avelumab

Avelumab is a medication used in the treatment of certain types of advanced or metastatic skin cancers and cancers of the urinary tract. Avelumab may be used as a first-line treatment, maintenance treatment, or in combination with axitinib, another cancer drug. Avelumab is administered as an intravenous infusion over 60 minutes. Avelumab does not directly kill cancer cells but enhances the body’s own immune system’s ability to destroy the cancer cells, reducing tumor cell growth and proliferation.

Avelumab is a human immunoglobulin G1 (IgG1) lambda monoclonal antibody produced in the lab using recombinant DNA technology. Avelumab is specifically designed to act against certain proteins that tumor cells and T-cells in the tumor microenvironment express, which help the cancer cells escape death. T-cells are immune cells that normally induce programmed death (apoptosis) in damaged and mutated (cancer) cells, but in many cancers, cancer cells develop cell mechanisms to escape apoptosis.

Programmed cell death ligand-1 (PD-L1) is a protein that cancer cells and immune cells in the tumor microenvironment express to evade apoptosis. PD-L1 binds to PD-1 and B7.1 receptors in T-cells and suppresses the activation and proliferation of T-cells and release of inflammatory proteins (cytokines) that can kill cancer cells. Avelumab binds to PD-L1 and prevents its suppressive action on T-cells, enhancing their ability to destroy the tumor cells. Avelumab may also kill cancer cells by inducing antibody-dependent cell-mediated cytotoxicity (ADCC).

Avelumab is approved by the FDA for the following:

• Treatment of metastatic Merkel cell carcinoma, a rare and aggressive form of skin cancer, in adults and children 12 years or older
• Treatment of adults with locally advanced or metastatic urothelial carcinoma, a cancer that begins in the urothelial cells, which form the inner lining of the urinary tract, including the urethra, bladder, ureters and renal pelvis.
• First-line treatment in combination with axitinib, in adults with advanced renal cell carcinoma, a cancer that begins in the kidneys

Avelumab is used off-label to treat adults with chemotherapy-resistant, gestational trophoblastic neoplasia, a rare cancer that begins in the uterus at the place where the placenta attaches to the uterus.

• Avelumab can cause immune-related adverse effects, which may be severe and sometimes fatal, because avelumab enhances immune activity. Immune-mediated reactions mostly occur during treatment but can occur after discontinuation.
  • Monitor patients closely for signs and symptoms of immune-mediated reactions, during and after treatment, for early identification and management.
  • Immune-mediated adverse reactions can involve any organ. Monitor lung function, liver enzymes, pancreatic enzymes, thyroid function, blood glucose levels, creatinine levels, kidney function and complete blood count with appropriate tests regularly during treatment.
  • Withhold or permanently discontinue avelumab as recommended, based on the severity and type of reaction, and initiate appropriate treatment.
  • Immune-mediated inflammatory adverse reactions include:
    • Pneumonitis
    • Liver toxicity and hepatitis
    • Colitis
    • Adrenal insufficiency
    • Thyroid disorders including thyroiditis, underactive or overactive thyroid (hypothyroidism or hyperthyroidism)
    • Pituitary gland inflammation (hypophysitis) and hypopituitarism
    • Diabetes mellitus and diabetic ketoacidosis
    • Impairment of kidney function and kidney inflammation (nephritis)
    • Pancreatitis
    • Cardiac and vascular inflammations
    • Gastrointestinal inflammations
    • Musculoskeletal and connective tissue disorders
    • Nervous system inflammations
    • Blood disorders
    • Lymphatic system inflammations
    • Ocular inflammations
    • Severe skin inflammations
• Avelumab can cause severe or life-threatening infusion-related reactions.
  • Premedicate with acetaminophen and antihistamines for the first 4 infusions.
  • Monitor patients for signs and symptoms of infusion-related reactions.
  • Interrupt or slow the rate of infusion for mild and moderate reactions.
  • Permanently discontinue avelumab in case of severe (Grade 3) or life-threatening (Grade 4) reactions.
• Avelumab administered with axitinib can cause major adverse cardiovascular events (MACE) that can be severe or fatal.
  • Monitor patients for signs and symptoms of cardiovascular events and consider baseline and periodic monitoring of left ventricular ejection fraction.
  • Manage cardiovascular risk factors appropriately.
  • Discontinue avelumab and axitinib in case of Grade 3 or 4 cardiovascular events.
• Avelumab can cause fetal harm. Apprise women of the potential risk to the fetus if avelumab is administered during pregnancy or if a woman becomes pregnant during treatment. Advise women of reproductive potential to use effective contraception during therapy and at least for 1 month after discontinuation of treatment.

