emDOCs Podcast – Episode 113: Immune Checkpoint Inhibitor Adverse Events

• Several cancers (melanoma, non-small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, others) suppress the innate T-lymphocyte function by activating checkpoint signals.
• Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that prevent the suppression signal from the cancer cell to the T-lymphocytes.
• Variety of classes and types of ICIs: 
  • Anti-CTLA-4:Ipilimumab/Yervoy, Tremelimumab/Imjudo
  • Anti-PD-1: Pembrolizumab/Keytruda, Nivolumab/Opdivo, Cemiplimab/Libtayo
  • Anti-PD-L1: Avelumab/Bavencio, Atezolizumab/Tecentriq, Durvalumab/Imfinzi
  • Anti-LAG-3/Anti-PD-1: Relatlimab and Nivolumab
• 20-90% of patients receiving ICIs will experience an adverse event; most within 3-6 months of treatment initiation
• National Cancer Institute Scale:
  • Grade 1: Mild/minimal symptoms
  • Grade 2: Moderate symptoms
  • Grade 3: Severe or medically significant but not immediately life-threatening 
  • Grade 4: Life-threatening consequences
  • Grade 5: Death
• Over 90% of adverse events are Grade 1/2
• Treatment depends on grade
  • Grade 1: May continue ICI, monitor, treat symptoms
  • Grade 2: Stop ICI, monitor, steroids, treat symptoms
  • Grade 3: Stop ICI, higher dose steroids, treat symptoms 
  • Grade 4: Stop ICI, resuscitate, steroids
• Gastrointestinal:
  • Colitis occurs in 8-33%, presents with diarrhea and abdominal pain
  • Severe colitis: fever, hypotension, peritonitis, toxic megacolon
  • Obtain stools studies, CT
  • Steroids for grade 2 or higher
• Pulmonary:
  • 19%; pneumonitis is most common cause of mortality due to adverse event
  • Pneumonitis presents with dyspnea, chest pain, cough
  • Obtain imaging (CXR vs. CT)
  • Steroids and antibiotics for grade 2 or higher
• Dermatologic:
  • 40-50%; local vs. severe (SJS/TEN/DRESS)
  • Topical vs. systemic steroids
• Endocrine: 
  • 17%; hypophysitis (pituitary gland inflammation), hypo- or hyperthyroidism, diabetes, adrenal insufficiency
• Renal:
  • 30%; AKI, glomerulonephritis, IgA nephritis, interstitial nephritis
  • Pyuria, hematuria, hypertension, low urine output
  • Labs, renal studies including US
  • Steroids
• Hepatoxicity
  • 1-30%
  • Exclude other causes; obtain labs and RUQ US
  • Steroids for grade 2 and higher
• Neurologic
  • <6%; headache, sleep and mood disturbances
  • Myasthenia gravis and encephalitis have 20% mortality rate
  • Exclude other causes 
  • Steroids
  • Administer IV antivirals and antibiotics as well for encephalitis
• Cardiology
  • < 1%; arrhythmia, pericarditis, myocarditis, ACS, HF
  • Labs, ECG, chest imaging
  • Steroids
• Hematologic
  • Rare; hemolytic anemia, thrombocytopenia, lymphopenia, ITP, TTP
  • Consult hematology

References: 

• Yoo MJ, Long B, Brady WJ, Holian A, Sudhir A, Gottlieb M. Immune checkpoint inhibitors: An emergency medicine focused review. Am J Emerg Med. 2021 Dec;50:335-344.