Zongertinib (Hernexeos): A Comprehensive Monograph on a Novel HER2-Selective Tyrosine Kinase Inhibitor for Non-Small Cell Lung Cancer

I. Executive Summary & Regulatory Context

Overview of Zongertinib

Zongertinib, marketed under the brand name Hernexeos, is a first-in-class, orally administered, irreversible tyrosine kinase inhibitor (TKI) developed by Boehringer Ingelheim.[1] It represents a pivotal advancement in the field of precision oncology, specifically targeting a molecularly defined subset of non-small cell lung cancer (NSCLC).[3] As a highly selective antineoplastic agent, Zongertinib is designed to interfere with the growth of cancer cells by potently blocking the human epidermal growth factor receptor 2 (HER2), also known as ERBB2.[4]

Primary Indication

Zongertinib is indicated for the treatment of adult patients with unresectable (cannot be removed by surgery) or metastatic (has spread to other parts of the body) non-squamous NSCLC.[4] A critical requirement for its use is the presence of activating mutations within the tyrosine kinase domain (TKD) of the HER2 gene in the patient's tumor, which must be detected by a U.S. Food and Drug Administration (FDA)-approved test.[1] The current approval is for patients who have received prior systemic therapy, positioning Zongertinib as a crucial second-line or later treatment option.[7] This indication addresses a significant unmet medical need for a patient population that has historically faced a poor prognosis and had limited effective therapeutic options.[8]

Synopsis of Efficacy and Safety

The regulatory approval of Zongertinib is supported by compelling efficacy and safety data from the pivotal Phase Ib portion of the Beamion LUNG-1 clinical trial.[11] In the primary efficacy cohort of previously treated, antibody-drug conjugate (ADC)-naïve patients, Zongertinib demonstrated a remarkably high objective response rate (ORR) of 71%, with a median duration of response (DoR) of 14.1 months.[12] This level of activity signifies a substantial improvement over historical outcomes in this setting.

The safety profile of Zongertinib is a key differentiator and is considered generally manageable.[3] The most common adverse events include diarrhea, rash, and hepatotoxicity, which are predominantly low-grade and can be managed with supportive care and dose modifications.[6] Notably, the trial data reported a very low incidence of severe (Grade 3 or higher) adverse events and, critically, a lack of significant class-specific toxicities such as drug-related interstitial lung disease (ILD) or pneumonitis—a known risk with other HER2-targeted agents.[3]

Regulatory Journey and Global Status

FDA Accelerated Approval

On August 8, 2025, the U.S. FDA granted Accelerated Approval to Zongertinib for its specified indication in NSCLC.[1] The Accelerated Approval pathway is designed to allow for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint that is reasonably likely to predict clinical benefit.[6] For Zongertinib, the high ORR and durable responses observed in the Beamion LUNG-1 trial served as this surrogate endpoint.[15] As is standard for this pathway, continued approval for this indication is contingent upon the verification and description of clinical benefit in confirmatory trials.[6] The ongoing Phase III Beamion LUNG-2 trial is designed to serve this purpose.[3]

Expedited Programs

The development and review of Zongertinib were significantly expedited by the FDA through several of its specialized programs, underscoring the agency's recognition of the drug's potential to provide a substantial therapeutic advance. Zongertinib received Fast Track Designation in 2023, Breakthrough Therapy Designation in 2024, and Priority Review in February 2025.[1] These designations are reserved for therapies that demonstrate the potential for substantial improvement over available treatments for serious or life-threatening diseases and facilitate more frequent communication with the FDA and a shortened review timeline.[3]

The confluence of these multiple expedited designations is noteworthy. It reflects a high degree of confidence from the regulatory body based on the strength of the preliminary clinical evidence. Historically, HER2 mutations in NSCLC, which affect a small subset of patients (2-4%), were considered an "orphan" target with limited therapeutic avenues beyond the ADC trastuzumab deruxtecan.[8] The FDA's aggressive support for Zongertinib's development signifies a strategic validation of HER2 TKD mutations as a high-priority, clinically actionable biomarker. This regulatory momentum not only brought a new drug to patients rapidly but also serves to elevate the importance of routine HER2 testing in NSCLC, potentially accelerating the development of other next-generation HER2-targeted therapies.

