avelumab

Antineoplastic Monoclonal Antibodies Targeting Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways

Emetic Risk
Minimal

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Dilution
Add the required amount/volume of drug to a 250 mL bag of 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.
Mix by gentle inversion; avoid foaming or excessive shearing.
Discard any unused drug left in the vial.
Storage following dilution: Store at room temperature (up to 25 degrees C or 77 degrees F) for up to 4 hours from the time of dilution, or refrigerated (2 to 8 degrees C; 36 to 46 degrees F) for up to 24 hours from the time of dilution. If refrigerated, allow the diluted solution to warm to room temperature prior to administration. Do not freeze or shake; protect from light.[61826]
Administration
Administer the diluted solution IV over 60 minutes.
Use a sterile, non-pyrogenic, low-protein-binding 0.2-micron in-line filter.
Do not administer other drugs through the same infusion line.[61826]

lymphopenia / Delayed / 0-19.0
hepatotoxicity / Delayed / 0-9.0
anemia / Delayed / 3.0-9.0
hyperglycemia / Delayed / 0-7.0
hypertension / Early / 3.0-6.0
infection / Delayed / 3.0-6.0
elevated hepatic enzymes / Delayed / 1.0-5.0
hyperamylasemia / Delayed / 1.0-5.0
musculoskeletal pain / Early / 1.2-3.2
dyspnea / Early / 0-3.0
hyponatremia / Delayed / 0-3.0
anorexia / Delayed / 0.3-2.0
rash / Early / 0-1.2
vomiting / Early / 0-1.2
hyperbilirubinemia / Delayed / 0-1.0
constipation / Delayed / 0.6-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
myelitis / Delayed / 0-1.0
arthralgia / Delayed / 0.6-1.0
myocarditis / Delayed / 0-1.0
pericarditis / Delayed / 0-1.0
pancreatitis / Delayed / 0-1.0
neutropenia / Delayed / 0-1.0
uveitis / Delayed / 0-1.0
vasculitis / Delayed / 0-1.0
aplastic anemia / Delayed / 0-1.0
hemolytic anemia / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
organ transplant rejection / Delayed / 0-1.0
infusion-related reactions / Rapid / 0-0.9
hepatitis / Delayed / 0.7-0.7
diarrhea / Early / 0-0.6
pneumonitis / Delayed / 0.5-0.5
dysphonia / Delayed / 0-0.5
colitis / Delayed / 0.4-0.4
peripheral edema / Delayed / 0-0.4
cough / Delayed / 0-0.3
hypothyroidism / Delayed / 0-0.3
fever / Early / 0-0.3
pruritus / Rapid / 0-0.3
nausea / Early / 0-0.3
adrenocortical insufficiency / Delayed / 0.1-0.1
abdominal pain / Early / 1.4
renal failure (unspecified) / Delayed / 2.0
fatigue / Early / 1.7
ileus / Delayed / Incidence not known
GI obstruction / Delayed / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
pericardial effusion / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
visual impairment / Early / Incidence not known
retinal detachment / Delayed / Incidence not known
Vogt-Koyanagi-Harada syndrome / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known
sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
graft-versus-host disease (GVHD) / Delayed / Incidence not known
veno-occlusive disease (VOD) / Delayed / Incidence not known

antibody formation / Delayed / 4.1-15.0
gastritis / Delayed / 0-1.0
paresis / Delayed / 0-1.0
hyperthyroidism / Delayed / 0.4-0.4
diabetes mellitus / Delayed / 0.1-0.1
dehydration / Delayed / 2.0
hematuria / Delayed / 1.5
hypophysitis / Delayed / Incidence not known
hypopituitarism / Delayed / Incidence not known
bone pain / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
hypertriglyceridemia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known
cystitis / Delayed / Incidence not known
pyuria / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
erythema / Early / Incidence not known
bullous rash / Early / Incidence not known
iritis / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known

weight loss / Delayed / 0-20.0
dizziness / Early / 0-14.0
headache / Early / 0-10.0
malaise / Early / Incidence not known
asthenia / Delayed / Incidence not known
back pain / Delayed / Incidence not known
myalgia / Early / Incidence not known
chills / Rapid / Incidence not known
flushing / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
lichen planus-like eruption / Delayed / Incidence not known
acneiform rash / Delayed / Incidence not known

BAVENCIO

Rx

Programmed death ligand-1 (PD-L1) blocking monoclonal antibody
Used for certain types of Merkel cell carcinoma, renal cell, and urothelial carcinoma
Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

800 mg IV every 2 weeks until disease progression. Premedicate patients with an antihistamine and acetaminophen at 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. Therapy interruption or discontinuation may be necessary in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions.[61826] In 88 patients (median age, 72.5 years) with metastatic Merkel cell carcinoma who had received at least 1 prior line of systemic chemotherapy for metastatic disease, treatment with avelumab resulted in a confirmed overall response rate of 31.8% (complete response, 9%) in part A of a multinational, phase 2 (JAVELIN Merkel 200) trial. At a median follow-up time of 10.4 months, the median progression-free survival (PFS) and overall survival (OS) times were 2.7 months and 11.3 months, respectively.[61829] In 116 patients (median age, 74 years) with metastatic Merkel cell carcinoma who had not previously received systemic chemotherapy for metastatic disease, treatment with avelumab resulted in an objective response rate lasting at least 6 months (primary endpoint) of 30.2% and a confirmed best overall response rate of 39.7% (complete response, 16.4%) in part B of the JAVELIN Merkel 200 trial. At a median follow-up time of 21.2 (range, 14.9 to 36.6) months, the median PFS and OS times were 4.1 months and 20.3 months, respectively.

