avelumab (Rx)

Adverse effects include all grades unless otherwise stated

>10%

Fatigue (41-50%)

Lymphopenia (49%)

Anemia (35%)

Increased AST (34%)

Infusion-related reaction (22-30%)

Thrombocytopenia (27%)

Musculoskeletal pain (25%)

Diarrhea (18-23%)

Nausea (22-24%)

Rash (15-22%)

Urinary tract infection (21%)

Decreased appetite (20-21%)

Peripheral edema (17-20%)

Increased ALT (20%)

Lymphopenia, grade 3-4 (19%)

Abdominal pain (16-19%)

Decreased weight (15-19%)

Increased creatinine/renal failure (16%)

Pyrexia/increased temperature (16%)

Increased lipase (14%)

Cough (14-18%)

Constipation (17-18%)

Dyspnea (11-17%)

Hyponatremia (16%)

Arthralgia (16%)

Dizziness (14%)

Vomiting/retching (13-14%)

Hypertension (13%)

Increased GGT (12%)

1-10%

Pruritus (10%)

Headache (10%)

Hypertension (10%)

Anemia, grade 3-4 (9%)

Increased amylase (8%)

Hyperglycemia, grade 3-4 (7%)

Increased bilirubin (6%)

Neutropenia, grade 3-4 (6%)

Thyroid disorders (6%)

Hypertension, grade 3 or 4 (5-6%)

Increased ALT, grade 3-4 (5%)

Urinary tract infection, grade 3-4 (5%)

Increased lipase, grade 3-4 (4%)

Musculoskeletal pain, grade 3-4 (3%)

Increased creatinine/renal failure, grade 3 or 4 (3%)

Dyspnea, grade 3 or 4 (2%)

Decreased appetite, grade 3 or 4 (2%)

Abdominal pain, grade 3 or 4 (2%)

Musculoskeletal pain, grade 3 or 4 (2%)

Fatigue, grade 3 or 4 (2%)

Dyspnea, grade 3 or 4 (2%)

Colitis (1.5%)

Pneumonitis (1.2%)

Constipation, grade 3 or 4 (1%)

Arthralgia, grade 3 or 4 (1%)

Increased AST, grade 3-4 (1%)

Increased amylase, grade 3-4 (1%)

Increased bilirubin, grade 3-4 (1%)

Thrombocytopenia, grade 3-4 (1%)

Neutropenia, grade 3-4 (1%)

Pyrexia/increased temperature, grade 3-4 (1%)

<1%

Hepatitis

Adrenal insufficiency

Type 1 diabetes mellitus

Nephritis

Postmarketing Reports

Pancreatitis

Myocarditis

Myositis

Congestive heart failure

Myocardial infarction

Contraindications

None

Cautions

Embryofetal toxicity is possible based on its mechanism of action (see Pregnancy)

The patient should contact healthcare provider when experiencing lung symptoms, including cough shortness of breath, chest pain, gastrointestinal symptoms, including diarrhea (loose stools) or more frequent bowel movements than usual, stools that are black, tarry, sticky, or have blood or mucus, or severe stomach-area (abdomen) pain or tenderness, and hepatic symptoms, including yellowing of the skin or the whites of eyes, dark urine (tea colored, severe nausea or vomiting bleeding, or bruising more easily than normal, pain on the right side of your stomach-area (abdomen)

Infusion reactions

• Infusion-related reactions, including severe and life-threatening reactions, reported
• Monitor for signs and symptoms of infusion-related reactions (eg, rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, fever)
• Premedicate with an antihistamine and acetaminophen

Hepatotoxicity

• In combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation
• Consider more frequent monitoring of liver enzymes as compared to when drugs are used as monotherapy
• Withhold combination therapy for moderate (Grade 2) hepatotoxicity and permanently discontinue for severe or life-threatening (Grade 3 or 4) hepatotoxicity
• Administer corticosteroids as needed

Cardiovascular effects

• In combination with axitinib, can cause severe and fatal cardiovascular events
• Consider baseline and periodic evaluations of left ventricular ejection fraction; monitor for signs and symptoms of cardiovascular events
• Optimize management of cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia)
• Discontinue avelumab and axitinib for Grade 3-4 cardiovascular events
• Also see Dosage Modifications

