Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are monoclonal antibodies that block inhibitory receptors on T cells (PD-1, CTLA-4) or their ligands (PD-L1), releasing the restraint on tumour-specific immune responses. They produce durable responses in melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial, head and neck, hepatocellular and many other cancers, and in tumours with mismatch repair deficiency or high microsatellite instability.

Classification. Anti-PD-1 (pembrolizumab, nivolumab, cemiplimab, dostarlimab), anti-PD-L1 (atezolizumab, durvalumab, avelumab), and anti-CTLA-4 (ipilimumab, tremelimumab).

Pharmacokinetics. Long half life (about 3 to 4 weeks), no dose adjustment for kidney or liver impairment; effects can persist for months after the last dose.

• Pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks.
• Nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks.
• Atezolizumab 1,200 mg every 3 weeks; durvalumab 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks; cemiplimab 350 mg every 3 weeks.
• Ipilimumab 3 mg/kg every 3 weeks for 4 doses (1 mg/kg with nivolumab 3 mg/kg in combination, then nivolumab alone).

Differences. Combined anti-PD-1 and anti-CTLA-4 treatment gives higher response rates and much more immune toxicity (about 55 to 60 percent grade 3 to 4 events) than anti-PD-1 alone.

• Indications: melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial cancer, head and neck cancer, hepatocellular carcinoma, Hodgkin lymphoma, and any mismatch repair deficient solid tumour.
• Biomarkers: PD-L1 expression, microsatellite instability or mismatch repair deficiency, tumour mutational burden.
• Before treatment: thyroid function, morning cortisol, glucose, liver enzymes, creatinine, hepatitis B and C, HIV, and tuberculosis assessment (latent tuberculosis can reactivate).
• Duration: usually until progression or up to 2 years; stop earlier for toxicity.
• Management of immune-related adverse events by grade: grade 1, continue with monitoring; grade 2, hold treatment and give prednisolone 0.5 to 1 mg/kg daily; grade 3 to 4, stop (permanently for most) and give methylprednisolone 1 to 2 mg/kg intravenously daily, tapering over 4 to 6 weeks once improved to grade 1.
• Steroid-refractory disease: infliximab 5 mg/kg or vedolizumab for colitis; mycophenolate for hepatitis (avoid infliximab); intravenous immunoglobulin or plasma exchange for neurological disease; add antifungal and pneumocystis prophylaxis during prolonged steroids.
• Endocrine events: replace hormones (levothyroxine, hydrocortisone, insulin) and continue the checkpoint inhibitor once stable.

Selection. Avoid in active untreated autoimmune disease (case by case), organ transplant recipients (rejection risk), and uncontrolled infection. Cost and access limit use in East Africa.

Contraindications. Pregnancy; severe active autoimmune disease needing high-dose immunosuppression; previous severe immune-related event for the same drug (relative).

Adverse effects. Immune-related events at any time, including months after stopping: dermatitis, colitis and diarrhoea, hepatitis, pneumonitis, thyroiditis, hypophysitis, adrenal insufficiency, type 1 diabetes, nephritis, myocarditis, myasthenia-like syndromes, and encephalitis; also infusion reactions and fatigue.

Interactions. Systemic steroids before starting reduce efficacy (avoid over 10 mg prednisolone equivalent daily if possible, apart from replacement); live vaccines are avoided; antibiotics and proton pump inhibitors may reduce benefit.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: limited data.
• Older adults: similar efficacy; watch for toxicity.
• Kidney and liver impairment: no adjustment.
• HIV, hepatitis B and C: treatment is feasible with viral control.

Monitoring. Thyroid function every 4 to 6 weeks, liver enzymes and creatinine before each dose, glucose, cortisol if symptomatic, bowel frequency, cough and oxygen saturation, and troponin and electrocardiogram if myocarditis is suspected.

Referral and escalation. 4 or more stools over baseline, dyspnoea or cough, jaundice, severe headache or visual loss, adrenal crisis, chest pain with raised troponin, and neurological weakness need same-day assessment.