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  • CLASSES

    Antineoplastic Monoclonal Antibodies

    DEA CLASS

    Rx

    DESCRIPTION

    Humanized monoclonal antibody that binds to and blocks programmed death-ligand 1
    Used for locally advanced or metastatic urothelial carcinoma and platinum-resistant metastatic non-small cell lung cancer
    Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

    COMMON BRAND NAMES

    Tecentriq

    HOW SUPPLIED

    Tecentriq Intravenous Inj Sol: 1mL, 60mg

    DOSAGE & INDICATIONS

    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers.
    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers, in patients who progress during or following any platinum-containing chemotherapy.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be infused over 30 minutes. In a multicenter, open-label clinical trial, atezolizumab was administered to patients with locally advanced or metastatic urothelial cancer (n = 310); 19% of patients had progression following platinum-containing neoadjuvant or adjuvant therapy, while 41% had received 2 or more systemic regimens for metastatic disease. After a median follow-up of 14.4 months, the objective response rate (ORR) was 14.8% (95% CI, 11.1% to 19.3%) and the median duration of response had not been reached (range, 2.1+ months to 13.8+ months). In a subgroup analysis, those with less than 5% PD-L1 expression in tumor-infiltrating immune cells (ICs) had an ORR of 9.5% and a median duration of 12.7 months; the ORR was 26% and median duration not reached in those with 5% or more PD-L1 expression in ICs.

    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers, in patients who progress within 12 months of neoadjuvant or adjuvant chemotherapy.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be infused over 30 minutes. In a multicenter, open-label clinical trial, atezolizumab was administered to patients with locally advanced or metastatic urothelial cancer (n = 310); 19% of patients had progression following platinum-containing neoadjuvant or adjuvant therapy, while 41% had received 2 or more systemic regimens for metastatic disease. After a median follow-up of 14.4 months, the objective response rate (ORR) was 14.8% (95% CI, 11.1% to 19.3%) and the median duration of response had not been reached (range, 2.1+ months to 13.8+ months). In a subgroup analysis, those with less than 5% PD-L1 expression in tumor-infiltrating immune cells (ICs) had an ORR of 9.5% and a median duration of 12.7 months; the ORR was 26% and median duration not reached in those with 5% or more PD-L1 expression in ICs.

    For the treatment of locally advanced or metastatic urothelial carcinoma, including bladder cancer and other urinary system cancers, in patients who are not eligible for cisplatin-containing chemotherapy.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be infused over 30 minutes. Atezolizumab was administered to patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy (n = 119). After a median follow-up of 14.4 months, the objective response rate (ORR) was 23.5% (95% CI, 16.2% to 32.2%) and the median duration of response had not been reached (range, 3.7 months to 16.6+ months); 6.7% of patients experienced a complete response (CR), while a partial response (PR) was achieved in 16.8%. In a subgroup analysis, patients with less than 5% PD-L1 expression in tumor-infiltrating immune cells (ICs) (n = 87) had an ORR of 21.8% (CR, 6.9%; PR, 14.9%), while the ORR was 28.1% (CR, 6.3%; PR, 21.9%) in those with 5% or more PD-L1 expression in ICs; the median duration of response was not reached in either group.

    For the treatment of metastatic non-small cell lung cancer (NSCLC), with disease progression on or after platinum-containing chemotherapy, and after progression on FDA-approved EGFR- or ALK-targeted therapy if applicable.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes on day 1, every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, subsequent doses may be given over 30 minutes. In clinical trials, atezolizumab could be continued beyond disease progression, as long as clinical benefit was evident. In a multicenter, randomized, open-label phase 2 clinical trial, second-line treatment of platinum-resistant NSCLC with atezolizumab improved overall survival (12.6 months vs. 9.7 months; p = 0.04) compared with docetaxel; progression-free survival (PFS) and objective response rate (ORR) were not significantly different. In a pre-planned subgroup analysis, the benefit of atezolizumab was greater in patients with >= 1% of PD-L1 expressing tumor cells or tumor-infiltrating cells. Atezolizumab was better tolerated than docetaxel.

    MAXIMUM DOSAGE

    Adults

    1,200 mg IV every 3 weeks.

