled safety population, 6% of patients treated with zongertinib experienced a decrease in LVEF, including 1.9% Grade 3.1 Permanent discontinuation was required in 2 patients with Grade 3 decrease in LVEF.1 The median time to onset of decreased LVEF was 9 weeks (range, 2.9 to 63 weeks).1
Evaluate LVEF at baseline and at regular intervals during treatment and as clinically indicated.1 Interrupt, reduce the dose, or permanently discontinue zongertinib based on the severity of the adverse reaction.1
Interstitial Lung Disease (ILD)/Pneumonitis
Zongertinib may cause severe and life-threatening ILD/pneumonitis.1 In a pooled safety population, ILD/pneumonitis occurred in 1.2% of patients treated with zongertinib.1 The median time to first onset of ILD/pneumonitis was 19 weeks (range, 6 to 65 weeks).1 Therapy was resumed after resolution of pneumonitis in 1 patient.1 Permanent discontinuation was required in another patient, and 1 patient died with unresolved pneumonitis more than 30 days after discontinuing therapy.1
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).1 Interrupt, reduce the dose, or permanently discontinue zongertinib based on the severity of confirmed ILD/pneumonitis.1
Fetal/Neonatal Morbidity and Mortality
Based on findings from animal studies and its mechanism of action, zongertinib can cause fetal harm.1 When administered to pregnant rats, structural abnormalities and alterations to growth occurred at maternal exposures ≥19 times the human exposure based on AUC at the recommended dose.1
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Advise females of reproductive potential to use effective contraception during treatment with zongertinib and for 2 weeks after the last dose.1
There are no available human data on zongertinib use in pregnant women; however, based on animal studies, zongertinib can cause fetal harm when administered during pregnancy.1 When administered to pregnant rats, structural abnormalities and alterations to growth occurred at maternal exposures ≥19 times the human exposure based on AUC at the recommended dose.1
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1
It is not known whether zongertinib is distributed into human milk, or if the drug has any effects on the breastfed infant or on milk production.1
Advise women not to breastfeed during treatment with zongertinib and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
Based on animal studies, zongertinib can cause embryo-fetal harm when administered to a pregnant woman.1 Verify pregnancy status prior to initiating treatment with zongertinib.1 Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose.1
Based on animal studies, zongertinib may impair fertility in males and females.1 The effects in female animals were reversible.1 The effect on males was not reversible within a 4 week recovery period.1
Safety and efficacy of zongertinib have not been established in pediatric patients.1
Of the 260 patients with non-squamous non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor (HER)2 (ERBB2) mutations who were treated with zongertinib, 46% were 65 years of age or older and 12% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between elderly and younger patients.1
No clinically significant differences in the pharmacokinetics of zongertinib were observed in patients with mild hepatic impairment.1 Zongertinib has not been adequately studied in patients with moderate or severe hepatic impairment.1
No clinically significant differences in the pharmacokinetics of zongertinib were observed in patients with mild renal impairment.1 Zongertinib has not been adequately studied in patients with moderate to severe renal impairment or end-stage renal disease.1
The most common adverse reactions (≥20%) reported with zongertinib are diarrhea, hepatotoxicity, rash, fatigue, and nausea.1
The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased ALT, increased AST, decreased potassium, and increased gamma glutamyl transferase.1
Zongertinib is a substrate of cytochrome P-450 (CYP) isoenzyme 3A and an inhibitor of breast cancer resistance protein (BCRP).1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
No clinically significant differences in the pharmacokinetics of midazolam (a CYP3A substrate) or repaglinide (a sensitive CYP2C8 substrate) were observed when used concomitantly with zongertinib.1
Concomitant administration of zongertinib with strong CYP3A inhibitors did not affect the pharmacokinetics of zongertinib.1
