Hernexeos Drug Information

Generic name: ZONGERTINIB

Kinase Inhibitor [EPC]

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Uses of Hernexeos

HERNEXEOS is indicated for the treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain activating mutations, as detected by an FDA-authorized test. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Dosage & Administration of Hernexeos

Patient Selection

Select patients for treatment of unresectable or metastatic NSCLC based on the presence of HER2 (ERBB2) tyrosine kinase domain activating mutations in tumor or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-authorized tests for HER2 (ERBB2) tyrosine kinase domain activating mutations is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage and Administration

The recommended dosage of HERNEXEOS is based on body weight: Patients weighing less than 90 kg: 120 mg Patients weighing 90 kg or greater: 180 mg Take HERNEXEOS orally once daily with or without food until disease progression or unacceptable toxicity. Swallow HERNEXEOS tablets whole with water. Do not split, crush, or chew tablets. Missed Dose If a dose is missed within 12 hours, take the dose. Vomited Dose If a dose is vomited, do not take an additional dose. Take the next dose at the regularly scheduled time.

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are presented in Table 1. Table 2 Recommended HERNEXEOS s for Drug Interactions Strong CYP3A Inducers Avoid concomitant use of strong CYP3A inducers with HERNEXEOS.

Table 1 Recommended HERNEXEOS Dose Reductions for Adverse Reactions
Current HERNEXEOS Dose	First Reduction	Second Reduction
180 mg	120 mg	60 mg
120 mg	60 mg	Permanently discontinue
Permanently discontinue HERNEXEOS in patients who are unable to tolerate 60 mg once daily.

Table 2 Recommended HERNEXEOS Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity*	Dosage Modification
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
*Based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Hepatotoxicity [see Warnings and Precautions (5.1) ]	Grade 3 or 4 ALT and/or AST without increased total bilirubin	Interrupt HERNEXEOS until recovered to ≤ Grade 1 or baseline. Resume HERNEXEOS at reduced dose level.
	Grade 3 total bilirubin	Interrupt HERNEXEOS until recovered to ≤ Grade 1 or baseline. Resume HERNEXEOS at reduced dose level.
	Grade 4 total bilirubin	Permanently discontinue HERNEXEOS.
	ALT or AST ≥ 3× ULN with total bilirubin ≥ 2× ULN	Permanently discontinue HERNEXEOS.
Left Ventricular Dysfunction [see Warnings and Precautions (5.2) ]	LVEF 40 to 50% and decrease from baseline of 10 to 19%	Interrupt HERNEXEOS until recovered to ≤ Grade 1 or within 10% from baseline. If recovered to ≤ Grade 1 in ≤ 4 weeks, resume HERNEXEOS at the same dose level. If not recovered to ≤ Grade 1 within 4 weeks, permanently discontinue HERNEXEOS.
	LVEF 20 to 39% or ≥ 20% decrease from baseline	Interrupt HERNEXEOS until recovered to ≤ Grade 1 or within 10% from baseline. If recovered to ≤ Grade 1 in ≤ 4 weeks, resume HERNEXEOS at the reduced dose level. If not recovered to ≤ Grade 1 within 4 weeks, permanently discontinue HERNEXEOS.
	Symptomatic Congestive Heart Failure	Permanently discontinue HERNEXEOS.
Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3) ]	Grade 2	Withhold HERNEXEOS until resolution. Resume HERNEXEOS at reduced dose level. Permanently discontinue HERNEXEOS for recurrent ILD/pneumonitis.
	Grade 3 or Grade 4	Permanently discontinue HERNEXEOS.
Diarrhea [see Adverse Reactions (6.1) ]	Grade 2	Maintain HERNEXEOS dose. Initiate anti-diarrheal treatment.
	Grade 2 lasting ≥ 2 days despite anti-diarrheal treatment	Interrupt HERNEXEOS until recovered to ≤ Grade 1. Resume HERNEXEOS at reduced dose level.
	Grade 3 or Grade 4	Interrupt HERNEXEOS until recovered to ≤ Grade 1. Resume HERNEXEOS at reduced dose level. Permanently discontinue HERNEXEOS 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 [see Adverse Reactions (6.1) ]	Grade 3	Interrupt HERNEXEOS until recovered to ≤ Grade 1 or baseline. Resume HERNEXEOS at reduced dose level.
Other Adverse Reactions [see Adverse Reactions (6.1) ]	Grade 4	Permanently discontinue HERNEXEOS.

