HERNEXEOS

1 INDICATIONS AND USAGE 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 [see Dosage and Administration (2.1) ] . This indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. HERNEXEOS is a kinase inhibitor 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. ( 1 ) 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Select patients for treatment with HERNEXEOS based on the presence of HER2 (ERBB2) tyrosine kinase domain activating mutations. ( 2.1 ) The recommended dosage of HERNEXEOS is based on body weight: ( 2.2 ) Patients weighing less than 90 kg: 120 mg ( 2.2 ) Patients weighing 90 kg or greater: 180 mg ( 2.2 ) Take HERNEXEOS orally once daily with or without food until disease progression or unacceptable toxicity. ( 2.2 ) 2.1 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 specimens [see Clinical Studies (14) ] . Information on FDA-authorized tests for HER2 (ERBB2) tyrosine kinase domain activating mutations is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 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. If a dose is missed by more than 12 hours, skip the missed dose and take the next scheduled dose. Vomited Dose If a dose is vomited, do not take an additional dose. Take the next dose at the regularly scheduled time. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are presented in Table 1. 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. The recommended dosage modifications for adverse reactions are presented in Table 2. 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. Grade 4 Permanently discontinue HERNEXEOS. 2.4 Dosage Modifications for Drug Interactions 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 Drug Interactions (7.1) ] : 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.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to administration, 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 severity. ( 5.1 ) Left Ventricular Dysfunction : Monitor LVEF at baseline prior to administration and at regular intervals during treatment and as clinically indicated. Interrupt, reduce the dose, or permanently discontinue HERNEXEOS based on severity. ( 5.2 ) Interstitial Lung Disease/Pneumonitis : Monitor 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. ( 5.3 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.4 ) 5.1 Hepatotoxicity HERNEXEOS can cause severe and life-threatening hepatotoxicity, including drug induced liver injury. In the pooled safety population [see Adverse Reactions (6.1) ], based on adverse reaction data, hepatotoxicity occurred in 27% of patients treated with HERNEXEOS. Grade 3 drug induced liver injury occurred in 1.4% and Grade 4 in 0.3% of patients treated with HERNEXEOS. Grade 3 hepatic failure occurred in 0.3% of patients treated with HERNEXEOS. Based on laboratory data, 37% of patients treated with HERNEXEOS experienced increased alanine aminotransferase (ALT), including 4.9% Grade 3 and 1% Grade 4. Increased aspartate aminotransferase (AST) occurred in 31% of patients treated with HERNEXEOS, including 3.8% Grade 3 and 0.7% Grade 4. Increased bilirubin occurred in 20% of patients treated with HERNEXEOS, including 1% Grade 3 and 0.3% Grade 4. 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 [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 1.7% 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. 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 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 [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) ].

7 DRUG INTERACTIONS Strong CYP3A Inducers : Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose. ( 7.1 ) BCRP Substrates : Avoid concomitant use with certain BCRP substrates where minimal concentration increase may lead to serious adverse reactions and consider alternative therapies. If concomitant use cannot be avoided, monitor patients closely for adverse reactions and follow recommendations provided in the BCRP substrate approved product labeling. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate. ( 7.2 ) 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.

6 ADVERSE REACTIONS 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) ] Most common adverse reactions (≥ 20%) are diarrhea, rash, hepatotoxicity, fatigue, nausea, musculoskeletal pain, and upper respiratory tract infection. ( 6.1 ) The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma glutamyl transferase, decreased potassium, and decreased neutrophils. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 [see Clinical Studies (14) ] . Among 292 patients who received HERNEXEOS, 59% of patients were exposed for 6 months or longer and 28% were exposed for greater than one year. In this pooled safety population, the most common (> 20%) adverse reactions were diarrhea (54%), rash (28%), hepatotoxicity (27%), fatigue (25%), nausea (23%), musculoskeletal pain (21%), and upper respiratory tract infection (20%). The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (10%), increased alanine aminotransferase (6%), increased aspartate aminotransferase (4.5%), increased gamma glutamyl transferase (2.8%), decreased potassium (2.4%), and decreased neutrophils (2.4%). 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) [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, 74% were exposed for 6 months or longer and 42% were exposed for greater than one year. The median age of patients who received HERNEXEOS was 63 years (range 30 to 88), 61% were female, 41% White, 48% Asian, and 0.6% Black or African American; 11% had unknown race data; 3.4% were of Hispanic or Latino ethnicity; and 38% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 and 62% had an ECOG performance score of 1. Serious adverse reactions occurred in 36% of patients receiving HERNEXEOS. Serious adverse reactions in ≥ 2% of patients included pulmonary embolism (4%), dyspnea (3.4%), pneumonia (2.8%), hepatotoxicity, pleural effusion, and pericardial effusion (2.3%). 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 Adverse Reaction HERNEXEOS N = 177 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 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 Laboratory Parameter HERNEXEOS N = 177 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 phosphate increased 20 1.7

8.1 Pregnancy 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.