Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors are small molecules that block the ATP-binding site of oncogenic tyrosine kinases, preventing downstream signalling for proliferation and survival. They are oral, taken continuously, and chosen by tumour genotype; the first success was imatinib in chronic myeloid leukaemia, which changed the disease to a chronic condition for many patients.

Classification. By target:

• BCR-ABL (imatinib, dasatinib, nilotinib, bosutinib, ponatinib).
• BTK (ibrutinib, acalabrutinib, zanubrutinib).
• ALK, ROS1 and RET (crizotinib, alectinib, lorlatinib).
• FLT3 (midostaurin, gilteritinib).
• JAK (ruxolitinib).
• EGFR and HER2 (erlotinib, gefitinib, osimertinib, afatinib, lapatinib).
• Multi-targeted anti-angiogenic drugs (sunitinib, sorafenib, pazopanib, lenvatinib, cabozantinib).

Pharmacokinetics. Mostly CYP3A4 metabolised, many are substrates of P-glycoprotein, and several need an acidic stomach for absorption, so interactions are common.

• Imatinib 400 mg orally daily with food (chronic myeloid leukaemia, gastrointestinal stromal tumour); 600 to 800 mg daily in accelerated phase or blast crisis or with resistance; adjuvant gastrointestinal stromal tumour 400 mg daily for 3 years.
• Dasatinib 100 mg daily; nilotinib 300 mg twice daily on an empty stomach; bosutinib 400 mg daily; ponatinib 45 mg daily (15 mg after response; for T315I mutations).
• Ibrutinib 420 mg daily (chronic lymphocytic leukaemia) or 560 mg daily (mantle cell lymphoma); acalabrutinib 100 mg twice daily; zanubrutinib 160 mg twice daily.
• Alectinib 600 mg twice daily; lorlatinib 100 mg daily; crizotinib 250 mg twice daily.
• Midostaurin 50 mg twice daily; gilteritinib 120 mg daily.
• Ruxolitinib 5 to 20 mg twice daily by platelet count.

Differences. Each has a distinct toxicity: imatinib (oedema, nausea, myalgia, hepatotoxicity), dasatinib (pleural effusion, thrombocytopenia), nilotinib (QT prolongation, pancreatitis, hyperglycaemia, arterial events), ponatinib (arterial occlusion), ibrutinib (atrial fibrillation, bleeding, hypertension).

• Chronic myeloid leukaemia: imatinib first-line (generic imatinib is widely available and low cost); second-generation drugs for resistance, intolerance or high risk. Monitor BCR-ABL transcripts by quantitative PCR every 3 months (response targets: 10 percent or less at 3 months, under 1 percent at 6 months, 0.1 percent or less at 12 months). Do not stop without specialist supervision.
• Gastrointestinal stromal tumour: imatinib 400 mg daily; escalate to 800 mg daily in KIT exon 9 mutations.
• Chronic lymphocytic leukaemia and mantle cell lymphoma: BTK inhibitors.
• Lung cancer with ALK rearrangement: ALK inhibitors.
• Before starting: confirm the genotype; check hepatitis B status (reactivation risk), ECG with nilotinib, and drug interactions.

Selection. Match the drug to the molecular target and tumour; choose by cardiovascular risk and comorbidity.

Contraindications. Pregnancy; QT prolongation or hypokalaemia (nilotinib); concurrent strong CYP3A4 inducers; active serious infection for some.

Adverse effects. Diarrhoea, rash, fluid retention, hepatotoxicity, myelosuppression, hypertension, QT prolongation, cardiac failure, hypothyroidism, hypophosphataemia, and drug-specific events such as pleural effusion, QT prolongation and arterial occlusion.

Interactions. Rifampicin and phenytoin reduce imatinib exposure markedly (increase imatinib dose by at least 50 percent if unavoidable); ketoconazole and ritonavir raise levels; acid suppressants reduce dasatinib, erlotinib, gefitinib absorption (avoid proton pump inhibitors); warfarin with imatinib needs switching to heparin; nilotinib with QT-prolonging drugs.

Special groups.

• Pregnancy: avoid; effective contraception during treatment.
• Breastfeeding: avoid.
• Children: imatinib is used in paediatric chronic myeloid leukaemia at 260 to 340 mg/m2 daily.
• Older adults: lower doses may be needed.
• Kidney impairment: imatinib 400 mg maximum at creatinine clearance 20 to 39 mL/min.
• Liver impairment: reduce imatinib and others by severity.

Monitoring. Full blood count weekly for 1 month then monthly, liver function, ECG (nilotinib), blood pressure, glucose, thyroid function, weight and oedema, and BCR-ABL PCR in chronic myeloid leukaemia.

Referral and escalation. Chest pain, arrhythmia, severe bleeding, grade 3 to 4 hepatotoxicity, treatment failure by response targets, and pregnancy need specialist review.