Label: TECENTRIQ- atezolizumab injection, solution

  • NDC Code(s): 50242-917-01, 50242-917-86, 50242-918-01, 50242-918-86
  • Packager: Genentech, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated June 3, 2020

If you are a consumer or patient please visit this version.

  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use TECENTRIQ safely and effectively. See full prescribing information for TECENTRIQ.

    TECENTRIQ® (atezolizumab) injection, for intravenous use
    Initial U.S. Approval: 2016

    RECENT MAJOR CHANGES

    Indications and Usage, Non-Small Cell Lung Cancer (1.2)5/2020
    Indications and Usage, Hepatocellular Carcinoma (1.5)5/2020
    Dosage and Administration (2.1, 2.3, 2.6)12/2019
    Dosage and Administration (2.7)5/2020

    INDICATIONS AND USAGE

    TECENTRIQ is a programmed death-ligand 1 (PD-L1) blocking antibody indicated:

    Urothelial Carcinoma

    • for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:
      • are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area), as determined by an FDA-approved test, or
      • are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, or
      • have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy. (1.1)
      This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). (1.1)

    Non-Small Cell Lung Cancer (NSCLC)

    • for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%] ), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. (1.2)
    • in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. (1.2)
    • in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (1.2)
    • for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ. (1.2)

    Triple-Negative Breast Cancer (TNBC)

    • in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA approved test. This indication is approved under accelerated approval based on progression free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). (1.3)

    Small Cell Lung Cancer (SCLC)

    • in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.4)

    Heptatocellular Carcinoma (HCC)

    • in combination with bevacizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy (1.5)

    DOSAGE AND ADMINISTRATION

    Administer TECENTRIQ intravenously over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

    Urothelial Carcinoma (2.2)

    • Administer TECENTRIQ as a single agent as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.

    NSCLC (2.3)

    • Administer TECENTRIQ as a single agent as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.
    • When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ 1200 mg every 3 weeks prior to chemotherapy and bevacizumab
    • Following completion of 4-6 cycles of chemotherapy, and if bevacizumab is discontinued, administer TECENTRIQ 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.

    Metastatic Treatment of TNBC (2.4)

    • Administer TECENTRIQ 840 mg, followed by 100 mg/m2 paclitaxel protein-bound. For each 28 day cycle, TECENTRIQ is administered on days 1 and 15, and paclitaxel protein-bound is administered on days 1, 8, and 15.

    Small Cell Lung Cancer (2.5)

    • When administering with carboplatin and etoposide, administer TECENTRIQ 1200 mg every 3 weeks prior to chemotherapy.
    • Following completion of 4 cycles of carboplatin and etoposide, administer TECENTRIQ 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.

    Hepatocellular Carcinoma (2.6)

    • Administer TECENTRIQ 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks
    • If bevacizumab is discontinued, administer TECENTRIQ as:
      • 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks

    DOSAGE FORMS AND STRENGTHS

    Injection: 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) solution in a single-dose vial (3)

    CONTRAINDICATIONS

    None. (4)

    WARNINGS AND PRECAUTIONS

    • Immune-Mediated Pneumonitis: Withhold or permanently discontinue based on severity of pneumonitis. (2.6, 5.1)
    • Immune-Mediated Hepatitis: Monitor for changes in liver function. Withhold or permanently discontinue based on severity of transaminase or total bilirubin elevation. (2.6, 5.2)
    • Immune-Mediated Colitis: Withhold or permanently discontinue based on severity of colitis. (2.6, 5.3)
    • Immune-Mediated Endocrinopathies (2.6, 5.4):
      • Hypophysitis: Withhold based on severity of hypophysitis.
      • Thyroid Disorders: Monitor for changes in thyroid function. Withhold based on severity of hyperthyroidism.
      • Adrenal Insufficiency: Withhold based on severity of adrenal insufficiency.
      • Type 1 Diabetes Mellitus: Withhold based on severity of hyperglycemia.
    • Infections: Withhold for severe or life-threatening infection. (2.6, 5.6)
    • Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue based on severity of infusion reactions. (2.6, 5.7)
    • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.8, 8.1, 8.3)

    ADVERSE REACTIONS

    • Most common adverse reactions (≥ 20%) with TECENTRIQ as a single-agent were fatigue/asthenia, nausea, cough, dyspnea, and decreased appetite. (6.1)
    • Most common adverse reactions (≥ 20%) with TECENTRIQ in combination with other antineoplastic drugs in patients with NSCLC and SCLC were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite (6.1)
    • The most common adverse reactions (≥ 20%) with TECENTRIQ in combination with paclitaxel protein-bound in patients with TNBC were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. (6.1)
    • The most common adverse reactions (reported in ≥ 20% of patients) with TECENTRIQ in combination with bevacizumab in patients with HCC were hypertension, fatigue and proteinuria. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    USE IN SPECIFIC POPULATIONS

    Lactation: Advise not to breastfeed. (8.2)

    See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

    Revised: 5/2020

  • Table of Contents

    FULL PRESCRIBING INFORMATION: CONTENTS*

    1 INDICATIONS AND USAGE

    1.1 Urothelial Carcinoma

    1.2 Non-Small Cell Lung Cancer

    1.3 Locally Advanced or Metastatic Triple-Negative Breast Cancer

    1.4 Small Cell Lung Cancer

    1.5 Hepatocellular Carcinoma

    2 DOSAGE AND ADMINISTRATION

    2.1 Patient Selection for Treatment of Urothelial Carcinoma and Triple-Negative Breast Cancer, or Non-Small Cell Lung Cancer

    2.2 Recommended Dosage for Urothelial Carcinoma

    2.3 Recommended Dosage for NSCLC

    2.4 Recommended Dosage for Locally Advanced or Metastatic TNBC

    2.5 Recommended Dosage for SCLC

    2.6 Recommended Dosage for HCC

    2.7 Dosage Modifications for Adverse Reactions

    2.8 Preparation and Administration

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1 Immune-Mediated Pneumonitis

    5.2 Immune-Mediated Hepatitis

    5.3 Immune-Mediated Colitis

    5.4 Immune-Mediated Endocrinopathies

    5.5 Other Immune-Mediated Adverse Reactions

    5.6 Infections

    5.7 Infusion-Related Reactions

    5.8 Embryo-Fetal Toxicity

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    6.2 Immunogenicity

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.3 Females and Males of Reproductive Potential

    8.4 Pediatric Use

    8.5 Geriatric Use

    11 DESCRIPTION

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    12.3 Pharmacokinetics

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    13.2 Animal Toxicology and/or Pharmacology

    14 CLINICAL STUDIES

    14.1 Urothelial Carcinoma

    14.2 Non-Small Cell Lung Cancer

    14.3 Locally Advanced or Metastatic Triple-Negative Breast Cancer

    14.4 Small Cell Lung Cancer

    14.5 Hepatocellular Carcinoma

    16 HOW SUPPLIED/STORAGE AND HANDLING

    17 PATIENT COUNSELING INFORMATION

    *
    Sections or subsections omitted from the full prescribing information are not listed.
  • 1 INDICATIONS AND USAGE

    1.1 Urothelial Carcinoma

    TECENTRIQ is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:

    • are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area), as determined by an FDA-approved test [see Dosage and Administration (2.1)], or
    • are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, or
    • have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy

    This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

    1.2 Non-Small Cell Lung Cancer

    • TECENTRIQ, as a single agent, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
    • TECENTRIQ, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
    • TECENTRIQ, in combination with paclitaxel protein-bound and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
    • TECENTRIQ, as a single-agent, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ.

    1.3 Locally Advanced or Metastatic Triple-Negative Breast Cancer

    TECENTRIQ, in combination with paclitaxel protein-bound, is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on progression free survival [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

    1.4 Small Cell Lung Cancer

    TECENTRIQ, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

    1.5 Hepatocellular Carcinoma

    TECENTRIQ, in combination with bevacizumab, is indicated for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Patient Selection for Treatment of Urothelial Carcinoma and Triple-Negative Breast Cancer, or Non-Small Cell Lung Cancer

    Select cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma for treatment with TECENTRIQ based on the PD-L1 expression on tumor-infiltrating immune cells [see Clinical Studies (14.1)].

    Select patients with first-line metastatic non-small cell lung cancer for treatment with TECENTRIQ as a single agent based on the PD-L1 expression on tumor cells or on tumor infiltrating immune cells [see Clinical Studies (14.2)].

    Select patients with locally advanced or metastatic triple-negative breast cancer for treatment with TECENTRIQ in combination with paclitaxel protein-bound based on the PD-L1 expression on tumor infiltrating immune cells [see Clinical Studies (14.3)].

    Information on FDA-approved tests for the determination of PD-L1 expression in locally advanced or metastatic urothelial carcinoma, triple-negative breast cancer, or non-small cell lung cancer are available at: http://www.fda.gov/CompanionDiagnostics

    2.2 Recommended Dosage for Urothelial Carcinoma

    The recommended dosage of TECENTRIQ is:

    • 840 mg every 2 weeks or
    • 1200 mg every 3 weeks or
    • 1680 mg every 4 weeks

    administered intravenously over 60 minutes until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

    2.3 Recommended Dosage for NSCLC

    Single Agent

    The recommended dosage of TECENTRIQ is:

    • 840 mg every 2 weeks or
    • 1200 mg every 3 weeks or
    • 1680 mg every 4 weeks

    administered intravenously over 60 minutes until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

    TECENTRIQ with Platinum-based Chemotherapy

    The recommended dosage of TECENTRIQ is 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity.

    Administer TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day. Refer to the Prescribing Information for the chemotherapy agents or bevacizumab administered in combination with TECENTRIQ for recommended dosing information.

    Following completion of 4-6 cycles of chemotherapy, and if bevacizumab is discontinued, the recommended dosage of TECENTRIQ is:

    • 840 mg every 2 weeks or
    • 1200 mg every 3 weeks or
    • 1680 mg every 4 weeks

    administered intravenously until disease progression or unacceptable toxicity.

    Administer the initial infusion of TECENTRIQ over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

    2.4 Recommended Dosage for Locally Advanced or Metastatic TNBC

    The recommended dosage of TECENTRIQ is 840 mg administered intravenously over 60 minutes, followed by 100 mg/m2 paclitaxel protein-bound.

    For each 28 day cycle, TECENTRIQ is administered on days 1 and 15, and paclitaxel protein-bound is administered on days 1, 8, and 15 until disease progression or unacceptable toxicity.

    TECENTRIQ and paclitaxel protein-bound may be discontinued for toxicity independently of each other.

    If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Refer to the Prescribing Information for paclitaxel protein-bound for recommended dosing information.

    2.5 Recommended Dosage for SCLC

    The recommended dosage of TECENTRIQ is 1200 mg intravenously every 3 weeks, when administered in combination with carboplatin and etoposide, until disease progression or unacceptable toxicity.

    Administer TECENTRIQ prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with TECENTRIQ for recommended dosing information.