800 mg IV every 2 weeks until disease progression. Premedicate patients with an antihistamine and acetaminophen at 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. Therapy interruption or discontinuation may be necessary in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult patients and from pharmacokinetic data suggesting that drug exposure is comparable between adults and pediatric patients aged 12 years and older.

800 mg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 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. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, open-label, single arm clinical trial, a cohort of patients from the Javelin Solid Tumor trial who had platinum-resistant, locally advanced or metastatic urothelial cancer were treated with avelumab. In this cohort, the objective response rate was 13.3% (complete response (CR), 4%; partial response (PR), 9.3%) after at least 13 weeks of follow-up (n = 226), and 16.1% (CR, 5.6%; PR, 10.6%) after at least 6 months of follow-up (n = 161). The median duration of response was not estimable but ranged from 1.4 to 17.4+ months.[61826]

800 mg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 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. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Maintenance therapy with avelumab significantly improved the median overall survival (OS) compared with best supportive care in patients with unresectable, locally advanced or metastatic urothelial cancer that did not progress with first-line platinum-based chemotherapy in a multicenter, open-label clinical trial (23.8 months vs. 15 months). In a prespecified endpoint of OS based on PD-L1 status, the effect of avelumab maintenance therapy remained statistically significant for patients with PD-L1 positive tumors. The effect was not significant in patients with PD-L1 negative tumors in an exploratory analysis.[61826]

800 mg IV over 1 hour every 2 weeks, in combination with axitinib (initial dose, 5 mg PO twice daily) until disease progression or unacceptable toxicity. The axitinib dosage may be increased to 7 mg twice daily and then to 10 mg twice daily in normotensive patients (not receiving antihypertensive medications) who tolerate the lower dosage for at least 2 consecutive weeks with no greater than grade 2 adverse reactions. 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. Avelumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Permanently discontinue therapy for severe or life-threatening infusion-related reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In the first interim analysis of an open-label phase 3 clinical trial (JAVELIN Renal 101), first-line combination therapy with avelumab and axitinib significantly improved PFS in patients with advanced renal cell carcinoma and PD-L1 expression of 1% or more compared with sunitinib monotherapy; the confirmed objective response rate almost doubled with combination therapy. Overall survival was not reached in either group and continues to be monitored.

Treatment-Related Immune-Mediated Hepatitis
Monotherapy
No Tumor Involvement of the LiverAST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue avelumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3 times the ULN: Permanently discontinue avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).Tumor Involvement of the LiverBaseline AST or ALT level at the ULN or less: Hold or permanently discontinue avelumab based on recommendations for hepatitis with no tumor involvement of the liver.Baseline AST or ALT level of more than 1 to 3 times the ULNAST or ALT level of more than 5 to 10 times the ULN: Hold avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue avelumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Baseline AST or ALT level of more than 3 to 5 times the ULNAST or ALT level of more than 8 to 10 times the ULN: Hold avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue avelumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Any Baseline AST or ALT levelAST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3-times the ULN: Permanently discontinue avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Combination Therapy with Axitinib
AST or ALT level of 3 to less than 10 times the ULN and a total bilirubin level of less than 2 times the ULN: Hold both avelumab and axitinib and consider corticosteroid therapy. Consider rechallenge with avelumab or axitinib (or sequential rechallenge with both) when hepatic enzymes recover to grade 1 or less. Per axitinib manufacturer guidance, consider a dose reduction if rechallenging with axitinib.AST or ALT level of 10 times the ULN or more OR an AST or ALT level more than 3 times the ULN and a total bilirubin level 2 times the ULN or more: Permanently discontinue avelumab and axitinib and consider corticosteroid therapy.

Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction Grade 2 or 3 increased serum creatinine (SCr) level: Hold avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue avelumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. Grade 4 increased SCr level: Permanently discontinue avelumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).

Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

BAVENCIO Intravenous Inj Sol: 1mL, 20mg

800 mg IV every 2 weeks.

800 mg IV every 2 weeks.

800 mg IV every 2 weeks.

Children 12 years of age: 800 mg IV every 2 weeks.
Children less than 12 years: safety and effectiveness not established.

Avelumab is a human IgG1 lambda monoclonal antibody that binds to the programmed death ligand-1 (PD-L1). PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to inhibition of the anti-tumor 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 of PD-L1 with PD-1 and B7.1 receptors. Blocking the PD-1/PD-L1 pathway improves the anti-tumor immune response by reducing immunosuppressive signals between immune cells and tumor cells. Additionally, avelumab induced antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In mice models, inhibiting PD-1 activity deceased tumor growth.

Avelumab is administered intravenously. In a population pharmacokinetic analysis in patients with solid tumors who received avelumab 10 mg/kg IV, the total systemic clearance was 0.59 L/day and the terminal half-life was 6.1 days. Clearance decreased from baseline by 32.1% (coefficient of variation, 36.2%) over time in a subpopulation of patients with Merkel cell carcinoma, which is not considered clinically important; there was no evidence to suggest a change of avelumab clearance over time in patients with urothelial or renal cell carcinoma. The geometric mean steady-state volume of distribution (Vd) was 4.72 L. Avelumab is eliminated primarily by proteolytic degradation.

In a population pharmacokinetic analysis (n = 1,629), steady-state avelumab concentrations were reached at approximately 4 to 6 weeks following an every 2-week dosing regimen; the systemic accumulation was approximately 1.25-fold after 4 to 6 weeks. Avelumab exposure increased proportionally in the dose range of 10 to 20 mg/kg IV every 2 weeks. Based on exposure efficacy and exposure safety relationships, there are no expected clinically meaningful differences in the safety, efficacy, or exposure of avelumab administered every 2 weeks at a dose of either 800 mg or 10 mg/kg.[61826]

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.    

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.