SAFETY

ADVERSE REACTIONS WERE ASSESSED IN A POOLED
POPULATION OF 287 PATIENTS1

The pooled safety population reflects exposure to HYRNUO® at 20 mg orally twice daily in 287 patients with
locally advanced or metastatic NSCLC harboring HER2 activating and/or other mutations from the SOHO-01 study.

Of the 287 patients who received 20 mg of HYRNUO orally, twice daily:

  • 61% were exposed for >6 months
  • 37% were exposed for >12 months

Most common (>20%) 

adverse reactions (N=287)

Diarrhea

Rash

Paronychia

Nausea

Vomiting

Stomatitis

Most common (≥2%) Grade 3 or 4 laboratory abnormalities (N=287)

Decreased potassium

Increased lipase

Decreased phosphate

Decreased lymphocyte count

Decreased sodium

Increased amylase

Decreased hemoglobin

Increased ALT

Increased AST

Decreased calcium

    Navigation Text
    See adverse events observed in the SOHO-01 safety population (N=191)

    ADVERSE REACTIONS OBSERVED IN THE SOHO-01
    SAFETY POPULATION: NO GRADE 4 EVENTS REPORTED
    AMONG ADVERSE REACTIONS LISTED BELOW1

    The established safety profile of HYRNUO is based on data from 191 patients*

    • Diarrhea was the most common adverse reaction and was reported in 90% of patients
    • There were no discontinuations due to diarrhea
    • Serious adverse reactions occurred in 33% of patients
      • Most common (≥2%): diarrhea (3.7%), dyspnea (3.1%), vomiting (3.7%), pneumonia (2.6%), and pleural effusion (2.1%) 
      • A fatal adverse reaction of cerebral infarction occurred in one patient (0.5%)

    Adverse reactions occurring in ≥15% of patients*

    Adverse reactions†All Grades (%)Grades 3 or 4‡ (%)
    Gastrointestinal disorders
    Diarrhea§9014
    Stomatitis§371
    Nausea222.1
    Vomiting§194.2
    Skin and subcutaneous tissue disorders
    Rash§761.6
    Paronychia§361
    Dry skin§180
    Pruritus161
    Investigations
    Weight decreased220.5
    Metabolism and nutrition disorders
    Decreased appetite192.6
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain§180
    General disorders and administration site conditions
    Fatigue§172.6
    Eye disorders
    Ocular toxicity§160.5

    *In SOHO-01, safety was evaluated in 191 patients, including treatment naive patients, patients who had received prior systemic therapy but were naive to
    HER2-targeted therapy, and patients who had received prior systemic therapy including HER2-targeting ADCs.

    †Graded per NCI CTCAE version 5.

    ‡No Grade 4 were reported.

    §Grouped term.

    †Graded per NCI CTCAE version 5.

    ‡No Grade 4 events were reported.

    §Stomatitis includes aphthous ulcer, cheilitis, mouth ulceration, mucosal inflammation, and stomatitis.

    ‖Abdominal pain includes abdominal pain and abdominal pain upper.

    Rash includes acne, dermatitis acneiform, drug eruption, eczema, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash maculopapular, rash papular, rash pruritic, rash pustular, and skin exfoliation.

    #Paronychia includes ingrowing nail, nail disorder, nail infection, onychoclasis, onycholysis, onychomadesis, and paronychia.

    **Dry skin includes dry skin and xeroderma. 

    ††Fatigue includes asthenia and fatigue. 

    ‡‡Ocular toxicity includes blindness unilateral, cataract, conjunctivitis, conjunctivitis allergic, corneal epithelial microcysts, dry eye, eye discharge, eye pain, lacrimation increased, ocular hyperemia, ocular hypertension, ocular toxicity, vision blurred, visual acuity reduced, visual impairment, and xerophthalmia. 

    §§Cardiac arrhythmia includes arrhythmia, atrioventricular block complete, electrocardiogram QT prolonged, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, and ventricular extrasystoles. 

    LOW DISCONTINUATION RATES DUE TO ADVERSE
    REACTIONS*1

    Majority of patients continued treatment without dose reductions or interruptions

    4.2%

    discontinued treatment due to adverse reactions

    (N=8/191)

    Adverse reactions leading to discontinuation:

    corneal epithelial microcysts, hepatic function abnormal, increased blood alkaline phosphatase, electrocardiogram QT prolonged, pain in extremity, renal failure, dyspnea (1 patient each)

    68%

    were treated with no dose reductions

    (N=130/191)

    Dose reductions due to adverse reactions occurred in 32% of patients who received HYRNUO

    Adverse reactions leading to dose reductions in >2% of patients:

    diarrhea, hepatotoxicity, rash, potassium decreased, stomatitis, vomiting, decreased appetite

    51%

    were treated with no dose interruptions

    (N=97/191)

    Dose interruptions due to adverse reactions occurred in 49% of patients who received HYRNUO

    Adverse reactions leading to dose interruptions in >2% of patients:

    diarrhea, potassium decreased, hepatotoxicity, nausea, vomiting, rash, pneumonia, paronychia, decreased appetite, pruritus, acute kidney injury, stomatitis

    *In SOHO-01, safety was evaluated in 191 patients, including treatment naive patients, patients who had received prior systemic therapy but were naive to HER2-targeted therapy, and patients who had received prior systemic therapy including HER2-targeting ADCs. 

