Get your patient on Hernexeos - Zongertinib tablet, Film Coated (Zongertinib)

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.

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.

The recommended dose reductions for adverse reactions are presented in Table 1.

The recommended dosage modifications for adverse reactions are presented in Table 2.

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) ] .

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

Of the 292 patients with non-squamous NSCLC with HER2 (ERBB2) mutations who received HERNEXEOS in clinical studies, 47% were 65 years of age and older and 13% were 75 years and older. No overall differences in safety or effectiveness of HERNEXEOS were observed between older and younger adult patients.

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) ].

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) ].

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) ].

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) ].

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%).

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.

Zongertinib is a kinase inhibitor of human epidermal growth factor receptor 2 (HER2). In vitro, zongertinib inhibited phosphorylation of HER2, downstream signaling of HER2 (phosphorylation of ERK), and proliferation of lung cancer cells harboring HER2 tyrosine kinase domain activating mutations. In vivo, zongertinib demonstrated anti-tumor activity in mouse xenograft models of NSCLC harboring HER2 tyrosine kinase domain activating mutations.

The exposure-response relationship and time-course of pharmacodynamic response of zongertinib have not been fully characterized.

Zongertinib pharmacokinetics were observed at steady state in patients with advanced or metastatic solid tumors with HER2 aberrations at the approved recommended dosage and are presented as geometric mean (CV%), unless otherwise specified.

Zongertinib maximum concentration (C _max,ss ) is 3.0 (37%) µmol/L and the total systemic exposure (AUC) is 34 (34%) µmol•h/L following HERNEXEOS 120 mg orally daily. Zongertinib C _max and AUC increase in an approximately dose proportional manner across the dose range of 60 mg (0.5 times the approved recommended dosage) to 360 mg (3 times the approved recommended dosage). Zongertinib accumulation is approximately 1.5-fold for AUC and 1.3-fold for C _max at the approved recommended dosage. Steady state is achieved within 2.5 days.

In a 4-week repeat-dose toxicology study in dogs, oral administration of zongertinib induced lesions of the oral mucosa (hard palate, buccal mucosa, tongue, lips) at doses ≥ 10 mg/kg/day (≥ 0.3 times the human exposure based on AUC at the recommended dose), which correlated with histologic erosion/ulcer and impaired food consumption. These findings were not present following a 4-week recovery period.

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). While 86% (37/43) of samples were positive for HER2 (ERBB2) TKD mutations; 14% (6/43) were unevaluable.

The baseline demographic and disease characteristics of the efficacy population were: 67 years (range: 35 to 88); 50% female, 47% Asian, 42% White, 1.4% Black or African American; 10% had unknown race data; 6% were of Hispanic or Latino ethnicity; 44% Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 and 56% ECOG PS 1; 65% never smoked; 100% had metastatic disease; and 31% had brain metastases.

Efficacy results are summarized in Table 5.

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). While 84% (31/37) of samples were positive for HER2 (ERBB2) TKD mutations, 2.7% (1/37) did not have HER2 (ERBB2) TKD mutations identified, and 13.5% (5/37) were unevaluable.

The baseline demographic and disease characteristics of the efficacy population were: 62 years (range: 30 to 80); 70% female, 55% Asian, 35% White, 0% Black or African American; 10% had unknown race data; 1.4% were of Hispanic or Latino ethnicity; 39% Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 and 61% ECOG PS 1; 65% never smoked; 100% metastatic disease; and 37% with brain metastases. The median number of prior therapies was 1 (range: 1 to 10); 100% of patients had prior platinum therapy and 78% had prior treatment with anti-PD-1/PD-L1 antibody. 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.

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. The median age was 58 years (range: 31 to 85); 65% female, 35% Asian, 50% White, 0% Black or African American; 15% had unknown race data; and 2.9% were of Hispanic or Latino ethnicity. Baseline ECOG performance status was 0 (21%) or 1 (79%); 65% never smoked; 100% of patients had metastatic disease and 74% had brain metastases. The median number of prior therapies was 3 (range: 1 to 8); 100% of patients had prior platinum therapy and 77% had prior treatment with anti-PD-1/PD-L1 antibody; 2.9% of patients had received previous treatment with a HER2-targeted TKI. Confirmed ORR by RECIST v1.1 based on BICR was 44% (95% CI 29, 61), with 2.9% of patients having a complete response. Median DOR was 5.4 months (95% CI 2.8, not estimable), and 27% of responders had an observed DOR ≥ 6 months.

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store in the original container to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccants. Once opened, use within 3 months. Discard any unused tablets 3 months after opening the bottle.