VEGF Pathway Inhibitors

VEGF pathway inhibitors block vascular endothelial growth factor signalling and tumour angiogenesis, reduce vessel permeability and normalise tumour blood supply, which helps cytotoxic drugs reach tumour cells. They are used in colorectal, lung, kidney, liver, thyroid, ovarian, cervical and gastric cancers and in gastrointestinal stromal tumour.

Classification. Antibodies and traps (bevacizumab, ramucirumab, ziv-aflibercept) and multi-targeted tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib, axitinib, lenvatinib, cabozantinib, regorafenib).

Pharmacokinetics. Antibodies have long half lives; kinase inhibitors are metabolised by CYP3A4 and are mostly taken orally.

• Bevacizumab 5 mg/kg every 2 weeks or 7.5 to 15 mg/kg every 3 weeks.
• Ramucirumab 8 mg/kg every 2 weeks (gastric, colorectal) or 10 mg/kg every 3 weeks (lung).
• Ziv-aflibercept 4 mg/kg every 2 weeks with FOLFIRI.
• Sunitinib 50 mg once daily for 4 weeks, then 2 weeks off.
• Sorafenib 400 mg twice daily on an empty stomach.
• Pazopanib 800 mg once daily on an empty stomach.
• Axitinib 5 mg twice daily (titrate to 7 mg then 10 mg twice daily).
• Lenvatinib 24 mg daily (thyroid cancer), 14 mg or 18 mg with pembrolizumab or everolimus (renal and endometrial cancer), 8 to 12 mg daily (hepatocellular carcinoma by weight).
• Cabozantinib 60 mg once daily (40 mg in combination with nivolumab).
• Regorafenib 160 mg once daily for 21 days of 28.

Differences. Antibodies cause hypertension, proteinuria, bleeding and perforation; oral drugs add hand and foot reaction, diarrhoea, hypothyroidism, fatigue, and (pazopanib, sunitinib) hepatotoxicity.

• Colorectal cancer: bevacizumab with fluoropyrimidine and oxaliplatin or irinotecan; later regorafenib.
• Non-small cell lung (non-squamous) and ovarian cancer: bevacizumab with chemotherapy or maintenance.
• Renal cell carcinoma: sunitinib, pazopanib, axitinib (with pembrolizumab), cabozantinib.
• Hepatocellular carcinoma: sorafenib, lenvatinib, or bevacizumab with atezolizumab.
• Thyroid cancer: lenvatinib, sorafenib, cabozantinib.
• Hypertension control: measure blood pressure before each dose; treat above 140/90 mmHg with an ACE inhibitor, angiotensin receptor blocker or amlodipine; avoid diltiazem and verapamil (CYP3A4 inhibition); hold the drug for severe or uncontrolled hypertension.
• Surgery: stop bevacizumab at least 28 days before elective surgery and restart 28 days after, with wound healing complete.

Selection. Choose by tumour type, comorbidity (cardiovascular risk, bleeding), and cost; generic sunitinib, sorafenib and pazopanib are lower-cost options.

Contraindications. Recent haemoptysis or serious bleeding; gastrointestinal perforation or fistula; uncontrolled hypertension; recent major surgery or unhealed wound; arterial thromboembolism within 6 months; pregnancy.

Adverse effects. Hypertension, proteinuria and nephrotic syndrome, bleeding, arterial and venous thromboembolism, gastrointestinal perforation, impaired wound healing, hand and foot skin reaction, diarrhoea, fatigue, hypothyroidism, QT prolongation (sunitinib, vandetanib), posterior reversible encephalopathy syndrome, cardiomyopathy, and hepatotoxicity (pazopanib, sunitinib, regorafenib).

Interactions. Strong CYP3A4 inhibitors raise exposure (reduce sunitinib to 37.5 mg, pazopanib to 400 mg); inducers (rifampicin, phenytoin) lower it; proton pump inhibitors lower pazopanib absorption; warfarin interactions; antihypertensives may need adjustment.

Special groups.

• Pregnancy: contraindicated; contraception during and for 6 months after.
• Breastfeeding: avoid.
• Older adults: more hypertension, bleeding and fatigue.
• Kidney impairment: no adjustment for most; stop for nephrotic range proteinuria (3 g or more daily).
• Liver impairment: reduce pazopanib (200 mg) and sunitinib in severe impairment; avoid some.

Monitoring. Blood pressure weekly for the first 6 weeks then each visit; urine protein; full blood count; liver function every 2 weeks for 2 months then monthly (pazopanib); thyroid function every 4 to 8 weeks; ECG for QT drugs; and skin.

Referral and escalation. Severe hypertension with headache, confusion or visual disturbance, major bleeding, severe abdominal pain, chest pain, and haemoptysis need emergency care.