When the strong CYP3A inducer carbamazepine (600 mg once daily for 7 days) was administered concomitantly with zongertinib, peak plasma concentrations of zongertinib decreased by 43% and AUC decreased by 63%.1 The effect of concomitant use of moderate CYP3A inducers on zongertinib peak plasma concentrations and AUC are unknown.1
Because of the potential for reduced efficacy of zongertinib, concomitant administration of zongertinib and strong CYP3A4 inducers (e.g., carbamazepine) should be avoided.1 If concomitant use cannot be avoided, dosage of zongertinib should be increased.1
Drugs Affecting or Affected by Transport Systems
Concomitant use of zongertinib and drugs that are substrates of BCRP (e.g., rosuvastatin) may increase exposure and toxicity of the BCRP substrate.1 When the BCRP substrate rosuvastatin was administered concomitantly with zongertinib (single 120 mg dose), peak plasma concentrations and AUC of rosuvastatin were increased 3- and 2.3-fold, respectively.1 Avoid concomitant use of zongertinib with certain BCRP substrates where minimal concentration increase may lead to serious adverse reactions and consider alternative therapies.1 If concomitant use cannot be avoided, monitor patients closely for adverse reactions and follow recommendations provided in the BCRP substrate approved product labeling.1 For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate.1
Concomitant administration of zongertinib with strong P-glycoprotein (P-gp) and BCRP inhibitors did not affect the pharmacokinetics of zongertinib.1
No clinically significant differences in the pharmacokinetics of dabigatran (a P-gp substrate) or metformin [an organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporter (MATE) 1/2-K substrate] were observed when used concomitantly with zongertinib.1
Drugs Affecting Gastric Acidity
Concomitant administration of zongertinib with rabeprazole (proton pump inhibitor) did not affect the pharmacokinetics of zongertinib.1
Zongertinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing epidermal growth factor receptor (EGFR).1, 3 In vitro studies demonstrated that zongertinib inhibited HER2 phosphorylation, suppressed downstream HER2 signaling pathways, and reduced proliferation of lung cancer cells with activating mutations in the HER2 tyrosine kinase domain.1 In vivo, zongertinib exhibited antitumor activity in murine xenograft models of non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain activating mutations.1
Following oral administration of zongertinib, median time to peak plasma concentration is approximately 2 hours with steady-state concentrations achieved within approximately 2.5 days.1 Zongertinib absolute bioavailability is 76%.1 Administration of zongertinib with a high-fat meal did not affect AUC or peak plasma concentrations.1 Zongertinib plasma protein binding is >99%.1 The effective half-life is 12 hours.1 CYP-mediated oxidation pathways represent 48% to 62% (mainly CYP3A4 and CYP3A5), glucuronidation 13% to 25% [mainly UDP glucuronosyltransferase (UGT) 1A4], and glutathione conjugation 13% to 26% of total hepatic metabolism.1 Following oral administration of zongertinib, 93% of the dose was eliminated in the feces (31% unchanged) and 1.3% in urine (0.2% unchanged).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Zongertinib is available only from designated specialty pharmacies.5 Contact the manufacturer or consult the zongertinib website ([Web]) for more information.6
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 60 mg | Hernexeos® | Boehringer Ingelheim |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions December 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Boehringer Ingelheim Pharmaceuticals, Inc.. HERNEXEOS® (zongertinib) ORAL prescribing information. 2025 Aug. [Web]
2. US Food and Drug Administration. Center for Drug Evaluations and Research Application Number: 219042Orig1s000 Multi-Discipline Review. From the FDA website. Accessed 2025 Sept 25.
3. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in previously treated HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
4. Owen DH, Halmos B, Puri S, et al. Therapy for stage IV non-small cell lung cancer without driver alterations: ASCO Living Guideline, Version 2025.1. J Clin Oncol. 2025;43(24):e45-e58. doi:10.1200/JCO-25-01062
5. About Hernexeos (Zongertinib). From Onco360 Oncology Pharmacy website. Accessed 2025 Sept 25. [Web]
6. HERNEXEOS® (zongertinib tablets) is NOW APPROVED. From boehringer-ingelheim website. Accessed 2025 Oct 8. [Web]