Companion Diagnostic

The approval of Zongertinib was granted in tandem with the approval of the Oncomine Dx Target Test (manufactured by Life Technologies Corporation) as a companion diagnostic device.[1] This establishes a clear precision medicine paradigm, ensuring that Zongertinib is prescribed to the patient population most likely to benefit by confirming the presence of the requisite HER2 TKD activating mutations.[18]

International Status

As of late 2025, Zongertinib's regulatory approval is limited to the United States. There is no active marketing authorization application filed with the European Medicines Agency (EMA) or the UK's Medicines and Healthcare products Regulatory Agency (MHRA), suggesting that its availability in Europe and the United Kingdom is not expected in the immediate future.[19] However, the drug has received Orphan Drug Designation from Japan's Pharmaceuticals and Medical Devices Agency, indicating a pathway for development in that region.[3]

II. Pharmacological Profile: A Highly Selective Mechanism of Action

The HER2 (ERBB2) Pathway in NSCLC

The human epidermal growth factor receptor (HER) family, also known as the ErbB family, comprises four receptor tyrosine kinases: EGFR (HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4).[20] These receptors are crucial regulators of normal cellular processes, including proliferation, survival, and differentiation.[20] Aberrant activation of these pathways is a well-established driver of oncogenesis in numerous human malignancies.[20]

In NSCLC, activating mutations in the HER2 gene are identified in approximately 2-4% of cases and function as potent oncogenic drivers.[8] These mutations, which are distinct from the HER2 gene amplification commonly seen in breast and gastric cancers, lead to constitutive (uncontrolled) activation of the kinase, promoting downstream signaling that results in unchecked cell growth and survival.[9] The most prevalent HER2 mutations in NSCLC are in-frame insertions in exon 20 of the tyrosine kinase domain.[5] Patients with HER2-mutant NSCLC have a historically poor prognosis and a higher incidence of developing brain metastases, highlighting the critical need for effective targeted therapies.[9]

Molecular Mechanism of Zongertinib

Zongertinib is classified as a selective, irreversible tyrosine kinase inhibitor of HER2.[3] Its mechanism of action is highly specific and potent. The drug molecule contains an acrylamide moiety, which is designed to form a covalent bond with the cysteine 805 (Cys805) residue located within the ATP-binding pocket of the HER2 receptor protein.[5] This covalent, irreversible binding permanently inactivates the kinase function of the receptor.

By locking the HER2 receptor in an inactive state, Zongertinib effectively blocks its autophosphorylation and prevents the subsequent activation of critical downstream oncogenic signaling cascades, most notably the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways.[5] The inhibition of these pathways directly leads to the suppression of proliferation and induction of apoptosis (programmed cell death) in lung cancer cells that are dependent on HER2 TKD activating mutations for their growth and survival.[5]

The Critical Advantage of EGFR Sparing

A defining and clinically crucial characteristic of Zongertinib is its remarkable selectivity for the HER2 receptor while actively sparing the wild-type epidermal growth factor receptor (EGFR).[5] This feature represents a significant evolution in drug design compared to earlier, less selective pan-ErbB inhibitors. Preclinical assays have quantified this selectivity, demonstrating a profound difference in binding affinity. The half maximal inhibitory concentration (

IC50​) of Zongertinib for wild-type EGFR is 1,540 nM, whereas for the common HER2YVMA mutation, it is only 16 nM—a nearly 100-fold greater selectivity for the intended target.[5]

This high degree of selectivity is not merely an incremental improvement in safety; it is the fundamental enabling factor for Zongertinib's therapeutic efficacy in HER2-mutant NSCLC. Previous generations of pan-ErbB TKIs, such as lapatinib and neratinib, failed to show significant clinical benefit in this disease setting precisely because of their lack of selectivity.[8] These older agents inhibit both HER2 and wild-type EGFR. To achieve a drug concentration high enough to effectively inhibit the HER2 mutation in tumor cells, patients would experience severe and dose-limiting toxicities from the simultaneous inhibition of EGFR in healthy tissues, particularly the skin and gastrointestinal tract (leading to severe rash and diarrhea).[17] This created a non-existent or impractically narrow therapeutic window.