    Following completion of 4 cycles of carboplatin and etoposide, the recommended dosage of TECENTRIQ is:

    • 840 mg every 2 weeks or
    • 1200 mg every 3 weeks or
    • 1680 mg every 4 weeks

    administered intravenously until disease progression or unacceptable toxicity.

    Administer the initial infusion of TECENTRIQ over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

    2.6 Recommended Dosage for HCC

    The recommended dosage of TECENTRIQ is 1,200 mg administered as an intravenous infusion over 60 minutes, followed by 15 mg/kg of bevacizumab on the same day, every 3 weeks until disease progression or unacceptable toxicity.

    Refer to the Prescribing Information for bevacizumab prior to initiation.

    If bevacizumab is discontinued for toxicity, the recommended dosage of TECENTRIQ is:

    • 840 mg every 2 weeks or
    • 1,200 mg every 3 weeks or
    • 1,680 mg every 4 weeks

    administered intravenously until disease progression or unacceptable toxicity.

    If the first infusion of TECENTRIQ is tolerated, all subsequent infusions may be delivered over 30 minutes

    2.7 Dosage Modifications for Adverse Reactions

    No dose reductions of TECENTRIQ are recommended. Recommendations for dosage modifications are provided in Table 1.

    Table 1: Recommended Dosage Modifications for Adverse Reactions
    Adverse ReactionSeverity of Adverse Reaction*Dosage Modifications
    *
    National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0
    HCC: Hepatocellular Carcinoma
    Pneumonitis [see Warnings and Precautions (5.1)]Grade 2Withhold dose until Grade 1 or resolved and corticosteroid dose is less than or equal to prednisone 10 mg per day (or equivalent)
    Grade 3 or 4Permanently discontinue
    Hepatitis in patients with cancers other than HCC [see Warnings and Precautions (5.2)]AST or ALT more than 3 and up to 8 times the upper limit of normal (ULN) or total bilirubin more than 1.5 and up to 3 times the upper limit of normal (ULN)Withhold dose until Grade 1 or resolved and corticosteroid dose is less than or equal to prednisone 10 mg per day (or equivalent)
    AST or ALT more than 8 times the upper limit of normal (ULN) or total bilirubin more than 3 times the upper limit of normal (ULN)Permanently discontinue
    Hepatitis in patients with HCC [see Warnings and Precautions (5.2)]
    • AST or ALT is within normal limits at baseline and increases to more than 3 and up to 10 times the ULN
    • AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times the ULN
    • AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times the ULN
    Withhold dose until Grade 1 or resolved and corticosteroid dose is less than or equal to prednisone 10 mg per day (or equivalent)
    AST or ALT increases to more than 10 times the ULN or total bilirubin increases to more than 3 times the ULNPermanently discontinue
    Colitis or diarrhea [see Warnings and Precautions (5.3)]Grade 2 or 3Withhold dose until Grade 1 or resolved and corticosteroid dose is less than or equal to prednisone 10 mg per day (or equivalent)
    Grade 4Permanently discontinue
    Endocrinopathies (including but not limited to hypophysitis, adrenal insufficiency, hyperthyroidism, and type 1 diabetes mellitus) [see Warnings and Precautions (5.4)]Grade 2, 3, or 4Withhold dose until Grade 1 or resolved and clinically stable on hormone replacement therapy.
    Other immune-mediated adverse reactions involving a major organ [see Warnings and Precautions (5.5)]
    Grade 3Withhold dose until Grade 1 or resolved and corticosteroid dose is less than or equal to prednisone 10 mg per day (or equivalent)
    Grade 4Permanently discontinue
    Infections [see Warnings and Precautions (5.6)]Grade 3 or 4Withhold dose until Grade 1 or resolved
    Infusion-Related Reactions [see Warnings and Precautions (5.7)]Grade 1 or 2Interrupt or slow the rate of infusion
    Grade 3 or 4Permanently discontinue
    Persistent Grade 2 or 3 adverse reaction (excluding endocrinopathies)Grade 2 or 3 adverse reaction that does not recover to Grade 0 or 1 within 12 weeks after last TECENTRIQ dosePermanently discontinue
    Inability to taper corticosteroidInability to reduce to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks after last TECENTRIQ dosePermanently discontinue
    Recurrent Grade 3 or 4 adverse reactionRecurrent Grade 3 or 4 (severe or life-threatening) adverse reactionPermanently discontinue

    2.8 Preparation and Administration

    Preparation

    Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial.

    Prepare the solution for infusion as follows:

    • Select the appropriate vial(s) based on the prescribed dose.
    • Withdraw the required volume of TECENTRIQ 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, USP.
    • Dilute with only 0.9% Sodium Chloride Injection, USP.
    • Mix diluted solution by gentle inversion. Do not shake.
    • Discard used or empty vials of TECENTRIQ.

    Storage of Infusion Solution

    This product does not contain a preservative.

    Administer immediately once prepared. If diluted TECENTRIQ infusion solution is not used immediately, store solution either:

    • At room temperature for no more than 6 hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration of the infusion, or
    • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of preparation.

    Do not freeze.

    Do not shake.

    Administration

    Administer the initial infusion over 60 minutes through an intravenous line with or without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron). If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

    Do not coadminister other drugs through the same intravenous line.

    Do not administer as an intravenous push or bolus.

  • 3 DOSAGE FORMS AND STRENGTHS

    Injection: 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in a single-dose vial.

  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Immune-Mediated Pneumonitis

    TECENTRIQ can cause immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids, including fatal cases. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids, prednisone 1–2 mg/kg/day or equivalents, followed by a taper for Grade 2 or higher pneumonitis. Withhold or permanently discontinue TECENTRIQ based on the severity [see Dosage and Administration (2.7)].

    In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], pneumonitis occurred in 2.5% of patients, including Grade 3 (0.6%), Grade 4 (0.1%), and Grade 5 (< 0.1%) immune-mediated pneumonitis. The median time to onset of pneumonitis was 3.6 months (3 days to 20.5 months) and median duration of pneumonitis was 1.4 months (1 day to 15.1 months). Pneumonitis resolved in 67% of patients. Pneumonitis led to discontinuation of TECENTRIQ in 0.4% of the 2616 patients. Systemic corticosteroids were required in 1.5% of patients, including 0.8% who received high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) for a median duration of 4 days (1 day to 45 days) followed by a corticosteroid taper.

    In clinical studies enrolling 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with platinum-based chemotherapy [see Adverse Reactions (6.1)], immune-mediated pneumonitis occurred in 5.5% of patients, including Grades 3-4 in 1.4% of patients. Systemic corticosteroids were required in 4.2% of patients, including 3.1% who received high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) for a median duration of 5 days (1 day to 98 days) followed by a corticosteroid taper.

    5.2 Immune-Mediated Hepatitis

    TECENTRIQ can cause liver test abnormalities and immune-mediated hepatitis, defined as requiring use of systemic corticosteroids. Fatal cases have been reported. Monitor patients for signs and symptoms of hepatitis, during and after discontinuation of TECENTRIQ, including clinical chemistry monitoring. Administer corticosteroids, prednisone 1–2 mg/kg/day or equivalents, followed by a taper for Grade 2 or higher elevations of ALT, AST and/or total bilirubin. Interrupt or permanently discontinue TECENTRIQ based on the severity [see Dosage and Administration (2.7)].

    In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], hepatitis occurred in 9% of patients, including Grade 3 (2.3%), Grade 4 (0.6%), and Grade 5 (< 0.1%). The median time to onset of hepatitis was 1.4 months (1 day to 25.8 months) and median duration was 24 days (1 day to 13 months). Hepatitis resolved in 71% of patients. Hepatitis led to discontinuation of TECENTRIQ in 0.4% of 2616 patients. Systemic corticosteroids were required in 2% of the patients, with 1.3% requiring high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) for a median duration of 3 days (1 day to 35 days) followed by a corticosteroid taper.

    In clinical studies enrolling 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with platinum-based chemotherapy [see Adverse Reactions (6.1)], immune-mediated hepatitis occurred in 14% of patients, including Grades 3-4 in 4.1% of patients. Systemic corticosteroids were required in 4.8% of patients, including 3.4% who received high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) for a median duration of 6 days (1 day to 144 days) followed by a corticosteroid taper.

    5.3 Immune-Mediated Colitis

    TECENTRIQ can cause immune-mediated colitis or diarrhea, defined as requiring use of systemic corticosteroids. Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with TECENTRIQ for Grade 2 or 3 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer corticosteroids, prednisone 1–2 mg/kg/day or equivalents, followed by a taper for Grade 2 diarrhea or colitis. Interrupt or permanently discontinue TECENTRIQ based on the severity [see Dosage and Administration (2.6) and Adverse Reactions (6.1)].

    In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], diarrhea or colitis occurred in 20% of patients, including Grade 3 (1.4%) events. The median time to onset of diarrhea or colitis was 1.5 months (1 day to 41 months). Diarrhea and colitis resolved in 85% of the patients. Diarrhea or colitis led to discontinuation of TECENTRIQ in 0.2% of 2616 patients. Systemic corticosteroids were required in 1.1% of patients and high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) was required in 0.4% patients with a median duration of 3 days (1 day to 11 days) followed by a corticosteroid taper.

    In clinical studies enrolling 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with platinum-based chemotherapy [see Adverse Reactions (6.1)], diarrhea or colitis occurred in 29% of patients, including Grade 3-4 in 4.3% of patients. Systemic corticosteroids were required in 4.7% of patients, including 2.9% who received high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) for a median duration of 4 days (1 day to 170 days) followed by a corticosteroid taper.

    5.4 Immune-Mediated Endocrinopathies

    TECENTRIQ can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, and type 1 diabetes mellitus, including diabetic ketoacidosis, and hypophysitis/hypopituitarism.

    Thyroid Disorders: Monitor thyroid function prior to and periodically during treatment with TECENTRIQ. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Continue TECENTRIQ for hypothyroidism and interrupt for hyperthyroidism based on the severity [see Dosage and Administration (2.7)].

    In clinical studies enrolling 2616 patients who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], hypothyroidism occurred in 4.6% of patients, and 3.8% of patients required the use of hormone replacement therapy. Hyperthyroidism occurred in 1.6% of patients. One patient experienced acute thyroiditis.

    In clinical studies enrolling 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with platinum-based chemotherapy [see Adverse Reactions (6.1)], hypothyroidism occurred in 11% of patients, including Grades 3-4 in 0.3% of patients; 8.2% of the 2421 patients required the use of hormone replacement therapy. The frequency and severity of hyperthyroidism and thyroiditis were similar whether TECENTRIQ was given as a single-agent in patients with various cancers or in combination with other antineoplastic drugs in NSCLC and SCLC.

    Adrenal Insufficiency: Monitor patients for clinical signs and symptoms of adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate prednisone 1to 2 mg/kg/day or equivalents, followed by a taper and hormone replacement as clinically indicated. Interrupt TECENTRIQ based on the severity [see Dosage and Administration (2.7)].

