Source: FDA, National Drug Code (US) Revision Year: 2025
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.
At 2.6 times the mean maximal concentration provided by the recommended dose of 120 mg, a mean increase in the QTc interval >20 ms was not observed.
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 (Cmax,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 Cmax 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 Cmax at the approved recommended dosage. Steady state is achieved within 2.5 days.
Zongertinib median (min, max) time to maximum plasma concentration (Tmax) is approximately 2 hours (min, max: 2, 6 hours). Zongertinib absolute oral bioavailability is 76%.
No clinically significant differences in zongertinib Cmax and AUC were observed following administration of a single 240 mg dose (2 times the approved recommended dose) with a high-fat meal (approximately 1,000 calories, approximately 50% fat).
Zongertinib plasma protein binding is >99%. The apparent (oral) volume of distribution is 118 L (29%).
Zongertinib effective half-life is 12 hours (21%) with an apparent (oral) clearance of 115 mL/min (31%).
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.
After a single oral dose of radiolabeled zongertinib 60 mg to healthy participants, approximately 93% of the dose was recovered in feces (31% unchanged) and 1.3% in urine (0.2% unchanged).
The apparent volume of distribution and clearance of zongertinib increase with increasing body weight (34 to 122 kg).
No clinically significant differences in the pharmacokinetics of zongertinib were observed based on age (30 to 88 years), sex, race (36% White, 49% Asian, 1.3% Black/African American), mild renal impairment (eGFR 60 to <90 mL/min) or mild hepatic impairment (AST > ULN and total bilirubin ≤ ULN; or total bilirubin >1 to 1.5× ULN and any AST). The effect of moderate renal impairment (eGFR 30 to <60 mL/min), severe renal impairment (eGFR 15 to <30 mL/min), end-stage renal disease (eGFR <15 mL/min), moderate hepatic impairment (total bilirubin >1.5 to 3× ULN and any AST) or severe hepatic impairment (total bilirubin >3× ULN and any AST) on the pharmacokinetics of zongertinib have not been studied.
Zongertinib AUC decreased by 63% and Cmax decreased by 43% following concomitant use of carbamazepine (strong CYP3A inducer) 600 mg once daily for 7 days. The effect of concomitant use of moderate CYP3A inducers on zongertinib Cmax and AUC are unknown.
Rosuvastatin (BCRP substrate) Cmax increased by 3-fold and AUC by 2.3-fold following concomitant use of a single dose of HERNEXEOS 120 mg daily for 12 days.
No clinically significant differences in zongertinib pharmacokinetics were observed when used concomitantly with strong CYP3A, P-gp, BCRP inhibitors and rabeprazole (proton pump inhibitor). No clinically significant differences in the pharmacokinetics of the following were observed when used concomitantly with HERNEXEOS: midazolam (a CYP3A substrate), dabigatran (a P-gp substrate), metformin (a OCT2 and MATE1/2-K substrate), or repaglinide (a sensitive CYP2C8 substrate).
Carcinogenicity studies have not been conducted with zongertinib.
Zongertinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Zongertinib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA breaks in a comet assay in liver or duodenum.
Dedicated animal fertility studies have not been conducted with zongertinib. In a 13-week repeat-dose toxicity study in rats, oral administration of zongertinib induced dose-dependent vacuolation in the testis at doses ≥10 mg/kg/day (≥5.7 times the human exposure based on AUC at the recommended dose), atrophy in the prostate gland at doses ≥30 mg/kg/day (≥8.4 times the human exposure based on AUC at the recommended dose), and atrophy in the uterus and hyperplasia/hyperkeratosis of the cervix and vagina at a dose of 90 mg/kg/day (approximately 17 times the human exposure based on AUC at the recommended dose). Findings in reproductive organs in female rats and prostate gland atrophy in male rats were reversible following a 4-week recovery period. Vacuolation in the testis of male rats was not reversible within a 4-week recovery period.
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.
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).
The efficacy population included 71 patients with unresectable or metastatic, non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain (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 5.
Table 5. Efficacy Results for Beamion LUNG-1:
| Efficacy Parameter | HERNEXEOS N=71 |
|---|---|
| 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 months2, % | 58 |
Abbreviation: CI = Confidence Interval, +: Ongoing response.
1 Based on Wilson confidence interval.
2 Based on observed duration of response.
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% 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.
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