Hernexeos Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1. 1.

   Indications ....................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................. 4

   1.2. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 4.

   Dosage and Administration ............................................................................................. 4

   4.1. Dosing Considerations .............................................................................................. 4

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 4

   4.4. Administration .......................................................................................................... 7

   4.5. Missed Dose ............................................................................................................. 7

4. 5. Overdose ......................................................................................................................... 7
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 8
6. 7.

   Warnings and Precautions ............................................................................................... 8

   General ................................................................................................................................. 8

   Cardiovascular ...................................................................................................................... 8

   Driving and Operating Machinery ......................................................................................... 9

   Hepatic/Biliary/Pancreatic .................................................................................................... 9

   Respiratory ........................................................................................................................... 9

   Reproductive Health ........................................................................................................... 10

   7.1. Special Populations ................................................................................................ 10

   7.1.1. Pregnancy ...................................................................................................... 10

   7.1.2. Breastfeeding ................................................................................................ 11

   7.1.3. Pediatrics ....................................................................................................... 11

   7.1.4. Geriatrics ....................................................................................................... 11

7. 8.

   Adverse Reactions ......................................................................................................... 11

   8.1. Adverse Reaction Overview .................................................................................... 11

   8.2. Clinical Trial Adverse Reactions .............................................................................. 12

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................... 13

8. 9.

   Drug Interactions ........................................................................................................... 15

   9.2. Drug Interactions Overview .................................................................................... 15

   9.3. Drug-Behaviour Interactions .................................................................................. 15

   9.4. Drug-Drug Interactions ........................................................................................... 15

   9.5. Drug-Food Interactions........................................................................................... 17

   9.6. Drug-Herb Interactions ........................................................................................... 17

   9.7. Drug-Laboratory Test Interactions ......................................................................... 17

9. 10.

   Clinical Pharmacology ................................................................................................... 17

   10.1. Mechanism of Action .............................................................................................. 17

   10.2. Pharmacodynamics ................................................................................................ 18

   10.3. Pharmacokinetics ................................................................................................... 18

10. 11. Storage, Stability, and Disposal ...................................................................................... 19

Part 2: Scientific Information ................................................................................................ 20

1. 13. Pharmaceutical Information .......................................................................................... 20
2. 14.

   Clinical Trials .................................................................................................................. 21

   14.1. Clinical Trials by Indication ..................................................................................... 21

3. 16. Non-Clinical Toxicology .................................................................................................. 23

Patient Medication Information ........................................................................................... 24

Part 1: Healthcare Professional Information

1. Indications

HERNEXEOS (zongertinib) is indicated for:

• the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have HER2 (ERBB2) tyrosine kinase domain activating mutations and who have received prior systemic therapy.

This indication has been issued market authorization with conditions, pending the results of a confirmatory trial to verify its clinical benefit. The authorization is based on objective response rate and duration of response (see 14.1 Clinicals Trials by Indication).

1.1. Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of HERNEXEOS have not been established in pediatric patients.

1.2. Geriatrics

Geriatrics (> 65 years of age): No overall differences in safety and efficacy were observed for elderly patients compared to patients aged below 65 years.

2. Contraindications

• HERNEXEOS is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Composition and Packaging.

4. Dosage and Administration

4.1. Dosing Considerations

• Testing prior to HERNEXEOS administration

  • Patient Selection

    • Treatment with HERNEXEOS should be initiated following confirmation of a HER2 (ERBB2) mutation in a tumour specimen using a validated test (see 14.1 Clinical Trials by Indication).

4.2. Recommended Dose and Dosage Adjustment

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.
• Treatment should be continued until disease progression or unacceptable toxicity occurs.
• Dosage adjustments due to adverse reactions
• Recommended dose adjustments for adverse reactions are outlined in Table 1. Treatment must be permanently discontinued in patients who are unable to tolerate HERNEXEOS after one dose reduction to 60 mg once daily (see 8 ADVERSE REACTIONS and for further details on management of specific drug related Adverse Events (AEs) see 7 WARNINGS AND PRECAUTIONS).

