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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

    Humanized monoclonal antibody that binds to and blocks programmed death-ligand 1
    Used for certain types of melanoma, urothelial carcinoma, hepatocellular cancer, lung cancer, and breast 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, 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

    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. 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 32.9 months, the objective response rate (ORR) was 14.8% (95% CI, 11.1% to 19.3%) and the median duration of response was 27.7 months (range, 2.1+ months to 33.4+ 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 20.9 months; the ORR was 26% and median duration 29.7 months 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

    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. 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 32.9 months, the objective response rate (ORR) was 14.8% (95% CI, 11.1% to 19.3%) and the median duration of response was 27.7 months (range, 2.1+ months to 33.4+ 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 20.9 months; the ORR was 26% and median duration 29.7 months 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 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: http://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 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

    1,200 mg IV over 60 minutes on day 1, followed by bevacizumab (15 mg/kg IV over 90 minutes), paclitaxel (200 mg/m2 IV over 3 hours, 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. The sequence of administration should be atezolizumab, followed by bevacizumab, then paclitaxel, and finally carboplatin. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be infused over 30 minutes. If the first bevacizumab infusion is well tolerated, the second infusion may be given over 60 minutes; if the 60-minute infusion is well tolerated, subsequent infusions may be given over 30 minutes. After completion of 4 to 6 cycles of chemotherapy, continue atezolizumab 1,200 mg IV followed by bevacizumab (15 mg/kg IV) on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. If bevacizumab is discontinued, atezolizumab may be continued as monotherapy at 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. To prevent hypersensitivity reactions, premedicate all patients with dexamethasone 20 mg PO approximately 12 and 6 hours before paclitaxel, diphenhydramine (or equivalent) 50 mg IV 30 to 60 minutes before paclitaxel, and ranitidine 50 mg IV (or equivalent) 30 to 60 minutes before paclitaxel. In a multicenter, randomized, open-label, phase 3 clinical trial, treatment with atezolizumab/bevacizumab/paclitaxel/carboplatin (ABCP) significantly improved overall survival in patients with metastatic nonsquamous NSCLC compared with bevacizumab/paclitaxel/carboplatin (BCP) (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 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, 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 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

    1,200 mg IV over 60 minutes on day 1, followed by nab-paclitaxel (100 mg/m2 IV over 30 minutes 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. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be infused over 30 minutes. After completion of 4 to 6 cycles of chemotherapy, continue atezolizumab monotherapy at a dose of 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. 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 http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    840 mg IV over 60 minutes every 2 weeks; OR 1,200 mg IV over 60 minutes every 3 weeks; OR 1,680 mg IV every 4 weeks until disease progression or unacceptable toxicity. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be infused over 30 minutes. 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 wtih 5 months in the chemotherapy arm; the confirmed objective response rate was 38% versus 29%, respectively.

    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

    1,200 mg IV over 60 minutes on day 1, followed by carboplatin (AUC 5 IV over 30 to 60 minutes on day 1) and then etoposide (100 mg/m2 IV over 60 minutes on days 1, 2, and 3), every 3 weeks for 4 cycles. Administer atezolizumab prior to chemotherapy when given on the same day. If the first infusion of atezolizumab is tolerated, all subsequent infusions may be infused over 30 minutes. Upon completion of 4 cycles of chemotherapy, continue atezolizumab 1,200 mg IV every 3 weeks until disease progression or unacceptable toxicity; alternatively, atezolizumab may be dosed at 840 mg IV every 2 weeks OR atezolizumab 1,680 mg every 4 weeks. In a randomized, double-blind, phase 3 clinical trial (IMpower133), the addition of atezolizumab to carboplatin plus etoposide (n = 201) 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 (n = 202). 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 breast cancer.
    NOTE: Patients should be selected using an FDA-approved test based on the PD-L1 expression on tumor-infiltrating immune cells. Information on FDA-approved tests for the determination of PD-L1 expression is available at http://www.fda.gov/CompanionDiagnostics.
    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: Do not substitute nab-paclitaxel with paclitaxel. In a phase 3 clinical trial (the IMpassion131 trial), treatment with atezolizumab and paclitaxel did not significantly reduce the risk of cancer progression and death compared with placebo and paclitaxel in the PD-L1-positive population; interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population.
    Intravenous dosage
    Adults