Common side effects of avelumab include:

• Fatigue
• Weakness (asthenia)
• Feeling unwell (malaise)
• Musculoskeletal pain
• Joint pain (arthralgia)
• Dizziness
• Headache
• Fever (pyrexia)
• Infusion-related reactions including:
  • Chills
  • Fever
  • Flushing
  • Low blood pressure (hypotension)
  • Shortness of breath (dyspnea)
  • Wheezing
  • Back pain
  • Abdominal pain
  • Hives (urticaria)
• Swelling of extremities (peripheral edema)
• Urinary tract infection
• Urinary tract hemorrhage
• Blood in urine (hematuria)
• Renal failure syndrome
• Diarrhea
• Constipation
• Abdominal pain
• Inflammation of mucous membranes (mucositis)
• Nausea
• Vomiting
• Decrease in appetite
• Decrease in weight
• Colon inflammation (colitis)
• Intestinal obstruction
• Blood disorders including:
  • Low count of lymphocyte immune cell (lymphopenia)
  • Low red blood cell count (anemia)
  • Low platelet count (thrombocytopenia)
  • Low count of neutrophil immune cells (neutropenia)
  • Low hemoglobin level
• Liver toxicity (hepatotoxicity)
• Increase in liver enzymes AST and ALT
• Increase in alkaline phosphatase
• Increase in bilirubin
• Increase in pancreatic enzymes lipase and amylase
• Increase in blood creatinine
• Decrease in blood sodium
• Increase in blood potassium
• Increase in blood triglycerides
• Increase in blood cholesterol
• Decrease in phosphate
• Increase in creatine phosphokinase (CPK)
• High blood glucose levels (hyperglycemia)
• Rash
• Itching (pruritus)
• Hand-foot syndrome (palmar-plantar erythrodysesthesia)
• Cough
• Shortness of breath (dyspnea)
• Voice disorder (dysphonia)
• Lung inflammation (pneumonitis)
• High blood pressure (hypertension)
• Underactive thyroid (hypothyroidism)
• Dehydration

Less common side effects of avelumab include:

• Heart muscle inflammation (myocarditis)
• Inflammation of the membrane around the heart (pericarditis)
• Fluid around the heart (pericardial effusion)
• Blood vessel inflammation (vasculitis)
• Gastrointestinal inflammations including:
  • Gastritis
  • Duodenitis
  • Esophagitis
• Pancreatitis
• Hepatitis
• Bile duct inflammation (cholangitis)
• Gallbladder inflammation (cholecystitis)
• Kidney inflammation (nephritis)
• Acute kidney injury
• Thyroiditis
• Overactive thyroid (hyperthyroidism)
• Hypoparathyroidism
• Inflammation of pituitary gland (hypophysitis)
• Pituitary insufficiency
• Adrenocortical insufficiency
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• Hemophagocytic lymphohistiocytosis, a rare inflammatory disorder
• Inflammation of lymph nodes (lymphadenitis)
• Histiocytic necrotizing lymphadenitis, a rare type of lymphadenitis
• Anemia due to lack of red cell production (aplastic anemia)
• Anemia due to premature destruction of red cells (hemolytic anemia)
• Bruising (purpura) from immune thrombocytopenia
• Antibody development
• Systemic inflammatory response syndrome
• Organ transplant rejection
• Guillain-Barre syndrome, a condition in which the immune system attacks the nerves
• Autoimmune nerve disease (neuropathy)
• Inflammation of the brain membrane (meningitis)
• Brain inflammation (encephalitis)
• Inflammation of the spinal cord (myelitis)
• Damage to myelin sheath that protects nerve fibers (demyelinating disease)
• Muscle weakness (myasthenia)
• New onset or exacerbation of myasthenia gravis
• Joint inflammation (arthritis)
• Muscle pain (myalgia)
• Polymyalgia rheumatica
• Inflammatory muscle disease (polymyositis)
• Muscle breakdown (rhabdomyolysis)
• Severe life-threatening skin reactions such as:
  • Pemphigoid
  • Stevens-Johnson syndrome
  • Toxic epidermal necrosis
  • Drug rash with eosinophilia and systemic symptoms (DRESS)
• Dry eye syndrome
• Inflammation of uvea in the eye (uveitis)
• Inflammation of the iris (iritis)
• Vision impairment
• Sjogren’s syndrome

