HERNEXEOS Film-coated tablet Ref.[115777] Active ingredients: Zongertinib

5.1 Hepatotoxicity

HERNEXEOS can cause severe and life-threatening hepatotoxicity, including drug induced liver injury. In a pooled safety population [see Adverse Reaction (6.1)], based on adverse reaction data, hepatotoxicity occurred in 27% of patients treated with HERNEXEOS. Grade 3 drug induced liver injury occurred in 1.5% and Grade 4 in 0.4% of patients treated with HERNEXEOS. Grade 3 hepatic failure occurred in 0.4% of patients treated with HERNEXEOS.

Based on laboratory data, 35% of patients treated with HERNEXEOS experienced increased alanine aminotransferase (ALT), including 4.3% Grade 3 and 1.2% Grade 4. Increased aspartate aminotransferase (AST) occurred in 31% of patients treated with HERNEXEOS, including 3.5% Grade 3 and 0.8% Grade 4. Increased bilirubin occurred in 20% of patients treated with HERNEXEOS, including 0.8% Grade 3 and 0.4% Grade 4.

HERNEXEOS was interrupted for an adverse reaction of hepatotoxicity in 8% of patients, the dose was reduced in 3.5% and permanently discontinued in 1.5%.

Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration of HERNEXEOS, every 2 weeks during the first 12 weeks, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on the severity of the adverse reaction [see Dosage and Administration (2.3)].

5.2 Left Ventricular Dysfunction

HERNEXEOS can cause severe left ventricular dysfunction. Left ventricular ejection fractions (LVEF) decrease occurred with anti-HER2 therapies, including HERNEXEOS. Treatment with HERNEXEOS 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 [see Adverse Reactions (6.1)], LVEF decrease occurred in 6% of patients treated with HERNEXEOS, including 1.9% Grade 3. Two patients with Grade 3 LVEF decrease required permanent discontinuation. The median time to onset of decreased LVEF was 9 weeks (range: 2.9 to 63 weeks).

Before initiating HERNEXEOS, evaluate LVEF and monitor at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on the severity of the adverse reaction [see Dosage and Administration (2.3)].

5.3 Interstitial Lung Disease/Pneumonitis

HERNEXEOS can cause severe and life-threatening interstitial lung disease (ILD)/pneumonitis.

In the pooled safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 1.2% of patients (N=3) treated with HERNEXEOS. The median time to first onset of ILD/pneumonitis was 19 weeks (range: 6 to 65 weeks). One patient was able to resume therapy after resolution of pneumonitis. One patient required permanent discontinuation and one patient died with unresolved pneumonitis >30 days after discontinuing HERNEXEOS.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Interrupt, reduce the dose or permanently discontinue HERNEXEOS based on severity of confirmed ILD/pneumonitis [see Dosage and Administration (2.3)].

5.4 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, HERNEXEOS can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of zongertinib to pregnant rats during the period of organogenesis caused structural abnormalities and alterations to growth at maternal exposures ≥19 times the human exposure based on AUC at the recommended dose.

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 HERNEXEOS and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hepatotoxicity [see Warnings and Precautions (5.1)]
• Left Ventricular Dysfunction [see Warnings and Precautions (5.2)]
• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to HERNEXEOS in 260 patients with unresectable or metastatic non-squamous NSCLC with HER2 (ERBB2) mutations who received HERNEXEOS as a single agent at 120 mg orally once daily until disease progression or unacceptable toxicity in Beamion LUNG-1 [see Clinical Studies (14)]. Among 260 patients who received HERNEXEOS, 58% of patients were exposed for 6 months or longer and 13% were exposed for greater than one year. In this pooled safety population, the most common (>20%) adverse reactions were diarrhea (53%), hepatotoxicity (27%), rash (27%), fatigue (22%), and nausea (21%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (9%), increased alanine aminotransferase (5%), increased aspartate aminotransferase (4.3%), decreased potassium (2.7%), and increased gamma glutamyl transferase (2.7%).

Beamion LUNG-1

The safety of HERNEXEOS was evaluated in Beamion LUNG-1 in 105 patients with previously treated unresectable or metastatic non-squamous NSCLC with HER2 tyrosine kinase domain (TKD) mutations; all patients had received prior platinum-based chemotherapy, and 34 patients had received prior treatment with a HER2-directed antibody drug conjugate (ADC) [see Clinical Studies (14)]. Patients received HERNEXEOS as a single agent at 120 mg once daily until disease progression or unacceptable toxicity. Among patients who received HERNEXEOS, 72% were exposed for 6 months or longer and 30% were exposed for greater than one year. The median age of patients who received HERNEXEOS was 61 years (range 30 to 85), 69% were female, 40% White, 49% Asian, and 0% Black or African American; 11% had unknown race data; 1.9% were of Hispanic or Latino ethnicity; and 33% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 and 67% had an ECOG performance score of 1.