Zongertinib's rational design circumvents this critical limitation. By sparing wild-type EGFR, it dramatically widens the therapeutic window, allowing for systemic administration at doses that are sufficient to potently and durably inhibit the HER2 oncogenic driver in the tumor, without causing the prohibitive off-target toxicities associated with EGFR blockade. This EGFR-sparing mechanism is the key that unlocks the drug's clinical potential, making the high response rates observed in the Beamion LUNG-1 trial achievable.

Activity Against Diverse HER2 Mutations and Resistance Mechanisms

Zongertinib has demonstrated broad activity against the spectrum of known HER2 TKD activating mutations, including the most common exon 20 insertion variants such as A775-G776YVMA and P780-Y781insGSP.[5] Furthermore, an important aspect of its clinical profile is its activity in the context of acquired resistance to other therapies. Preclinical models have shown that Zongertinib can inhibit the growth of HER2-dependent cancer cells that have become resistant to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd).[8] This finding, which has been corroborated by clinical data showing responses in patients who have previously progressed on ADCs, indicates a distinct mechanism of action and a lack of complete cross-resistance, positioning Zongertinib as a valuable therapeutic option in the post-ADC setting.

III. Clinical Pharmacokinetics and Metabolism

The pharmacokinetic (PK) profile of Zongertinib describes its absorption, distribution, metabolism, and excretion (ADME) within the body. Understanding these properties is essential for defining its optimal dosing regimen, anticipating potential drug-drug interactions, and explaining its clinical behavior.

The key pharmacokinetic parameters of Zongertinib are summarized in the table below.

Table 1: Summary of Key Pharmacokinetic Parameters for Zongertinib

Pharmacokinetic Parameter	Value/Description	Source(s)
Absolute Oral Bioavailability	76.2%	5
Time to Max. Concentration (Tmax​)	Median of ~2 hours	5
Effect of Food	No significant effect on Cmax​ or AUC	4
Steady-State Cmax,ss​ (120 mg dose)	3.0 µmol/L	5
Steady-State AUC (120 mg dose)	34 µmol·h/L	5
Time to Steady State	Within 2.5 days	5
Volume of Distribution (Vd​)	118 L	5
Plasma Protein Binding	>99%	23
Effective Half-Life (steady state)	~12 hours	5
Primary Metabolism Pathways	Hepatic: CYP3A4/5 oxidation, UGT1A4 glucuronidation, glutathione conjugation	5
Primary Excretion Route	Feces (~93%); 31% as unchanged drug	5

Absorption and Bioavailability

Zongertinib is well-absorbed following oral administration, with a high absolute oral bioavailability of 76.2%.[5] Peak plasma concentrations are achieved rapidly, with a median

Tmax​ of approximately 2 hours.[5] A key feature for patient convenience is that Zongertinib can be taken with or without food. A clinical study showed that administration with a high-fat meal did not result in a clinically significant change in its maximum concentration (

Cmax​) or total exposure (AUC), providing flexibility in its daily administration schedule.[4]

The drug's exposure increases in a dose-proportional manner across the clinically evaluated range of 60 mg to 360 mg, indicating predictable pharmacokinetics.[5] Upon initiation of once-daily dosing, steady-state plasma concentrations are reached quickly, within 2.5 days. There is only modest accumulation of the drug, with steady-state AUC being approximately 1.5-fold higher than after a single dose.[5]

Distribution

Zongertinib exhibits extensive distribution into body tissues, as evidenced by its large apparent oral volume of distribution (Vd​) of 118 L.[5] This value, which is significantly larger than the volume of total body water, indicates that the drug does not remain confined to the bloodstream but partitions extensively into peripheral tissues. This pharmacokinetic property is a likely contributor to the drug's robust activity against central nervous system (CNS) metastases. While

Vd​ does not directly prove blood-brain barrier (BBB) penetration, it is a characteristic shared by many small molecule TKIs that are sufficiently lipophilic to cross the BBB and achieve therapeutic concentrations within the CNS. This PK/PD relationship provides a mechanistic basis for the significant intracranial response rates observed in clinical trials, making Zongertinib a particularly valuable agent for a patient population with a high incidence of brain metastases.[10] In plasma, Zongertinib is highly bound to proteins (>99%).[23]