    In clinical studies enrolling 2616 patients who received TECENTRIQ as a single-agent, adrenal insufficiency occurred in 0.4% of patients, including Grade 3 (< 0.1%) adrenal insufficiency. Median time to onset was 5.7 months (3 days to 19 months). There was insufficient information to adequately characterize the median duration of adrenal insufficiency. Adrenal insufficiency resolved in 27% of patients. Systemic corticosteroids were required in 0.3% of 2616 patients, including 0.1% who required high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent). The frequency and severity of adrenal insufficiency were similar whether TECENTRIQ was given as a single-agent in patients with various cancers or in combination with other antineoplastic drugs in NSCLC and SCLC.

    Type 1 Diabetes Mellitus: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Interrupt TECENTRIQ based on the severity [see Dosage and Administration (2.7)].

    In clinical studies enrolling 2616 patients who received TECENTRIQ as a single-agent, type 1 diabetes mellitus occurred in < 0.1% of patients. Insulin was required in one patient. The frequency and severity of diabetes mellitus were similar whether TECENTRIQ was given as a single-agent in patients with various cancers or in combination with other antineoplastic drugs in NSCLC and SCLC.

    Hypophysitis: For Grade 2 or higher hypophysitis, initiate prednisone 1–2 mg/kg/day or equivalents, followed by a taper and hormone replacement therapy as clinically indicated. Interrupt TECENTRIQ based on the severity [see Dosage and Administration (2.7)].

    In clinical studies enrolling 2616 patients who received TECENTRIQ as a single-agent, Grade 2 hypophysitis occurred in < 0.1% of patients. The frequency and severity of hypophysitis were similar whether TECENTRIQ was given as a single-agent in patients with various cancers or in combination with other antineoplastic drugs in NSCLC and SCLC.

    5.5 Other Immune-Mediated Adverse Reactions

    TECENTRIQ can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with TECENTRIQ, immune-mediated adverse reactions can also manifest after discontinuation of TECENTRIQ.

    For suspected Grade 2 immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. For severe (Grades 3 or 4) adverse reactions, administer corticosteroids, prednisone 1 to 2 mg/kg/day or equivalents, followed by a taper. Interrupt or permanently discontinue TECENTRIQ, based on the severity of the reaction [see Dosage and Administration (2.6)].

    If uveitis occurs in combination with other immune-mediated adverse reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

    The following clinically significant, immune-mediated adverse reactions occurred at an incidence of < 1% in 2616 patients who received TECENTRIQ as a single-agent and in 2421 patients who received TECENTRIQ in combination with platinum-based chemotherapy or were reported in other products in this class [see Adverse Reactions (6.1)]:

    Cardiac: myocarditis

    Dermatologic: bullous dermatitis, pemphigoid, erythema multiforme, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN).

    Gastrointestinal: pancreatitis, including increases in serum amylase or lipase levels

    General: systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis

    Hematological: autoimmune hemolytic anemia, immune thrombocytopenic purpura.

    Musculoskeletal: myositis, rhabdomyolysis.

    Neurological: Guillain-Barre syndrome, myasthenia syndrome/myasthenia gravis, demyelination, immune-related meningoencephalitis, aseptic meningitis, encephalitis, facial and abducens nerve paresis, polymyalgia rheumatica, autoimmune neuropathy, and Vogt-Koyanagi-Harada syndrome.

    Ophthalmological: uveitis, iritis.

    Renal: nephrotic syndrome, nephritis.

    Vascular: vasculitis

    5.6 Infections

    TECENTRIQ can cause severe infections including fatal cases. Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold TECENTRIQ and resume once clinically stable [see Dosage and Administration (2.7) and Adverse Reactions (6.1)].

    In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], infections occurred in 42% of patients, including Grade 3 (8.7%), Grade 4 (1.5%), and Grade 5 (1%). In patients with urothelial carcinoma, the most common Grade 3 or higher infection was urinary tract infections, occurring in 6.5% of patients. In patients with NSCLC, the most common Grade 3 or higher infection was pneumonia, occurring in 3.8% of patients. The frequency and severity of infections were similar whether TECENTRIQ was given as a single-agent in patients with various cancers or in combination with other antineoplastic drugs in NSCLC and SCLC.

    5.7 Infusion-Related Reactions

    TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity [see Dosage and Administration (2.7)]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

    In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], infusion-related reactions occurred in 1.3% of patients, including Grade 3 (0.2%). The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as a single-agent in patients with various cancers, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range (840 mg Q2W to 1680 mg Q4W).

    5.8 Embryo-Fetal Toxicity

    Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death.

    Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

  • 6 ADVERSE REACTIONS

    The following clinically significant adverse reactions are described elsewhere in the labeling:

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as a single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and four open-label, single arm studies (PCD4989g, IMvigor210, BIRCH, FIR) which enrolled 524 patients with metastatic urothelial carcinoma, 1636 patients with metastatic NSCLC, and 456 patients with other tumor types. TECENTRIQ was administered at a dose of 1200 mg intravenously every 3 weeks in all studies except PCD4989g. Among the 2616 patients who received a single-agent TECENTRIQ, 36% were exposed for longer than 6 months and 20% were exposed for longer than 12 months. Using the dataset described for patients who received TECENTRIQ as a single-agent, the most common adverse reactions in ≥ 20% of patients were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%).

    In addition, the data reflect exposure to TECENTRIQ in combination with other antineoplastic drugs in 2421 patients with NSCLC (N = 2223) or SCLC (N = 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133. Among the 2421 patients, 53% were exposed to TECENTRIQ for longer than 6 months and 29% were exposed to TECENTRIQ for longer than 12 months. Among the 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with other antineoplastic drugs, the most common adverse reactions in ≥20% of patients were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%) and decreased appetite (27%).

    Urothelial Carcinoma

    Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

    The safety of TECENTRIQ was evaluated in IMvigor 210 (Cohort 1), a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients received TECENTRIQ 1200 mg intravenously every 3 weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15 weeks (0 to 87 weeks).

    Five patients (4.2%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. One additional patient (0.8%) was experiencing herpetic meningoencephalitis and disease progression at the time of death.

    Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (≥ 2%) were diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure.

    TECENTRIQ was discontinued for adverse reactions in 4.2% of patients. The adverse reactions leading to discontinuation were diarrhea/colitis (1.7%), fatigue (0.8%), hypersensitivity (0.8%), and dyspnea (0.8%).

    Adverse reactions leading to interruption occurred in 35% of patients; the most common (≥ 1%) were intestinal obstruction, fatigue, diarrhea, urinary tract infection, infusion- related reaction, cough, abdominal pain, peripheral edema, pyrexia, respiratory tract infection, upper respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, pruritus, and venous thromboembolism.

    Tables 2 and 3 summarize the adverse reactions and Grades 3–4 selected laboratory abnormalities, respectively, in patients who received TECENTRIQ in IMvigor210 (Cohort 1).

    Table 2: Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)
    Adverse ReactionTECENTRIQ
    N = 119
    All Grades
    (%)
    Grades 3–4
    (%)
    *
    Includes fatigue, asthenia, lethargy, and malaise
    Includes edema peripheral, scrotal edema, lymphedema, and edema
    Includes diarrhea, colitis, frequent bowel movements, autoimmune colitis
    §
    Includes abdominal pain, upper abdominal pain, lower abdominal pain, and flank pain
    Includes decreased appetite and early satiety
    #
    Includes rash, dermatitis, dermatitis acneiform, rash maculo-papular, rash erythematous, rash pruritic, rash macular, and rash papular
    Þ
    Includes urinary tract infection, urinary tract infection bacterial, cystitis, and urosepsis
    ß
    Includes cough and productive cough
    à
    Includes dyspnea and exertional dyspnea
    General
    Fatigue*528
    Peripheral edema172
    Pyrexia140.8
    Gastrointestinal
    Diarrhea245
    Nausea222
    Vomiting160.8
    Constipation152
    Abdominal pain§150.8
    Metabolism and Nutrition
    Decreased appetite243
    Musculoskeletal and Connective Tissue
    Back/Neck pain183
    Arthralgia130
    Skin and Subcutaneous Tissue
    Pruritus180.8
    Rash#170.8
    Infections
    Urinary tract infectionÞ175
    Respiratory, Thoracic, and Mediastinal
    Coughß140
    Dyspneaà120
    Table 3: Grades 3–4 Laboratory Abnormalities in ≥ 1% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)
    Laboratory AbnormalityGrades 3–4
    (%)
    Graded per NCI CTCAE v4.0.
    Chemistry
    Hyponatremia15
    Hyperglycemia10
    Increased Alkaline Phosphatase7
    Increased Creatinine5
    Hypophosphatemia4
    Increased ALT4
    Increased AST4
    Hyperkalemia3
    Hypermagnesemia3
    Hyperbilirubinemia3
    Hematology
    Lymphopenia9
    Anemia7

    Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma

    The safety of TECENTRIQ was evaluated in IMvigor210 (Cohort 2), a multicenter, open-label, single-arm trial that included 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (0.1 to 46 weeks).

    Three patients (1%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, pneumonitis, or intestinal obstruction.

    TECENTRIQ was discontinued for adverse reactions in 3.2% of patients. Sepsis led to discontinuation in 0.6% of patients.

    Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state.

    Adverse reactions leading to interruption occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis.

    Tables 4 and 5 summarize the adverse reactions and Grades 3–4 selected laboratory abnormalities, respectively, in patients who received TECENTRIQ in IMvigor210 (Cohort 2).

    Table 4: Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 2)
    Adverse ReactionTECENTRIQ
    N = 310
    All Grades
    (%)
    Grades 3–4
    (%)
    General
    Fatigue526
    Pyrexia211
    Peripheral edema181
    Metabolism and Nutrition
    Decreased appetite261
    Gastrointestinal
    Nausea252
    Constipation210.3
    Diarrhea181
    Abdominal pain174
    Vomiting171
    Infections
    Urinary tract infection229
    Respiratory, Thoracic, and Mediastinal
    Dyspnea164
    Cough140.3
    Musculoskeletal and Connective Tissue
    Back/Neck pain152
    Arthralgia141
    Skin and Subcutaneous Tissue
    Rash150.3
    Pruritus130.3
    Renal and Urinary
    Hematuria143
    Table 5: Grades 3–4 Laboratory Abnormalities in ≥ 1% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 2)
    Laboratory AbnormalityGrades 3–4
    (%)
    Graded per NCI CTCAE v4.0.
    Chemistry
    Hyponatremia10
    Hyperglycemia5
    Increased Alkaline Phosphatase4
    Increased Creatinine3
    Increased ALT2
    Increased AST2
    Hypoalbuminemia1
    Hematology
    Lymphopenia10
    Anemia8

    Non-small Cell Lung Cancer (NSCLC)

    IMpower110

    The safety of TECENTRIQ was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received TECENTRIQ 1200 mg every 3 weeks (n=286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n=263) until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area). The median duration of exposure to TECENTRIQ was 5.3 months (0 to 33 months).

    Fatal adverse reactions occurred in 3.8% of patients receiving TECENTRIQ; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infraction, and device occlusion (1 patient each).