    840 mg IV over 60 minutes on days 1 and 15, followed by nab-paclitaxel (100 mg/m2 IV over 30 minutes on days 1, 8, and 15), repeated every 28 days until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated, all subsequent atezolizumab infusions may be infused over 30 minutes. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. First-line treatment with atezolizumab plus nab-paclitaxel significantly improved progression-free survival (PFS) compared with placebo plus nab-paclitaxel in the first interim analysis of a phase 3 clinical trial (IMpassion130). In the subgroup of patients with PD-L1 expression of 1% or more, PFS was 7.4 months in the atezolizumab arm compared with 4.8 months in the placebo arm; the objective response rate was 53% versus 33% for a median duration of 9.2 months versus 6.2 months, respectively. Overall survival was not significantly improved in the intent-to-treat population, and testing was not performed in the PD-L1 positive subgroup; however, numerical improvements were evident in both groups, and the final analysis may shed more light on this outcome.[63669] [60793]

    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

    1,200 mg IV over 60 minutes on day 1 prior to administration of bevacizumab (15 mg/kg IV over 90 minutes), every 3 weeks until disease progression or unacceptable toxicity. If the first atezolizumab infusion is tolerated, subsequent doses may be given 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. If bevacizumab is discontinued for toxicity, atezolizumab may be continued as monotherapy at 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; OR 1,680 mg IV every 4 weeks. 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 http://www.fda.gov/CompanionDiagnostics.
    Intravenous dosage
    Adults

    840 mg IV repeated every 2 weeks until disease progression starting on cycle 2 (28 days after starting cobimetinib and vemurafenib therapy); give atezolizumab in combination with cobimetinib 60 mg orally once daily on days 1 to 21 and vemurafenib 720 mg orally twice daily on cycle 2 and beyond. 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. Treatment cycles are repeated every 28 days. 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; hazard ratio (HR) = 0.78; 95% CI, 0.63 to 0.97; p = 0.025) 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; HR = 0.85; 95% CI, 0.67 to 1.07; p = 0.16). At the time of analysis, mortality was lower in the atezolizumab arm (93 deaths vs. 112 deaths; HR = 0.85; 95% CI, 0.64 to 1.11; p = 0.23); 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or urothelial cancer: 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; 1,680 mg IV every 4 weeks.
    Breast cancer: 840 mg IV every 2 weeks.

    Geriatric

    Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or urothelial cancer: 840 mg IV every 2 weeks; 1,200 mg IV every 3 weeks; 1,680 mg IV every 4 weeks.
    Breast cancer: 840 mg IV every 2 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 in Patients WITHOUT Hepatocellular Cancer
    AST/ALT 3 to 8 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 prednisone 1 to 2 mg/kg per day (or equivalent), followed by steroid taper. Resume therapy at the original dose when the AST or ALT recover to grade 1 or less and the corticosteroid dose is prednisone 10 mg per day (or equivalent) or less. Dosage adjustments of atezolizumab are not recommended. Permanently discontinue atezolizumab if resolution to grade 1 or less does not occur within 12 weeks, if steroids are unable to be tapered to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks, or for recurrent grade 3 or 4 hepatotoxicity.
    AST/ALT more than 8 times ULN or total bilirubin more than 3 times ULN (grade 3 or higher): Permanently discontinue atezolizumab and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent) followed by steroid taper.
     
    Treatment-Related Hepatotoxicity in Patients WITH Hepatocellular Cancer
    Normal baseline AST/ALT, with an increase to 3 to 10 times ULN: Hold atezolizumab therapy and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent), followed by steroid taper. Resume therapy at the original dose when the AST or ALT recover to grade 1 or less and the corticosteroid dose is prednisone 10 mg per day (or equivalent) or less. Dosage adjustments of atezolizumab are not recommended. Permanently discontinue atezolizumab if resolution to grade 1 or less does not occur within 12 weeks, if steroids are unable to be tapered to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks, or for recurrent grade 3 or 4 hepatotoxicity.
    Baseline AST/ALT 1.1 to 3 times ULN, with an increase to 5 to 10 times ULN: Hold atezolizumab therapy and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent), followed by steroid taper. Resume therapy at the original dose when the AST or ALT recover to grade 1 or less and the corticosteroid dose is prednisone 10 mg per day (or equivalent) or less. Dosage adjustments of atezolizumab are not recommended. Permanently discontinue atezolizumab if resolution to grade 1 or less does not occur within 12 weeks, if steroids are unable to be tapered to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks, or for recurrent grade 3 or 4 hepatotoxicity.
    Baseline AST/ALT 3.1 to 5 times ULN, with an increase to 8 to 10 times ULN: Hold atezolizumab therapy and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent), followed by steroid taper. Resume therapy at the original dose when the AST or ALT recover to grade 1 or less and the corticosteroid dose is prednisone 10 mg per day (or equivalent) or less. Dosage adjustments of atezolizumab are not recommended. Permanently discontinue atezolizumab if resolution to grade 1 or less does not occur within 12 weeks, if steroids are unable to be tapered to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks, or for recurrent grade 3 or 4 hepatotoxicity.
    Any baseline AST/ALT with an increase to more than 10 times ULN: Permanently discontinue atezolizumab and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent) followed by steroid taper.
    Total bilirubin increasd to more than 3 times ULN: Permanently discontinue atezolizumab and initiate therapy with prednisone 1 to 2 mg/kg per day (or equivalent) followed by steroid taper.