Metabolism and Elimination

Zongertinib is primarily cleared from the body via hepatic metabolism through three main pathways: CYP-mediated oxidation (accounting for 48-62% of metabolism), glucuronidation (13-25%), and glutathione conjugation (13-26%).[5] The principal enzymes responsible for its metabolism are Cytochrome P450 3A4 and 3A5 (CYP3A4/5) for the oxidative pathway and UDP-glucuronosyltransferase 1A4 (UGT1A4) for glucuronidation.[5] This heavy reliance on the CYP3A4/5 pathway is the basis for the clinically significant drug-drug interaction warnings associated with strong inducers of these enzymes.

While 14 metabolites have been identified, the two most abundant in circulation, M551(1) (a mono-oxidation product) and M656(1) (a cysteine conjugate), account for only a small percentage of the total drug-related material in plasma, suggesting that the parent Zongertinib molecule is the primary active pharmacological entity.[5]

Excretion of Zongertinib and its metabolites occurs predominantly through the feces. Following a single oral radiolabeled dose, approximately 93% of the dose was recovered in the feces, with a negligible amount (1.3%) found in the urine. A substantial portion of the fecal content (31% of the total dose) was unchanged parent drug, indicating that both metabolism and direct biliary excretion contribute to its clearance.[5] The effective half-life of Zongertinib at steady state is approximately 12 hours, which supports the convenience of a once-daily dosing schedule.[5]

IV. Clinical Efficacy in HER2-Mutant NSCLC: Deep Dive into the Beamion Clinical Program

The clinical development of Zongertinib is centered around the comprehensive Beamion program, with the Beamion LUNG-1 trial providing the pivotal data for its accelerated approval.

Overview of the Beamion LUNG-1 Trial (NCT04886804)

Beamion LUNG-1 is a multicenter, open-label, first-in-human clinical trial designed with two distinct parts. Phase Ia was a dose-escalation study conducted in patients with various advanced solid tumors harboring HER2 aberrations, with the primary goal of determining the maximum tolerated dose (MTD) and recommended dose for expansion.[21] This phase established that the MTD was not reached and identified 120 mg and 240 mg once daily as safe and active doses for further investigation.[16]

Phase Ib is a dose-expansion part of the study, focusing on specific cohorts of patients with HER2-mutant NSCLC to evaluate efficacy and further characterize safety.[28] An interim analysis of the initial randomized portion of Cohort 1 led to the selection of the 120 mg once-daily dose as the optimal dose for continued evaluation in this and subsequent cohorts.[16] The trial enrolled patients with histologically confirmed NSCLC, prior exposure to platinum-based chemotherapy, and an ECOG performance status of 0 or 1.[30]

The table below summarizes the key efficacy outcomes from the three main pre-treated patient cohorts evaluated in the Beamion LUNG-1 trial at the 120 mg dose level.

Table 2: Summary of Efficacy Outcomes from the Beamion LUNG-1 Trial Across Key Cohorts (120 mg Dose)

Efficacy Endpoint	Cohort 1 (Pre-treated, ADC-Naïve, TKD mutation; n=75)	Cohort 5 (Pre-treated, Post-ADC, TKD mutation; n=31)	Cohort 3 (Pre-treated, Non-TKD mutation; n=20)
Objective Response Rate (ORR)	71% (95% CI: 60-80)	48% (95% CI: 32-65)	30% (95% CI: 15-52)
Disease Control Rate (DCR)	96% (95% CI: 89-99)	97% (95% CI: 84-99)	65% (95% CI: 43-82)
Median Duration of Response (DoR)	14.1 months (95% CI: 6.9-NE)	5.3 months (95% CI: 2.8-NE)	Not Mature
Median Progression-Free Survival (PFS)	12.4 months (95% CI: 8.2-NE)	6.8 months (95% CI: 5.4-NE)	Not Mature
NE = Not Evaluable. Data compiled from sources.12

Efficacy in Pre-treated, ADC-Naïve Patients (Cohort 1)

Cohort 1, comprising 75 patients with HER2 TKD mutations who had received prior platinum-based chemotherapy but no prior HER2-targeted ADC or TKI, represents the primary efficacy population that formed the basis for the FDA's accelerated approval.[1] The results in this cohort were exceptionally strong.

