• Monitor for other immune-mediated reactions (including but not limited to myocarditis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, bullous dermatitis, - pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis). May occur during or after last dose of avelumab. Interrupt or discontinue avelumab depending on severity and administer systemic corticosteroid therapy (1–2 mg/kg/day prednisone or equivalent until improved to ≤Grade 1. Upon improvement, initiate corticosteroid taper and continue taper over at least 1 mo.
• Monitor for signs and symptoms of pneumonitis (new or worsening cough, chest pain, shortness of breath) during therapy. Evaluate with x-ray. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper. For Grade 2 pneumonitis: hold avelumab and resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. For Grade 3 or 4 or recurrent Grade 2 pneumonitis: permanently discontinue avelumab.
• Assess for signs and symptoms of colitis (diarrhea, severe abdominal pain, bloody or tarry stools) periodically during therapy. If symptoms occur administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper. If Grade 2 or 3 diarrhea or colitis occurs: hold avelumab and resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. If Grade 4 diarrhea or colitis occurs: permanently discontinue avelumab.
• Monitor for signs and symptoms of hypophysitis (headache, photophobia, visual field defects) during therapy. May cause hypopituitarism. Begin hormone replacement therapy. Hold or permanently discontinue avelumab based on severity.
• Assess for skin reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) (prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash) during therapy. Treat mild to moderate non-exfoliative rashes with topical emollients and/or topical corticosteroids. If SJS, TEN, or DRESS is suspected, hold avelumab; if confirmed, permanently discontinue avelumab.
• Monitor for signs and symptoms of neurologic toxicity (headache, neck stiffness, change in consciousness, weakness) periodically during therapy. If Grade 2 symptoms occur, hold avelumab. If Grade 3 or 4 symptoms occur, discontinue avelumab permanently.
• Monitor for signs and symptoms of infusion-related reactions (fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, urticaria) during infusion. For Grade 1 or 2 infusion-related reactions: interrupt or slow rate of infusion. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions: stop infusion and permanently discontinue avelumab.
• Monitor for signs and symptoms of cardiovascular events during therapy. Assess left ventricular ejection fraction at baseline and periodically during therapy. Manage cardiovascular risk factors (hypertension, diabetes, dyslipidemia). Discontinue avelumab for Grade 2, 3, or 4 cardiovascular events.

Lab Test Considerations:

• May cause hepatitis; monitor liver function tests prior to and periodically during therapy. For monotherapy:If levels increase: administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper. For hepatitis with no tumor involvement of the liver:If AST or ALT ↑ >3 times to <8 times (ULN) or total bilirubin ↑ >1.5 times to <3 times ULN: hold avelumab and resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. If AST or ALT >8 times ULN or total bilirubin >3 times ULN: discontinue avelumab permanently. For hepatitis with tumor involvement of the liver: If baseline AST or ALT >1 to 3 times ULN and increases to >5 to 10 times ULN or if baseline AST or ALT >3 to 5 times ULN and increases to >8 to 10 times ULN: hold avelumab. If AST or ALT >10 times ULN or if total bilirubin >3 times ULN: permanently discontinue avelumab. For combination therapy with axitinib:If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN: hold both avelumab and axitinib until recover to Grades 0–1. Consider rechallenge avelumab or axitinib or sequential rechallenge with both avelumab and axitinib after recovery. If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN: Permanently discontinue both avelumab and axitinib.
  • Monitor for signs and symptoms of adrenal insufficiency, including but not limited to hypothyroidism, hyperthyroidism, adrenal insufficiency, and hyperglycemia during and after treatment. Administer corticosteroids as appropriate, followed by a corticosteroid taper. If Grade 3 or 4 endocrinopathies occur: hold avelumab until clinically stable or permanently discontinue base on severity, treat low levels, and resume with complete or partial resolution (Grade 0 to 1) after corticosteroid taper.
  • May cause nephritis; monitor for ↑ serum creatinine prior to and periodically during therapy. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper. If serum creatinine >1.5 times ULN and <6 times ULN: hold avelumab and resume with complete or partial resolution (Grade 0 to 1) of nephritis and renal dysfunction after corticosteroid taper. If serum creatinine >6 times ULN: permanently discontinue avelumab.