Table 1 Recommended dose adjustments for HERNEXEOS

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ULN = upper limit of normal

• Dosage adjustment for strong CYP3A inducers

  • Avoid concomitant use of strong CYP3A inducers with HERNEXEOS.

  • If concomitant use cannot be avoided, increase the HERNEXEOS dose based on body weight (see 9.4 Drug-Drug Interactions):

    • Patients weighing less than 90 kg: from 120 mg to 240 mg
    • Patients weighing 90 kg or greater: from 180 mg to 360 mg

After discontinuing a CYP3A inducer, resume the HERNEXEOS dose (7 to 14 days after discontinuing the CYP3A inducer) that was taken prior to initiating the CYP3A inducer.

Special populations

• Pediatrics (< 18 years of age):

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

• Geriatrics (> 65 years of age)

  • No dose adjustment is required in elderly patients (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics).

• Hepatic impairment

  • Zongertinib is predominantly eliminated via hepatic metabolism and fecal excretion (>90%). No formal studies have been conducted to evaluate the effect of hepatic impairment on the exposure to HERNEXEOS.
  • Mild hepatic impairment (NCI-ODWG criteria: AST >ULN and total bilirubin ≤ULN; or total bilirubin >1 to ≤1.5 × ULN and any AST) has no influence on the exposure to HERNEXEOS based on a population PK analysis. No dose adjustment is required for patients with mild hepatic impairment.
  • The safety and efficacy of HERNEXEOS have not been established in patients with pre-existing moderate (total bilirubin >1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin >3 × ULN and any AST). Treatment of patients with pre-existing moderate or severe hepatic impairment with HERNEXEOS is not recommended (see 10.3 Pharmacokinetics).

• Renal impairment

  • Less than 2% of a single dose of HERNEXEOS is excreted via the kidney. No clinically relevant effect on exposure was observed in patients with mild renal impairment. No dose adjustment is required in patients with mild renal impairment (eGFR ≥60 and <90 mL/min/1.73m², based on CKD-EPI formula) (see 10.3 Pharmacokinetics)
  • The safety, efficacy and pharmacokinetics in patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73m²), severe renal impairment (eGFR ≥15 and <30 mL/min/1.73m²) or end stage renal disease (eGFR <15 mL/min/1.73m²) have not been studied.

4.4. Administration

HERNEXEOS is for oral use. The film-coated tablets should be swallowed whole with water. HERNEXEOS can be taken with or without food (see 10.3 Pharmacokinetics).

4.5. Missed Dose

If a dose of HERNEXEOS is missed, it should be taken during the same day as soon as the patient remembers. If the next dose is within 12 hours, then the missed dose must be skipped, and the next scheduled dose awaited.

5. Overdose

In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and symptomatic treatment be instituted as appropriate.

In Beamion LUNG-1, an overdose in one patient who ingested 600 mg of HERNEXEOS resulted in nausea and vomiting. The patient recovered from these adverse events.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 2 – Dosage Forms, Strengths, and Composition

Description

HERNEXEOS film-coated tablets, 60 mg are yellow, oval, biconvex tablets of a size of about 15 x 7 mm. One side is debossed with ‘L6’ and the other side is debossed with a Boehringer Ingelheim company symbol. They are packaged in a bottle containing 60 tablets each, along with two silica gel desiccants and a child-resistant closure.

7. Warnings and Precautions

General

Physicians should monitor patients as frequently as clinically indicated for adverse reactions and according to the instructions of 4 Dosage and Administration and 9 Drug Interactions. For significant side effects, the treatment of symptoms and dose reduction or interruption of HERNEXEOS should be considered.

Cardiovascular

• Left Ventricular Dysfunction

Cases of severe LVD were reported in association with HERNEXEOS treatment. 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, LVEF decrease

occurred in 5.4% of patients treated with HERNEXEOS, including 1.8% Grade 3. 2 patients with Grade 3 LVEF decrease required permanent discontinuation. The median time to onset of decreased LVEF was 9.1 weeks (range: 2.9 to 63.1 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.