    Geriatric

    1,200 mg IV every 3 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Based on a population pharmacokinetic analysis, no dose adjustment of atezolizumab is recommended for patients with mild hepatic impairment. Atezolizumab has not been studied in patients with moderate or severe hepatic impairment.
    Treatment-Related Hepatotoxicity
    AST/ALT 3 to 5 times the upper limit of normal (ULN) or total bilirubin 1.5 to 3 times ULN (grade 2): Hold atezolizumab therapy and initiate therapy with corticosteroids (1 to 2 mg/kg/day of prednisone equivalents followed by steroid taper). Resume therapy at the original dose when the AST or ALT recover to less than 3 times ULN or bilirubin is less than 1.5 times ULN. Dosage adjustments of atezolizumab are not recommended.
    AST/ALT more than 5 times ULN or total bilirubin more than 3 times ULN (grade 3 or higher): Permanently discontinue atezolizumab and initiate therapy with corticosteroids (1 to 2 mg/kg/day of prednisone equivalents followed by steroid taper).

    Renal Impairment

    Based on a population pharmacokinetic analysis, no dose adjustment of atezolizumab is recommended for patients with renal impairment.

    ADMINISTRATION

    Injectable Administration

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

    Intravenous Administration

    Administer the first dose intravenously, with or without a sterile, non-pyrogenic, low-protein binding in-line filter (0.2 to 0.22 micron), over 60 minutes. If tolerated, all subsequent infusions may be infused over 30 minutes.
    Interrupt or slow administration for grade 2 infusion-related reactions; the infusion may resume when symptoms have resolved to grade 0 or 1.
    Permanently discontinue atezolizumab for grade 3 or 4 infusion-related reactions.
    Do not administer atezolizumab as an IV push or bolus.
    Do not infuse through the same IV line with other drugs.
     
    Dilution
    Withdraw 20 mL (1,200 mg) atezolizumab from the vial and dilute into a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 250 mL of 0.9% Sodium Chloride Injection. Mix by gentle inversion; do not shake.
    Store diluted solution at room temperature for no more than 6 hours (including infusion time), or under refrigeration (2 to 8 degrees C; 36 to 46 degrees F) for no more than 24 hours.

    STORAGE

    Tecentriq :
    - 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)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis

    Immune-mediated pneumonitis or interstitial lung disease, including fatalities, has been reported with atezolizumab therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath); if suspected, confirm with radiographic imaging. Therapy may need to be temporarily withheld or permanently discontinued. Corticosteroids should be administered in patients who develop grade 2 or greater immune-mediated pneumonitis. The median time to onset of immune-mediated pneumonitis in patients with urothelial carcinoma was 2.6 months (range, 15 days to 4.2 months), with a median duration of 15 days (range, 6 days to greater than 3.1 months); in patients with NSCLC, the median onset was 3.3 months (range, 3 days to 18.7 months) with a median duration of 1.4 months (range, 0 days to greater than 12.6 months).

    Hepatic disease, hepatitis

    Immune-mediated hepatitis, requiring the use of corticosteroids and with no clear alternate etiology, has occurred in patients treated with atezolizumab. The median time to onset was 28 days to 1.1 months (range, 0.4 to 7.7 months). Evaluate liver function tests (LFTs) prior to beginning treatment with atezolizumab and periodically during therapy; monitor for signs and symptoms of hepatitis. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids. No initial dosage adjustments are necessary in patients with mild hepatic impairment; atezolizumab has not been studied in patients with moderate or severe hepatic disease.

    Autoimmune disease

    Atezolizumab treatment has been associated with serious and sometimes fatal immune-mediated toxicities. Cautious use of atezolizumab may be warranted in patients with a history of autoimmune disease or who are receiving systemic immunostimulatory agents or immunosuppressive therapy, as these patients were excluded from clinical trials.

    Colitis, diarrhea

    Atezolizumab treatment can result in severe and fatal immune-mediated colitis or diarrhea, without a clear alternate etiology and requiring the use of corticosteroids. Monitor patients for signs and symptoms of enterocolitis (diarrhea, abdominal pain, and mucus or blood in stool) and bowel perforation (peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms; an interruption or discontinuation of therapy may be necessary, along with antidiarrheals and high-dose corticosteroids. The median time to onset of immune-mediated colitis or diarrhea was 3 weeks to 1.7 months (range, 12 days to 3.4 months). Treatment with corticosteroids resulted in resolution in 7 of 9 patients, while the other 2 patients died (due to diarrhea-associated renal failure and progressive disease). Cautious use of atezolizumab in patients with inflammatory bowel disease such as ulcerative colitis or Crohn's disease may be warranted; patients with a history of autoimmune disease were excluded from clinical trials.

