HER2 inhibitors

• Definition and Target
HER2 inhibitors are a group of targeted antineoplastic agents that block the activity of the human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase receptor involved in cell growth, differentiation, and survival. HER2 overexpression or amplification occurs in various cancers, particularly breast and gastric cancers, and is associated with aggressive tumor growth and poor prognosis.

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• Mechanism of Action

• Monoclonal antibodies (mAbs) bind to the extracellular domain of HER2, preventing ligand-independent receptor activation and promoting immune-mediated cytotoxicity.

• Tyrosine kinase inhibitors (TKIs) block the intracellular tyrosine kinase domain, inhibiting downstream signaling pathways such as PI3K/AKT and MAPK.

• Antibody–drug conjugates (ADCs) combine HER2-targeted antibodies with cytotoxic agents, enabling selective delivery of chemotherapy to HER2-expressing cells.

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• Types of HER2 Inhibitors

1. Monoclonal Antibodies

   • Trastuzumab – binds to subdomain IV of HER2 extracellular domain; inhibits signaling, induces antibody-dependent cell-mediated cytotoxicity (ADCC).

   • Pertuzumab – binds to subdomain II of HER2 extracellular domain; prevents dimerization with other HER receptors, especially HER3.

   • Margetuximab – engineered Fc region enhances ADCC compared to trastuzumab.

2. Tyrosine Kinase Inhibitors (TKIs)

   • Lapatinib – dual inhibitor of HER2 and EGFR (ErbB1).

   • Neratinib – irreversible pan-HER inhibitor (HER1, HER2, HER4).

   • Tucatinib – selective HER2 TKI with minimal EGFR inhibition, improving tolerability.

   • Pyrotinib – irreversible pan-HER inhibitor (not approved in all regions).

3. Antibody–Drug Conjugates (ADCs)

   • Trastuzumab emtansine (T-DM1) – trastuzumab linked to DM1, a microtubule inhibitor.

   • Trastuzumab deruxtecan (T-DXd) – trastuzumab linked to a topoisomerase I inhibitor payload.

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• Therapeutic Uses

• HER2-positive breast cancer (early-stage, metastatic, neoadjuvant/adjuvant settings)

• HER2-positive gastric and gastroesophageal junction cancer

• HER2-positive colorectal cancer (in combination regimens)

• HER2-mutated non-small cell lung cancer (specific TKIs)

• Ongoing investigations in other HER2-expressing solid tumors

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• Administration Routes and Formulations

• Intravenous infusion (trastuzumab, pertuzumab, margetuximab, ADCs)

• Oral tablets/capsules (lapatinib, neratinib, tucatinib, pyrotinib)

• Fixed-dose combination (trastuzumab + pertuzumab + hyaluronidase subcutaneous formulation)

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• Dosage Considerations

• Weight-based dosing for IV antibodies

• Oral TKIs given daily with/without food depending on formulation

• ADC dosing every 3 weeks in most regimens

• Dose adjustments for hepatic impairment and in case of severe toxicity

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• Contraindications

• Known hypersensitivity to the active drug or excipients

• Severe baseline cardiac dysfunction (especially with trastuzumab)

• Pregnancy (risk of fetal harm)

• Certain uncontrolled infections or concurrent serious illness

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• Side Effects

Monoclonal Antibodies

• Infusion-related reactions (fever, chills, hypotension)

• Cardiotoxicity (decline in left ventricular ejection fraction, congestive heart failure)

• Fatigue, diarrhea, rash

Tyrosine Kinase Inhibitors

• Diarrhea, nausea, vomiting

• Hand-foot syndrome (especially with neratinib)

• Hepatotoxicity

• Rash and mucositis

Antibody–Drug Conjugates

• Myelosuppression (thrombocytopenia, neutropenia)

• Interstitial lung disease/pneumonitis (notably with trastuzumab deruxtecan)

• Peripheral neuropathy (T-DM1)

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• Precautions

• Baseline and periodic cardiac function monitoring (Echocardiogram or MUGA scan)

• Monitor liver enzymes and complete blood counts

• Manage diarrhea aggressively with anti-diarrheal therapy in TKIs

• Avoid live vaccines during treatment

• Use effective contraception during and after treatment for recommended duration

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• Drug Interactions

• TKIs: affected by CYP3A4 inhibitors/inducers (e.g., ketoconazole, rifampin)

• P-glycoprotein substrates or inhibitors may alter TKI pharmacokinetics

• Trastuzumab and other mAbs generally have low potential for CYP-mediated interactions

• Concomitant anthracycline use increases risk of cardiotoxicity

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• Clinical Considerations

• Selection of agent depends on disease stage, prior therapy, resistance profile, and patient comorbidities

• Combination therapy (e.g., trastuzumab + pertuzumab + docetaxel) offers synergistic benefit in first-line metastatic settings

• Extended adjuvant neratinib can reduce recurrence risk after trastuzumab-based therapy in early breast cancer

• Emerging resistance mechanisms include HER2 mutations, alternative pathway activation, and receptor downregulation, prompting research into novel agents