Driving and Operating Machinery

No studies on the effects on the ability to drive or operate machinery have been performed.

Hepatic/Biliary/Pancreatic

• Hepatotoxicity

In a pooled safety population (277 patients treated with 120 mg once daily of HERNEXEOS), ALT increased occurred in 16.6% of patients treated with HERNEXEOS and AST increased in 16.2%, of which 4.3% and 2.9%, respectively, were Grade 3. Grade 4 ALT increased occurred in 0.7% of patients, while no Grade 4 events of AST increased were seen. Among patients who had ALT or AST increased, first onset occurred within 12 weeks of treatment initiation in 71.7% and 68.9% of patients, respectively. Dose discontinuation for ALT and AST increased was required in 1.4% and 1.1% of patients, respectively.

In this pooled safety population, 52.3% of patients were previously treated with PD-1/PD-L1/CTLA-4 blocking antibodies. Of those, ALT increased and AST increased were reported in 17.2% and 16.6% of patients, respectively.

Liver enzymes (hepatic transaminase) and bilirubin levels should be monitored upon initiation of treatment with HERNEXEOS, once every 2 weeks during the first 8 weeks, at week 12, and periodically thereafter or as clinically indicated.

Based on the severity of the hepatic adverse reactions, the dose should be interrupted, reduced or permanently discontinued (see 4.2 Recommended Dose and Dosage Adjustment).

Respiratory

• Interstitial Lung Disease/Pneumonitis

Cases of severe and potentially life-threatening interstitial lung disease (ILD)/pneumonitis were reported in association with HERNEXEOS treatment. In the pooled safety population, ILD/pneumonitis occurred in 1.1% of patients (N=3) treated with HERNEXEOS. The time to first onset was 41, 134 and 458 days for the three patients. One patient was able to continue therapy with HERNEXEOS. Treatment was permanently discontinued in the other two patient; out of which 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.

Reproductive Health

• Fertility

  There are no data on the impact of HERNEXEOS on human fertility.

  Based on findings from animal studies, HERNEXEOS may impair fertility in females of reproductive potential (see 16 Non-Clinical Toxicology).

• Contraception

  Females of reproductive potential should be advised to avoid becoming pregnant while taking HERNEXEOS and to use effective contraceptive methods during treatment with HERNEXEOS and for 10 days after the last dose.

  It is unknown whether HERNEXEOS may reduce the efficacy of hormonal contraceptives. Therefore, women using hormonal contraceptives should be advised to use or add an alternative effective non-hormonal contraceptive measure.

• Embryo-fetal toxicity

  Based on findings from animal studies and the mechanism of action, HERNEXEOS can cause embryo-fetal harm when administered to a pregnant woman. A study in pregnant rats with zongertinib has shown embryo-fetal lethality at 29-times the human exposure at the recommended dose of 120 mg daily (see 16 Non-Clinical Toxicology).

  Pregnancy status should be verified prior to initiation of treatment with HERNEXEOS and during treatment as appropriate. Females of reproductive potential should be advised not to become pregnant while taking HERNEXEOS (see 7.1.1 Pregnancy and 7.12 Breastfeeding).

7.1. Special Populations

7.1.1. Pregnancy

There is no information on the use of HERNEXEOS in pregnant women.

Based on findings from animal studies and the mechanism of action, HERNEXEOS can cause embryo-fetal harm when administered to a pregnant woman. A study in pregnant rats has shown embryo-fetal lethality at 29-times the human exposure at the recommended dose of 120 mg daily. (see 16 Non-Clinical Toxicology).

Females of reproductive potential should be advised to avoid becoming pregnant while taking HERNEXEOS.

Pregnancy status should be verified in females of reproductive potential prior to treatment with HERNEXEOS and during treatment as appropriate. Female patients should be advised to notify their healthcare provider if they become pregnant or suspect they may be pregnant during therapy with HERNEXEOS. Pregnant women and females of reproductive potential should be advised of the potential risk to a foetus (see 7 Warnings and Precautions, Reproductive Health/Embryo-fetal toxicity).