    Adrenal insufficiency, hyperthyroidism, hypophysitis, hypopituitarism, hypothyroidism, thyroid disease

    Atezolizumab can result in severe and life-threatening immune-mediated endocrinopathies, including hypophysitis and thyroid disorders. An interruption or discontinuation of therapy along with initiation of corticosteroid treatment may be necessary. Begin appropriate hormone replacement therapy as clinically indicated. Assess patients for signs and symptoms of endocrinopathy such as hypophysitis, hypopituitarism, adrenal insufficiency (including adrenal crisis), hyperthyroidism, and hypothyroidism; presentation may include fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, hypotension, or other nonspecific symptoms. Evaluate thyroid function tests at baseline and periodically during treatment. The median time to onset of hypothyroidism was 4.8 to 5.4 months (range, 15 days to 31 months), while hyperthyroidism occurred at a median onset of 3.2 to 4.9 months (range, 3 weeks to 31 months). Cautious use of atezolizumab may be warranted for patients with pre-existing thyroid disease or Addison's disease; patients with a history of autoimmune disease were excluded from clinical trials.

    Diabetes mellitus, diabetic ketoacidosis

    New onset diabetes mellitus with diabetic ketoacidosis has occurred in patients treated with atezolizumab. Initiate treatment with insulin for type 1 diabetes mellitus; withhold atezolizumab therapy for blood sugars over 250 mg/dL, resuming treatment when metabolic control is achieved. Cautious use of atezolizumab may be necessary in patients with pre-existing diabetes mellitus; patients with a history of autoimmune disease were excluded from clinical trials.

    Guillain-Barre syndrome, myasthenia gravis, myocarditis, ocular inflammation, visual disturbance, visual impairment

    Immune-mediated meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, and ocular inflammation have all been reported with atezolizumab treatment. Myocarditis, which may be immune-related, has also been reported. Monitor patients for signs and symptoms of encephalitis, motor and sensory neuropathy, myocarditis, and any visual disturbance/visual impairment. An interruption or discontinuation of therapy may be necessary, as well as treatment with corticosteroids.

    Pancreatitis

    Immune-mediated pancreatitis has been reported with atezolizumab treatment across clinical trials. Monitor patients for signs and symptoms of pancreatitis, including amylase and lipase levels. An interruption or discontinuation of therapy may be necessary, as well as treatment with corticosteroids.

    Herpes infection, infection, mycobacterial infection

    Severe infection, including sepsis, herpes encephalitis (i.e., herpes infection), and mycobacterial infection, have occurred in patients treated with atezolizumab across clinical trials and include 5 fatalities. The most common infections were urinary tract infections and pneumonia. Monitor patients for signs and symptoms of infection and treat with antibiotic or antiviral therapy as appropriate. Hold atezolizumab therapy for grade 3 or higher infections.

    Infusion-related reactions

    Severe infusion-related reactions have occurred during administration of atezolizumab in clinical trials. Interrupt or slow the rate of infusion for mild to moderate reactions; permanently discontinue atezolizumab for grade 3 or 4 infusion-related reactions.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during treatment and for at least 5 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, atezolizumab can cause fetal harm or death, including increased stillbirths and abortion, when administered during pregnancy based on its mechanism of action. A central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining a maternal immune tolerance of the fetus. Animal studies have shown that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of a developing fetus, leading to fetal death. In mouse models, blocking the PD-1 pathway resulted in increased fetal loss. There were no fetal malformations identified in literature reports; however, fetal exposure to atezolizumab may increase the risk of developing immune-related disorders or altering the normal immune response.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during atezolizumab treatment. Atezolizumab can increase the risk of fetal loss, or may result in altered immune responses in surviving fetuses, if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during treatment with atezolizumab and for at least 5 months after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of atezolizumab. Women who become pregnant while receiving atezolizumab should be apprised of the potential hazard to the fetus. In addition, atezolizumab caused irregular menstrual cycles and lack of newly formed corpora lutea in the ovaries of female monkeys; there was no effect on male reproductive organs. Atezolizumab treatment may result in impaired fertility or infertility in females of reproductive potential.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from atezolizumab, advise women to discontinue breast-feeding during treatment and for 5 months after the final dose. It is not known whether atezolizumab is present in human milk. Many drugs are excreted in human milk including antibodies.