Side Effects of Hernexeos

Clinical Trials Experience

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 292 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. Beamion LUNG-1 The safety of HERNEXEOS was evaluated in Beamion LUNG-1 in 177 patients with unresectable or metastatic non-squamous NSCLC with HER2 tyrosine kinase domain (TKD) mutations; 72 patients had not received prior treatment; 105 patients had received prior platinum-based chemotherapy, and out of those patients, 34 patients had received prior treatment with a HER2-directed antibody drug conjugate (ADC).

Among patients who received HERNEXEOS, 74% were exposed for 6 months or longer and 42% were exposed for greater than one year. Serious adverse reactions occurred in 36% of patients receiving HERNEXEOS. Fatal adverse reactions occurred in one patient (0.6%) who received HERNEXEOS, due to pneumonia.

Permanent discontinuation of HERNEXEOS due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of HERNEXEOS were hepatotoxicity, decreased ejection fraction, anemia, increased blood alkaline phosphatase, diarrhea, dyspnea, increased gamma-glutamyl transferase, hemoptysis, pericardial effusion, pneumonitis, and pyrexia. Dosage interruption of HERNEXEOS due to an adverse reaction occurred in 34% of patients.

Adverse reactions which required dosage interruption in ≥ 2% of patients were hepatotoxicity, decreased ejection fraction, diarrhea, COVID-19, rash, and vomiting. Dose reductions of HERNEXEOS due to adverse reactions occurred in 9% of patients. Adverse reactions which required dose reductions in ≥ 1% of patients were hepatotoxicity, decreased ejection fraction, and diarrhea.

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 0 Clinically relevant adverse reactions in < 15% of patients who received HERNEXEOS included vomiting, dyspnea, dysgeusia, and dry skin. Table 4 Select Laboratory Abnormalities (≥ 20%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS 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
Adverse Reaction	HERNEXEOS N = 177
Adverse Reaction	All Grades 1 %	Grade 3 or 4 %
Events were graded using NCI CTCAE version 5.0.
1 No Grade 4 or Grade 5 adverse reactions occurred.
*Grouped term.
Gastrointestinal Disorders
Diarrhea*	56	2.8
Nausea	25	0.6
Stomatitis*	21	0
Skin and Subcutaneous Tissue Disorders
Rash*	32	0.6
Nail disorders*	21	0.6
Pruritus	15	0
General Disorders
Fatigue*	26	0.6
Headache	16	0.6
Respiratory, Thoracic and Mediastinal Disorders
Cough*	23	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain*	23	2.3
Infections and Infestations
Upper respiratory tract infections*	23	0

Table 4 Select Laboratory Abnormalities (≥ 20%) in Patients with Non-Squamous NSCLC with HER2 TKD Mutations Who Received HERNEXEOS in Beamion LUNG-1
Laboratory Parameter	HERNEXEOS N = 177
Laboratory Parameter	All Grades 1 %	Grade 3 or 4 %
Events were graded using NCI CTCAE version 5.0.
1 No Grade 5 adverse reactions occurred.
Hematology
Lymphocytes decreased	56	12
Hemoglobin decreased	37	1.1
Leukocytes decreased	35	1.1
Activated partial thromboplastin time increased	23	0
Platelets decreased	20	1.1
Chemistry
Alanine aminotransferase increased	41	7
Aspartate aminotransferase increased	35	5
Creatinine kinase increased	28	1.7
Calcium decreased	28	0.6
Albumin decreased	26	0
Bilirubin increased	25	1.1
Lipase increased	25	0
Triglycerides increased	25	0
Sodium decreased	22	0.6
Bicarbonate decreased	22	0
Magnesium decreased	21	1.1
Potassium decreased	21	1.7
Alkaline phosphatase increased	20	1.7

Warnings & Cautions for Hernexeos

Hepatotoxicity HERNEXEOS can cause severe and life-threatening hepatotoxicity, including drug induced liver injury. In the pooled safety population, based on adverse reaction data, hepatotoxicity occurred in 27% of patients treated with HERNEXEOS. Grade 3 hepatic failure occurred in 0.3% of patients treated with HERNEXEOS.

HERNEXEOS was interrupted for an adverse reaction of hepatotoxicity in 8% of patients, the dose was reduced in 3.8% and permanently discontinued in 1%. 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.

Left Ventricular Dysfunction HERNEXEOS can cause severe left ventricular dysfunction. Decreases in left ventricular ejection fraction (LVEF) have 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, LVEF decrease occurred in 6% of patients treated with HERNEXEOS, including 1.7% Grade 3. Two patients with Grade 3 LVEF decrease required permanent discontinuation of HERNEXEOS. The median time to onset of decreased LVEF was 12 weeks (range: 2.9 to 63 weeks).

