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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

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

    COMMON BRAND NAMES

    Tecentriq

    HOW SUPPLIED

    Atezolizumab/Tecentriq Intravenous Inj Sol: 1mL, 60mg

    DOSAGE & INDICATIONS

    For the treatment of urothelial carcinoma.
    For the treatment of locally advanced or metastatic urothelial carcinoma in patients who progress during or following any platinum-containing chemotherapy†.
    NOTE: FDA approval was removed for this indication in April 2021 after initial accelerated approval due to failure to meet the primary end point of overall survival in the IMvigor211 trial.
    Intravenous dosage
    Adults

    Dosage not established.

    For the treatment of locally advanced or metastatic urothelial carcinoma in patients who progress within 12 months of neoadjuvant or adjuvant chemotherapy†.
    NOTE: FDA approval was removed for this indication in April 2021 after initial accelerated approval due to failure to meet the primary endpoint of overall survival in the IMvigor211 trial.
    Intravenous dosage
    Adults

    Dosage not established.

    For the treatment of locally advanced or metastatic urothelial carcinoma in patients whose tumors express PD-L1 (5% or more) as determined by an FDA-approved test and are ineligible for cisplatin-containing chemotherapy or in patients who are not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status.
    NOTE: Select cisplatin-ineligible patients based on the PD-L1 expression on tumor-infiltrating immune cells. Information on FDA-approved tests for the determination of PD-L1 expression in locally advanced or metastatic urothelial carcinoma is available at: www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    840 mg IV over 60 minutes every 2 weeks until disease progression or unacceptable toxicity; alternatively, atezolizumab may be dosed at 1,200 mg IV over 60 minutes every 3 weeks OR atezolizumab 1,680 mg IV over 60 minutes every 4 weeks. 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. In an ongoing multicenter, randomized trial in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy (IMvigor130), patients with PD-L1 expression of less than 5% had decreased survival with atezolizumab monotherapy compared to those who received platinum-based chemotherapy; the monotherapy arm of this trial was closed to accrual for patients with low PD-L1 expression upon the recommendation of the independent Data Monitoring Committee.

    For the first-line treatment of locally advanced or metastatic urothelial carcinoma, in combination with gemcitabine and cisplatin†.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes on day 1, in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8) and cisplatin (70 mg/m2 IV on day 1), every 21 days for up to 6 cycles; may continue atezolizumab monotherapy after the completion of chemotherapy until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated, all subsequent infusions may be administered over 30 minutes. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.

    For the first-line treatment of locally advanced or metastatic urothelial carcinoma, in combination with gemcitabine and carboplatin†.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes on day 1, in combination with gemcitabine (1,000 mg/m2 IV on days 1 and 8) and carboplatin (AUC 4.5 IV on day 1), every 21 days for up to 6 cycles; may continue atezolizumab monotherapy after the completion of chemotherapy until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated, all subsequent infusions may be administered over 30 minutes. In a randomized phase 3 trial (the IMvigor 130 trial), the addition of atezolizumab to platinum-based chemotherapy in patients with metastatic urothelial cancer significantly improved progression-free survival (PFS) compared with platinum-based chemotherapy alone in the intent-to-treat population; the PFS benefit in the atezolizumab arm was seen across all subgroups, although it was not statistically significant in several including patients with PD-L1 0/1 expression and in patients receiving carboplatin- versus cisplatin-based regimens. At an interim analysis after 11.8 months of follow-up, overall survival was not significantly different between groups.

    For the treatment of non-small cell lung cancer (NSCLC).
    For the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in combination with bevacizumab, paclitaxel, and carboplatin.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Administer in combination with bevacizumab (15 mg/kg IV), paclitaxel (200 mg/m2 IV, or 175 mg/m2 IV in Asian patients), and carboplatin (AUC 6 IV), every 3 weeks for a maximum of 4 to 6 cycles of chemotherapy. Administer atezolizumab prior to bevacizumab and chemotherapy when given on the same day. In a multicenter, randomized, open-label, phase 3 clinical trial (IMpower150), treatment with atezolizumab plus bevacizumab/paclitaxel/carboplatin (ABCP) significantly improved overall survival in patients with metastatic nonsquamous NSCLC compared with BCP without atezolizumab (19.2 months vs. 14.7 months); overall survival with atezolizumab/paclitaxel/carboplatin was not significantly different from BCP. Progression-free survival was also significantly improved in the ABCP arm compared with BCP (8.5 months vs. 7 months). The objective response rate was 55% (complete response [CR], 4%) versus 42% (CR, 1%), respectively, for a median duration of 10.8 months and 6.5 months, respectively.[60793] [63819]