    ADVERSE REACTIONS

    Severe

    hyponatremia / Delayed / 10.0-13.0
    infection / Delayed / 2.0-11.5
    lymphopenia / Delayed / 0-10.0
    anemia / Delayed / 2.0-8.0
    fatigue / Early / 2.0-6.0
    hypoalbuminemia / Delayed / 1.0-5.0
    hyperglycemia / Delayed / 5.0-5.0
    abdominal pain / Early / 4.0-4.0
    hematuria / Delayed / 0-3.0
    hyperbilirubinemia / Delayed / 0.6-2.1
    nausea / Early / 0-2.0
    back pain / Delayed / 0-2.0
    hypokalemia / Delayed / 0-2.0
    diarrhea / Early / 0.2-1.9
    pulmonary embolism / Delayed / 0-1.4
    colitis / Delayed / 0.2-1.2
    Guillain-Barre syndrome / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    fever / Early / 0-1.0
    vomiting / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    peripheral edema / Delayed / 0-1.0
    pneumothorax / Early / 0-0.7
    hepatitis / Delayed / 0.2-0.5
    constipation / Delayed / 0.3-0.3
    hypothyroidism / Delayed / 0-0.3
    pruritus / Rapid / 0-0.3
    rash (unspecified) / Early / 0-0.3
    pleural effusion / Delayed / 2.0
    hypoxia / Early / 2.0
    elevated hepatic enzymes / Delayed / 1.3
    GI obstruction / Delayed / 2.0
    dehydration / Delayed / 2.0
    musculoskeletal pain / Early / 2.0
    renal failure (unspecified) / Delayed / 2.0
    thromboembolism / Delayed / 2.0
    dysphagia / Delayed / 2.0
    GI bleeding / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    retroperitoneal bleeding / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 41.5-54.1
    hypercalcemia / Delayed / 0-13.0
    hyperthyroidism / Delayed / 0.6-1.1
    myasthenia / Delayed / 0-1.0
    hyperamylasemia / Delayed / 0-1.0
    ocular inflammation / Early / 0-1.0
    hypophysitis / Delayed / 0.2-0.2
    diabetes mellitus / Delayed / 0-0.2
    confusion / Early / 2.0
    chest pain (unspecified) / Early / Incidence not known
    encephalopathy / Delayed / Incidence not known
    meningitis / Delayed / Incidence not known
    infusion-related reactions / Rapid / Incidence not known

    Mild

    arthralgia / Delayed / 13.0-14.0
    insomnia / Early / 0-14.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Atezolizumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during treatment and for at least 5 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, atezolizumab can cause fetal harm or death, including increased stillbirths and abortion, when administered during pregnancy based on its mechanism of action. A central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining a maternal immune tolerance of the fetus. Animal studies have shown that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of a developing fetus, leading to fetal death. In mouse models, blocking the PD-1 pathway resulted in increased fetal loss. There were no fetal malformations identified in literature reports; however, fetal exposure to atezolizumab may increase the risk of developing immune-related disorders or altering the normal immune response.

    Due to the potential for serious adverse reactions in nursing infants from atezolizumab, advise women to discontinue breast-feeding during treatment and for 5 months after the final dose. It is not known whether atezolizumab is present in human milk. Many drugs are excreted in human milk including antibodies.

    MECHANISM OF ACTION

    Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that inhibits programmed death ligand 1 (PD-L1) interactions with the PD-1 and B7.1 receptors. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells, 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. Binding of PD-L1 to the PD-1 and B7.1 receptors suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production; PD-L1 expression in a tumor cell may provide adaptive immune resistance and lead to poor outcomes. Atezolizumab binds to PD-L1 and prevents its interaction with both PD-1 and B7.1 receptors, releasing the PD-L1/PD-1 mediated inhibition of an anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

    PHARMACOKINETICS

    Atezolizumab is administered intravenously. Exposure to atezolizumab increases in a dose proportional manner over a range of 1 mg/kg to 20 mg/kg, including the recommended fixed dose of 1,200 mg. Based on a population analysis (n = 472), clearance was 0.2 L/day and volume of distribution (Vd) was 6.9 L. In a post-hoc analysis, atezolizumab clearance was found to decrease over time, with a mean maximal reduction (% coefficient of variation; CV%) from baseline value of approximately 17.1% (CV%, 40.6%); however, this was not considered statistically significant. The terminal half-life was 27 days, with steady-state reached after 6 to 9 weeks of repeated dosing (2 to 3 cycles).
     
    Affected cytochrome (CYP) 450 isoenzymes: None.

    Intravenous Route

    Based on a population pharmacokinetic analysis, the systemic accumulation at steady-state in AUC, Cmax, and Cmin was 1.91-, 1.46-, and 2.75-fold, respectively.