• Objective Response Rate (ORR): Treatment with Zongertinib led to an ORR of 71% as assessed by blinded independent central review (BICR) (95% CI: 60-80). This included a 7% rate of complete responses (CR) and a 64% rate of partial responses (PR).[12] This result was highly statistically significant (p<0.0001) when tested against a pre-specified historical response rate benchmark of 30% or less, demonstrating a profound level of anti-tumor activity.[13]
• Disease Control Rate (DCR): The DCR was 96% (95% CI: 89-99), indicating that nearly all patients in this cohort derived some clinical benefit, ranging from tumor shrinkage to disease stabilization.[12]
• Duration of Response (DoR) and Progression-Free Survival (PFS): The responses observed were not only frequent but also highly durable. The median DoR was 14.1 months, and the median PFS was 12.4 months, signifying a prolonged period of disease control for responding patients.[12]

Activity in Patients with Prior HER2-Directed ADC Therapy (Cohort 5)

Cohort 5 was designed to assess the activity of Zongertinib in a more heavily pre-treated population of 31 patients whose disease had progressed on or after treatment with a HER2-directed ADC, such as trastuzumab deruxtecan.[13] Even in this setting of acquired resistance to a prior HER2-targeted agent, Zongertinib demonstrated substantial clinical activity.

• The ORR in this post-ADC cohort was 48% (95% CI: 32-65), with a near-universal DCR of 97%.[17]
• The median DoR was 5.3 months, and the median PFS was 6.8 months.[31]

This 48% response rate in patients who have already failed a potent HER2-directed therapy is a clinically transformative finding. It provides strong evidence for a lack of complete cross-resistance between Zongertinib and ADCs. The mechanisms of action are fundamentally different: ADCs rely on antibody-mediated delivery of a cytotoxic payload, whereas Zongertinib directly inhibits intracellular kinase signaling. Resistance to an ADC could arise from factors unrelated to the HER2 kinase domain itself, such as altered drug-payload metabolism or changes in cellular trafficking, which would not impact the ability of a TKI to bind its target. This data establishes a clear, evidence-based treatment sequence for HER2-mutant NSCLC. It provides clinicians with a highly viable targeted therapy option following progression on an ADC, creating a much-needed "second shot on goal" that can significantly extend the duration of disease control for this patient population.

Performance in Non-TKD Mutations (Exploratory Cohort 3)

In a smaller exploratory cohort of 20 patients with less common HER2 mutations located outside of the canonical tyrosine kinase domain, Zongertinib still showed activity. The investigator-assessed ORR was 30% (95% CI: 15-52), with a DCR of 65%.[12] While lower than in the TKD-mutant population, this response rate suggests that Zongertinib's activity may extend to a broader range of HER2 alterations.

Intracranial Efficacy (CNS Metastases)

Consistent with its favorable pharmacokinetic properties, Zongertinib demonstrated robust and clinically meaningful activity in patients with baseline brain metastases. Across various analyses of evaluable patients, the intracranial ORR was reported to be between 33% and 41%, with CNS disease control rates ranging from 74% to 88%.[11] This confirms that Zongertinib effectively crosses the blood-brain barrier and can induce responses in the CNS, a common and challenging site of disease progression in HER2-mutant NSCLC.

V. Comprehensive Safety and Tolerability Assessment

Overview of the Safety Profile

The safety profile of Zongertinib is a cornerstone of its clinical value. It is generally well-tolerated, with the majority of treatment-related adverse events (TRAEs) being low-grade (Grade 1 or 2) and manageable through standard supportive care or dose adjustments.[3] This favorable tolerability is a direct consequence of its highly selective, EGFR-sparing mechanism of action, which minimizes the off-target toxicities that have limited the utility of previous pan-ErbB inhibitors.[14] The tolerability is further evidenced by the very low rates of treatment discontinuation due to adverse events, reported to be only 3% in pivotal trial cohorts.[26]

The most common adverse reactions and notable laboratory abnormalities are detailed in the table below.