Before initiating HERNEXEOS, evaluate LVEF and monitor at regular intervals during treatment and as clinically indicated.

Interstitial Lung Disease/Pneumonitis HERNEXEOS can cause severe and life-threatening interstitial lung disease (ILD)/pneumonitis. In the pooled safety population, ILD/pneumonitis occurred in 2.1% of patients treated with HERNEXEOS. The median time to first onset of ILD/pneumonitis was 13 weeks (range: 1.4 to 65 weeks).

One patient was able to resume therapy after resolution of pneumonitis. Two patients 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.

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.

Drug Interactions with Hernexeos

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. Zongertinib is a CYP3A substrate.

Strong CYP3A inducers decrease zongertinib exposure, which may reduce effectiveness of HERNEXEOS.

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, which may increase the risk of adverse reactions related to these substrates.

Pregnancy Safety for Hernexeos

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, 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.

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 respectively. 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.

Pediatric Use of Hernexeos

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

Overdosage Information for Hernexeos

Overdose in one patient who ingested 600 mg of HERNEXEOS resulted in nausea and vomiting.

Clinical Studies of Hernexeos

HERNEXEOS was evaluated in Beamion LUNG-1 (NCT04886804), a single arm, open-label, multi-center, multi-cohort trial. Eligible patients were required to have unresectable or metastatic NSCLC with HER2 (ERBB2) mutations. Patients with stable brain metastases were eligible to enroll.

The study excluded patients who had a history of non-infectious interstitial lung disease/pneumonitis. Patients received HERNEXEOS 120 mg orally once daily until disease progression or unacceptable toxicity. 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).

Previously Untreated Unresectable or Metastatic Non-Squamous NSCLC The efficacy population included 72 patients with unresectable or metastatic, non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain (TKD) mutations based on prospective local testing, who had not received prior systemic therapy for advanced disease. Of those, tumor tissue samples from 60% (43/72) of patients were retrospectively tested using Oncomine™ Dx Target Test (Life Technologies Corporation, Tissue-test). Efficacy results are summarized in Table 5.

Table 5 Efficacy Results for Beamion LUNG-1 in Previously Untreated Non-Squamous NSCLC Previously Treated Unresectable or Metastatic Non-Squamous NSCLC The efficacy population included 71 patients with unresectable or metastatic, non-squamous NSCLC with HER2 (ERBB2) TKD mutations based on prospective local testing. Of those, tumor tissue samples from 52% (37/71) of patients were retrospectively tested using Oncomine™ Dx Target Test (Life Technologies Corporation, Tissue-test). No patient had received previous treatment with a HER2-targeted tyrosine kinase inhibitor (TKI) or HER2-targeted antibody-drug conjugate (ADC).

Efficacy results are summarized in Table 6. Table 6 Efficacy Results for Beamion LUNG-1 in Previously Treated Non-Squamous NSCLC Among the 71 patients, 5 patients had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months prior to treatment with HERNEXEOS. Based on Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria per BICR, responses were observed in 3 patients.

HERNEXEOS 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 ADC. Eligibility criteria were otherwise similar to the efficacy population described above. Baseline ECOG performance status was never smoked; 100% of patients had metastatic disease and 74% had brain metastases.

Confirmed ORR by RECIST v1.1 based on BICR was of patients having a complete response.

Table 5 Efficacy Results for Beamion LUNG-1 in Previously Untreated Non-Squamous NSCLC
Efficacy Parameter	HERNEXEOS N = 72
Abbreviation: CI = Confidence Interval, +: Ongoing response.
1 Based on Wilson confidence interval.
2 Based on observed duration of response.
Objective Response Rate (ORR), % (95% CI) 1	76 (65, 85)
Complete response, %	11
Partial response, %	65
Duration of Response (DOR)	N = 55
Range, months	1.4, 18+
DOR ≥ 6 months, 2 %	64
DOR ≥ 12 months, 2 %	44

Table 6 Efficacy Results for Beamion LUNG-1 in Previously Treated Non-Squamous NSCLC
Efficacy Parameter	HERNEXEOS N = 71
Abbreviation: CI = Confidence Interval, +: Ongoing response.
1 Based on Wilson confidence interval.
2 Based on observed duration of response.
Objective Response Rate (ORR), % (95% CI) 1	75 (63, 83)
Complete response, %	6
Partial response, %	69
Duration of Response (DOR)	N = 53
Range, months	1.3+, 15+
DOR ≥ 6 months, 2 %	58

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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