    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, as monotherapy.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks until disease progression or unacceptable toxicity; alternatively, atezolizumab may be dosed at 1,200 mg IV every 3 weeks OR atezolizumab 1,680 mg IV every 4 weeks. 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 significantly improved overall survival compared with docetaxel (12.6 months vs. 9.7 months); 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% or more PD-L1 expressing tumor cells or tumor-infiltrating cells. Atezolizumab was better tolerated than docetaxel.[61208]

    For the first-line treatment of metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in combination with nanoparticle albumin-bound (nab) paclitaxel and carboplatin.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Administer in combination with nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) and carboplatin (AUC 6 IV on day 1), every 3 weeks for a maximum of 4 to 6 cycles of chemotherapy. Administer atezolizumab prior to chemotherapy when given on the same day. First-line treatment of EGFR- and ALK-negative metastatic NSCLC with atezolizumab plus nab-paclitaxel and carboplatin significantly improved median overall survival (18.6 months vs. 13.9 months) and median progression-free survival (7.2 months vs. 6.5 months) compared with nab-paclitaxel and carboplatin alone in a multicenter, randomized, open-label trial (IMpower130). The overall response rate was 46% (complete response [CR], 5%) in the atezolizumab arm compared with 32% (CR, 1%) in the control arm, for a median duration of 10.8 months versus 7.8 months, respectively.

    For the first-line treatment of metastatic non-small cell lung cancer (NSCLC) without EGFR or ALK mutations, in patients whose tumors have high PD-L1 expression (at least 50% of tumor cells, or PD-L1 stained tumor-infiltrating immune cells covering at least 10% of the tumor area), as monotherapy.
    NOTE: Patients should be selected based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells. Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Treatment with atezolizumab significantly improved median overall survival compared with platinum-based chemotherapy (20.2 months vs. 13.1 months) in patients with metastatic NSCLC and high PD-L1 expression, without EGFR or ALK mutations in a randomized, open-label trial (IMpower110). Investigator-assessed median progression-free survival was 8.1 months in the atezolizumab arm compared with 5 months in the chemotherapy arm; the confirmed objective response rate was 38% versus 29%, respectively.

    For the adjuvant treatment of stage II to IIIA NSCLC as monotherapy in patients with PD-L1 expression on 1% or more of tumor cells, following resection and platinum-based chemotherapy.
    NOTE: Patients should be selected based on the PD-L1 expression on tumor cells.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks for up to 1 year, unless there is disease recurrence or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial (IMpower010), patients with stage IB to IIIA NSCLC who had complete tumor resection and received cisplatin-based adjuvant chemotherapy were randomized to treatment with atezolizumab or best supportive care (BSC). Treatment with atezolizumab significantly improved the primary endpoint of median disease-free survival (DFS) in stage II to IIIA NSCLC patients with PD-L1 expression in 1% or more of tumor cells compared with BSC (not reached vs. 35.3 months). In a prespecified secondary subgroup analysis of stage II to IIIA NSCLC patients with PD-L1 expression in 50% or more of tumor cells, median DFS was not reached versus 35.7 months, respectively; median DFS was 32.8 months versus 31.4 months, respectively, in an exploratory subgroup analysis of patients with PD-L1 expression in 1% to 49% of tumor cells.

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

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. Administer in combination with carboplatin (AUC 5 IV on day 1) and etoposide (100 mg/m2 IV on days 1, 2, and 3), every 3 weeks for 4 cycles. Administer atezolizumab prior to chemotherapy when given on the same day. In a randomized, double-blind, phase 3 clinical trial (IMpower133), the addition of atezolizumab to carboplatin plus etoposide significantly improved overall survival (12.3 months vs. 10.3 months) and progression-free survival (5.2 months vs. 4.3 months) compared with placebo plus carboplatin/etoposide. Survival at 1 year was 51.7% versus 38.2%, respectively. Treatment was well-tolerated, with 56.5% of patients in the atezolizumab arm experiencing grade 3 or 4 adverse reactions compared with 56.1% of those in the placebo arm. Immune-related adverse reactions occurred in 39.9% versus 24.5% of patients, respectively.[63611]