Serious adverse reactions occurred in 34% of patients receiving HERNEXEOS. Serious adverse reactions in ≥2% of patients included dyspnea (4.8%), pulmonary embolism (4.8%), hepatotoxicity (2.9%), and pneumonia (2.9%). Fatal adverse reactions occurred in 1% of patients who received HERNEXEOS, due to pneumonia.

Permanent discontinuation of HERNEXEOS due to an adverse reaction occurred in 2.9% of patients. Adverse reactions which resulted in permanent discontinuation of HERNEXEOS were hepatotoxicity, increased blood alkaline phosphatase, dyspnea, increased gamma-glutamyl transferase, hemoptysis, and pyrexia.

Dosage interruption of HERNEXEOS due to an adverse reaction occurred in 28% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were hepatotoxicity, decreased ejection fraction, and rash.

Dose reductions of HERNEXEOS due to adverse reactions occurred in 7% of patients. Adverse reactions which required dose reductions in ≥1% of patients were hepatotoxicity, decreased ejection fraction, increased blood creatinine phosphokinase, increased gamma-glutamyl transferase, and decreased neutrophil count.

Tables 3 and 4 summarize adverse reactions and laboratory abnormalities observed in Beamion LUNG-1.

Table 3. Adverse Reactions (≥15%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1:

Events were graded using NCI CTCAE version 5.0.
¹ No Grade 4 or Grade 5 adverse reactions occurred.
^* Grouped term.

Clinically relevant adverse reactions in <15% of patients who received HERNEXEOS included stomatitis, dry skin, pruritus, and peripheral neuropathy.

Table 4. Select Laboratory Abnormalities (≥20%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1:

Events were graded using NCI CTCAE version 5.0.
¹ No Grade 5 adverse reactions occurred.

7.1 Effects of Other Drugs on HERNEXEOS

Avoid concomitant use of HERNEXEOS with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose as recommended [see Dosage and Administration (2.4)].

Zongertinib is a CYP3A substrate. Strong CYP3A4 inducers decrease zongertinib exposure [see Clinical Pharmacology (12.3)], which may reduce effectiveness of HERNEXEOS.

7.2 Effects of HERNEXEOS on Other Drugs

BCRP Substrates

Avoid concomitant use of HERNEXEOS with certain BCRP substrates where minimal concentration changes may lead to serious adverse reactions. If coadministration cannot be avoided, monitor for increased adverse reactions and follow recommendations provided in the approved product labeling for the BCRP substrate. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate.

Zongertinib is a BCRP inhibitor. HERNEXEOS increases exposure of BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], HERNEXEOS can cause fetal harm when administered to a pregnant woman. There are no available data on the use of HERNEXEOS in pregnant women to inform a drug-associated risk. Oral administration of zongertinib to pregnant rats during the period of organogenesis caused structural abnormalities and alterations to growth at maternal exposures ≥19 times the human exposure based on AUC at the recommended dose [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study, pregnant rats received oral doses of 10, 30, or 60 mg/kg/day of zongertinib during the period of organogenesis (gestation day 7 to 18). Zongertinib caused decreased fetal weights, delayed development of the urinary system, and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose). In an embryo-fetal development study in rabbits, there were no adverse embryo-fetal findings in pregnant animals administered oral doses of zongertinib up to 120 mg/kg/day (2.4 times the human exposure based on AUC at the recommended dose) during the period of organogenesis (gestation day 6 to 19).

A literature-based assessment of the effects on reproduction demonstrated that mice expressing catalytically inactive HER2 die at mid-gestation due to cardiac dysfunction.

Risk Summary

There are no data on the presence of zongertinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with HERNEXEOS and for 2 weeks after the last dose.

Based on findings from animal studies and its mechanism of action, HERNEXEOS can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating HERNEXEOS.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with HERNEXEOS and for 2 weeks after the last dose.

Infertility

Females

Based on findings from animal studies, HERNEXEOS may impair fertility in females. The effects in female animals were reversible [see Nonclinical Toxicology 13.1].

Males

Based on findings from animal studies, HERNEXEOS may impair fertility in males of reproductive potential. The effect on testes in animals was not reversible within a 4-week recovery period [see Nonclinical Toxicology 13.1].

The safety and effectiveness of HERNEXEOS have not been established in pediatric patients.

Of the 260 patients with non-squamous NSCLC with HER2 (ERBB2) mutations who received HERNEXEOS in clinical studies, 46% were 65 years of age and older and 12% were 75 years and older. No overall differences in safety or effectiveness of HERNEXEOS were observed between older and younger adult patients.