Table 3: Common Adverse Reactions and Laboratory Abnormalities (≥10% Incidence) with Zongertinib

Adverse Reaction / Lab Abnormality	All Grades (%)	Grade 3-4 (%)	Source(s)
Clinical Adverse Reactions
Diarrhea	51-56	1	3
Rash	27-33	0	6
Alanine Aminotransferase (ALT) Increased	20-39	7-8	6
Aspartate Aminotransferase (AST) Increased	21-24	5-7	6
Fatigue	≥20	*	6
Nausea	≥20	*	6
Dry Skin	12-15	0	35
Pruritus (Itching)	12-13	0	35
Anemia	12	0	35
Decreased Appetite	10	1	29
Decreased Neutrophil Count	11	1	35
Laboratory Abnormalities
Lymphocytes Decreased	52	15	6
Leukocytes Decreased	43	*	6
Potassium Decreased	*	≥2	6
Gamma-Glutamyl Transferase Increased	*	≥2	6
Grade 3-4 data not specified for all events in provided sources.

Management of Common Adverse Events

• Diarrhea: This is the most frequently reported TRAE, affecting approximately half of the patients.[3] However, it is crucial to note that the vast majority of cases are mild (Grade 1 or 2). Grade 3 diarrhea is rare, occurring in only 1% of patients.[14] Management typically involves the use of standard anti-diarrheal medications (e.g., loperamide) and dietary modifications, such as adopting a low-fiber, bland diet.[37]
• Rash: Skin rash is the second most common side effect, occurring in about a third of patients.[6] Similar to diarrhea, the rash is almost exclusively low-grade, and no Grade 3 or higher events were reported in key trial cohorts.[16] Management strategies include using thick, alcohol-free emollients, avoiding sun exposure, using high-SPF sunscreen, and, if necessary, using topical or oral medications as prescribed by the healthcare team.[37]
• Hepatotoxicity (Transaminitis): Elevations in liver enzymes (ALT and AST) are common laboratory findings, though often asymptomatic.[6] Grade 3 or higher elevations occur in a minority of patients (around 7-9%).[16] This potential for liver toxicity necessitates a strict monitoring schedule as outlined in the prescribing information.[7]

Warnings and Precautions in Detail

The prescribing information for Zongertinib includes several important warnings and precautions that require careful clinical attention.

• Hepatotoxicity: Zongertinib can cause severe and potentially life-threatening liver injury. It is mandatory to monitor liver function tests (ALT, AST, and total bilirubin) at baseline, every two weeks during the first 12 weeks of treatment, and then monthly thereafter or as clinically indicated. More frequent monitoring is required for patients who develop transaminase elevations.[4]
• Left Ventricular Dysfunction (LVD): The medication may impair the heart's ability to pump blood effectively. Left ventricular ejection fraction (LVEF) should be evaluated before starting treatment and monitored at regular intervals during therapy, as well as any time clinical signs or symptoms of heart failure develop.[6]
• Interstitial Lung Disease (ILD)/Pneumonitis: This is a serious potential risk for many drugs used to treat NSCLC. Patients must be monitored for any new or worsening respiratory symptoms such as cough, fever, or dyspnea (trouble breathing).[4] However, the absence of any reported cases of drug-related ILD in the pivotal Beamion LUNG-1 trial data represents a profound clinical advantage for Zongertinib.[3] This stands in stark contrast to the known safety profile of trastuzumab deruxtecan, for which ILD is a black-box warning and a significant cause of morbidity.[24] For clinicians treating NSCLC patients—a population often burdened with pre-existing pulmonary comorbidities from smoking or prior therapies—this superior pulmonary safety profile is a critical differentiator. In a patient with underlying COPD, pulmonary fibrosis, or a history of radiation pneumonitis, Zongertinib may be the clear preferred agent over an ADC, making this safety distinction a decisive factor in clinical decision-making.
• Embryo-Fetal Toxicity and Fertility: Zongertinib can cause harm to a developing fetus. The pregnancy status of females of reproductive potential must be verified before initiating therapy. Effective contraception must be used during treatment and for at least two weeks following the final dose.[4] The medication may also impair fertility in both males and females, a risk that should be discussed with patients planning to have children.[4]

VI. Prescribing Information and Clinical Management

Patient Selection

The use of Zongertinib is strictly limited to patients whose tumors have been confirmed to harbor HER2 (ERBB2) tyrosine kinase domain activating mutations. This must be determined using an FDA-approved diagnostic test, such as the Oncomine Dx Target Test, performed on a tumor specimen.[1] This ensures that the therapy is targeted to the population with the specific molecular driver that the drug is designed to inhibit.