    Serious adverse reactions occurred in 28% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%)

    TECENTRIQ was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (≥2 patients) leading to TECENTRIQ discontinuation were peripheral neuropathy and pneumonitis.

    Adverse reactions leading to interruption of TECENTRIQ occurred in 26% of patients; the most common (>1%) were ALT increased (2.1%), AST increased (2.1%), pneumonitis (2.1%), pyrexia (1.4%), pneumonia (1.4%) and upper respiratory tract infection (1.4%).

    Tables 6 and 7 summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower110.

    Table 6: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving TECENTRIQ in IMpower110
    Adverse ReactionTECENTRIQ
    N = 286
    Platinum-Based Chemotherapy
    N = 263
    All Grades
    (%)
    Grades 3–4*
    (%)
    All Grades*
    (%)
    Grades 3–4
    (%)
    Graded per NCI CTCAE v4.0
    Gastrointestinal
    Nausea140.3341.9
    Constipation121.0220.8
    Diarrhea110120.8
    General
    Fatigue/asthenia251.4344.2
    Pyrexia14090.4
    Metabolism and Nutrition
    Decreased appetite150.7190
    Respiratory, Thoracic and Mediastinal
    Dyspnea140.7100
    Cough120.3100
    Table 7: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower110
    Laboratory AbnormalityTECENTRIQPlatinum Based Chemotherapy
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: TECENTRIQ (range: 278-281); platinum-based chemotherapy (range:256-260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range.
    Hematology
    Anemia691.89420
    Lymphopenia4795917
    Chemistry
    Hypoalbuminemia480.4392
    Increased alkaline phosphatase462.5421.2
    Hyponatremia449367
    Increased ALT383.2320.8
    Increased AST363.2320.8
    Hyperkalemia293.9362.7
    Hypocalcemia241.4242.7
    Increased blood creatinine240.7331.5
    Hypophosphatemia233.6212

    IMpower150

    The safety of TECENTRIQ with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, a multicenter, international, randomized, open-label trial in which 393 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC 6 mg/mL/min intravenously every 3 weeks for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg with bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. The median duration of exposure to TECENTRIQ was 8.3 months in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin.

    Fatal adverse reactions occurred in 6% of patients receiving TECENTRIQ; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection.

    Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (>2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis.

    TECENTRIQ was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%).

    Adverse reactions leading to interruption of TECENTRIQ occurred in 48%; the most common (>1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria.

    Tables 8 and 9 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin in IMpower150.

    Table 8: Adverse Reactions Occurring in ≥15% of Patients with NSCLC Receiving TECENTRIQ in IMpower150
    Adverse ReactionTECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin
    N = 393
    Bevacizumab, Paclitaxel and Carboplatin
    N = 394
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Graded per NCI CTCAE v4.0
    *
    Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paraesthesia, dysesthesia, polyneuropathy.
    Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform.
    Includes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, backpain, myalgia, and bone pain.
    §
    Includes diarrhea, gastroenteritis, colitis, enterocolitis.
    Data based on Preferred Terms since laboratory data for proteinuria were not systematically collected.
    Nervous System
    Neuropathy*563473
    Headache160.8130
    General
    Fatigue/Asthenia506466
    Pyrexia190.390.5
    Skin and Subcutaneous Tissue
    Alopecia480460
    Rash232100.3
    Musculoskeletal and Connective Tissue
    Myalgia/Pain423342
    Arthralgia261221
    Gastrointestinal
    Nausea394322
    Diarrhea§336250.5
    Constipation300.3230.3
    Vomiting192181
    Metabolism and Nutrition
    Decreased appetite294210.8
    Vascular
    Hypertension259228
    Respiratory
    Cough200.8190.3
    Epistaxis171220.3
    Renal
    Proteinuria163153
    Table 9: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower150
    Laboratory AbnormalityTECENTRIQ with Bevacizumab, Paclitaxel, and CarboplatinBevacizumab, Paclitaxel and Carboplatin
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with bevacizumab, paclitaxel, and carboplatin range: 337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0
    *
    NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities
    Hematology
    Anemia8310839
    Neutropenia52314526
    Lymphopenia48173813
    Chemistry
    Hyperglycemia610600
    Increased BUN52NA*44NA*
    Hypomagnesemia422361
    Hypoalbuminemia403312
    Increased AST404280.8
    Hyponatremia3810369
    Increased Alkaline Phosphatase372321
    Increased ALT376280.5
    Increased TSH30NA*20NA*
    Hyperkalemia283252
    Increased Creatinine281192
    Hypocalcemia263213
    Hypophosphatemia254184
    Hypokalemia237144
    Hyperphosphatemia25NA*19NA*

    IMpower130

    The safety of TECENTRIQ with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, a multicenter, international, randomized, open-label trial in which 473 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m2 intravenously on Day 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg intravenously every 3 weeks until disease progression or unacceptability toxicity [see Clinical Studies (14.2)]. Among patients receiving TECENTRIQ, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.

    Fatal adverse reactions occurred in 5.3% of patients receiving TECENTRIQ; these included including pneumonia (1.1%), pulmonary embolism (0.8%), myocardial infarction (0.6%), cardiac arrest (0.4%) and pneumonitis (0.4%) and sepsis, septic shock, staphylococcal sepsis, aspiration, respiratory distress, cardiorespiratory arrest, ventricular tachycardia, death (not otherwise specified), and hepatic cirrhosis (0.2% each).

    Serious adverse reactions occurred in 51% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (≥2%) were pneumonia (6%), diarrhea (3%), lung infection (3.0%), pulmonary embolism (3%), chronic obstructive pulmonary disease exacerbation (2.5%), dyspnea (2.3%), and febrile neutropenia (1.9%).

    TECENTRIQ was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia (0.8%), pulmonary embolism (0.8%), fatigue (0.6%), dyspnea (0.6%), pneumonitis (0.6%), neutropenia (0.4%), nausea (0.4%), renal failure (0.4%), cardiac arrest (0.4%), and septic shock (0.4%).

    Adverse reactions leading to interruption of TECENTRIQ occurred in 62% of patients; the most common (>1%) were neutropenia, thrombocytopenia, anemia, diarrhea, fatigue/asthenia, pneumonia, dyspnea, pneumonitis, pyrexia, nausea, acute kidney injury, vomiting, pulmonary embolism, arthralgia, infusion-related reaction, abdominal pain, chronic obstructive pulmonary disease exacerbation, dehydration, and hypokalemia.

    Tables 10 and 11 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with paclitaxel protein-bound and carboplatin in IMpower130.

    Table 10: Adverse Reactions Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower130
    Adverse ReactionTECENTRIQ with Paclitaxel Protein-Bound and Carboplatin
    N = 473
    Paclitaxel Protein-Bound and Carboplatin
    N = 232
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Graded per NCI CTCAE v4.0
    *
    Includes diarrhea, colitis, and gastroenteritis
    Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort
    Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy
    §
    Includes dyspnea, dyspnea exertional and wheezing
    Includes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular.
    General
    Fatigue/Asthenia6111608
    Gastrointestinal
    Nausea503.4462.2
    Diarrhea *436326
    Constipation361.1310
    Vomiting272.7192.2
    Musculoskeletal and Connective Tissue
    Myalgia/Pain 383220.4
    Nervous System
    Neuropathy 332.5282.2
    Respiratory, Thoracic and Mediastinal
    Dyspnea §324.9251.3
    Cough270.6170
    Skin and Subcutaneous Tissue
    Alopecia320270
    Rash 200.6110.9
    Metabolism and Nutrition
    Decreased appetite302.1262.2
    Table 11: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower130
    Laboratory AbnormalityTECENTRIQ with Paclitaxel Protein-Bound and Carboplatin
    N = 473
    Paclitaxel Protein-Bound and Carboplatin
    N = 232
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4 (%)
    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with paclitaxel protein bound and carboplatin (range: 423 - 467); paclitaxel protein bound and carboplatin (range: 218- 229). Graded per NCI CTCAE v4.0.
    *
    NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities
    Hematology
    Anemia92338725
    Neutropenia75506739
    Thrombocytopenia73195913
    Lymphopenia71236116
    Chemistry
    Hyperglycemia758668
    Hypomagnesemia503.4423.2
    Hyponatremia379287
    Hypoalbuminemia351.3310
    Increased ALT312.8243.9
    Hypocalcemia312.6271.8
    Hypophosphatemia296203.2
    Increased AST282.2241.8
    Increased TSH26NA*5NA*
    Hypokalemia266244.4
    Increased Alkaline Phosphatase252.6221.3
    Increased Blood Creatinine232.8160.4
    Hyperphosphatemia21NA*13NA*

    Previously Treated Metastatic NSCLC

    The safety of TECENTRIQ was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.2)]. A total of 609 patients received TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n=578) 75 mg/m2 intravenously every 3 weeks until unacceptable toxicity or disease progression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The median duration of exposure was 3.4 months (0 to 26 months) in TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.

    The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had ECOG performance status of 1.

    Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure.

    Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (>1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection.

    TECENTRIQ was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to TECENTRIQ discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of TECENTRIQ occurred in 25% of patients; the most common (>1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain.

    Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.

    Table 12: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving TECENTRIQ in OAK
    Adverse ReactionTECENTRIQ
    N = 609
    Docetaxel
    N = 578
    All Grades
    (%)
    Grades 3-4
    (%)
    All Grades
    (%)
    Grades 3-4
    (%)
    Graded per NCI CTCAE v4.0
    *
    Includes fatigue and asthenia
    Includes cough and exertional cough
    Includes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia
    §
    Includes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid
    General
    Fatigue/Asthenia*444536
    Pyrexia18<113<1
    Respiratory
    Cough26<121<1
    Dyspnea222.8212.6
    Metabolism and Nutrition
    Decreased appetite23<1241.6
    Musculoskeletal
    Myalgia/Pain201.320<1
    Arthralgia120.5100.2
    Gastrointestinal
    Nausea18<123<1
    Constipation18<114<1
    Diarrhea16<1242
    Skin
    Rash§12<1100
    Table 13: Laboratory Abnormalities Worsening From Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in OAK
    Laboratory AbnormalityTECENTRIQDocetaxel
    All Grades
    (%)
    Grades 3-4
    (%)
    All Grades
    (%)
    Grades 3-4
    (%)
    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0
    Hematology
    Anemia673827
    Lymphocytopenia49146021
    Chemistry
    Hypoalbuminemia484503
    Hyponatremia427316
    Increased Alkaline Phosphatase392251
    Increased AST313160.5
    Increased ALT273140.5
    Hypophosphatemia275234
    Hypomagnesemia261211
    Increased Creatinine232161

    Metastatic Triple Negative Breast Cancer (TNBC)

    The safety of TECENTRIQ in combination with paclitaxel protein-bound was evaluated in IMpassion130, a multicenter, international, randomized, double-blinded placebo-controlled trial in patients with locally advanced or metastatic TNBC who have not received prior chemotherapy for metastatic disease [see Clinical Studies (14.3)]. Patients received TECENTRIQ 840 mg (n=452) or placebo (n=438) intravenously followed by paclitaxel protein-bound (100 mg/m2) intravenously. For each 28 day cycle, TECENTRIQ was administered on days 1 and 15 and paclitaxel protein-bound was administered on days 1, 8, and 15 until disease progression or unacceptable toxicity. In the safety-evaluable population, the median duration of exposure to TECENTRIQ was 5.5 months (range: 0-32 months) and paclitaxel protein-bound was 5.1 months (range: 0-31.5 months) in the TECENTRIQ and paclitaxel protein-bound arm. The median duration of exposure to placebo was 5.1 months (range: 0-25.1 months) and paclitaxel protein-bound was 5.0 months (range: 0-23.7 months) in the placebo and paclitaxel protein-bound arm.