    Renal Impairment

    Baseline Renal Impairment
    Based on a population pharmacokinetic analysis, no dose adjustment of atezolizumab is recommended for patients with renal impairment.
     
    Treatment-Related Immune-Mediated Nephritis
    Grade 2: Hold atezolizumab therapy and initiate treatment with corticosteroids and/or additional immunosuppressive agents as clinically indicated; refer patients to a renal specialist and consider renal biopsy and supportive measures. Resume atezolizumab at the original dose when nephritis is resolved or improves to grade 1 or less.
    Grade 3 or 4: Permanently discontinue atezolizumab therapy. Initiate treatment with corticosteroids and/or additional immunosuppressive agents as clinically indicated; refer patients to a renal specialist and consider renal biopsy and supportive measures.

    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, pulmonary disease

    Use atezolizumab with caution in patients with pre-existing pulmonary disease. 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.

    Hepatic disease, hepatitis

    Use atezolizumab with caution in patients with baseline moderate to severe hepatic disease, as it has not been studied in this patient population; no initial dose adjustment is necessary for patients with mild hepatic impairment. Immune-mediated hepatitis requiring the use of corticosteroids has occurred in patients treated with atezolizumab. Monitor patients for signs and symptoms of hepatitis, including monitoring liver function tests (LFTs), prior to beginning treatment with atezolizumab, periodically during therapy, and after discontinuation of atezolizumab. An interruption or discontinuation of therapy may be necessary, along with treatment with high-dose corticosteroids.

    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 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 high-dose corticosteroids. 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. 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

    Type 1 diabetes mellitus, including diabetic ketoacidosis, can occur in patients treated with atezolizumab. Initiate treatment with insulin as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. 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.

    Immune-mediated reactions

    Atezolizumab can cause severe and fatal immune-mediated reactions that may involve any organ system. These immune-mediated reactions usually occur during treatment, but can also occur after discontinuation of atezolizumab therapy. If an immune-mediated reaction occurs, an interruption or discontinuation of therapy may be necessary, along with treatment with high-dose 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.

    Infection

    Severe infection, including fatal cases, have occurred in patients treated with atezolizumab across clinical trials. The most common severe 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 and resume once clinically stable.

    Infusion-related reactions

    Severe or life-threatening infusion-related reactions have occurred during administration of atezolizumab in clinical trials. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for mild to moderate reactions; consider premedication with subsequent doses of atezolizumab. Permanently discontinue atezolizumab for grade 3 or 4 infusion-related reactions.

    Myocarditis

    Myocarditis has been reported in patients treated with atezolizumab in clinical trials. Myocarditis may be immune-related, as has occurred with other similar-in-class drugs. Monitor patients for signs and symptoms of myocarditis. If myocarditis develops, consider treatment with systemic corticosteroids; an interruption or discontinuation of therapy may be necessary.

    Uveitis

    Immune-mediated ocular toxicity has been reported with atezolizumab therapy; monitor patients for signs or symptoms of blurred vision and reduced visual acuity. Consider a diagnosis of Vogt-Koyanagi-Harada-like syndrome if uveitis occurs in combination with other immune-mediated adverse reactions; this syndrome has been reported with other products in this class. Patients with Vogt-Koyanagi-Harada-like syndrome may require treatment with systemic steroids to reduce the risk of permanent vision loss.

