PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    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 the treatment of patients with locally advanced or metastatic urothelial carcinoma, or unresectable stage III NSCLC that has not progressed on platinum-based chemoradiotherapy
    Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

    COMMON BRAND NAMES

    IMFINZI

    HOW SUPPLIED

    IMFINZI Intravenous Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    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

    10 mg/kg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. In a multicenter, open-label clinical trial, patients with locally advanced or metastatic urothelial carcinoma who had progressed on or after platinum-based chemotherapy received treatment with durvalumab; patients with a history of immunodeficiency or autoimmune disease were excluded, along with patients who had medical conditions requiring immunosuppression. After a median follow-up of 5.6 months, the objective response rate (ORR) was 17% (complete response (CR), 2.7%; partial response (PR), 14.3%); the median duration of response was not reached (range, 0.9+ to 19.9+ months). Response rates were higher in patients with high levels of PD-L1 expression (ORR 26.3%; CR 3.2%; PR 23.2%) or PD-L1 expression not evaluable (ORR 21.4%; CR 7.1%; PR 14.3%) compared to low or negative PD-L1 expression (ORR 4.1%; CR 1.4%; PR 2.7%). In these patients, the median duration of response was not reached in patients with high PD-L1 or PD-L1 not evaluable and was 12.3 months for patients with low or negative PD-L1 expression. Among the total 31 responding patients, 14 patients (45%) had ongoing responses of 6 months or longer and five patients (16%) had ongoing responses of 12 months or longer.

    For the treatment of unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemoradiotherapy.
    Intravenous dosage
    Adults

    10 mg/kg IV over 60 minutes, every 2 weeks until disease progression or unacceptable toxicity for up to 12 months. In a planned interim analysis of a multicenter, randomized, double-blind, phase 3 clinical trial (the PACIFIC trial), consolidation treatment for up to 12 months with durvalumab after standard platinum-based chemoradiotherapy significantly prolonged median PFS by blinded independent central review (BICR) in patients with locally advanced or unresectable non-small cell lung cancer (NSCLC) compared with placebo (16.8 months vs. 5.6 months). The benefit in PFS was consistent across 35 prespecified subgroups, including PD-L1 25% or higher, PD-L1 less than 25%, and never smokers; hazard ratios for patients who were EGFR mutation-positive or -unknown were not clinically significant. Median overall survival was also significantly improved in the durvalumab arm (not reached vs. 28.7 months).[62499] [61913]

    For the treatment of small cell lung cancer (SCLC)†.
    NOTE: Durvalumab has been designated by the FDA as an orphan drug for the treatment of SCLC.
    For the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with carboplatin and etoposide†.
    Intravenous dosage
    Adults

    1,500 mg IV on day 1 plus carboplatin (AUC 5 to 6 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for up to 4 cycles. After completion of up to 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.

    For the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with cisplatin and etoposide†.
    Intravenous dosage
    Adults

    1,500 mg IV on day 1 plus cisplatin (75 to 80 mg/m2 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for up to 4 cycles. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. After completion of up to 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    10 mg/kg IV every 2 weeks.

    Geriatric

    10 mg/kg IV every 2 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild hepatic impairment: No dosage adjustments are necessary.
    Moderate (bilirubin 1.5 to 3 times the upper limit of normal (ULN) and any AST) or severe (bilirubin greater than 3 times ULN and any AST): Specific guidelines for dosage adjustments are not available; the effect of moderate to severe hepatic impairment on the pharmacokinetics of durvalumab is unknown.
     
    Management of Immune-Mediated Hepatitis
    ALT/AST 3.1 to 8 times ULN or total bilirubin 1.6 to 5 times ULN: Hold durvalumab therapy and initiate treatment with high-dose corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent). When hepatitis improves to grade 1 or less, begin a steroid taper over at least 1 month. Treatment may be resumed without a dose reduction when hepatitis is less than or equal to grade 1 and the corticosteroid dose has been reduced to less than 10 mg of prednisone or equivalent per day. Permanently discontinue durvalumab therapy for grade 2 or higher hepatotoxicity that does not recover to grade 1 or less within 12 weeks after the last dose of durvalumab, for the inability to reduce the dose of corticosteroids to less than or equal to 10 mg per day of prednisone equivalents within 12 weeks of the last dose of durvalumab, or for recurrent grade 3 or 4 hepatotoxicity.
    ALT/AST greater than 8 times ULN or total bilirubin greater than 5 times ULN: Permanently discontinue durvalumab therapy and initiate treatment with high-dose corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent). When hepatitis improves to grade 1 or less, begin a steroid taper over at least 1 month. Permanently discontinue durvalumab therapy for grade 2 or higher hepatotoxicity that does not recover to grade 1 or less within 12 weeks after the last dose of durvalumab, for the inability to reduce the dose of corticosteroids to less than or equal to 10 mg per day of prednisone equivalents within 12 weeks of the last dose of durvalumab, or for recurrent grade 3 or 4 hepatotoxicity.
    Concurrent ALT/AST greater than 3 times ULN and total bilirubin greater than 2 times ULN with no other cause: Permanently discontinue durvalumab therapy and initiate treatment with high-dose corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent). When hepatitis improves to grade 1 or less, begin a steroid taper over at least 1 month. Permanently discontinue durvalumab therapy for grade 2 or higher hepatotoxicity that does not recover to grade 1 or less within 12 weeks after the last dose of durvalumab, for the inability to reduce the dose of corticosteroids to less than or equal to 10 mg per day of prednisone equivalents within 12 weeks of the last dose of durvalumab, or for recurrent grade 3 or 4 hepatotoxicity.