    Fatal adverse reactions occurred in 1.3%) of patients in the TECENTRIQ and paclitaxel protein-bound arm; these included septic shock, mucosal inflammation, auto-immune hepatitis, aspiration, pneumonia, pulmonary embolism.

    Serious adverse reactions occurred in 23% of patients. The most frequent serious adverse reactions were pneumonia (2%), urinary tract infection (1%), dyspnea (1%), and pyrexia (1%).

    Adverse reactions leading to discontinuation of TECENTRIQ occurred in 6% (29/452) of patients in the TECENTRIQ and paclitaxel protein-bound arm. The most common adverse reaction leading to TECENTRIQ discontinuation was peripheral neuropathy (<1%).

    Adverse reactions leading to interruption of TECENTRIQ occurred in 31% of patients; the most common (≥ 2%) were neutropenia, neutrophil count decreased, hyperthyroidism, and pyrexia.

    Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 13% (59/452) of patients in the TECENTRIQ and paclitaxel protein-bound arm.

    Tables 14 and 15 summarize adverse reactions and selected laboratory abnormalities worsening from baseline in the TECENTRIQ treated patients.

    Table 14: Adverse Reactions Occurring in ≥10% of Patients with TNBC in IMpassion130
    Adverse ReactionTECENTRIQ with Paclitaxel Protein-Bound
    N = 452
    Placebo with Paclitaxel Protein-Bound
    N = 438
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Graded per NCI CTCAE v4.0
    *
    Includes peripheral neuropathy, peripheral sensory neuropathy, paresthesia, and polyneuropathy
    Skin and Subcutaneous Tissue
    Alopecia56<158<1
    Rash17<116<1
    Pruritus140100
    Nervous System
    Peripheral neuropathies*479445
    Headache23<122<1
    Dysgeusia140140
    Dizziness140110
    General
    Fatigue474453.4
    Pyrexia19<1110
    Peripheral Edema15<1161.4
    Asthenia12<111<1
    Gastrointestinal
    Nausea461.1381.8
    Diarrhea331.3342.1
    Constipation25<125<1
    Vomiting20<1171.1
    Abdominal pain10<112<1
    Respiratory, Thoracic, and Mediastinal
    Cough250190
    Dyspnea16<115<1
    Metabolism and Nutrition
    Decreased Appetite20<118<1
    Musculoskeletal and Connective Tissue
    Arthralgia18<116<1
    Back pain151.313<1
    Myalgia14<115<1
    Pain in extremity11<110<1
    Endocrine
    Hypothyroidism1403.40
    Infections
    Urinary tract infection12<111<1
    Upper respiratory tract infection111.190
    Nasopharyngitis11080
    Table 15: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with TNBC in IMpassion130
    Laboratory AbnormalityTECENTRIQ with Paclitaxel Protein-BoundPlacebo in combination with Paclitaxel Protein-Bound
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: TECENTRIQ with paclitaxel protein-bound (range: 316-452); placebo with paclitaxel protein-bound (range: 299-438). Graded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for grade 1 events (NCI CTCAE v5.0).
    Hematology
    Decreased Hemoglobin793.8733
    Decreased Leukocytes7614719
    Decreased Neutrophils58135413
    Decreased Lymphocytes5413478
    Increased Prothrombin INR 25<125<1
    Chemistry
    Increased ALT436342.7
    Increased AST424.9343.4
    Decreased Calcium281.126<1
    Decreased Sodium274.2252.7
    Decreased Albumin27<125<1
    Increased Alkaline Phosphatase253.3222.7
    Decreased Phosphate223.6193.7
    Increased Creatinine21<116<1

    Small Cell Lung Cancer (SCLC)

    The safety of TECENTRIQ with carboplatin and etoposide was evaluated in IMpower133, a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received TECENTRIQ 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by TECENTRIQ 1200 mg every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.4)]. Among 198 patients receiving TECENTRIQ, 32% were exposed for 6 months or longer and 12% were exposed for 12 months or longer.

    Fatal adverse reactions occurred in 2% of patients receiving TECENTRIQ. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).

    Serious adverse reactions occurred in 37% of patients receiving TECENTRIQ. Serious adverse reactions in >2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%).

    TECENTRIQ was discontinued due to adverse reactions in 11% of patients. The most frequent adverse reaction requiring permanent discontinuation in >2% of patients was infusion-related reactions (2.5%).

    Adverse reactions leading to interruption of TECENTRIQ occurred in 59% of patients; the most common (>1%) were neutropenia (22%), anemia (9%), leukopenia (7%), thrombocytopenia (5%), fatigue (4.0%), infusion-related reaction (3.5%), pneumonia (2.0%), febrile neutropenia (1.5%), increased ALT (1.5%), and nausea (1.5%).

    Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower133.

    Table 16: Adverse Reactions Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133
    Adverse ReactionTECENTRIQ with Carboplatin and Etoposide
    N = 198
    Placebo with Carboplatin and Etoposide
    N = 196
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Graded per NCI CTCAE v4.0
    General
    Fatigue/asthenia395333
    Gastrointestinal
    Nausea381331
    Constipation261301
    Vomiting202173
    Skin and Subcutaneous Tissue
    Alopecia370350
    Metabolism and Nutrition
    Decreased appetite271180
    Table 17: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133
    Laboratory AbnormalityTECENTRIQ with Carboplatin and EtoposidePlacebo with Carboplatin and Etoposide
    All Grades
    (%)
    Grades 3–4
    (%)
    All Grades
    (%)
    Grades 3–4
    (%)
    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 181-193); Placebo (range: 181-196). Graded per NCI CTCAE v4.0
    *
    TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories.
    NA= Not applicable.
    Hematology
    Anemia94179319
    Neutropenia73457648
    Thrombocytopenia58205317
    Lymphopenia46143811
    Chemistry
    Hyperglycemia6710658
    Increased Alkaline Phosphatase381352
    Hyponatremia34153311
    Hypoalbuminemia321300
    Decreased TSH*28NA15NA
    Hypomagnesemia315356
    Hypocalcemia263285
    Increased ALT263311
    Increased AST221212
    Increased Blood Creatinine224151
    Hyperphosphatemia21NA23NA
    Increased TSH*21NA7NA

    Hepatocellular Carcinoma (HCC)

    The safety of TECENTRIQ in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocelullar carcinoma who have not received prior systemic treatment [see Clinical Studies (14.5)]. Patients received 1,200 mg of TECENTRIQ intravenously followed by 15 mg/kg bevacizumab (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months).

    Fatal adverse reactions occurred in 4.6% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).

    Serious adverse reactions occurred in 38% of patients in the TECENTRIQ and bevacizumab arm. The most frequent serious adverse reactions (≥ 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%).

    Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to TECENTRIQ discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%).

    Adverse reactions leading to interruption of TECENTRIQ occurred in 41% of patients in the TECENTRIQ and bevacizumab arm; the most common (≥ 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatate (8%); infections (6%); gastrointestinal hemorrhages (3.6%); thrombocytopenia/decreased platelet count (3.6%); hyperthyroidism (2.7%); and pyrexia (2.1%).

    Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 12% of patients in the TECENTRIQ and bevacizumab arm.

    Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ and bevacizumab in IMbrave150.

    Table 18: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving TECENTRIQ in IMbrave150
    Adverse ReactionTECENTRIQ in combination with bevacizumab
    (n = 329)
    Sorafenib
    (n=156)
    All Grades*
    (%)
    Grades 3–4*
    (%)
    All Grades*
    (%)
    Grades 3–4*
    (%)
    2 Graded per NCI CTCAE v4.0
    *
    Includes fatigue and asthenia
    Vascular Disorders
    Hypertension30152412
    General Disorders and Administration Site Conditions
    Fatigue/asthenia*262326
    Pyrexia180100
    Renal and Urinary Disorders
    Proteinuria20370.6
    Investigations
    Weight Decreased110100
    Skin and Subcutaneous Tissue Disorders
    Pruritus190100
    Rash120172.6
    Gastrointestinal Disorders
    Diarrhea191.8495
    Constipation130140
    Abdominal Pain120170
    Nausea120160
    Vomiting10080
    Metabolism and Nutrition Disorders
    Decreased Appetite181.2243.8
    Respiratory, Thoracic and Mediastinal Disorders
    Cough120100
    Epistaxis1004.50
    Injury, Poisoning and Procedural Complications
    Infusion Related Reaction112.400
    Table 19: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with HCC Receiving TECENTRIQ in IMbrave150
    Laboratory AbnormalityTECENTRIQ in combination with bevacizumab
    (n=329)
    Sorafenib
    (n=156)
    All Grades*
    (%)
    Grades 3–4*
    (%)
    All Grades*
    (%)
    Grades 3–4*
    (%)
    Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ plus bevacizumab (222-323) and sorafenib (90-153) NA = Not applicable.
    *
    Graded per NCI CTCAE v4.0
    Chemistry
    Increased AST86169016
    Increased Alkaline Phosphatase704764.6
    Increased ALT628704.6
    Decreased Albumin601.5540.7
    Decreased Sodium5413499
    Increased Glucose489434.6
    Decreased Calcium300.3351.3
    Decreased Phosphorus264.75816
    Increased Potassium231.9162
    Hypomagnesemia220220
    Hematology
    Decreased Platelet687634.6
    Decreased Lymphocytes62135811
    Decreased Hemoglobin583.1623.9
    Increased Bilirubin5785914
    Decreased Leukocyte323.4291.3
    Decreased Neutrophil232.3161.1

    6.2 Immunogenicity

    As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to atezolizumab in the studies described above with the incidence of antibodies in other studies or to other products may be misleading.

    Among 565 patients with NSCLC in OAK, 30% tested positive for treatment-emergent anti-drug antibodies (ADA) at one or more post-dose time points. The median onset time to ADA formation was 3 weeks. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposure [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA positive by week 4 (21%; 118/560) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 [see Clinical Studies (14.2)]. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.

    Among 275 patients with urothelial carcinoma in IMvigor210 (Cohort 2), 42% tested positive for treatment-emergent ADA at one or more post-dose time points. Among 111 patients in IMvigor210 (Cohort 1), 48% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposures. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.