    For the treatment of hepatocellular cancer.
    For the treatment of unresectable or metastatic hepatocellular cancer (HCC) in patients who have not received prior systemic therapy, in combination with bevacizumab.
    NOTE: Atezolizumab in combination with bevacizumab is designated by the FDA as an orphan drug for this indication.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. Administer in combination with bevacizumab 15 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity. Administer atezolizumab prior to bevacizumab when given on the same day. In a multicenter, randomized, open-label clinical trial (IMbrave150), treatment with atezolizumab followed by bevacizumab significantly improved overall survival (not estimable vs. 13.2 months) and progression-free survival (6.8 months vs. 4.3 months) compared with sorafenib in patients with unresectable or metastatic HCC who have not received prior systemic therapy. The overall response rate was also significantly improved for patients treated with bevacizumab/atezolizumab by both RECIST1.1 criteria (28% vs. 12%; complete response [CR], 7% vs. 0%) and mRECIST criteria (33% vs. 13%; CR, 11% vs. 1.8%); the median duration of response was not estimable versus 6.3 months, respectively.

    For the treatment of malignant melanoma.
    Note: Atezolizumab has been designated by the FDA as an orphan drug for the treatment of stage llb, llc, lll, and IV melanoma.
    For the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma, in combination with cobimetinib and vemurafenib.
    NOTE: Patients should be selected using an FDA-approved test confirming the presence of a BRAF V600 mutation. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks; OR 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks, starting on cycle 2 (28 days after starting cobimetinib and vemurafenib therapy). Administer in combination with cobimetinib (60 mg orally once daily on days 1 to 21, every 28 days) and vemurafenib (720 mg orally twice daily). Cycle 1 consists of cobimetinib and vemurafenib only given as follows: cobimetinib 60 mg orally once daily on days 1 to 21 and vemurafenib 960 mg orally twice daily on days 1 to 21 and then 720 mg orally twice daily on days 22 to 28. At a median follow-up time of 18.9 months, the investigator-assessed median progression-free survival (PFS) time was significantly longer in patients who received atezolizumab, vemurafenib, and cobimetinib compared with placebo, vemurafenib, and cobimetinib (15.1 months vs. 10.6 months) in an international, randomized, double-blind, placebo-controlled, phase 3 trial (n = 514; the IMspire150 trial). When PFS was assessed by an independent review committee, the median PFS time was non-significantly longer in the atezolizumab arm (16.1 months vs. 12.3 months). At the time of analysis, mortality was lower in the atezolizumab arm (93 deaths vs. 112 deaths); however, overall survival data were not mature. Patients (age range, 43 to 64 years) in this trial had BRAF V600 mutation-positive unresectable stage IIIc or stage IV melanoma and had not received previous systemic therapy for metastatic disease; patients with untreated or actively progressing brain metastases were excluded.

    For the treatment of renal cell cancer†.
    For the first-line treatment of advanced or metastatic renal cell cancer, in combination with bevacizumab†.
    Intravenous dosage
    Adults

    1,200 mg IV over 60 minutes plus bevacizumab (15 mg/kg IV over 90 minutes), repeated every 3 weeks until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated over 60 minutes, all subsequent infusions may be infused over 30 minutes. If the first bevacizumab infusion is tolerated over 90 minutes, the second infusion may be given over 60 minutes and if well-tolerated, subsequent bevacizumab infusions may be given over 30 minutes. In a randomized, phase 3 clinical trial, first-line treatment with atezolizumab plus bevacizumab significantly improved median investigator-assessed PFS in patients with advanced or metastatic RCC compared with sunitinib; however, these results were not supported by an independent review committee (IRC) which found a nonsignificant trend toward improved PFS. An exploratory analysis found that treatment with atezolizumab plus bevacizumab significantly improved investigator-assessed PFS in intent-to-treat patients with sarcamoid histology, which has a particularly poor prognosis. Treatment with atezolizumab plus bevacizumab did not significantly improve overall survival compared with sunitinib in this patient population, but patients who received combination therapy experienced a longer time to clinically relevant decline.