    Renal Impairment

    Baseline Renal Impairment
    Mild to moderate renal impairment (CrCL greater than or equal to 30 mL/min): No dosage adjustments are necessary.
    Severe renal impairment (CrCL 15 to 29 mL/min): Specific guidelines for dosage adjustments in renal impairment are not available; the effect of severe renal impairment on the pharmacokinetics of durvalumab is unknown.
     
    Management of Immune-Mediated Nephritis
    Grade 2 (SCr greater than 1.5 to 3 times ULN): Hold durvalumab therapy and initiate treatment with high-dose corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent). When nephritis improves to grade 1 or less, begin a steroid taper over at least 1 month. Treatment may be resumed without a dose reduction when nephritis is less than or equal to grade 1 and the corticosteroid dose has been reduced to less than 10 mg of prednisone or equivalent per day. Permanently discontinue durvalumab therapy for grade 2 nephritis that does not recover to grade 1 or less within 12 weeks after the last dose of durvalumab or for the inability to reduce the dose of corticosteroids to less than or equal to 10 mg per day of prednisone equivalents within 12 weeks of the last dose of durvalumab.
    Grade 3 or 4 (SCr greater than 3 times ULN): Permanently discontinue durvalumab therapy and initiate treatment with high-dose corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent). When nephritis improves to grade 1 or less, begin a steroid taper over at least 1 month. Permanently discontinue durvalumab therapy for grade 3 or 4 nephritis that does not recover to grade 1 or less within 12 weeks after the last dose of durvalumab, for the inability to reduce the dose of corticosteroids to less than or equal to 10 mg per day of prednisone equivalents within 12 weeks of the last dose of durvalumab, or for recurrent grade 3 or 4 nephritis.

    ADMINISTRATION

    Injectable Administration

    Visually inspect drug product for particulate matter and discoloration. Durvalumab is clear to opalescent, colorless to slightly yellow solution, free from visible particles. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
    Do not shake durvalumab.

    Intravenous Administration

    Preparation:
    Withdraw the required volume of drug and transfer into an intravenous container containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection, to prepare an infusion with a final concentration ranging from 1 mg/mL to 15 mg/mL.
    Mix diluted solution by gentle inversion. Do not shake.
    Discard partially used or empty vials of durvalumab.
    Storage of Diluted Solution:
    Durvalumab does not contain a preservative; administer immediately after preparation.
    If storage of the diluted solution is necessary, the total time from vial puncture to the start of administration should be less than 24 hours if refrigerated (2 to 8 degrees C; 36 to 46 degrees F), or less than 4 hours at room temperature (up to 25 degrees C; up to 77 degrees F). Do not freeze.
    Intravenous Infusion:
    Administer the diluted infusion over 60 minutes through an intravenous line containing sterile, low protein binding 0.2 or 0.22 micron in-line filter.
    Do not coadminister with other drugs through the same intravenous line.

    STORAGE

    IMFINZI:
    - 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
    - See package insert for detailed storage information
    - Store between 36 to 46 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, pulmonary disease

    Use durvalumab with caution in patients with pre-existing pulmonary disease. Immune-mediated pneumonitis or interstitial lung disease (ILD) has been reported with durvalumab therapy; one case was fatal. Monitor patients for signs or symptoms (e.g., new or worsening chest pain or shortness of breath) of pneumonitis. If patients have suspected pneumonitis, evaluate with radiographic imaging; an interruption or discontinuation of therapy and treatment with high-dose corticosteroids (followed by a steroid taper) may be necessary.