    Among 364 ADA-evaluable patients with NSCLC who received TECENTRIQ with bevacizumab, paclitaxel and carboplatin in IMpower150, 36% (n=132) tested positive for treatment-emergent ADA at one or more post-dose time points and 83% of these 132 patients tested ADA positive prior to receiving the second dose of atezolizumab. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA negative [see Clinical Pharmacology (12.3)]. The presence of ADA did not increase the incidence or severity of adverse reactions [see Clinical Studies (14.2)].

    Among 434 patients with TNBC in IMpassion130, 13% tested positive for treatment-emergent ADA at one or more post-dose time points. Among 178 patients in PD-L1 positive subgroup with TNBC in IMpassion130, 12% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had decreased systemic atezolizumab exposure [see Clinical Pharmacology (12.3)]. There are insufficient numbers of patients in the PD-L1 positive subgroup with ADA to determine whether ADA alters the efficacy of atezolizumab. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.

    Among 315 ADA-evaluable patients with HCC who received TECENTRIQ and bevacizumab in IMbrave150, 28% (n=88) tested positive for treatment-emergent ADA at one or more post-dose time points and 66% (58/88) of these 88 patients tested ADA-positive prior to receiving the third dose of TECENTRIQ. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA-positive by week 6 (20%; 58/288) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 6; [see Clinical Studies (14.5)]. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on its mechanism of action [see Clinical Pharmacology (12.1)], TECENTRIQ can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women.

    Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death (see Data). Advise females of reproductive potential of the potential risk to a fetus.

    In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

    Data

    Animal Data

    Animal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.

    8.2 Lactation

    Risk Summary

    There is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise women not to breastfeed during treatment and for at least 5 months after the last dose.

    8.3 Females and Males of Reproductive Potential

    Pregnancy Testing

    Verify pregnancy status in females of reproductive potential prior to initiating TECENTRIQ [see Use in Specific Populations (8.1)].

    Contraception

    Females

    Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months following the last dose.

    Infertility

    Females

    Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].

    8.4 Pediatric Use

    The safety and effectiveness of TECENTRIQ have not been established in pediatric patients.

    8.5 Geriatric Use

    Of 2810 patients with urothelial carcinoma, lung cancer, triple-negative breast cancer, and hepatocellular carcinoma who were treated with TECENTRIQ in clinical studies, 45% were 65 years and over and 12% were 75 years and over. No overall differences in safety or effectiveness were observed between patients aged 65 years or older and younger patients.

  • 11 DESCRIPTION

    Atezolizumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa.

    TECENTRIQ (atezolizumab) injection for intravenous use is a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials. Each 20 mL vial contains 1200 mg of atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 mg), with a pH of 5.8. Each 14 mL vial contains 840 mg of atezolizumab and is formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) with a pH of 5.8.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    PD-L1 may be expressed on tumor cells and/or tumor infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.

    Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune response, including activation of the anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

    12.3 Pharmacokinetics

    Patients' exposure to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg, including a dose of 1200 mg administered every 3 weeks. The clearance (CV%) was 0.20 L/day (29%), the volume of distribution at steady state was 6.9 L, and the terminal half-life was 27 days. Steady state was achieved after 6 to 9 weeks following multiple doses. The systemic accumulation ratio for every 2 weeks administration and every 3 weeks administration was 3.3- and 1.9- fold, respectively. Atezolizumab clearance was found to decrease over time, with a mean maximal reduction (CV%) from baseline value of approximately 17% (41%); however, the decrease in clearance was not considered clinically relevant.

    Specific Populations

    Age (21 to 89 years), body weight, sex, albumin levels, tumor burden, region or race, mild or moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2], mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5 × ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3× ULN and any AST), level of PD-L1 expression, or performance status had no clinically significant effect on the systemic exposure of atezolizumab. In OAK, IMpower150 (TECENTRIQ, bevacizumab, paclitaxel, carboplatin arm only), IMpassion130 (TECENTRIQ and paclitaxel protein-bound) and IMbrave150 (TECENTRIQ and bevacizumab), atezolizumab clearance in patients who tested positive for treatment-emergent anti-drug antibodies (ADA) was 25%, 18%, 22% and 49% higher, respectively, as compared to clearance in patients who tested negative for treatment-emergent ADA.

    The effect of severe renal impairment or severe hepatic impairment on the pharmacokinetics of atezolizumab is unknown.

    Drug Interaction Studies

    The drug interaction potential of atezolizumab is unknown.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No studies have been performed to test the potential of atezolizumab for carcinogenicity or genotoxicity.

    Animal fertility studies have not been conducted with atezolizumab; however, an assessment of the male and female reproductive organs was included in a 26-week, repeat-dose toxicity study in cynomolgus monkeys. Weekly administration of atezolizumab to female monkeys at the highest dose tested caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose and was reversible. There was no effect on the male monkey reproductive organs.

    13.2 Animal Toxicology and/or Pharmacology

    In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

  • 14 CLINICAL STUDIES

    14.1 Urothelial Carcinoma

    Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

    The efficacy of TECENTRIQ was investigated in IMvigor210 (Cohort 1) (NCT02951767), a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. Patients were considered cisplatin-ineligible if they met any one of the following criteria at study entry: impaired renal function [creatinine clearance (CLcr) of 30 to 59 mL/min], Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, hearing loss of ≥ 25 decibels (dB) at two contiguous frequencies, or Grades 2-4 peripheral neuropathy. This study excluded patients who had: a history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of a live, attenuated vaccine within 28 days prior to enrollment; or administration of systemic immunostimulatory agents within 6 weeks or systemic immunosuppressive medications within 2 weeks prior to enrollment. Patients received TECENTRIQ 1200 mg as an intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Tumor response assessments were conducted every 9 weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed overall response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), duration of response (DoR) and overall survival (OS).

    In this study, the median age was 73 years, 81% were male, and 91% were White. Thirty-five percent of patients had non-bladder urothelial carcinoma and 66% had visceral metastases. Eighty percent of patients had an ECOG PS of 0 or 1. Reasons for ineligibility for cisplatin-containing chemotherapy were: 70% had impaired renal function, 20% had an ECOG PS of 2, 14% had a hearing loss of ≥ 25dB, and 6% had Grades 2-4 peripheral neuropathy at baseline. Twenty percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.

    Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory, and the results were used to define subgroups for pre-specified analyses. Of the 119 patients, 27% were classified as having PD-L1 expression of ≥ 5% (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area). The remaining 73% of patients were classified as having PD-L1 expression of < 5% (PD-L1 stained tumor-infiltrating IC covering < 5% of the tumor area).

    Among the 32 patients with PD-L1 expression of ≥ 5%, median age was 67 years, 81% were male, 19% female, and 88% were White. Twenty-eight percent of patients had non-bladder urothelial carcinoma and 56% had visceral metastases. Seventy-two percent of patients had an ECOG PS of 0 or 1. Reasons for ineligibility for cisplatin-containing chemotherapy were: 66% had impaired renal function, 28% had an ECOG PS of 2, 16% had a hearing loss ≥ 25 dB, and 9% had Grades 2-4 peripheral neuropathy at baseline. Thirty-one percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.

    Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 20. The median follow-up time for this study was 14.4 months. In 24 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 33% (95% CI: 16%, 55%).

    Table 20: Efficacy Results in IMvigor210 (Cohort 1)
    All PatientsPD-L1 Expression Subgroups
    N = 119PD-L1
    Expression of < 5% in ICs*
    N = 87
    PD-L1
    Expression of ≥ 5% in ICs*
    N = 32
    NR = Not reached
    *
    PD-L1 expression in tumor-infiltrating immune cells (ICs)
    Denotes a censored value
    Number of IRF-assessed Confirmed Responders 28199
    ORR % (95% CI)23.5% (16.2, 32.2)21.8% (13.7, 32)28.1% (13.8, 46.8)
    Complete Response6.7%6.9%6.3%
    Partial Response16.8%14.9%21.9%
    Median DoR, months
    (range)
    NR
    (3.7, 16.6)
    NR
    (3.7, 16.6)
    NR
    (8.1, 15.6)

    IMvigor130 (NCT02807636) is an ongoing multicenter, randomized study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study contains three arms: TECENTRIQ monotherapy, TECENTRIQ with platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine), and platinum-based chemotherapy alone (comparator). Both cisplatin-eligible and cisplatin-ineligible patients are included in the study. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory. The independent Data Monitoring Committee (iDMC) for the study conducted a review of early data and found that patients classified as having PD-L1 expression of <5% when treated with TECENTRIQ monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended closure of the monotherapy arm to further accrual of patients with low PD-L1 expression, however, no other changes were recommended for the study, including any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm.

    Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma

    The efficacy of TECENTRIQ was investigated in IMvigor210 (Cohort 2) (NCT02108652), a multicenter, open-label, single-arm trial that included 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following a platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. This study excluded patients who had: a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrollment, or administration of systemic immunostimulatory agents within 6 weeks or systemic immunosuppressive medications within 2 weeks prior to enrollment. Patients received TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 9 weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as assessed by IRF using RECIST v1.1 and DoR.

    In this study, the median age was 66 years, 78% were male, 91% of patients were White. Twenty-six percent had non-bladder urothelial carcinoma and 78% of patients had visceral metastases. Sixty-two percent of patients had an ECOG PS of 1 and 35% of patients had a baseline CLcr < 60 mL/min. Nineteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Forty-one percent of patients had received 2 or more prior systemic regimens in the metastatic setting. Seventy-three percent of patients received prior cisplatin, 26% had prior carboplatin, and 1% were treated with other platinum-based regimens.

    Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 310 patients, 32% were classified as having PD-L1 expression of ≥ 5%. The remaining 68% of patients were classified as having PD-L1 expression of < 5%.

    Confirmed ORR and median DOR in all patients and the two PD-L1 subgroups are summarized in Table 21. The median follow-up time for this study was 32.9 months. In 59 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 22.0% (95% CI: 12.3%, 34.7%).

    Table 21: Efficacy Results in IMvigor210 (Cohort 2)
    All PatientsPD-L1 Expression Subgroups
    N = 310PD-L1
    Expression of < 5% in IC*
    N = 210
    PD-L1
    Expression of ≥ 5% in IC*
    N = 100
    *
    PD-L1 expression in tumor-infiltrating immune cells (IC)
    Denotes a censored value
    Number of IRF-assessed Confirmed Responders 462026
    ORR % (95% CI)14.8% (11.2, 19.3)9.5% (5.9, 14.3)26% (17.7, 35.7)
    Complete Response5.5%2.4%12.0%
    Partial Response9.4%7.1%14.0%
    Median DOR, months
    (range)
    27.7
    (2.1, 33.4)
    20.9
    (2.1, 33.4)
    29.7
    (4.2, 31.2)

    14.2 Non-Small Cell Lung Cancer

    Metastatic Chemotherapy-Naïve NSCLC with High PD-L1 Expression

    The efficacy of TECENTRIQ was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in patients with stage IV NSCLC whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC ≥ 1%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area [IC ≥ 1%]), who had received no prior chemotherapy for metastatic disease. PD-L1 tumor status was determined based on immunohistochemistry (IHC) testing using the VENTANA PD-L1 (SP142) Assay. The evaluation of efficacy is based on the subgroup of patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), excluding those with EGFR or ALK genomic tumor aberrations. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization.

