HER2 Targeted Therapy

HER2 targeted therapy blocks the HER2 receptor, which is overexpressed or amplified in about 15 to 20 percent of breast cancers and in some gastric, gastro-oesophageal and other cancers. It changed the prognosis of HER2-positive disease from poor to favourable. Treatment may be monoclonal antibodies, tyrosine kinase inhibitors or antibody drug conjugates.

Classification. Antibodies (trastuzumab, pertuzumab), tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib), and antibody drug conjugates (trastuzumab emtansine, trastuzumab deruxtecan).

Pharmacokinetics. Antibodies have a half life of about 3 weeks; small molecules are metabolised by CYP3A4; the conjugates deliver cytotoxic payloads to HER2-expressing cells.

• Trastuzumab 8 mg/kg intravenously loading dose then 6 mg/kg every 3 weeks; subcutaneous fixed dose 600 mg every 3 weeks.
• Pertuzumab 840 mg intravenously loading dose then 420 mg every 3 weeks, with trastuzumab.
• Trastuzumab emtansine 3.6 mg/kg every 3 weeks; trastuzumab deruxtecan 5.4 mg/kg every 3 weeks.
• Lapatinib 1,250 mg daily with capecitabine (1,000 mg/m2 twice daily on days 1 to 14), or 1,500 mg daily with letrozole.
• Neratinib 240 mg daily with food for 1 year after trastuzumab.
• Tucatinib 300 mg twice daily with trastuzumab and capecitabine.

Differences. Trastuzumab and pertuzumab can cause cardiomyopathy; trastuzumab deruxtecan causes interstitial lung disease and nausea; lapatinib and neratinib cause diarrhoea and rash; tucatinib crosses the blood-brain barrier.

• HER2-positive early breast cancer: trastuzumab for 1 year (with chemotherapy, usually a taxane, and with pertuzumab in node-positive or large tumours); extended neratinib in high-risk hormone receptor-positive disease; trastuzumab emtansine for residual disease after neoadjuvant therapy.
• Metastatic breast cancer: first-line trastuzumab, pertuzumab and a taxane; second-line trastuzumab deruxtecan or trastuzumab emtansine; later lapatinib or tucatinib combinations.
• Gastric and gastro-oesophageal cancer: trastuzumab with chemotherapy when HER2-positive.
• Definition of HER2 positivity: immunohistochemistry 3+, or 2+ with amplification on in situ hybridisation.
• Cardiac assessment: left ventricular ejection fraction before starting, every 3 months during therapy and 6 months after; hold if ejection fraction falls by 10 points or more to under 50 percent, and repeat in 4 weeks.
• Diarrhoea prophylaxis with neratinib: loperamide 4 mg then 2 mg every 4 hours for the first 2 weeks.

Selection. Use biosimilar trastuzumab where available to reduce cost; avoid anthracyclines at the same time as trastuzumab.

Contraindications. Pregnancy (oligohydramnios, foetal harm); left ventricular ejection fraction under 50 percent or severe heart failure; severe hypersensitivity; interstitial lung disease (trastuzumab deruxtecan).

Adverse effects. Infusion reactions (first dose), cardiomyopathy, diarrhoea, rash, nausea, fatigue, hepatotoxicity (lapatinib, tucatinib, trastuzumab emtansine), thrombocytopenia (trastuzumab emtansine), interstitial lung disease (trastuzumab deruxtecan, 10 to 15 percent), and neuropathy.

Interactions. Anthracyclines raise cardiac toxicity; strong CYP3A4 inhibitors and inducers affect lapatinib, neratinib and tucatinib; proton pump inhibitors reduce lapatinib and neratinib absorption; tucatinib raises levels of CYP3A4 substrates.

Special groups.

• Pregnancy: contraindicated; contraception during treatment and for 7 months after trastuzumab.
• Breastfeeding: avoid during treatment and for 7 months after.
• Older adults: higher cardiac risk.
• Kidney impairment: no adjustment for antibodies.
• Liver impairment: reduce lapatinib to 750 mg and tucatinib to 200 mg twice daily in severe impairment.

Monitoring. Left ventricular ejection fraction every 3 months, liver function, full blood count, chest imaging for new cough or dyspnoea, and blood pressure.

Referral and escalation. Heart failure symptoms, new cough or dyspnoea with trastuzumab deruxtecan, severe diarrhoea, and anaphylaxis need urgent care.