Recommended Dosing and Administration

The recommended dosage of Zongertinib is based on the patient's body weight, a strategy intended to normalize drug exposure across different patient sizes.[4]

• For patients weighing less than 90 kilograms (kg), the recommended dose is 120 mg orally once daily.
• For patients weighing 90 kilograms (kg) or more, the recommended dose is 180 mg orally once daily.

Zongertinib is supplied as 60 mg tablets.[7] The tablets should be taken once a day, at approximately the same time each day, and may be administered with or without food. Patients should be instructed to swallow the tablets whole with water and to not split, crush, or chew them.[4]

If a dose is missed, the patient should take it as soon as they remember, provided it is within 12 hours of the scheduled time. If more than 12 hours have passed, the missed dose should be skipped, and the patient should resume the regular dosing schedule with the next planned dose. Patients should not take two doses at once to make up for a missed dose.[4] If a patient vomits after taking a dose, they should not take an extra dose but wait until the next scheduled time.[4]

Guidelines for Dose Modifications

Managing adverse reactions is a key component of treatment. The prescribing information provides specific guidelines for dose interruption, reduction, or permanent discontinuation based on the type and severity of toxicity. A structured approach to dose modification is essential for safely managing side effects and allowing patients to continue benefiting from the therapy.

Table 4: Guidelines for Zongertinib Dose Modifications for Adverse Reactions

Adverse Reaction	Severity / Grade	Recommended Action
Dose Reduction Schedule	First Reduction	Second Reduction
180 mg daily starting dose	120 mg daily	60 mg daily
120 mg daily starting dose	60 mg daily	Permanently discontinue
Hepatotoxicity	Grade 3 ALT/AST or Grade 3 total bilirubin	Interrupt until recovery to ≤ Grade 1 or baseline. Resume at a reduced dose.
	Grade 4 total bilirubin OR ALT/AST ≥3x ULN with total bilirubin ≥2x ULN	Permanently discontinue.
Left Ventricular Dysfunction (LVD)	LVEF 40-50% AND decrease from baseline of 10-19%	Interrupt. If recovers within 4 weeks, resume at the same dose. If not, permanently discontinue.
	LVEF 20-39% OR ≥20% decrease from baseline	Interrupt. If recovers within 4 weeks, resume at a reduced dose. If not, permanently discontinue.
Diarrhea	Grade 2 lasting ≥2 days despite treatment	Interrupt until recovery to ≤ Grade 1. Resume at a reduced dose.
	Grade 3 or 4	Interrupt until recovery to ≤ Grade 1. Resume at a reduced dose. Permanently discontinue if not resolved within 14 days.
Other Adverse Reactions	Grade 3	Interrupt until recovery to ≤ Grade 1 or baseline. Resume at a reduced dose.
ULN = Upper Limit of Normal. LVEF = Left Ventricular Ejection Fraction. This table is a summary based on prescribing information from sources.6

Management of Drug Interactions

Zongertinib's metabolism primarily via CYP3A4 and its role as a BCRP inhibitor necessitate careful management of concomitant medications.

