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Immune Checkpoint Inhibitors: Adverse Effects, Contraindications and Monitoring

Immune checkpoints are molecular biological "brakes" on the immune system. Tumors can influence immune checkpoints through the expression of proteins and thus evade elimination. Relevant immune checkpoints in urology are the programmed cell death-1 receptor and its ligand PD-L1 or the cytotoxic T lymphocyte antigen (CTLA)-4 receptor. Checkpoint inhibitors (CPIs) are used to treat advanced bladder cancer and metastatic renal cell carcinoma.

Treatment with immune checkpoint inhibitors (atezolizumab, avelumab, nivolumab, pembrolizumab) is associated with immune-mediated adverse events, which can occur many months after the last dose. Depending on the severity (grade) of the adverse event, clinicians should interrupt or permanently discontinue treatment. Corticosteroid therapy is required according to toxicity grade (typically prednisone 0.5–2 mg/kg/day). In severe or steroid-refractory cases, add additional immunosuppressive agents.

Almost all patients report adverse effects from immune checkpoint inhibition, and most are manageable. Severe or life-threatening grade 3–4 events occur in 10–30% of patients (depending on the combination treatment), and 7–12% of patients require treatment discontinuation.

The rate of fatal adverse events for PD-1/PD-L1 monotherapy is 0.3–1.3%, with causes including cardiac toxicity, pneumonitis with ARDS, renal failure, toxic epidermal necrolysis, hypopituitarism, neurologic events, colitis, bowel perforation, hepatitis, pancytopenia, or rhabdomyolysis.

Adverse Effects Of CPI By Organ System

The incidence of adverse effects varies by tumor type and regimen; the higher end is more common in combination therapy.

• Skin: From mild exanthems (very common), inflammatory dermatoses, bullous dermatoses to severe cutaneous reactions, such as toxic epidermal necrolysis or Stevens–Johnson syndrome. Grade 3 and higher adverse effects occur in up to 3% of patients receiving monotherapy.
• Nervous system: Including myasthenia gravis, Guillain–Barré syndrome, encephalitis, aseptic meningitis, peripheral neuropathy, and demyelinating disorders. Grade 3 or higher adverse events are below 1% for monotherapy, but have a higher fatality rate than other AEs.
• Immune system: Infusion-related reactions; anaphylaxis or vasculitis occurs occasionally.
• Lungs: Pneumonitis (3%) leads to dyspnea, cough, hypoxemia, and radiographic abnormalities on chest imaging. Fatal ARDS is possible.
• Cardiovascular AE: including myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism. Cardiovascular AEs are rare but mortality is high.
• GI tract: mild Diarrhea is common (20%). Colitis (1–4%) with abdominal pain, diarrhea, mucus or blood in stool.
• Liver: Transaminase elevation in up to 10%; grade 3–4 hepatitis may present with jaundice, coagulopathy, and encephalopathy.
• Kidneys: nephritis or acute kidney injury. Grade 3 or higher AKI is below 1% for monotherapy.
• Endocrinopathies: Thyroiditis with initial hyperthyroidism followed by hypothyroidism (15%); adrenalitis with adrenal insufficiency (1%); hypophysitis (1%); diabetes mellitus (<1%). Symptoms are nonspecific and can be difficult to distinguish from disease progression.
• Musculoskeletal AE: arthritis, myositis and polymyalgia-like syndrome. Mild AE are common (up to 40%).
• Hematologic: hemolytic or aplastic anemia (5%), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, leukopenia (1%), thrombocytopenia (2%), and hemophilia.
• Other adverse events (<1%): Pancreatitis, uveitis.

Drug Interactions

Systemic corticosteroids and other immunosuppressants may blunt the pharmacodynamic activity of checkpoint inhibitors and should be avoided unless clinically necessary to manage immune-mediated toxicity.

There is a complex interplay between the gut microbiome and checkpoint inhibitor activity. Prior or early exposure to systemic antibiotics has been associated with reduced efficacy in observational studies.

Monitoring During Therapy With Immune Checkpoint Inhibitors

Before each treatment cycle, assess for symptoms and laboratory abnormalities. Provide thorough patient education and perform targeted review of systems across all organ systems to ensure prompt diagnostics, treatment pause or discontinuation, and timely steroid initiation when indicated.

• Key symptoms:
  • General: Appetite? Thirst? Sleep problems? Night sweats? Body weight? Fever?
  • Head and neck: Vision? Headache? Dizziness? Sore throat? Lymph nodes?
  • Chest: Cough? Sputum? Dyspnea? Chest pain? Irregular pulse? Breast masses?
  • Abdomen: Diarrhea? Constipation? Blood in stool? Vomiting? Abdominal pain?
  • Genitourinary tract: Voiding symptoms? Urine color? Pain?
  • Musculoskeletal: Muscle or joint pain?
  • Other: Rash? Weakness or paralysis? Seizures?
• Physical examination: Inspect skin and oral mucosa; auscultate lungs; perform a focused neurologic examination; measure the blood pressure.
• Laboratory monitoring: Complete blood count with differential; electrolytes; liver function tests and bilirubin; lipase; creatine kinase and troponin; coagulation studies; blood glucose; creatinine; TSH and free T4; LDH; CRP.

References

L. Heinzerling, E. N. de Toni, G. Schett, G. Hundorfean, and L. Zimmer “Checkpoint inhibitors - diagnosis and treatment of side effects,” Deutsches Arzteblatt international, vol. 116, no. 8, pp. 119–126, 2019.

Schneider, B. J. et al., J Clin Oncol 2021. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. https://ascopubs.org/doi/10.1200/JCO.21.01440

  Deutsche Version: Nebenwirkungen der Immuncheckpoint-Inhibitoren

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