    DIARRHEA WAS THE MOST COMMON ADVERSE REACTION AND WAS MOSTLY GRADE 1 OR 21

    Incidence of Grade 3 and 4 diarrhea in the safety population (N=191)*1,2

    Grade 3 diarrhea in treatment naive patients (Group F)

    4.3%

    N=3/69

    Grade 3 diarrhea in pretreated patients (Groups D & E)

    20%

    N=24/122

    Grade 4 diarrhea in treatment naive patients and pretreated patients (Groups F, D, & E)

    0%

    N=0/191

    • Most diarrhea adverse reactions were Grade 1 or 2 and were reported in 76% of patients. Grade 3 diarrhea was reported in 14% of patients
    • No Grade 4 diarrhea was reported
    • In the pooled safety population (N=287), diarrhea usually occurred within the first week of treatment, with a median time to onset of 4 days†

    In the safety population, diarrhea resulted in no treatment discontinuations*1,2

    Dosage modificationGroup F:
    1L, treatment naive patients (N=69)    		Group D & E:
    Pretreated patients (N=122)
    Dose interruptions2.9%
    (n=2)    		18%
    (n=22)
    Dose reductions9%
    (n=6)    		12%
    (n=15)
    Dosage modification
    Group F:
    1L, treatment naive patients (N=69)
    Dose interruptions(n=2)
    2.9%
    Dose reductions(n=22)
    18%
    Group D & E:
    Pretreated patients (N=122)
    Dose interruptions(n=6)
    9%
    Dose reductions(n=15)
    12%

    March 2025 data cutoff.

    *In SOHO-01, safety was evaluated in 191 patients, including treatment naive patients, patients who had received prior systemic therapy but were naive to HER2-targeted therapy, and patients who had received prior systemic therapy including HER2-targeting ADCs.

    †In SOHO-01, the pooled safety population consisted of 287 patients with locally advanced or metastatic NSCLC harboring HER2 activating and/or other mutations.

    LEARN ABOUT DIARRHEA MANAGEMENT AND DOSE MODIFICATIONS WITH THE ADVERSE REACTION MANAGEMENT TOOL

    AE Management Tool
    Efficacy Data in Pretreated Patients
    Dosing

    Important Safety Information

    Warnings & Precautions

    Diarrhea

    HYRNUO can cause severe diarrhea that can lead to dehydration and electrolyte imbalances.

    In the pooled safety population, diarrhea was reported in 89% of patients who received HYRNUO including 16% Grade 3. The median time to first onset of any grade diarrhea was four days. Dosage interruptions occurred in 15% of patients, and dose reductions occurred in 14% of patients.

    At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment (e.g., loperamide), and to increase their fluid and electrolyte intake. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

    Hepatotoxicity

    HYRNUO can cause severe hepatotoxicity characterized by elevations of liver function tests.

    In the pooled safety population, based on adverse reaction data, hepatotoxicity occurred in 29% of patients treated with HYRNUO, including 3.1% Grade 3 and 0.3% Grade 4.

    Based on laboratory data, 41% of patients treated with HYRNUO experienced increased alanine aminotransferase (ALT), including 2.5% Grade 3 and 0.4% Grade 4. Increased aspartate aminotransferase (AST) occurred in 44% of patients treated with HYRNUO, including 2.5% Grade 3. Increased bilirubin occurred in 15% of patients treated with HYRNUO. The median time to first onset of AST or ALT elevation was 1.4 (range: 0.2 to 24.1) months.

    HYRNUO was interrupted for an adverse reaction of hepatotoxicity in 4.2% of patients, the dose was reduced in 4.9%, and permanently discontinued in 0.3%.

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

    Interstitial Lung Disease/Pneumonitis

    HYRNUO can cause severe interstitial lung disease (ILD)/pneumonitis.

    In the pooled safety population, ILD/pneumonitis occurred in four patients (1.4%) treated with HYRNUO, including 0.3% Grade 3. One patient required interruption of HYRNUO.

    Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Discontinue HYRNUO upon confirmation of ILD/pneumonitis.

    Left Ventricular Dysfunction

    HYRNUO can cause severe left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has occurred with anti-HER2 therapies, including HYRNUO.

    Treatment with HYRNUO 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 one patient (0.3%) treated with HYRNUO. This Grade 3 LVEF decrease required permanent discontinuation of HYRNUO, and the event recovered.