7.1.2. Breastfeeding

There are no data on the presence of zongertinib in human milk or its effects on either the breastfed child or on milk production.

Due to the potential for serious adverse reactions in breastfed children whose mothers are taking HERNEXEOS, women should be advised not to breastfeed during treatment with HERNEXEOS and for 10 days after the last dose.

7.1.3. Pediatrics

Pediatrics (<18 years of age): The safety and efficacy of HERNEXEOS has not been established in pediatric patients.

7.1.4. Geriatrics

Geriatrics (>65 years of age): HERNEXEOS has been studied in patients aged 30 to 80 years. There were 32 (43%) patients 65 years of age and older in the clinical study in patients with unresectable or metastatic NSCLC of which 6 (8%) were 75 years of age or older. No overall differences in safety and efficacy were observed for elderly patients compared to patients aged below 65 years. No dose adjustment is required in elderly patients. (see 10.3 Pharmacokinetics).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The pooled safety population referred to in 7 Warnings and Precautions reflects exposure to at least one dose of HERNEXEOS 120 mg QD in 277 patients with unresectable or metastatic solid tumors harboring HER2 mutations. Among the 277 patients who received HERNEXEOS, 55% were exposed for greater than 6 months and 12% were exposed for greater than one year. In this pooled safety population, the most common (> 20%) adverse reactions were diarrhea (51%), hepatotoxicity (25%), rash (26%), fatigue (21%), and nausea (20%). The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (10.0%), increased alanine aminotransferase (5.3%), increased aspartate aminotransferase (4.2%), decreased potassium (2.7%), and increased gamma glutamyl transferase (2.8%).

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 14.1 Clinical Trials by Indication; HER2-mutant Unresectable or Metastatic NSCLC After at Least One Line of Prior Systemic Therapy). 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.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The safety data described below reflect exposure to HERNEXEOS 120 mg once daily in 105 patients with unresectable or metastatic NSCLC who received at least one dose in Beamion LUNG-1 (see 14.1 Clinical Trials by Indication; HER2-mutant Unresectable or Metastatic NSCLC After at Least One Line of Prior Systemic Therapy)

Table 3 – Adverse reactions occurring in ≥ 15% of patients treated with HERNEXEOS by SOC and preferred term, sorted by frequency in Beamion LUNG-1

Events were graded using NCI CTCAE version 5.0.

¹ no Grade 4 or 5 adverse reactions were reported.

² Grouped term

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

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

Table 4 – Select Laboratory Abnormalities (≥ 20%) in Patients Treated with HERNEXEOS in Beamion LUNG-1.

Events were graded using NCI CTCAE version 5.0.

¹ No Grade 5 adverse reactions were reported.

9. Drug Interactions

9.2. Drug Interactions Overview

Based on in vitro data, zongertinib is a CYP3A4, P-gp and BCRP substrate (see 10.3 Pharmacokinetics). Concomitant use of zongertinib with strong CYP3A4 inducers decreases zongertinib exposure (see 9.4 Drug-Drug Interactions), which may result in reduced clinical response. Co-administration of HERNEXEOS with strong CYP3A4 inducers should be avoided. If coadministration cannot be avoided, increase the HERNEXEOS dose as recommended (see 4.2 Recommended Dose and Dosage Adjustment).

Based on in vitro data, zongertinib is a CYP3A4 inducer and time-dependent inhibitor. Zongertinib is a BCRP inhibitor. HERNEXEOS increases exposure of BCRP substrates (see 10.3 Pharmacokinetics), which may increase the risk of adverse reactions related to these substrates. Co-administration of HERNEXEOS with sensitive BCRP substrates is not recommended.

9.3. Drug-Behaviour Interactions

The interaction of HERNEXEOS with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 5 – Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical; PBPK = Physiologically based pharmacokinetic modeling; popPK = Population pharmacokinetic modeling

9.5. Drug-Food Interactions

HERNEXEOS may be taken with or without food (see 10.3 Pharmacokinetics).

