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    Monoclonal Antibodies that Target the Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways

    DEA CLASS

    Rx

    DESCRIPTION

    Human 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

    COMMON BRAND NAMES

    BAVENCIO

    HOW SUPPLIED

    BAVENCIO Intravenous Inj Sol: 1mL, 20mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic Merkel cell carcinoma.
    NOTE: The FDA has designated avelumab as an orphan drug for the treatment of Merkel cell carcinoma.
    Intravenous dosage
    Adults, Adolescents, and Children 12 years of age

    800 mg IV over 60 minutes every 2 weeks until disease progression. 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.[61826] The confirmed objective response rate (ORR) was 31.8% in patients with metastatic, chemotherapy-refractory Merkel cell carcinoma who received avelumab (median of 7 doses; median duration of therapy, 17 weeks) in a multinational, phase 2 study (n = 88); the complete response rate was 9%. The response duration ranged from 2.8 months to at least 17.5 months. The ORR was 26.1% in 46 patients with Merkel-cell polyomavirus (MCPyV)-positive tumors and 35.5% in 31 patients with MCPyV-negative tumors. The ORR was 34.5% in 58 patients with PD-L1-positive tumors and 18.8% in 16 patients with PD-L1-negative tumors. At a median follow-up time of 10.4 months, the median progression-free survival (PFS) time was 2.7 months and the 6-month PFS rate was 40%. Additionally, the median overall survival (OS) time was 11.3 months and the 6-month OS rate was 69%. Adult patients (median age, 72.5 years) with stage IV Merkel cell carcinoma that progressed after at least 1 prior line of chemotherapy for metastatic disease were eligible for study treatment.[61829] 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 age 12 years and older.[61826]

    For the treatment of urothelial carcinoma.
    For the treatment of locally advanced or metastatic urothelial carcinoma, in patients with disease progression on or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
    Intravenous dosage
    Adults

    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]

    For the treatment of renal cell cancer.
    For the first-line treatment of advanced renal cell cancer, in combination with axitinib.
    Intravenous dosage
    Adults

    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.

    MAXIMUM DOSAGE

    Adults

    800 mg IV every 2 weeks.

    Geriatric

    800 mg IV every 2 weeks.

    Adolescents

    800 mg IV every 2 weeks.

    Children

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

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    No dosage adjustments are necessary.
     
    Treatment-Related Hepatotoxicity
    Monotherapy
    Grade 2 hepatitis (AST/ALT 3.1 to 5 times the upper limit of normal (ULN) or total bilirubin 1.6 to 3 times ULN): Hold avelumab therapy and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper); resume therapy when liver function tests recover to grade 1 or less after a corticosteroid taper.
    Grade 3 or 4 hepatitis (AST/ALT more than 5 times ULN or total bilirubin more than 3 times ULN): Permanently discontinue avelumab therapy. Administer corticosteroids (e.g., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper).
    In combination with axitinib for renal cell carcinoma:
    AST/ALT 3 to 4.9 times ULN: Hold both avelumab and axitinib therapy until AST/ALT recover to grade 1 or less. If transaminitis is persistent (greater than 5 days), consider corticosteroid therapy at an initial dose of prednisone 0.5 to 1 mg/kg/day or equivalent, followed by a taper. Consider rechallenge with a single drug or sequential challenge with both drugs after recovery. Refer to the axitinib monograph for recommendations for dose reduction.
    AST/ALT 5 times ULN or more: Permanently discontinue both avelumab and axitinib therapy. Consider corticosteroid therapy at an initial dose of prednisone 1 to 2 mg/kg per day or equivalent, followed by a taper.
    Total bilirubin 1.5 to 2.9 times ULN: Hold both avelumab and axitinib therapy until total bilirubin recovers to grade 1 or less. If hyperbilirubinemia is persistent (greater than 5 days), consider corticosteroid therapy at an initial dose of prednisone 0.5 to 1 mg/kg/day or equivalent, followed by a taper. Consider rechallenge with a single drug or sequential challenge with both drugs after recovery. Refer to the axitinib monograph for recommendations for dose reduction.
    Total bilirubin 3 times ULN or more: Permanently discontinue both avelumab and axitinib therapy. Consider corticosteroid therapy at an initial dose of prednisone 1 to 2 mg/kg per day or equivalent, followed by a taper.
    Concurrent AST/ALT greater than 3 times ULN with total bilirubin 2 times ULN or more: Permanently discontinue both avelumab and axitinib therapy. Consider corticosteroid therapy at an initial dose of prednisone 1 to 2 mg/kg per day or equivalent, followed by a taper.

    Renal Impairment

    Baseline Renal Impairment
    No dosage adjustment is necessary.
     
    Treatment-Related Nephrotoxicity
    Grade 2 to 3 nephritis (serum creatinine 1.6 to 6 times ULN): Hold avelumab therapy and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper); resume therapy when serum creatinine recovers to grade 1 or less after a corticosteroid taper.
    Grade 4 nephritis (serum creatinine more than 6 times ULN): Permanently discontinue avelumab therapy. Administer corticosteroids (e.g., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper).