Immune-mediated adverse reactions

• Immune-mediated pneumonitis, including fatal cases; monitor for signs and symptoms of pneumonitis and evaluate patients with suspected pneumonitis with radiographic imaging
• Immune-mediated hepatitis, including fatal cases, reported; monitor LFTs before initiating and periodically during treatment
• In combination with axitinib, can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation; consider more frequent monitoring of liver enzymes
• Monitor for symptoms of immune-mediated colitis; administer systemic corticosteroids for grade 2 or higher colitis
• Immune-mediated adrenal insufficiency should be treated with corticosteroids as appropriate for the adrenal insufficiency; monitor for signs/symptoms of adrenal insufficiency during and after treatment
• Immune-mediated endocrinopathies (eg, hypothyroidism, hyperthyroidism) reported; monitor thyroid function before initiating drug and during treatment; treat hypothyroidism with hormone-replacement therapy; initiate medical management for control of hyperthyroidism
• Immune-mediated nephritis and renal dysfunction reported; monitor for elevated serum creatinine before treatment and periodically during treatment
• Type 1 diabetes mellitus, including diabetic ketoacidosis, reported; monitor for hyperglycemia or other signs and symptoms of diabetes; may resume avelumab when metabolic control is achieved with insulin or antihyperglycemics
• For Grade ≥2 immune-mediated adverse reactions, administer corticosteroids (initial dose of 1-2 mg/kg/day prednisone or equivalent, followed by taper) for Grade ≥2 nephritis until resolution

Complications of allogeneic HSCT

• Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody
• Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause)
• These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT
• Follow patients closely for evidence of transplant-related complications and intervene promptly; consider benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT

Pregnancy

Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman

Animal studies demonstrated that PD-1/PD-L1 pathway inhibition can lead to increased risk of immune-mediated rejection of the developing fetus, resulting in fetal death

Human IgG1 immunoglobulins (IgG1) are known to cross the placenta; therefore, transmission may potentially occur from the mother to the developing fetus

Advise patient of the potential risk to a fetus

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose

Lactation

Unknown if distributed in human breast milk

Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose, owing to the potential for serious adverse reactions in breastfed infants

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Anti-PD-L1 IgG1 monoclonal antibody

PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the antitumor immune response in the tumor microenvironment

Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production

Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby inhibiting PD-L1 and resulting in restoration of immune responses, including antitumor immune responses

Absorption

Steady-state: ~4-6 weeks (2-3 cycles)

Distribution

Vd: 4.72 L

Elimination

Half-life: 6.1 days

Primary elimination mechanism is proteolytic degradation

Total systemic clearance: 0.59 L/day

IV Compatibilities

0.45% NaCl

0.9% NaCl

IV Preparation

Visually inspect vial for particulate matter and discoloration; should appear as a clear, colorless to slightly yellow solution

Discard vial if solution is cloudy, discolored, or contains particulate matter

Withdraw required dosage volume and inject it into a 250-mL infusion bag containing either 0.9% or 0.45% NaCl

Gently invert bag to mix diluted solution and avoid foaming or excessive shearing

Inspect admixture solution to ensure it is clear, colorless, and free of visible particles

Discard any partially used or empty vials

IV Administration

Infuse IV over 60 minutes through an IV line containing a sterile, nonpyrogenic, low protein-binding inline filter (pore size of 0.2 micron)

Do not coadminister other drugs through the same IV line

Premedication

• Premedicate with an antihistamine and acetaminophen before the first 4 infusions
• Based clinical judgment, premedicate for subsequent doses and presence/severity of prior infusion reactions

Storage

Unopened vials

• Store refrigerated at 36-46ºF (2-8ºC) in original package to protect from light
• Do not freeze or shake vials
• Vial stopper is not made with natural rubber latex

Diluted solution

• Room temperature (up to 77°F [25°C]): Store for no more than 4 hr from the time of dilution, OR
• Refrigerated (36-46°F [2-8°C]): Store for no more than 24 hr from the time of dilution; if refrigerated, allow the diluted solution to come to room temperature before administering
• Do not freeze or shake diluted solution