    For the treatment of breast cancer†.
    For the treatment of unresectable locally advanced or metastatic hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in patients whose tumors express PD-L1 (1% or more) as determined by an FDA-approved test, in combination with nab-paclitaxel†.
    NOTE: FDA approval was removed for this indication in August 2021 after initial accelerated approval due to failure to meet the primary end point of progression-free survival in the IMpassion131 trial.
    Intravenous dosage
    Adults

    Dosage not established.

    For the neoadjuvant treatment of hormone receptor (HR)-negative, HER2-negative (triple-negative) breast cancer, in combination with sequential nab-paclitaxel followed by cyclophosphamide plus doxorubicin (dose-dense AC)†.
    NOTE: Do not substitute nab-paclitaxel with paclitaxel. In a phase 3 clinical trial (the IMpassion131 trial), treatment with atezolizumab and paclitaxel increased the risk of death compared with placebo and paclitaxel in the PD-L1-positive population.
    Intravenous dosage
    Adults

    840 mg IV every 2 weeks in combination with nab-paclitaxel (125 mg/m2 once weekly) for 12 weeks, followed by atezolizumab 840 mg IV every 2 weeks in combination with doxorubicin (60 mg/m2 IV) plus cyclophosphamide (600 mg/m2 IV every 2 weeks) for 8 weeks (dose-dense AC), followed by surgery. After surgery, continue atezolizumab 1,200 mg IV every 3 weeks for 11 cycles to complete approximately 12 months of atezolizumab therapy. In a randomized, phase 3 clinical trial (IMpassion031), neoadjuvant treatment with atezolizumab plus sequential nab-paclitaxel and AC chemotherapy significantly improved pCR compared with neoadjuvant placebo plus sequential nab-paclitaxel and AC chemotherapy in patients with early TNBC, regardless of PD-L1 status.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks.

    Geriatric

    840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 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

    Treatment-Related Immune-Mediated HepatitisNo 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 atezolizumab 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 atezolizumab 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 atezolizumab 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 atezolizumab 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 atezolizumab 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 atezolizumab 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 atezolizumab 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 atezolizumab 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 atezolizumab 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).

    Renal Impairment

    Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction Grade 2 or 3 increased serum creatinine (SCr) level: Hold atezolizumab 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 atezolizumab 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 atezolizumab 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).

    ADMINISTRATION

    Injectable Administration

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

    Intravenous Administration

    Dilution
    Withdraw the required volume of atezolizumab from the vial(s).
    Dilute to a final concentration between 3.2 mg/mL and 16.8 mg/mL in a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection.
    Mix by gentle inversion; do not shake.
    Storage after dilution: 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 from the time of preparation.[60793]
     
    Infusion
    Administer atezolizumab prior to chemotherapy or other antineoplastic agents when given on the same day.
    Do not infuse through the same IV line with other drugs.
    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; do not administer atezolizumab as an IV push or bolus. 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.[60793]

    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 carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Pneumonitis, radiation therapy

    Immune-mediated pneumonitis has been reported with atezolizumab therapy; some cases were fatal. The incidence of pneumonitis with other PD-1/PD-L1 inhibitors was higher in patients who have received prior thoracic radiation therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, atezolizumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.

    Hepatitis

    Immune-mediated hepatitis has been reported with atezolizumab therapy; some cases were fatal. Monitor hepatic function at baseline and periodically during treatment. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.

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

    Use atezolizumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1 inhibitor therapy.

    Colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, viral infection

    Immune-mediated colitis has been reported with atezolizumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use atezolizumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with atezolizumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.

    Diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus

    Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported with atezolizumab therapy. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold atezolizumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.

    Immune-mediated reactions

    Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as atezolizumab. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of atezolizumab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.

    Hyperthyroidism, hypothyroidism

    Atezolizumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Atezolizumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.

    Infusion-related reactions

    Severe infusion-related reactions have occurred with atezolizumab. Monitor patients for signs and symptoms of infusion reactions including fever chills, wheezing, pruritus, flushing, and rash. Consider premedication with subsequent doses in patients who develop a reaction. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions (grade 1 or 2); stop the infusion and permanently discontinue atezolizumab for severe or life-threatening infusion-related reactions (grade 3 or 4).

    Serious rash

    Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.