    ADMINISTRATION

    Injectable Administration

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

    Intravenous Administration

    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]

    STORAGE

    BAVENCIO:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - See package insert for detailed storage information
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis

    Immune-mediated pneumonitis has been reported with avelumab therapy; some cases were fatal. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, or shortness of breath). If pneumonitis is suspected, confirm with radiographic imaging. In patients who develop grade 2 or greater immune-mediated pneumonitis, hold therapy and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper). Permanently discontinue therapy in patients who develop grade 3 or grade 4 pneumonitis or recurrent grade 2 pneumonitis. The median time to onset of pneumonitis was 2.5 months for a median duration of 7 weeks.

    Hepatic disease, hepatitis, hepatotoxicity

    Immune-mediated hepatitis, including some cases that were fatal, has been reported with avelumab therapy; the median time to onset was 3.2 months with a median duration of 2.5 months. Avelumab in combination with axitinib can cause hepatotoxicity with higher than expected frequencies compared to either drug alone. Evaluate liver function tests prior to starting avelumab and periodically during therapy; consider more frequent monitoring when given in combination with axitinib. Treatment may need to be temporarily withheld or permanently discontinued if signs of hepatitis or hepatotoxicity occur. Treatment with corticosteroids may also be necessary. No initial avelumab dosage adjustments are necessary for patients with mild or moderate hepatic impairment; the effect of severe hepatic disease on avelumab exposure is unknown.

    Colitis

    Immune-mediated colitis has been reported with avelumab therapy. The median time to onset of colitis was 2.1 months with a median duration of 6 weeks.  Monitor patients for signs and symptoms of colitis (e.g., severe diarrhea or abdominal pain). In patients who develop grade 2 or greater immune-mediated colitis, hold therapy and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper). Permanently discontinue therapy in patients who develop recurrent grade 3 colitis or grade 4 colitis.

    Adrenal insufficiency

    Immune-mediated adrenal insufficiency has been reported with avelumab therapy. Monitor patients for signs and symptoms of adrenal insufficiency during and after therapy. Administer corticosteroids as appropriate. Hold therapy in patients who develop grade 3 or 4 immune-mediated adrenal insufficiency. The median time to onset of adrenal insufficiency was 2.5 months.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Immune-mediated thyroid disease including hypothyroidism, hyperthyroidism, and thyroiditis have been reported with avelumab therapy. They can occur at any time during treatment, although the median time to onset was 2.8 months. Evaluate thyroid function tests prior to starting avelumab therapy and periodically during therapy. Treat hypothyroidism with hormone-replacement therapy; initiate medical management for hyperthyroidism. Administer corticosteroids as appropriate. Hold therapy in patients who develop grade 3 or 4 immune-mediated thyroid disease.

    Diabetes mellitus, diabetic ketoacidosis, type 1 diabetes mellitus

    Avelumab therapy can cause type 1 diabetes mellitus, including diabetic ketoacidosis; use avelumab with caution in patients with pre-existing diabetes. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Hold therapy in patients who develop grade 3 or 4 hyperglycemia and administer antihyperglycemic or insulin as appropriate. Therapy may be resumed when metabolic control is achieved.[61826]

    Renal impairment

    Immune-mediated nephritis and renal impairment/dysfunction have been reported with avelumab therapy. Monitor serum creatinine prior to starting avelumab therapy and periodically during therapy. In patients who develop grade 2 or greater immune-mediated nephritis, hold therapy and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent initially, followed by a taper). Permanently discontinue therapy in patients who develop grade 4 nephritis.

    Immune-mediated reactions

    Immune-mediated reactions such as arthritis, myocarditis, myositis, exfoliative dermatitis, erythema multiforme, Guillain-Barre syndrome, hypopituitarism, pemphigoid, psoriasis, systemic inflammatory response (SIRS), and uveitis have been reported with avelumab therapy; some cases were fatal. Immune-mediated reactions may involve any organ system. Monitor patients for signs and symptoms of immune-mediated reactions; confirm etiology or exclude other causes. Immune-mediated reactions typically occur during avelumab therapy, although some cases may occur after avelumab therapy is discontinued. An interruption or discontinuation of therapy may be necessary. For endocrinopathies, administer hormone replacement as clinically indicated.

    Infusion-related reactions

    Severe or life-threatening infusion-related reactions have been reported with avelumab therapy. 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-related reactions such as fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Hold the infusion or slow the rate in patients who develop mild or moderate infusion-related reactions; permanently discontinue therapy in patients who experience a grade 3 or 4 infusion reaction.

    Autoimmune disease, immunosuppression, organ transplant

    Use avelumab with caution in patients with autoimmune disease or conditions that require immunosuppression, and in patients who have previously had an organ transplant. These patient populations were excluded from clinical trials; the mechanism of action of avelumab involves modulation of the immune system.

