Table 4.
Pembrolizumab toxicity and management
| Immune related Adverse Events (irAEs) | Toxicity grade (CTCAE V5.0) | Action with pembrolizumab | Corticosteroid and/or other therapies | Monitoring and follow-up |
|---|---|---|---|---|
| Pneumonitis | Grade 2 | Withhold |
Administer corticosteroids (initial dose of 1–2 mg/kg prednisone or equivalent) followed by taper Add prophylactic antibiotics for opportunistic infections |
Monitor participants for signs and symptoms of pneumonitis Evaluate participants with suspected pneumonitis with radiographic imaging and initiate corticosteroid treatment |
| Grade 3 or 4, or recurrent Grade 2 | Permanently discontinue | |||
| Diarrhea/Colitis | Grade 2 or 3 | Withhold | Administer corticosteroids (initial dose of 1–2 mg/kg prednisone or equivalent) followed by taper |
Monitor participants for signs and symptoms of enterocolitis (i.e., diarrhea, abdominal pain, blood or mucus in stool with or without fever) and of bowel perforation (i.e., peritoneal signs and ileus) Participants with ≥ Grade 2 diarrhea suspecting colitis should consider GI consultation and performing endoscopy to rule out colitis Participants with diarrhea/colitis should be advised to drink liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion |
| Grade 4 or recurrent Grade 3 | Permanently discontinue | |||
| AST or ALT elevation or Increased Bilirubin | Grade 2a | Withhold | Administer corticosteroids (initial dose of 0.5–1 mg/kg prednisone or equivalent) followed by taper | Monitor with liver function tests (consider weekly or more frequently until liver enzyme value returned to baseline or is stable) |
| Grade 3b or 4c | Permanently discontinue | Administer corticosteroids (initial dose of 1–2 mg/kg prednisone or equivalent) followed by taper | ||
| Type 1 diabetes mellitus (T1DM) or Hyperglycemia | New onset T1DM or Grade 3 or 4 hyperglycemia associated with evidence of β–cell failure | Withholdd |
Initiate insulin replacement therapy for participants with T1DM Administer anti-hyperglycemic in participants with hyperglycemia |
Monitor participants for hyperglycemia or other signs and symptoms of diabetes |
| Hypophysitis | Grade 2 | Withhold | Administer corticosteroids and initiate hormonal replacements as clinically indicated | Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency) |
| Grade 3 or 4 | Withhold or permanently discontinued | |||
| Hyperthyroidism | Grade 2 | Continue | Treat with non-selective beta-blockers (e.g., propranolol) or thionamides as appropriate | Monitor for signs and symptoms of thyroid disorders |
| Grade 3 or 4 | Withhold or permanently discontinued | |||
| Hypothyroidism | Grade 2, 3, or 4 | Continue | Initiate thyroid replacement hormones (e.g., levothyroxine or liothyronine) per standard of care | Monitor for signs and symptoms of thyroid disorders |
| Nephritis and renal dysfunction: grading according to increased creatinine or acute kidney injury | Grade 2 | Withhold | Administer corticosteroids (prednisone 1–2 mg/kg or equivalent) followed by taper | Monitor changes of renal function |
| Grade 3 or 4 | Permanently discontinue | |||
| Myocarditis | Grade 1 or 2 | Withhold | Based on severity of AE administer corticosteroids | Ensure adequate evaluation to confirm etiology and/or exclude other causes |
| Grade 3 or 4 | Permanently discontinue | |||
| All Other immune-related AEs | Intolerable/persistent Grade 2 | Withhold | Based on severity of AE administer corticosteroids | Ensure adequate evaluation to confirm etiology or exclude other causes |
| Grade 3 | Withhold or discontinue based on the evente | |||
| Grade 4 or recurrent Grade 3 | Permanently discontinue |
a AST/ALT: > 3.0–5.0 × ULN if baseline normal; > 3.0–5.0 × baseline, if baseline abnormal; bilirubin: > 1.5–3.0 × ULN if baseline normal; > 1.5–3.0 × baseline if baseline abnormal
b AST/ALT: > 5.0 to 20.0 × ULN, if baseline normal; > 5.0–20.0 × baseline, if baseline abnormal; bilirubin: > 3.0–10.0 × ULN if baseline normal; > 3.0 × 10.0 × baseline if baseline abnormal
c AST/ALT: > 20.0 × ULN, if baseline normal; > 20.0 × baseline, if baseline abnormal; bilirubin: > 10.0 × ULN if baseline normal; > 10.0× baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM)
e Events that require discontinuation include but are not limited to: Guillain–Barre Syndrome, encephalitis, Stevens-Johnson Syndrome and toxic epidermal necrolysis