    Renal failure, renal impairment

    Immune-mediated nephritis and renal failure have been reported with atezolizumab therapy. Monitor renal function at baseline and periodically during treatment. Atezolizumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.[63483]

    Allogeneic stem cell transplant

    Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as atezolizumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.

    Guillain-Barre syndrome, myasthenia gravis, neurological disease

    Immune-mediated neurotoxicity has been reported with atezolizumab or other PD-1/PD-L1 inhibitors. Use atezolizumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Atezolizumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.

    Pregnancy

    Based on its mechanism of action, atezolizumab may cause fetal harm if used during pregnancy. Atezolizumab is an immunoglobulin G1 antibody and may cross the placental barrier. Fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise women of reproductive potential 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 atezolizumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia.    

    Contraception requirements, infertility, pregnancy testing, 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 breastfed children, the manufacturer recommends that patients avoid breast-feeding during atezolizumab therapy and for 5 months after the final dose. It is not known if atezolizumab is present in human milk or if it has effects on the breastfed child or on milk production. Use atezolizumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because atezolizumab is a large protein molecule (molecular weight of 145,000 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.

    ADVERSE REACTIONS

    Severe

    hypophosphatemia / Delayed / 0-22.0
    hyponatremia / Delayed / 0-15.0
    lymphopenia / Delayed / 0-14.0
    fatigue / Early / 0-8.0
    anemia / Delayed / 0-7.0
    dyspnea / Early / 0-4.9
    asthenia / Delayed / 0-4.0
    hyperkalemia / Delayed / 3.0-3.9
    hypermagnesemia / Delayed / 0-3.0
    anorexia / Delayed / 0-3.0
    infusion-related reactions / Rapid / 0.2-2.4
    constipation / Delayed / 0-2.0
    nausea / Early / 0-2.0
    rash / Early / 0-2.0
    peripheral edema / Delayed / 0-2.0
    hypocalcemia / Delayed / 0-1.4
    cough / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    myelitis / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    hypomagnesemia / Delayed / 0-1.0
    pericarditis / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    fever / Early / 0-1.0
    organ transplant rejection / Delayed / 0-1.0
    abdominal pain / Early / 0-0.8
    vomiting / Early / 0-0.8
    hypothyroidism / Delayed / 0-0.6
    hyperthyroidism / Delayed / 0-0.4
    diabetes mellitus / Delayed / 0.2-0.2
    pleural effusion / Delayed / 1.0
    GI obstruction / Delayed / 2.0
    pulmonary embolism / Delayed / 2.0
    thromboembolism / Delayed / 1.0
    bowel ischemia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    retinal detachment / Delayed / Incidence not known
    Vogt-Koyanagi-Harada syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    hypertensive crisis / Early / Incidence not known
    stroke / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 13.0-48.0
    hepatotoxicity / Delayed / 0-29.0
    iritis / Delayed / 0-1.0
    sarcoidosis / Delayed / 0-1.0
    gastritis / Delayed / 0-1.0
    hypoparathyroidism / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-0.4
    confusion / Early / 2.0
    oral ulceration / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    dehydration / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    hypernatremia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    hemoptysis / Delayed / Incidence not known

    Mild

    purpura / Delayed / 0-1.0
    cheilitis / Delayed / Incidence not known
    dysesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    lichen planus-like eruption / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    headache / Early / Incidence not known
    syncope / Early / Incidence not known
    dizziness / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    weight loss / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    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.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    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, atezolizumab may cause fetal harm if used during pregnancy. Atezolizumab is an immunoglobulin G1 antibody and may cross the placental barrier. Fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise women of reproductive potential 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 atezolizumab, 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 atezolizumab therapy and for 5 months after the final dose. It is not known if atezolizumab is present in human milk or if it has effects on the breastfed child or on milk production. Use atezolizumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because atezolizumab is a large protein molecule (molecular weight of 145,000 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.

    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. Clearance was 0.2 L/day (CV, 29%) and volume of distribution (Vd) at steady-state was 6.9 L. 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%, 41%); however, this was not considered statistically relevant. The terminal half-life was 27 days, with steady-state reached after 6 to 9 weeks following multiple doses.[60793]
     
    Affected cytochrome (CYP) 450 isoenzymes: None.[60793]

    Intravenous Route

    The systemic accumulation ratio for atezolizumab was 3.3-fold when administered every 2 weeks and 1.9-fold when administered every 3 weeks.