    Renal impairment

    Cases of immune-mediated nephritis, including biopsy-confirmed cases, have been identified in a cumulative analysis of the safety and clinical databases of atezolizumab (n = 37,998). Monitor patients for signs and symptoms of renal impairment; an interruption or discontinuation of therapy may be necessary, as well as administration of corticosteroids and/or additional immunosuppressive agents. Refer patients to a renal specialist and consider renal biopsy and supportive measures as indicated.[63483]

    Treatment outside of a clinical trial

    Atezolizumab in combination with paclitaxel is not recommended for patients with locally advanced or metastatic triple-negative breast cancer (mTNBC) for treatment outside of a clinical trial. In a randomized, double-blind, placebo-controlled, phase 3 clinical trial (the IMpassion131 trial), treatment with atezolizumab and paclitaxel did not significantly reduce the risk of cancer progression and death compared with placebo and paclitaxel in the PD-L1-positive population; interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population. Atezolizumab in combination with paclitaxel is not approved for use in breast cancer; however, atezolizumab in combination with nab-paclitaxel is currently approved for the treatment of patients with PD-L1-positive mTNBC. Healthcare providers should not substitute nab-paclitaxel with paclitaxel in clinical practice. Patients taking atezolizumab and paclitaxel for other approved uses should continue to take their medication as directed by their health care professional. Any adverse events related to these products should be reported to the FDA's MedWatch program.

    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, 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 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

    neutropenia / Delayed / 0-50.0
    hyperkalemia / Delayed / 0-29.0
    rash / Early / 0.3-27.0
    lymphopenia / Delayed / 9.0-24.0
    hepatitis / Delayed / 2.9-22.0
    hypophosphatemia / Delayed / 3.6-22.0
    hepatotoxicity / Delayed / 0-21.0
    thrombocytopenia / Delayed / 0-20.0
    elevated hepatic enzymes / Delayed / 2.0-18.0
    hyponatremia / Delayed / 7.0-15.0
    hypertension / Early / 0-15.0
    leukopenia / Delayed / 0-14.0
    fatigue / Early / 0-11.0
    asthenia / Delayed / 0-11.0
    hyperglycemia / Delayed / 5.0-10.0
    hypertensive crisis / Early / 0-10.0
    infection / Delayed / 3.8-9.0
    anemia / Delayed / 1.8-8.0
    lethargy / Early / 0-8.0
    hypokalemia / Delayed / 0-7.0
    diarrhea / Early / 0-5.0
    colitis / Delayed / 1.4-4.3
    musculoskeletal pain / Early / 0-4.3
    dyspnea / Early / 0-4.0
    abdominal pain / Early / 0.8-4.0
    hypoalbuminemia / Delayed / 0-4.0
    hyperbilirubinemia / Delayed / 0-3.1
    hematuria / Delayed / 0-3.0
    hypermagnesemia / Delayed / 1.0-3.0
    back pain / Delayed / 2.0-3.0
    anorexia / Delayed / 0-3.0
    infusion-related reactions / Rapid / 0-2.6
    constipation / Delayed / 0-2.0
    nausea / Early / 0-2.0
    peripheral edema / Delayed / 1.0-2.0
    fever / Early / 0-1.7
    stomatitis / Delayed / 0-1.3
    hypocalcemia / Delayed / 0-1.3
    myalgia / Early / 0-1.3
    cough / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    Vogt-Koyanagi-Harada syndrome / Delayed / 0-1.0
    uveitis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    photosensitivity / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    nephrotic syndrome / Delayed / 0-1.0
    edema / Delayed / 0-1.0
    myocarditis / Delayed / 0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    hyperthyroidism / Delayed / 0-0.9
    hypothyroidism / Delayed / 0-0.3
    adrenocortical insufficiency / Delayed / 0-0.1
    pleural effusion / Delayed / 1.0
    GI obstruction / Delayed / 2.0
    renal failure (unspecified) / Delayed / 2.0
    pulmonary embolism / Delayed / 2.0
    thromboembolism / Delayed / 1.0
    enterocolitis / Delayed / Incidence not known
    bowel ischemia / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    stroke / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 13.0-48.0
    hypernatremia / Delayed / 0-20.0
    QT prolongation / Rapid / 0-10.0
    encephalopathy / Delayed / 0-1.0
    meningitis / Delayed / 0-1.0
    hyperamylasemia / Delayed / 0-1.0
    iritis / Delayed / 0-1.0
    bullous rash / Early / 0-1.0
    hypophysitis / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    dehydration / Delayed / 2.0
    confusion / Early / 2.0
    interstitial lung disease / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    psoriaform rash / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known

    Mild

    dizziness / Early / 0-14.0
    dysgeusia / Early / 0-14.0
    syncope / Early / 0-10.0
    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
    pharyngitis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    acneiform rash / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    headache / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    weight loss / Delayed / 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 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. 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.