    Hepatic disease, hepatitis

    Use durvalumab with caution in patients with pre-existing hepatic disease; the clinical trial resulting in FDA approval excluded patients with a history of hepatitis B or C infection, and the effect of moderate or severe hepatic impairment on the pharmacokinetics of durvalumab is unknown. Immune-mediated hepatitis has been reported with durvalumab therapy; one case was fatal. Monitor patients for abnormal liver tests prior to each cycle of treatment with durvalumab. Immune-mediated hepatitis should be managed with an interruption or discontinuation of therapy and treatment with high-dose corticosteroids (followed by a steroid taper).

    Colitis, Crohn's disease, diarrhea, inflammatory bowel disease, ulcerative colitis

    Use durvalumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Diarrhea and immune-mediated colitis have occurred with durvalumab therapy. Monitor patients for signs and symptoms of colitis (e.g., diarrhea or severe abdominal pain). Treatment with high-dose corticosteroids (followed by a steroid taper), along with an interruption or discontinuation of therapy, may be necessary.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Thyroid disease/disorders such as hypothyroidism and hyperthyroidism have occurred in patients who received durvalumab therapy. Monitor thyroid function tests (TFTs) at baseline and periodically during treatment. Hypothyroidism may be managed with hormone replacement therapy and does not require an interruption of durvalumab treatment. Interrupt durvalumab therapy until the patient is clinically stable for grade 2 or higher hyperthyroidism and manage medically.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Immune-mediated adrenal insufficiency and hypophysitis/hypopituitarism have occurred in patients treated with durvalumab. Monitor patients for signs and symptoms of adrenal insufficiency (e.g., hypotension, decreased cortisol level, fatigue, weakness, and weight loss) and hypophysitis (e.g., decreased pituitary hormone levels, pituitary gland inflammation, severe intractable headache, and vision impairment) during and after durvalumab treatment. An interruption of therapy, treatment with high-dose corticosteroids, and hormone replacement may be necessary.

    Autoimmune disease, immunosuppression, organ transplant, systemic lupus erythematosus (SLE)

    Use durvalumab with caution in patients with autoimmune disease (e.g., systemic lupus erythematosus (SLE)) or conditions that require immunosuppression (e.g., chronic corticosteroid use) and in patients who have previously had an organ transplant. These patient populations were excluded from clinical trials; the mechanism of action of durvalumab involves modulation of the immune system.

    Diabetes mellitus, type 1 diabetes mellitus

    Immune-related type 1 diabetes mellitus has occurred in patients receiving treatment with durvalumab. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Initiate insulin for type 1 diabetes; an interruption of durvalumab therapy may be necessary.

    Serious rash

    An immune-mediated serious rash has occurred in patients receiving treatment with durvalumab. Monitor patients for signs and symptoms of rash. An interruption or discontinuation of durvalumab therapy may be necessary, along with treatment with high-dose corticosteroids.

    Renal disease, renal impairment

    Immune-mediated nephritis has occurred in patients treated with durvalumab. Monitor renal function at baseline and before each cycle of treatment. No initial dose adjustment is recommended in patients with renal dysfunction; however, use durvalumab with caution in patients with renal disease or renal impairment. If immune-mediated nephritis occurs, an interruption or discontinuation of durvalumab therapy may be necessary, along with treatment with high-dose corticosteroids.

    Aseptic meningitis, hemolytic anemia, keratitis, myocarditis, uveitis

    Immune-mediated reactions such as aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity including uveitis and keratitis have occurred with durvalumab therapy. Monitor patients for signs and symptoms of immune-mediated reactions; confirm etiology or exclude other causes. Therapy may need to be temporarily withheld or permanently discontinued; administer corticosteroids as clinically indicated. If uveitis occurs in combination with other immune-mediated reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

    Infusion-related reactions

    Severe or life-threatening infusion-related reactions may occur in patients treated with durvalumab. Monitor patients for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions; consider premedications for subsequent doses in these patients. Permanently discontinue durvalumab in patients with grade 3 or 4 infusion reactions.

    Immune-mediated reactions

    Severe and fatal immune-mediated reactions can occur with durvalumab therapy; these reactions may involve any organ system. While they usually manifest during treatment with durvalumab, they may also occur after discontinuation of therapy. Monitor patients for immune-mediated reactions; an interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during durvalumab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, durvalumab can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus. The PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys at exposures approximately 6 to 20 times higher than those observed at the recommended dose of 10 mg/kg in humans resulted in increased premature delivery, fetal loss (abortion and stillbirth), and premature neonatal death. Based on its mechanism of action, fetal exposure to durvalumab mal also increase the risk of developing immune-mediated disorders or altering the normal immune response.