    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. Optimize management of cardiovascular risk factors such as hypertension, diabetes, or hyperlipidemia. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Discontinue avelumab and axitinib for grade 3 or 4 cardiovascular events.

    Pregnancy

    Based on its mechanism of action, avelumab may cause fetal harm if administered during pregnancy by increasing the risk of immune-mediated rejection of the developing fetus; increasing the risk of developing immune-related disorders or altering the normal immune response in the fetus is also possible. Human IgG1 immunoglobulins are known to cross the placenta; therefore, there may be drug exposure to the developing fetus. If avelumab is used during pregnancy or if a woman becomes pregnant while receiving it, the patient should be apprised of the potential hazard to the fetus. The programmed death receptor-1 (PD-1)/PD-1 ligand (PDL-1) pathway helps to preserve pregnancy by maintaining maternal tolerance to the fetus. Although there are no human or animal reproduction studies with avelumab, inhibiting PD-1/PDL-1 binding and signaling led to an increase in fetal loss in murine models. Potential risks for blocking the PD-1/PDL-1 pathway include an increased incidence of abortion or stillbirths.

    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.

    Breast-feeding

    It is not known if avelumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because many drugs including antibodies are excreted in human milk and there is a potential for adverse reactions in nursing infants from avelumab, women should discontinue breast-feeding during avelumab therapy and for at least 1 month after the last dose.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 11.0-19.0
    hyponatremia / Delayed / 9.0-16.0
    elevated hepatic enzymes / Delayed / 1.0-12.0
    hepatotoxicity / Delayed / 0-9.0
    hyperglycemia / Delayed / 7.0-9.0
    anemia / Delayed / 6.0-9.0
    fatigue / Early / 2.0-7.0
    hypertension / Early / 5.0-6.0
    infection / Delayed / 0-5.0
    musculoskeletal pain / Early / 2.0-3.2
    dyspnea / Early / 1.0-3.0
    renal failure (unspecified) / Delayed / 0-3.0
    hyperkalemia / Delayed / 3.0-3.0
    diarrhea / Early / 0-2.0
    abdominal pain / Early / 2.0-2.0
    anorexia / Delayed / 2.0-2.0
    hyperamylasemia / Delayed / 1.0-2.0
    hyperbilirubinemia / Delayed / 1.0-1.0
    vomiting / Early / 0-1.0
    constipation / Delayed / 1.0-1.0
    nausea / Early / 0-1.0
    Guillain-Barre syndrome / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    fever / Early / 0-1.0
    uveitis / Delayed / 0-1.0
    hepatitis / Delayed / 0.7-0.7
    infusion-related reactions / Rapid / 0-0.7
    pneumonitis / Delayed / 0.5-0.5
    colitis / Delayed / 0.4-0.4
    peripheral edema / Delayed / 0-0.4
    pruritus / Rapid / 0-0.4
    rash / Early / 0-0.4
    cough / Delayed / 0-0.2
    adrenocortical insufficiency / Delayed / 0.1-0.1
    interstitial nephritis / Delayed / 0.1-0.1
    GI obstruction / Delayed / Incidence not known
    ileus / 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
    erythema multiforme / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 4.1-15.0
    hypothyroidism / Delayed / 5.0-5.0
    hyperthyroidism / Delayed / 0.4-0.4
    diabetes mellitus / Delayed / 0.1-0.1
    dehydration / Delayed / 2.0
    hematuria / Delayed / 2.0
    stomatitis / Delayed / Incidence not known
    hypopituitarism / Delayed / Incidence not known
    hypophysitis / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    dysphonia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / 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
    psoriasis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    bullous rash / Early / Incidence not known

    Mild

    weight loss / Delayed / 15.0-19.0
    dizziness / Early / 0-14.0
    headache / Early / 0-10.0
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    myalgia / Early / Incidence not known
    back pain / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known

    DRUG INTERACTIONS

    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on its mechanism of action, avelumab may cause fetal harm if administered during pregnancy by increasing the risk of immune-mediated rejection of the developing fetus; increasing the risk of developing immune-related disorders or altering the normal immune response in the fetus is also possible. Human IgG1 immunoglobulins are known to cross the placenta; therefore, there may be drug exposure to the developing fetus. If avelumab is used during pregnancy or if a woman becomes pregnant while receiving it, the patient should be apprised of the potential hazard to the fetus. The programmed death receptor-1 (PD-1)/PD-1 ligand (PDL-1) pathway helps to preserve pregnancy by maintaining maternal tolerance to the fetus. Although there are no human or animal reproduction studies with avelumab, inhibiting PD-1/PDL-1 binding and signaling led to an increase in fetal loss in murine models. Potential risks for blocking the PD-1/PDL-1 pathway include an increased incidence of abortion or stillbirths.

    It is not known if avelumab is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because many drugs including antibodies are excreted in human milk and there is a potential for adverse reactions in nursing infants from avelumab, women should discontinue breast-feeding during avelumab therapy and for at least 1 month after the last dose.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    Intravenous Route

    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]