• Strong CYP3A Inducers: Co-administration with strong inducers of CYP3A (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) should be avoided whenever possible, as these agents can significantly decrease the plasma concentration of Zongertinib, potentially compromising its efficacy. If concomitant use is unavoidable, the dose of Zongertinib must be increased: from 120 mg to 240 mg daily for patients <90 kg, and from 180 mg to 360 mg daily for patients ≥90 kg. After the inducer is discontinued, the Zongertinib dose should be returned to the original dose after 7-14 days.[6]
• BCRP Substrates: Zongertinib is an inhibitor of the BCRP efflux transporter. This can increase the concentration of drugs that are BCRP substrates (e.g., rosuvastatin). Concomitant use with BCRP substrates that have a narrow therapeutic index should be avoided. For other BCRP substrates, patients should be monitored closely for increased adverse reactions.[6]

VII. Future Directions and Concluding Remarks

The Ongoing Phase III Beamion LUNG-2 Trial (NCT06151574)

The clinical development of Zongertinib is advancing into the first-line setting with the pivotal Beamion LUNG-2 trial. This is a Phase III, global, randomized, open-label, active-controlled study designed to evaluate the efficacy and safety of Zongertinib monotherapy compared with the current standard of care—pembrolizumab combined with platinum-pemetrexed chemotherapy.[3] The trial is enrolling treatment-naïve patients with unresectable, locally advanced, or metastatic non-squamous NSCLC whose tumors harbor activating HER2 TKD mutations.[12]

The primary endpoint of this trial is progression-free survival.[41] Its results will be critical for two reasons. First, it is designed to provide the confirmatory evidence of clinical benefit required by the FDA to convert Zongertinib's accelerated approval into a full approval.[15] Second, if positive, the trial has the potential to establish Zongertinib as the new standard of care in the first-line setting for this molecularly defined patient population, representing a major practice-changing development.

Potential for Pan-Tumor Application

The therapeutic potential of Zongertinib is being explored beyond NSCLC, recognizing that HER2 alterations can be oncogenic drivers in a variety of solid tumors. The broader Beamion clinical program includes several studies aimed at establishing a pan-tumor utility.

• Beamion PANTUMOR-1 (NCT06581432): This is a Phase II basket trial designed to evaluate the efficacy of Zongertinib in patients with various previously treated solid tumors that have either HER2 mutations or HER2 gene amplification/protein overexpression.[2]
• Beamion BCGC-1 (NCT06324357): This is a Phase Ib/II trial investigating Zongertinib both as a monotherapy and, significantly, in combination with other HER2-directed agents, including the ADCs trastuzumab deruxtecan and trastuzumab emtansine, in patients with HER2-positive metastatic breast cancer and gastroesophageal cancers.[2]

The design of the Beamion BCGC-1 trial is particularly insightful. It signals a sophisticated, long-term development strategy that goes beyond simple sequencing of therapies. By testing Zongertinib in combination with ADCs, researchers are actively investigating the potential for synergistic or additive effects. This approach could be used to enhance the efficacy of ADCs or to overcome mechanisms of resistance. Preclinical data have already suggested the potential for concurrent treatment with ADCs.[12] A successful outcome from this trial could establish novel, highly potent combination regimens for major HER2-driven cancers, transforming Zongertinib from a monotherapy for a niche lung cancer subtype into a foundational component of combination therapy in much larger cancer indications.

Zongertinib's Position in the Evolving Treatment Landscape

Zongertinib enters the clinical landscape as the first oral TKI approved for HER2-mutant NSCLC, offering a convenient and highly effective alternative to the intravenously administered ADC, trastuzumab deruxtecan.[3] Its distinct and favorable safety profile, particularly the absence of reported drug-related ILD, combined with its proven efficacy in patients whose disease has progressed after ADC therapy, establishes a clear and complementary role for Zongertinib in the comprehensive management of this disease.

Concluding Expert Assessment

Zongertinib represents a landmark achievement in the targeted therapy of non-small cell lung cancer and a testament to the power of rational drug design. Its high efficacy, durable systemic and intracranial responses, and favorable safety profile are direct results of its innovative design as a highly selective, irreversible HER2 inhibitor that spares wild-type EGFR. It is poised to become a new standard of care for pre-treated patients with HER2 TKD-mutant NSCLC, addressing a long-standing unmet need. The outcomes of the ongoing Beamion LUNG-2 trial will be paramount in defining its role in the first-line setting, while the broader Beamion program holds the promise of extending its benefits to patients with other HER2-driven malignancies. Zongertinib exemplifies the continued progress of precision oncology in delivering transformative therapies for molecularly defined patient populations.

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