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established. St. John’s wort (Hypericum perforatum) is an inducer of CYP3A4 that may decrease zongertinib plasma concentrations and should be avoided.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Zongertinib is a selective kinase inhibitor of human epidermal growth factor 2 (HER2). In vitro, zongertinib inhibits phosphorylation of HER2, downstream signalling of HER2 (phosphorylation of ERK)

and inhibits proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations. In vivo, zongertinib demonstrated anti-tumour activity in murine tumour xenograft models of NSCLC harboring HER2 tyrosine kinase domain activating mutations.

10.2. Pharmacodynamics

Cardiac electrophysiology

In Beamion LUNG-1, at 3 times the human exposure at the recommended HERNEXEOS dose of 120 mg, no mean increase in the QTc interval >20 ms was observed.

10.3. Pharmacokinetics

The pharmacokinetics of zongertinib were investigated in healthy volunteers and patients with advanced or metastatic solid tumours with HER2 aberrations.

Table 6 - Summary of zongertinib pharmacokinetic parameters in NSCLC patients

¹ Median (Min - Max)

In patients, zongertinib maximum concentration is 3000 nmol/L and the total systemic exposure is 34000 nmol*h/L following zongertinib 120 mg orally daily. Values are presented as geometric mean (CV%).

Plasma exposure after multiple oral administration of zongertinib increases approximately dose proportionally for doses between 15 mg – 150 mg twice daily and 60 mg – 360 mg once daily. Steady state was achieved within 2.5 days, and trough concentrations were maintained for at least 12 months.

With repeated once daily administration, zongertinib showed an accumulation ratio of 1.5 for AUC and 1.3 for C_max.

Absorption

Following oral administration of zongertinib under fasted conditions, the median time to peak plasma concentration (T_max) was approximately 2 hours (range: 1.5 to 6.0 hours). The geometric mean absolute bioavailability of zongertinib was 76%.

When administered with food, the absorption of zongertinib was delayed compared to fasted administration (T_max fasted 2 hours and T_max fed 4 hours). Zongertinib exposure (C_max and AUC) increased by approximately 26% in the presence of a high fat high calorie meal. This effect is not clinically relevant.

Distribution

The in vitro protein binding of zongertinib is > 99%. Zongertinib follows multiphasic disposition kinetics in human and has an apparent (oral) volume of distribution of 118 L.

Metabolism

Based on in vitro metabolite profiling, CYP-mediated oxidation pathways represent 48 to 62% (mainly CYP3A4 and CYP3A5), glucuronidation 13 to 25% (mainly UGT1A4), and glutathione conjugation 13 to 26% of total hepatic metabolism. Unchanged zongertinib represented the majority (75%) of total radioactivity in plasma (AUC_0-168h).

Elimination

Zongertinib is a low clearance drug with apparent (oral) clearance of 115 mL/min. The renal clearance of zongertinib is <0.25 mL/min. The effective half-life calculated based on population pharmacokinetics is 12 hours.

After oral administration of a single 60 mg dose of radiolabelled zongertinib approximately 94% of the radioactive dose was recovered after dosing, with 93% recovered in feces (31% unchanged) and 1.3% recovered in urine (0.2% of the dose unchanged).

Special populations and conditions

No clinically relevant differences in the pharmacokinetics of zongertinib were observed based on age (30 – 88 years), sex, body weight (33.6 – 122 kg), race (White, Asian, Black/African American), mild renal impairment (eGFR ≥ 60 and < 90 mL/min/1.73m²), or mild hepatic impairment (NCI-ODWG criteria: AST >ULN and total bilirubin ≤ULN; or total bilirubin >1 to ≤1.5 × ULN and any AST).