    Contraception requirements, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during durvalumab treatment. Durvalumab can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with durvalumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of durvalumab. Women who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from durvalumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether durvalumab is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 30.9-30.9
    lymphopenia / Delayed / 11.0-17.0
    hyponatremia / Delayed / 3.6-12.0
    infection / Delayed / 0.4-10.9
    hyperglycemia / Delayed / 3.0-8.0
    anemia / Delayed / 0-8.0
    fatigue / Early / 0.8-6.0
    hepatitis / Delayed / 5.0-5.0
    pneumonitis / Delayed / 1.2-4.5
    musculoskeletal pain / Early / 4.4-4.4
    elevated hepatic enzymes / Delayed / 1.0-4.0
    hypermagnesemia / Delayed / 0-4.0
    hepatotoxicity / Delayed / 0-3.3
    abdominal pain / Early / 0.4-3.0
    dyspnea / Early / 1.5-2.0
    nausea / Early / 0-2.0
    peripheral edema / Delayed / 0-2.0
    renal failure (unspecified) / Delayed / 0-1.4
    diarrhea / Early / 0.6-1.1
    colitis / Delayed / 0.6-1.1
    hyperbilirubinemia / Delayed / 0-1.0
    hypoalbuminemia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    rash / Early / 0.6-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    keratitis / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    aseptic meningitis / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    fever / Early / 0.2-1.0
    cough / Delayed / 0-0.6
    hypothyroidism / Delayed / 0-0.2
    hypocalcemia / Delayed / 0.2-0.2
    diabetes insipidus / Delayed / 0-0.1
    adrenocortical insufficiency / Delayed / 0-0.1
    pulmonary fibrosis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    myasthenia gravis / Delayed / Incidence not known

    Moderate

    dysuria / Early / 0-10.0
    dysphonia / Delayed / 0-10.0
    hyperthyroidism / Delayed / 7.0-7.0
    hypercalcemia / Delayed / 0-3.0
    antibody formation / Delayed / 2.9-2.9
    bullous rash / Early / 0-1.0
    iritis / Delayed / 0-1.0
    ocular inflammation / Early / 0-1.0
    hypokalemia / Delayed / 0-1.0
    infusion-related reactions / Rapid / 0.3-0.3
    hypopituitarism / Delayed / 0-0.1
    dehydration / Delayed / 3.0
    flank pain / Delayed / Incidence not known
    hypophysitis / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    erythema / Early / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    paresis / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 0-12.0
    night sweats / Early / 0-10.0
    purpura / Delayed / 0-1.0
    lichen planus-like eruption / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    laryngitis / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    back pain / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    malaise / 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

    Pregnancy should be avoided by females of reproductive potential during durvalumab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, durvalumab can cause fetal harm when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus. The PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys at exposures approximately 6 to 20 times higher than those observed at the recommended dose of 10 mg/kg in humans resulted in increased premature delivery, fetal loss (abortion and stillbirth), and premature neonatal death. Based on its mechanism of action, fetal exposure to durvalumab mal also increase the risk of developing immune-mediated disorders or altering the normal immune response.

    Due to the potential for serious adverse reactions in nursing infants from durvalumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether durvalumab is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    Durvalumab is a human IgG1 kappa (IgG1k) monoclonal antibody, produced in Chinese Hamster Ovary (CHO) cell suspension culture, that inhibits programmed death ligand 1 (PD-L1) interactions with the PD-1 and CD80 (B7.1) molecules. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells, can be induced by inflammatory signals (e.g., IFN-gamma), and can contribute to inhibition of the anti-tumor immune response in the tumor microenvironment; PD-1 and B7.1 receptors are found on T-cells and antigen-presenting cells. The PD-1 pathway regulates the balance between T-cell activation and protection of healthy tissues from immune-mediated damage. In cancer, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

    PHARMACOKINETICS

    Durvalumab is administered intravenously. Exposure to durvalumab increases more than dose-proportionally at doses less than 3 mg/kg (0.3 times the approved dosage), but increases in a dose-proportional manner at doses greater than or equal to 3 mg/kg every 2 weeks. In a pharmacokinetic study (n = 1,902), steady state was reached in approximately 16 weeks when administered at doses up to 2 times the recommended dosage every 2, 3, or 4 weeks. The geometric mean volume of distribution at steady state (% coefficient of variation, CV%) was 5.6 liters (CV%, 18%). The mean clearance of durvalumab at steady state is 8.2 mL/hour (CV%, 39%). Clearance decreases over time, with a mean maximal reduction from baseline of approximately 23% (CV%, 57%); however, the decrease in clearance at steady state is not clinically relevant. The mean terminal half-life was 18 days (CV%, 24%).