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injectable solution

• 20 mg/mL (200 mg/10 mL single-dose vial)

Adult:

Merkel Cell Carcinoma

• Indicated in adults with metastatic Merkel cell carcinoma (MCC)
• 800 mg intravenous (IV) once every 2 weeks
• Continue until disease progression or unacceptable toxicity

Urothelial Carcinoma

• Indicated for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy
• Also, indicated for locally advanced or metastatic UC in patients who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
• 800 mg IV once every 2 weeks
• Continue until disease progression or unacceptable toxicity

Renal Cell Carcinoma

• Indicated in combination with axitinib for first-line treatment in patients with advanced renal cell carcinoma (RCC)
• Avelumab 800 mg IV once every 2 weeks in combination with:
  • Axitinib 5 mg orally twice daily
• Continue until disease progression or unacceptable toxicity
• When axitinib is used in combination with avelumab, consider dose escalation of axitinib above the initial 5-mg dose at 2-week or longer intervals
• Refer also to prescribing information for axitinib dosing information

Dosage Modifications

• No dose reductions are recommended

Pneumonitis

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Colitis

• Grade 2 or 3: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of initiating steroids
• Grade 4: Permanently discontinue

Hepatitis with no tumor involvement of the liver

• AST or ALT increases to above 3 and up to 8 times upper limit of normal (ULN) or total bilirubin increases to above 1.5 and below 3 times ULN: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
• AST or ALT increases to above 8 times ULN or total bilirubin increases to above 3 times ULN: Permanently discontinue

Hepatitis with tumor involvement of the liver

• If AST and ALT are ULN or below at baseline, withhold or permanently discontinue treatment based on recommendations for hepatitis where there is no tumor involvement of the liver
• Withhold therapy
  • Baseline AST or ALT above 1 and up to 3 times ULN and increases to above 5 and up to 10 times ULN
  • Baseline AST or ALT above 3 and up to 5 times ULN and increases to above 8 and up to 10 times ULN
  • Resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
  • Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of initiating steroids
  • Permanently discontinue
    • AST or ALT increases to above 10 times ULN or total bilirubin increases to above 3 times ULN

Endocrinopathies

• Grade 3 or 4: Withhold until clinically stable or permanently discontinue depending on severity

Nephritis with renal dysfunction

• Grade 2 or 3 increased blood creatinine: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of initiating steroids
• Grade 4 increased blood creatinine: Permanently discontinue

Exfoliative dermatologic conditions

• Suspected Steven Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy
• Confirmed SJS, TEN, or DRESS: Permanently discontinue

Myocarditis

• Grade 2, 3, or 4: Permanently discontinue

Neurologic toxicities

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day (or equivalent) or less within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Infusion-related reactions

• Grade 1 or 2: Interrupt or slow infusion rate
• Grade 3 or 4: Permanently discontinue

RCC treated with avelumab in combination with axitinib

• ALT/AST 3 times to below 5 times ULN or total bilirubin 1.5 times to below 3 times ULN
  • Withhold both avelumab and axitinib until these reactions recover to grade 1 or lower
  • If persistent (longer than 5 days), consider corticosteroid therapy (initial dose of 0.5-1 mg/kg/day) prednisone or equivalent followed by a taper
  • Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery
  • If rechallenging axitinib, reduce dose per axitinib full prescribing information
• ALT/AST 5 or more times ULN or more than 3 times ULN with concurrent total bilirubin 2 or more times ULN or total bilirubin above 3 or more times ULN
  • Permanently discontinue both avelumab and axitinib
  • Consider corticosteroid therapy

