CONTRAINDICATIONS / PRECAUTIONS
Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as avelumab. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of avelumab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.
Pneumonitis, radiation therapy
Immune-mediated pneumonitis has been reported with avelumab therapy; some cases were fatal. The incidence of pneumonitis with other PD-1/PD-L1 inhibitors is higher in patients who have received prior thoracic radiation therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, avelumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated hepatitis has been reported with avelumab therapy. The incidence of hepatotoxicity was higher in patients treated with avelumab in combination with axitinib compared with avelumab alone. Monitor hepatic function at baseline and periodically during treatment; consider more frequent monitoring in patients receiving avelumab with axitinib. Avelumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.
Colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, viral infection
Immune-mediated colitis has been reported with avelumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use avelumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Avelumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Adrenal insufficiency, hypophysitis, hypopituitarism
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with avelumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Avelumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Avelumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Avelumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Diabetes mellitus, diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus
Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported with avelumab therapy. If avelumab and axitinib are used together, optimize the management of pre-existing diabetes mellitus, a cardiac risk factor with this combination. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold avelumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
Renal failure, renal impairment
Immune-mediated nephritis and renal failure have been reported with avelumab therapy. Monitor renal function at baseline and periodically during treatment. Avelumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Severe or life-threatening infusion-related reactions have occurred with avelumab. All patients should receive premedication with an antihistamine and acetaminophen 30 to 60 minutes prior to the first 4 avelumab infusions; premedication may be administered prior to subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion reactions including fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion related reactions (grade 1 or 2); stop the infusion and permanently discontinue avelumab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Autoimmune disease, organ transplant, systemic lupus erythematosus (SLE)
Use avelumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1 inhibitor therapy.
Cardiac disease, heart failure, hyperlipidemia, hypertension, myocardial infarction
Use avelumab in combination with axitinib with caution in patients with a history of cardiac disease; this combination can cause severe and fatal cardiovascular events including myocardial infarction and congestive heart failure. If avelumab and axitinib are used together, optimize the management of cardiovascular risk factors such as hypertension or hyperlipidemia; consider baseline and periodic evaluations of left ventricular ejection fraction; and monitor for signs and symptoms of cardiovascular events. Discontinue avelumab and axitinib for grade 3 or 4 cardiovascular events.
Allogeneic stem cell transplant
Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as avelumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.
Immune mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Avelumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.
Guillain-Barre syndrome, myasthenia gravis, neurological disease
Immune-mediated neurotoxicity has been reported with avelumab or other PD-1/PD-L1 inhibitors. Use avelumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Avelumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.
Based on its mechanism of action, avelumab may cause fetal harm if used during pregnancy. Avelumab is an immunoglobulin G1 antibody and may cross the placental barrier. Fetal exposure to avelumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise pregnant women of the risk to a fetus. The PD-1 pathway is associated with decidual CD8-positive T-cell function and the PD1/PD-L1 interaction may be important in maintaining fetal tolerance during pregnancy. PD1/PDL1 inhibitors, such as avelumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia.
Contraception requirements, reproductive risk
Counsel patients about the reproductive risk and contraception requirements during avelumab therapy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 month after the last avelumab dose. Women who become pregnant while receiving avelumab should be apprised of the potential hazard to the fetus. Fertility studies have not been conducted with avelumab; however, weekly administration of avelumab did not result in any notable effects in the male and female reproductive organs of Cynomolgus monkeys.
Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during avelumab therapy and for at least 1 month after the final dose. It is not known if avelumab is present in human milk or if it has effects on the breastfed child or on milk production. Use avelumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because avelumab is a large protein molecule (molecular weight of 147,000 Daltons), the amount of drug in milk is likely to be very low. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.