    Randomization was stratified by sex, ECOG performance status, histology (non-squamous vs. squamous) and PD-L1 expression (TC ≥ 1% and any IC vs. TC < 1% and IC ≥ 1%). Patients were randomized (1:1) to receive one of the following treatment arms:

    • Arm A: TECENTRIQ 1200 mg every 3 weeks until disease progression or unacceptable toxicity
    • Arm B: Platinum-based chemotherapy

    Arm B platinum-based chemotherapy regimens for non-squamous NSCLC consisted of cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) OR carboplatin (AUC 6 mg/mL/min) and pemetrexed (500 mg/m2) on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by pemetrexed 500 mg/m2 until disease progression or unacceptable toxicity.

    Arm B platinum-based chemotherapy regimens for squamous NSCLC consisted of cisplatin (75 mg/m2) on Day 1 with gemcitabine (1250 mg/m2) on Days 1 and 8 of each 21-day cycle OR carboplatin (AUC 5 mg/mL/min) on Day 1 with gemcitabine (1000 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 4 or 6 cycles followed by best supportive care until disease progression or unacceptable toxicity.

    Administration of TECENTRIQ was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses.

    The major efficacy outcome measure was overall survival (OS) sequentially tested in the following subgroups of patients, excluding those with EGFR or ALK genomic tumor aberrations: TC ≥50% or IC ≥10%; TC ≥5% or IC ≥5%; and TC ≥1% or IC ≥1%.

    Among the 205 chemotherapy-naïve patients with stage IV NSCLC with high PD-L1 expression (TC ≥ 50% or IC≥ 10%) excluding those with EGFR or ALK genomic tumor aberrations, the median age was 65.0 years (range: 33 to 87), and 70% of patients were male. The majority of patients were White (82%) and Asian (17%). Baseline ECOG performance status was 0 (36%) or 1 (64%); 88% were current or previous smokers; and 76% of patients had non-squamous disease while 24% of patients had squamous disease.

    The trial demonstrated a statistically significant improvement in OS for patients with high PD-L1 expression (TC ≥50% or IC ≥10%) at the time of the OS interim analysis. There was no statistically significant difference in OS for the other two PD-L1 subgroups (TC ≥5% or IC ≥5%; and TC ≥1% or IC ≥1%) at the interim or final analyses. Efficacy results for patients with NSCLC with high PD-L1 expression are presented in Table 22 and Figure 1.

    Table 22: Efficacy Results from IMpower110 in Patients with NSCLC with High PD-L1 Expression (TC ≥ 50% or IC ≥ 10%) and without EGFR or ALK Genomic Tumor Aberrations
    Arm A: TECENTRIQ
    N = 107
    Arm B: Platinum-Based Chemotherapy
    N = 98
    CI=confidence interval; NE=not estimable
    *
    Based on OS interim analysis. The median survival follow-up time in patients was 15.7 months.
    Stratified by sex and ECOG performance status
    Based on the stratified log-rank test compared to Arm A
    §
    Compared to the allocated alpha of 0.0413 (two-sided) for this interim analysis.
    Overall Survival*
      Deaths (%)44 (41%)57 (58%)
      Median, months20.213.1
      (95% CI)(16.5, NE)(7.4, 16.5)
      Hazard ratio (95% CI)0.59 (0.40, 0.89)
      p-value0.0106§

    Figure 1: Kaplan-Meier Plot of Overall Survival in IMpower110 in Patients with NSCLC with High PD-L1 Expression (TC ≥ 50% or IC ≥ 10%) and Without EGFR or ALK Genomic Tumor Aberrations

    Figure 1

    Investigator-assessed PFS showed a HR of 0.63 (95% CI: 0.45, 0.88), with median PFS of 8.1 months (95% CI: 6.8, 11.0) in the TECENTRIQ arm and 5 months (95% CI: 4.2, 5.7) in the platinum-based chemotherapy arm. The investigator-assessed confirmed ORR was 38% (95% CI: 29%, 48%) in the TECENTRIQ arm and 29% (95% CI: 20%, 39%) in the platinum-based chemotherapy arm.

    Metastatic Chemotherapy-Naive Non-Squamous NSCLC

    IMpower150

    The efficacy of TECENTRIQ with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), a multicenter, international, randomized (1:1:1), open-label trial in patients with metastatic non-squamous NSCLC. Patients with stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease but could have received prior EGFR or ALK kinase inhibitor if appropriate, regardless of PD-L1 or T-effector gene (tGE) status and ECOG performance status 0 or 1 were eligible. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization, or clear tumor infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions as seen on imaging. Randomization was stratified by sex, presence of liver metastases, and PD-L1 expression status on tumor cells (TC) and tumor-infiltrating immune cells (IC) as follows: TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Patients were randomized to one of the following three treatment arms.

    • Arm A: TECENTRIQ 1200 mg, paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles
    • Arm B: TECENTRIQ 1200 mg, bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m², and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles
    • Arm C: bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles

    Patients who had not experienced disease progression following the completion or cessation of platinum-based chemotherapy, received:

    • Arm A: TECENTRIQ 1200 mg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity
    • Arm B: TECENTRIQ 1200 mg and bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity
    • Arm C: bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity

    Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Tumor specimens were evaluated prior to randomization for PD-L1 tumor expression using the VENTANA PD-L1 (SP142) assay at a central laboratory. Tumor tissue was collected at baseline for expression of tGE signature and evaluation was performed using a clinical trial assay in a central laboratory prior to the analysis of efficacy outcome measures.

    Major efficacy outcome measures for comparison of Arms B and C were progression free survival (PFS) by RECIST v1.1 in the tGE-WT (patients with high expression of T-effector gene signature [tGE], excluding those with EGFR- and ALK-positive NSCLC [WT]) and in the ITT-WT subpopulations and overall survival (OS) in the ITT-WT subpopulation. Additional efficacy outcome measures for comparison of Arms B and C or Arms A and C were PFS and OS in the ITT population, OS in the tGE-WT subpopulation, and ORR/DoR in the tGE-WT and ITT-WT subpopulations.

    A total of 1202 patients were enrolled across the three arms of whom 1045 were in the ITT-WT subpopulation and 447 were in the tGE-WT subpopulation. The demographic information is limited to the 800 patients enrolled in Arms B and C where efficacy has been demonstrated. The median age was 63 years (range: 31 to 90), and 60% of patients were male. The majority of patients were White (82%), 13% of patients were Asian, 10% were Hispanic, and 2% of patients were Black. Clinical sites in Asia (enrolling 13% of the study population) received paclitaxel at a dose of 175 mg/m2 while the remaining 87% received paclitaxel at a dose of 200 mg/m2. Approximately 14% of patients had liver metastases at baseline, and most patients were current or previous smokers (80%). Baseline ECOG performance status was 0 (43%) or 1 (57%). PD-L1 was TC3 and any IC in 12%, TC0/1/2 and IC2/3 in 13%, and TC0/1/2 and IC0/1 in 75%. The demographics for the 696 patients in the ITT-WT subpopulation were similar to the ITT population except for the absence of patients with EGFR- or ALK-positive NSCLC.

    The trial demonstrated a statistically significant improvement in PFS between Arms B and C in both the tGE-WT and ITT-WT subpopulations, but did not demonstrate a significant difference for either subpopulation between Arms A and C based on the final PFS analyses. In the interim analysis of OS, a statistically significant improvement was observed for Arm B compared to Arm C, but not for Arm A compared to Arm C. Efficacy results for the ITT-WT subpopulation are presented in Table 23 and Figure 2.

    Table 23: Efficacy Results in ITT-WT Population in IMpower150
    Arm C: Bevacizumab, Paclitaxel and CarboplatinArm B: TECENTRIQ with Bevacizumab, Paclitaxel, and CarboplatinArm A: TECENTRIQ with Paclitaxel, and Carboplatin
    N = 337N = 359N = 349
    CI=confidence interval
    *
    Based on OS interim analysis .
    Stratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC
    Based on the stratified log-rank test compared to Arm C
    §
    Compared to the allocated α=0.0174 (two sided) for this interim analysis.
    Compared to the allocated α=0.0128 (two sided) for this interim analysis.
    #
    As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
    Þ
    Compared to the allocated α=0.006 (two sided) for the final PFS analysis.
    Overall Survival*
      Deaths (%)197 (59%)179 (50%)179 (51%)
      Median, months14.719.219.4
      (95% CI)(13.3, 16.9)(17.0, 23.8)(15.7, 21.3)
      Hazard ratio (95% CI)---0.78 (0.64, 0.96)0.84 (0.72, 1.08)
      p-value---0.016§0.204
    Progression-Free Survival#
      Number of events (%)247 (73%)247 (69%)245 (70%)
      Median, months7.08.56.7
      (95% CI)(6.3, 7.9)(7.3, 9.7)(5.6, 6.9)
      Hazard ratio (95% CI)---0.71 (0.59, 0.85)0.94 (0.79, 1.13)
      p-value---0.0002Þ0.5219
    Objective Response Rate#
      Number of responders (%)142 (42%)196 (55%)150 (43%)
      (95% CI)(37, 48)(49, 60)(38, 48)
      Complete Response3 (1%)14 (4%)9 (3%)
      Partial Response139 (41%)182 (51%)141 (40%)
    Duration of Response#n = 142n = 196n = 150
      Median, months6.510.89.5
      (95% CI)(5.6, 7.6)(8.4, 13.9)(7.0, 13.0)

    Figure 2: Kaplan-Meier Curves for Overall Survival in ITT-WT Population in IMpower150

    Figure 2

    Exploratory analyses showed that the subset of patients in the four drug regimen arm who were ADA positive by week 4 (30%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (70%) [see Adverse Reactions (6.2), Clinical Pharmacology (12.3)]. In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly ADA negative patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm were compared with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, tobacco history, metastatic site, TC level, and IC level. The hazard ratio comparing the ADA-positive subgroup with its matched control was 0.69 (95% CI: 0.44, 1.07). The hazard ratio comparing the ADA-negative subgroup with its matched control was 0.64 (95% CI: 0.46, 0.90).

    IMpower130

    The efficacy of TECENTRIQ with paclitaxel protein-bound and carboplatin was evaluated in IMpower130 (NCT02367781), a multicenter, randomized (2:1), open-label trial in patients with stage IV non-squamous NSCLC. Patients with Stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease, but could have received prior EGFR or ALK kinase inhibitor, if appropriate, were eligible. The trial excluded patients with history of autoimmune disease, administration of live attenuated vaccine within 28 days prior to randomization, administration of immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization, and active or untreated CNS metastases. Randomization was stratified by sex, presence of liver metastases, and PD-L1 tumor expression according to the VENTANA PD-L1 (SP142) assay as follows: TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Patients were randomized to one of the following treatment regimens:

    • TECENTRIQ 1200 mg on Day 1, paclitaxel protein-bound 100 mg/m² on Days 1, 8, and 15, and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by TECENTRIQ 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or
    • Paclitaxel protein-bound 100 mg/m² on Days 1, 8 and 15 and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by best supportive care or pemetrexed.