The pharmacokinetics of zongertinib have not been specifically studied in patients with moderate renal impairment (eGFR ≥ 30 and < 60 mL/min/1.73m²), severe renal impairment (eGFR ≥ 15 and < 30 mL/min/1.73m²), end-stage renal disease (eGFR < 15 mL/min/1.73m²), moderate hepatic impairment (total bilirubin > 1.5 to 3×ULN and any AST) or severe hepatic impairment (total bilirubin > 3×ULN and any AST).

1. 11. Storage, Stability, and Disposal

Store at 15 – 25^oC. Store in original container to protect from moisture. Keep the bottle tightly closed. Once opened, use within 3 months.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): Zongertinib

Chemical name: 2-Propenamide, N-[1-[8-[[3-methyl-4-[(1-methyl-1H-benzimidazol-5-yl)oxy]phenyl] amino]pyrimido[5,4-d]pyrimidin-2-yl]-4-piperidinyl]-

Molecular formula and molecular mass: C₂₉H₂₉N₉O_2, 535.6 g/mol

Structural formula:

Physicochemical properties:

Melting Point: 232.4^oC (onset 228.8^oC)

Dissociation Constants: pKa₁ = 3.6, pKa₂ = 5.4

Partition Coefficient: Log P = 4.7

pH Solubility Profile: Zongertinib is slightly soluble at pH 1.2, and practically insoluble at pHs 3.6, 4.5, 5.4 and 6.8.

Pharmaceutical standard: Company Standard

Product Characteristics:

Yellow to dark yellow or orange solid, slightly hygroscopic.

14. Clinical Trials

14.1. Clinical Trials by Indication

HER2-mutant Unresectable or Metastatic NSCLC After at Least One Line of Prior Systemic Therapy

Table 7 – Summary of Patient Demographics in Clinical Trial for Patients with HER2-mutant Unresectable or Metastatic NSCLC After at Least One Line of Prior Systemic Therapy (Beamion LUNG-1)

HERNEXEOS was evaluated in Beamion LUNG-1, a single arm, open-label, multi-centre, multi-cohort trial at doses ranging from 30 mg to 360 mg daily (0.25 times to 3 times the recommended dose). The results for the approved recommended dose of 120 mg once daily are described below.

Cohort 1:

The efficacy of HERNEXEOS was evaluated in patients (N= 71) with unresectable or metastatic non-squamous NSCLC who had HER2 (ERBB2) mutations in the tyrosine kinase domain (TKD), received at least one line of systemic therapy that included a platinum-based chemotherapy and excluded HER2 directed targeted therapy. Patients with active brain metastases and ECOG performance status >1 were excluded.

Patients were prospectively selected for treatment with HERNEXEOS based on the presence of HER2 (ERBB2) mutations by local testing. Samples from Beamion LUNG-1 were retrospectively tested using Oncomine™ Dx Target Test (Life Technologies Corporation, Tissue-test).

The major efficacy outcome measure was objective response (OR) by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 as assessed by blinded independent central review (BICR). Additional secondary outcome measure was duration of response (DOR) based on RECIST 1.1 as assessed by BICR.

Patients were treated with HERNEXEOS until disease progression or unacceptable toxicity. The study population characteristics were: female (70%), Asian (55%), White (35%), Black or African American (0%), Hispanic or Latino (1.4%), and unknown race (10%). The baseline ECOG performance status was 0

(39%) or 1 (61%). 65% were never smokers; 100% had a mutation in the ERBB2 kinase domain. The median age was 62 years (range: 30-80). All patients had metastases at screening; 37% had stable brain metastases.

The median number of prior regimens was 1 (range: 1-10); 100% of patients received platinum-based chemotherapy, 78% immunotherapy (i.e., PD-1/PD-L1/CTLA-4 blocking antibodies). No patient had received previous treatment with HER2 targeted TKI or antibody-drug conjugate (ADC).

Efficacy results are summarized in Table 8.