    Evaluate LVEF prior to initiation of HYRNUO and monitor at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

    Ocular Toxicity

    HYRNUO can cause ocular toxicity.

    In the pooled safety population, ocular toxicity occurred in 17% of patients treated with HYRNUO, including 11% Grade 1, 4.9% Grade 2, and 0.3% Grade 3 (one case of corneal epithelial microcysts with temporary unilateral blindness).

    Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

    Pancreatic Enzyme Elevation

    HYRNUO can cause elevations of amylase and lipase levels.

    In the pooled safety population, based on laboratory data, increased amylase occurred in 39% of patients treated with HYRNUO, including 3.9% Grade 3 and 0.7% Grade 4. Increased lipase occurred in 48% of patients treated with HYRNUO, including 13% Grade 3 and 1.1% Grade 4. Four patients (1.4%) required interruption of HYRNUO due to increased lipase and three (1%) required interruption of HYRNUO due to increased amylase. One patient (0.3%) required dose reduction of HYRNUO due to increased amylase. The median time to onset of increased amylase/lipase was 0.7 months (range: 0.2 to 20.4 months).

    Monitor amylase and lipase regularly during treatment with HYRNUO. Interrupt, reduce the dose, or permanently discontinue HYRNUO based on severity.

    Embryo-Fetal Toxicity

    Based on findings from animal studies and its mechanism of action, HYRNUO can cause fetal harm when administered to a pregnant woman. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality.

    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 HYRNUO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with HYRNUO and for 1 week after the last dose.

    Adverse Reactions

    In SOHO-01, serious adverse reactions occurred in 33% of patients who received HYRNUO. Serious adverse reactions in ≥2% of patients were diarrhea (3.7%), dyspnea (3.1%), vomiting (3.7%), pneumonia (2.6%), and pleural effusion (2.1%). A fatal adverse reaction of cerebral infarction occurred in one patient (0.5%) who received HYRNUO.

    The most common adverse reactions (>20%) in patients who received HYRNUO were diarrhea (90%), rash (76%), stomatitis (37%), paronychia (36%), nausea (22%) and weight decreased (22%).

    The most common (≥2%) Grade 3 or 4 laboratory abnormalities were lipase increased (18%), potassium decreased (18%), phosphate decreased (13%), lymphocyte count decreased (4.6%), sodium decreased (5%), amylase increased (5%), hemoglobin decreased (3.7%), ALT increased (3.2%), and increased AST (2.6%). Laboratory abnormalities in <20% of patients who received HYRNUO include bilirubin increased (19%; all were Grades 1 and 2), platelet count decreased, and neutrophil count decreased (16% each).

    Clinically relevant adverse reactions in <15% of patients who received HYRNUO included abdominal pain (14%), cardiac arrhythmia (10%; including arrhythmia, atrial fibrillation, atrial tachycardia, atrioventricular block complete, atrioventricular block first degree, electrocardiogram QT prolonged, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, and ventricular extrasystoles), and alopecia (7%).

    Drug Interactions

    Effects of Other Drugs on HYRNUO – Sevabertinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor may increase sevabertinib plasma concentrations, which may increase the risk of HYRNUO-associated adverse reactions. Monitor patients for increased HYRNUO-associated adverse reactions with moderate CYP3A inhibitors. Avoid concomitant use of HYRNUO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dose.

    Concomitant use with a strong or moderate CYP3A inducer may decrease sevabertinib plasma concentrations, which may decrease the effectiveness of HYRNUO. Avoid concomitant use of HYRNUO with strong or moderate CYP3A inducers.

    Effects of HYRNUO on Other Drugs – Sevabertinib is a weak to moderate CYP3A inhibitor. Sevabertinib increases exposure of CYP3A substrates, which may increase the risk of adverse reactions related to these substrates. Avoid concomitant use of HYRNUO with CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information of the CYP3A substrate.

    Sevabertinib is a P-gp inhibitor. Sevabertinib increases exposure of P-gp substrates, which may increase the risk of adverse reactions related to these substrates. Refer to the Prescribing Information for P-gp substrates where minimal increases in the concentration may lead to serious adverse reactions.

    Sevabertinib is an inhibitor of CYP1A1 in vitro. Sevabertinib may increase exposure of CYP1A1 substrates, which may increase the risk of adverse reactions related to these substrates. Refer to the Prescribing Information of CYP1A1 substrates.

    You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

    Please see full Prescribing Information. 

    Indication

    HYRNUO® is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test.

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

    ABBREVIATIONS

    1L=first line; ADC=antibody-drug conjugate; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HER2=human epidermal growth factor receptor 2; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

    REFERENCES

    1. HYRNUO (sevabertinib). Prescribing Information. 2026. 
    2. Data on file. Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ.

    Site last modified 09/2026

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