EGFR Targeted Therapy

Epidermal growth factor receptor targeted therapy blocks EGFR signalling by tyrosine kinase inhibitors that bind the intracellular domain, or by antibodies that bind the extracellular domain. Small molecules are used in non-small cell lung cancer with activating EGFR mutations (exon 19 deletion, L858R); antibodies are used in colorectal and head and neck cancer.

Classification. First- and second-generation tyrosine kinase inhibitors (gefitinib, erlotinib, afatinib, dacomitinib), third-generation (osimertinib), and antibodies (cetuximab, panitumumab, necitumumab, amivantamab).

Pharmacokinetics. Hepatic metabolism, mainly CYP3A4; gefitinib and erlotinib require stomach acidity for absorption, and smoking induces CYP1A2 and lowers erlotinib levels.

• Gefitinib 250 mg once daily; erlotinib 150 mg once daily on an empty stomach (100 mg in pancreatic cancer); afatinib 40 mg once daily on an empty stomach; dacomitinib 45 mg once daily; osimertinib 80 mg once daily.
• Cetuximab 400 mg/m2 loading dose then 250 mg/m2 weekly; panitumumab 6 mg/kg every 2 weeks.
• Amivantamab (exon 20 insertions and with lazertinib): weight-based dosing by specialist.

Differences. Osimertinib is active against the T790M resistance mutation, has central nervous system activity, and causes less rash and diarrhoea than earlier agents; afatinib causes the most diarrhoea and mucositis.

• Lung cancer with activating EGFR mutation: osimertinib first-line (also adjuvant for 3 years after resection); gefitinib or erlotinib where cost limits access, with progression testing for T790M.
• Resistance: at progression, repeat tissue or plasma testing for T790M and other mechanisms; switch to osimertinib if T790M is present or to platinum chemotherapy.
• Metastatic colorectal cancer: cetuximab or panitumumab only when tumour is RAS and BRAF wild-type and left-sided.
• Head and neck cancer: cetuximab with radiotherapy or chemotherapy.
• Rash management: doxycycline 100 mg twice daily for 6 weeks (prophylactic), emollients, and sunscreen; topical hydrocortisone 1 percent for established rash; reduce dose for grade 3.

Selection. Choose the drug by mutation type, prior treatment, brain metastases, and funding. EGFR mutations are more frequent in never-smokers and in women, and testing is not available everywhere in East Africa; request testing before starting.

Contraindications. Interstitial lung disease; pregnancy; hypersensitivity; RAS mutation (antibodies).

Adverse effects. Acneiform rash (most frequent), diarrhoea, paronychia, dry skin, stomatitis, interstitial lung disease (about 1 to 3 percent, fatal in a third), hepatotoxicity (gefitinib), QT prolongation, cardiomyopathy (osimertinib), keratitis, and hypomagnesaemia (antibodies).

Interactions. Proton pump inhibitors and H2 blockers lower gefitinib and erlotinib absorption (separate dosing or avoid); rifampicin and phenytoin lower exposure (increase gefitinib to 500 mg daily if unavoidable); ketoconazole and ritonavir raise levels; warfarin effect rises.

Special groups.

• Pregnancy: contraindicated.
• Breastfeeding: avoid.
• Older adults: lower starting doses of afatinib (30 mg).
• Kidney impairment: afatinib 30 mg at creatinine clearance 15 to 29 mL/min.
• Liver impairment: gefitinib caution in moderate to severe; erlotinib caution.

Monitoring. Skin and bowel symptoms each visit, liver function every 4 to 8 weeks, ECG and electrolytes (osimertinib), magnesium with antibodies, and chest imaging if cough or dyspnoea.

Referral and escalation. New or worsening dyspnoea, fever, cough or hypoxia (stop the drug and exclude interstitial lung disease), severe diarrhoea, and eye pain need urgent review.