Pediatric:

Merkel Cell Carcinoma

• Indicated for metastatic Merkel cell carcinoma (MCC) in pediatric patients aged 12 years or older
• Children below 12 years: Safety and efficacy not established
• Children 12 years or above: 800 mg IV once every 2 weeks
• Continue until disease progression or unacceptable toxicity

Dosage Modifications

• Interrupt or slow infusion rate: Grade 1 or 2 infusion-related reaction

Withhold treatment (resume when recovery to grade ≤1 after corticosteroid taper)

• Grade 2 pneumonitis
• Grade 2 or 3 diarrhea or colitis
• Grade 3 or 4 endocrinopathies (including but not limited to hypothyroidism, hyperthyroidism, adrenal insufficiency, or hyperglycemia)
• Serum creatinine above 1.5 and up to 6 times ULN
• AST or ALT above 3 times and up to 5 times ULN or total bilirubin above 1.5 and up to 3 times ULN
• Moderate or severe clinical signs or symptoms of an immune-mediated adverse reaction (including but not limited to myocarditis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, bullous dermatitis, Stevens Johnson syndrome [SJS]/toxic epidermal necrolysis [TEN], pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis)

Permanently discontinue

• Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy)
• Grade 3 or 4 pneumonitis or recurrent Grade 2 pneumonitis
• Grade 4 diarrhea or colitis or recurrent Grade 3 diarrhea or colitis
• Serum creatinine above 6 times ULN
• AST or ALT above 5 times ULN or total bilirubin above 3 times ULN
• Grade 3 or 4 infusion-related reactions
• Inability to reduce corticosteroid dose to 10 mg/day or less of prednisone or equivalent within 12 weeks
• Persistent Grade 2 or 3 immune-mediated adverse reactions lasting 12 weeks or longer
• Recurrent severe immune-mediated adverse reaction

Overdose

There is limited information on avelumab overdose. Avelumab infusion is administered in clinical settings and overdose is unlikely. Overdose may increase the intensity of the drug’s adverse reactions. In the event of overdose, the patient must be monitored closely and treated with appropriate symptomatic care, as needed.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Avelumab has no listed severe interactions with other drugs.
• Serious interactions of avelumab include:
  • systemic corticosteroids
• Moderate interactions of avelumab include:
  • acetaminophen
  • antibiotics
  • axitinib
  • efgartigimod alfa
  • inhibitors of the proton pump
  • ketoconazole
• Avelumab has no listed mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is no data on the use of avelumab in pregnant women, however, based on its mechanism of action and animal reproductive studies, avelumab can cause fetal harm if administered during pregnancy.
• Women of pregnancy potential must use effective contraception during treatment and for at least 1 month after the final dose of avelumab.
• There is no information on the presence of avelumab in breastmilk, or its effects on milk production and on the breastfed infant, however many drugs and antibodies are excreted in breastmilk.
• Nursing mothers should discontinue breastfeeding while on treatment with avelumab and for at least 1 month after the final dose because of the potential for serious adverse reactions in the breastfed infant.

• Avelumab can cause immune-mediated side effects because it stimulates the immune system, which can cause inflammation in any part of the body. Report to your treating physician immediately if you develop any new or worsening of symptoms related to any organ system in the body including lung, liver, kidney, gastrointestinal tract or others.
• Contact your physician immediately if you experience any infusion-related reactions such as fever, chills, flushing, low blood pressure, shortness of breath, wheezing, back pain, abdominal pain, and/or hives.
• If you are receiving avelumab and axitinib, report to your physician immediately if you experience any new or worsening of cardiovascular symptoms such as chest comfort, shortness of breath or swelling of limbs.
• You will need regular tests while on avelumab treatment. Follow up with your physician and do not miss your scheduled appointments.
• Inform your treating physician immediately if you suspect an overdose of avelumab.