Table 8 – Efficacy results for Beamion LUNG-1^a

^a data cut-off: 21 October 2024

^b based on Kaplan-Meier estimate

^c NE: Non estimable

^d Based on observed duration of response

Disease control was achieved in 95.8% of patients (n=68) treated with HERNEXEOS (95% CI: 88.3, 98.6). Overall, 21.1% of patients (n=15) experienced stable disease, while 74.6% (n=53) achieved an OR.

Among the 71 patients, 26 had stable brain metastases at baseline (measurable and non-measurable). Of these, 25 patients were Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) evaluable. CNS objective response was observed in 11 of these 25 patients (44.0%, 95% CI 26.7, 62.9), including 4 patients with a CNS complete response (16.0%) and 7 patients with a CNS partial response (28.0%); 63.6% of responders had an observed DOR ≥ 6 months.

Cohort 5:

HERNEXEOS was also evaluated in 34 patients with HER2 (ERBB2) kinase domain mutation-positive non-squamous NSCLC previously treated with platinum-based chemotherapy and HER2 directed antibody-drug conjugates.

Eligibility criteria were otherwise similar to the efficacy population described above. The median age was 58 years (range: 31 - 85); 65% female, 3% Asian, 50% White, 0% Black of African American, 15% unknown race, 2.9% Hispanic or Latino. Baseline ECOG performance status was 0 (21%) or 1 (79%); 65% never smoked. 100% had a mutation in the ERBB2 kinase domain. All patients had metastatic disease and 74% had brain metastases. The median number of prior therapies was 3 (range: 1-8); 100% received platinum-based chemotherapy, 77 % immunotherapy (anti-PD-1/PD-L1 antibody) and 2.9% of patients had received previous treatment with HER2-targeted TKI. At data cutoff of 21 October 2024, the confirmed ORR according to RECIST 1.1 based on BICR was 41.2%; 95% CI 26.4, 57.8). Of these patients, 38.2% had a partial response and 2.9% had a complete response. Median DOR was 5.3 months (95% CI 2.8, NE).

16. Non-Clinical Toxicology

General toxicology

In a 4-week dog study, redness and lesions of palate, tongue, buccal mucosa, and lips occurred at ≥10 mg/kg/day (≥ 0.3 times the human exposure based on AUC at the recommended dose). Histopathology demonstrated oral erosions and ulcers. At ≥20 mg/kg/day, reduced food intake and body-weight loss occurred. None of these findings were present following a 4-week recovery period. In a 13-week dog study, reversible redness of buccal mucosa, gums, and lower lip occurred at 6 mg/kg/day (corresponding to approximately 0.8-fold human exposure based on AUC at the recommended dose).

Genotoxicity: Zongertinib was not mutagenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay or in the combined in vivo Comet (liver and duodenum) assay and was not clastogenic in the in vivo peripheral blood Micronucleus test.

Carcinogenicity: Carcinogenicity studies have not been conducted with zongertinib.

Reproductive and developmental toxicology: In embryo-fetal developmental studies in rats and rabbits, zongertinib was administered for intervals coinciding with the first trimester period of organogenesis in humans. In the rat, zongertinib caused embryo-fetal lethality in a non-pivotal dose-range finding study approximately 29 times the human exposure based on AUC at the recommended dose. In the pivotal study, a non-adverse developmental delay was observed as reduced fetal weight in combination with reduced ossification and retardation of the urinary system at doses up to 19 times the human exposure based on AUC at the recommended dose. In the rabbit, zongertinib caused dose dependent maternal toxicity at all tested dose levels but no embryo-fetal toxicity was observed (at 2.4 times the human exposure based on AUC at the recommended dose).

Dedicated animal fertility studies have not been conducted with zongertinib. In a repeat-dose toxicity study partially reversible effects on female reproductive organs (uterus atrophy, hyperplasia/hyperkeratosis of cervix and vagina) were observed in rats (approximately 17 times the human exposure based on AUC at the recommended dose). In male rats reversible effects (atrophy of the prostate gland) and non-reversible effects (vacuolation in the testis) were observed at doses ≥ 8.4 times and ≥ 5.7 times, respectively, based on the human exposure at the recommended dose following a 4-week recovery period.