The treatment landscape for lung cancer continues to evolve rapidly, especially for tumors driven by specific genetic mutations. In August 2025, the FDA granted accelerated approval to HERNEXEOS® (zongertinib tablets)—a new HER2 (ERBB2) tyrosine kinase inhibitor (TKI)—marking an important milestone for patients with HER2-mutated non-small cell lung cancer (NSCLC).

This article provides a comprehensive look at its indications, dosing, efficacy pathway, side effects, monitoring guidelines, and what clinicians and patients should know.

What Is HERNEXEOS?

HERNEXEOS® (zongertinib) is an oral kinase inhibitor specifically designed to target tumors with:

• HER2 (ERBB2) tyrosine kinase domain activating mutations,

• in adults with unresectable or metastatic non-squamous NSCLC,

• who have already received prior systemic therapy.

How It Was Approved

The FDA granted accelerated approval, based on:

• Objective Response Rate (ORR)

• Duration of Response (DoR)

Full approval will depend on confirmatory trials demonstrating long-term clinical benefit.

How Does HERNEXEOS Work?

HER2 is a member of the EGFR family involved in regulating cell growth. Activating mutations in HER2 can drive uncontrolled tumor proliferation.

HERNEXEOS targets:

• HER2-mutated cancer cells

• Interrupts downstream signaling

• Limits tumor growth and spread

This makes it particularly valuable for a subset of lung cancer patients who previously had limited targeted treatment options.

Who Should Receive HERNEXEOS?

Eligible Patients

• Adults with unresectable or metastatic non-squamous NSCLC

• Tumor must have a confirmed HER2 (ERBB2) kinase-domain activating mutation

• Must have received at least one prior systemic therapy

Diagnostic Requirement

Treatment must be based on results from an FDA-approved HER2 mutation test, typically performed using tissue or plasma.

Dosage Based on Body Weight

Unlike many TKIs, HERNEXEOS uses a weight-based dosing strategy:

Administration:

• Take orally once daily

• With or without food

• Continue until disease progression or unacceptable toxicity

Safety Profile & Side Effects

Most Common Adverse Reactions (≥ 20%)

• Diarrhea

• Hepatotoxicity

• Rash

• Fatigue

• Nausea

These side effects are similar to other HER2-targeted TKIs but require proactive monitoring.

Serious Adverse Reactions & Monitoring

1. Hepatotoxicity (Liver Injury)

Why it matters:
HER2 inhibitors can elevate liver enzymes, sometimes severely.

Monitoring Requirements:

• Baseline ALT, AST, bilirubin

• Every 2 weeks for the first 12 weeks

• Monthly thereafter

• More frequently if abnormalities occur

Management:

• Dose interruption

• Dose reduction

• Permanent discontinuation depending on severity

2. Left Ventricular Dysfunction (Heart Function)

HER2-targeted agents can affect cardiac contractility.

Before starting treatment:

• Evaluate Left Ventricular Ejection Fraction (LVEF)

During treatment:

• Monitor LVEF regularly or as clinically indicated

3. Embryo-Fetal Toxicity

HERNEXEOS can cause fetal harm.

Recommendations:

• Use effective contraception

• Counsel patients on fetal risk

• Avoid use in pregnancy

• Do not breastfeed while taking HERNEXEOS

Laboratory Abnormalities

Grade 3 or 4 abnormalities (≥ 2%):

• ↓ Lymphocytes

• ↑ ALT

• ↑ AST

• ↓ Potassium

• ↑ GGT

These values emphasize the need for routine blood monitoring.

Drug Interactions

1. CYP3A Inducers

Examples: rifampin, phenytoin, carbamazepine

• Avoid if possible

• If unavoidable → increase HERNEXEOS dose

2. BCRP Substrates

Example: rosuvastatin, sulfasalazine

For certain BCRP substrates:

• Avoid use if small concentration increases can cause toxicity

• Consider alternative drugs

• If unavoidable → monitor closely and adjust doses

Special Populations

Pregnancy & Lactation

• Do NOT, under any circumstance, use during pregnancy

• Breastfeeding is contraindicated

There is no human data, but animal studies show significant fetal risk.

When to Stop or Modify Treatment

Dose interruption or discontinuation may be required for:

• Grade 3 or 4 liver enzyme elevations

• Persistent or severe diarrhea

• Severe rash

• Worsening cardiac function

• Any life-threatening adverse effect

Clinical judgment is crucial because HERNEXEOS is generally continued as long as toxicity is manageable.

Why HERNEXEOS Matters

HER2-mutated NSCLC accounts for 2–4% of lung cancers, a small but important group with limited targeted options.

HERNEXEOS offers:

• A mutation-specific therapy

• Oral once-daily convenience

• A promising response rate

• A new option for patients who previously relied only on chemotherapy or immunotherapy

As confirmatory trials progress, its role in lung cancer management will become clearer.

Key Takeaways

• HERNEXEOS (zongertinib) is a newly approved HER2-targeted oral therapy for metastatic non-squamous NSCLC.

• Requires confirmed HER2 KDD mutation and prior systemic therapy.

• Dosed based on weight (120 mg vs 180 mg).

• Major risks include hepatotoxicity, cardiac dysfunction, embryo-fetal toxicity, and drug interactions.

• Ongoing monitoring is essential, especially in the first 12 weeks.