    Tumor assessments were conducted every 6 weeks for the first 48 weeks, then every 9 weeks thereafter. Major efficacy outcome measures were PFS by RECIST v1.1 and OS in the subpopulation of patients evaluated for and documented to have no EGFR or ALK genomic tumor aberrations (ITT-WT).

    A total of 724 patients were enrolled; of these, 681 (94%) were in the ITT-WT population. The median age was 64 years (range: 18 to 86) and 59% were male. The majority of patients were white (90%), 2% of patients were Asian, 5% were Hispanic, and 4% were Black. Baseline ECOG performance status was 0 (41%) or 1 (58%). Most patients were current or previous smokers (90%). PD-L1 tumor expression was TC0/1/2 and IC0/1 in 73%; TC3 and any IC in 14%; and TC0/1/2 and IC2/3 in 13%.

    Efficacy results for the ITT-WT population are presented in Table 24 and Figure 3.

    Table 24: Efficacy Results from IMpower130
    TECENTRIQ with Paclitaxel Protein-Bound and CarboplatinPaclitaxel Protein-Bound and Carboplatin
    CI=confidence interval
    *
    Based on OS interim analysis
    Stratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC)
    Based on the stratified log-rank test
    §
    Compared to the allocated α=0.0428 (two sided) for this interim analysis
    As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
    #
    Compared to the allocated α=0.006 (two sided) for the final PFS analysis
    Þ
    Confirmed response
    Overall Survival*n=453n=228
      Deaths (%)228 (50%)131 (57%)
      Median, months18.613.9
      (95% CI)(15.7, 21.1)(12.0, 18.7)
      Hazard ratio (95% CI)0.80 (0.64, 0.99)
      p-value0.0384§
    Progression-Free Survivaln=453n=228
      Number of events (%)330 (73%)177 (78%)
      Median, months7.26.5
      (95% CI)(6.7, 8.3)(5.6, 7.4)
      Hazard ratio (95% CI)0.75 (0.63, 0.91)
      p-value0.0024#
    Overall Response Rate,Þn=453n=228
      Number of responders (%)207 (46%)74 (32%)
      (95% CI)(41, 50)(26, 39)
      Complete Response22 (5%)2 (1%)
      Partial Response185 (41%)72 (32%)
    Duration of Response,Þn=207n=74
      Median, months10.87.8
      (95% CI)(9.0, 14.4)(6.8, 10.9)
    Figure 3: Kaplan-Meier Curves for Overall Survival in IMpower130

    Figure 3

    Previously Treated Metastatic NSCLC

    The efficacy of TECENTRIQ was evaluated in a multicenter, international, randomized (1:1), open-label study (OAK; NCT02008227) conducted in patients with locally advanced or metastatic NSCLC whose disease progressed during or following a platinum-containing regimen. Patients with a history of autoimmune disease, symptomatic or corticosteroid-dependent brain metastases, or requiring systemic immunosuppression within 2 weeks prior to enrollment were ineligible. Randomization was stratified by PD-L1 expression tumor-infiltrating immune cells (IC), the number of prior chemotherapy regimens (1 vs. 2), and histology (squamous vs. non-squamous).

    Patients were randomized to receive TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel 75 mg/m2 intravenously every 3 weeks until unacceptable toxicity or disease progression. Tumor assessments were conducted every 6 weeks for the first 36 weeks and every 9 weeks thereafter. Major efficacy outcome measure was overall survival (OS) in the first 850 randomized patients and OS in the subgroup of patients with PD-L1-expressing tumors (defined as ≥ 1% PD-L1 expression on tumor cells [TC] or immune cells [IC]). Additional efficacy outcome measures were OS in all randomized patients (n = 1225), OS in subgroups based on PD-L1 expression, overall response rate (ORR), and progression free survival as assessed by the investigator per RECIST v.1.1.

    Among the first 850 randomized patients, the median age was 64 years (33 to 85 years) and 47% were ≥ 65 years old; 61% were male; 70% were White and 21% were Asian; 15% were current smokers and 67% were former smokers; and 37% had baseline ECOG PS of 0 and 63% had a baseline ECOG PS of 1. Nearly all (94%) had metastatic disease, 74% had non-squamous histology, 75% had received only one prior platinum-based chemotherapy regimen, and 55% of patients had PD-L1-expressing tumors.

    Efficacy results are presented in Table 25 and Figure 4.

    Table 25: Efficacy Results in OAK
    TECENTRIQDocetaxel
    CI=confidence interval; NE=not estimable
    *
    Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology
    Based on the stratified log-rank test
    Compared to the pre-specified allocated α of 0.03 for this analysis
    §
    Per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
    Compared to the allocated α of 0.0177 for this interim analysis based on 86% information using O'Brien-Fleming boundary
    Overall Survival in first 850 patients
      Number of patientsN=425N=425
      Deaths (%)271 (64%)298 (70%)
      Median, months13.89.6
      (95% CI)(11.8, 15.7)(8.6, 11.2)
      Hazard ratio* (95% CI)0.74 (0.63, 0.87)
      p-value0.0004
    Progression-Free Survival
      Number of PatientsN=425N=425
      Events (%)380 (89%)375 (88%)
      Progression (%)332 (78%)290 (68%)
      Deaths (%)48 (11%)85 (20%)
      Median, months2.84.0
      (95% CI)(2.6, 3.0)(3.3, 4.2)
      Hazard ratio* (95% CI)0.95 (0.82, 1.10)
    Overall Response Rate §
      Number of PatientsN=425N=425
      ORR, n (%)58 (14%)57 (13%)
      (95% CI)(11%, 17%)(10%, 17%)
      Complete Response6 (1%)1 (0.2%)
      Partial Response52 (12%)56 (13%)
    Duration of ResponseN=58N=57
      Median, months16.36.2
      (95% CI)(10.0, NE)(4.9, 7.6)
    Overall Survival in all 1225 patients
      Number of patientsN=613N=612
      Deaths (%)384 (63%)409 (67%)
      Median, months13.39.8
      (95% CI)(11.3, 14.9)(8.9, 11.3)
      Hazard ratio* (95% CI)0.79 (0.69, 0.91)
      p-value0.0013
    Figure 4: Kaplan-Meier Curves of Overall Survival in the First 850 Patients Randomized in OAK

    Figure 4

    Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define the PD-L1 expression subgroups for pre-specified analyses. Of the 850 patients, 16% were classified as having high PD-L1 expression, defined as having PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was 0.41 (95% CI: 0.27, 0.64) in the high PD-L1 expression subgroup and 0.82 (95% CI: 0.68, 0.98) in patients who did not have high PD-L1 expression.

    Exploratory analyses showed that the subset of patients who were ADA positive by week 4 (21%) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (79%) [see Adverse Reactions (6.2), Clinical Pharmacology (12.3)]. ADA positive patients by week 4 appeared to have similar OS compared to docetaxel-treated patients. In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the atezolizumab arm with a matched population in the docetaxel arm and ADA negative patients in the atezolizumab arm with a matched population in the docetaxel arm. Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, histology (squamous vs. non-squamous), baseline albumin, baseline LDH, gender, tobacco history, metastases status (advanced or local), metastatic site, TC level, and IC level. The hazard ratio comparing the ADA positive subgroup with its matched control was 0.89 (95% CI: 0.61, 1.3). The hazard ratio comparing the ADA negative subgroup with its matched control was 0.68 (95% CI: 0.55, 0.83).

    14.3 Locally Advanced or Metastatic Triple-Negative Breast Cancer

    The efficacy of TECENTRIQ in combination with paclitaxel protein-bound was investigated in IMpassion130 (NCT02425891), a multicenter, international, double-blinded, placebo-controlled, randomized (1:1) trial that included 902 unresectable locally advanced or metastatic triple-negative breast cancer patients that had not received prior chemotherapy for metastatic disease. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 4 weeks prior to randomization, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases. Randomization was stratified by presence of liver metastases, prior taxane treatment, and by PD-L1 expression status in tumor infiltrating immune cells (IC) (PD-L1 stained tumor-infiltrating immune cells [IC] <1% of tumor area vs. ≥ 1% of the tumor area) by the VENTANA PD-L1 (SP142) Assay. Of the 902 patients in the intent to treat population (ITT), 41% (369 patients) were classified as PD-L1 expression ≥ 1%. Patients were randomized to receive TECENTRIQ 840 mg or placebo intravenously on Days 1 and 15 of every 28-day cycle with paclitaxel protein-bound 100 mg/m2 intravenously on Days 1, 8 and 15 of every 28-day cycle. Patients received treatment until radiographic disease progression per RECIST v1.1, or unacceptable toxicity. Tumor assessments were performed every 8 weeks (± 1 week) for the first 12 months after Cycle 1, day 1 and every 12 weeks (± 1 week) thereafter. Major efficacy outcomes were investigator-assessed progression free survival (PFS) in the ITT and PD-L1 expressing patient population per RECIST v1.1 and overall survival (OS) in the ITT population.

    In IMpassion130, the median age was 55 years (range: 20-86). Overall, most patients were women (99.6%) and the majority of patients were white (68%), Asian (18%), Black or African American (7%), and American Indian or Alaskan Native (4.4%). The demographic and baseline disease characteristics of the study population were well balanced between the treatment arms. Baseline ECOG performance status was 0 (58%) or 1 (41%). Overall, 41% of enrolled patients had PD-L1 expression ≥ 1%, 27% had liver metastases and 7% brain metastases at baseline. Approximately half the patients had received a taxane (51%) or anthracycline (54%) in the (neo)adjuvant setting. Patient demographics and baseline tumor disease in the PD-L1 expressing population were generally representative of the broader study population.

    Tumor specimens (archival or fresh) were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used as a stratification factor for randomization and to define the PD-L1 expression subgroups for pre-specified analyses.

    Overall survival data were immature with 43% deaths in the ITT population. The efficacy results of IMpassion130 for the patient population with PD-L1 expression ≥ 1% are presented in Table 26 and Figure 5.

    Table 26: Efficacy Results from IMpassion130 in Patients with PD-L1 Expression ≥ 1%
    PD-L1 Expression ≥ 1%*
    TECENTRIQ in combination with paclitaxel protein-boundPlacebo in combination with paclitaxel protein-bound
    PFS=Progression-Free Survival; CI=Confidence Interval; ORR=Objective Response Rate; DOR=Duration of Response; NE=Not Estimable
    *
    PD-L1 expression in tumor-infiltrating immune cells (IC)
    As determined by investigator assessment
    per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
    §
    Stratified by presence of liver metastases, and by prior taxane treatment
    Patients with measurable disease at baseline
    #
    Confirmed responses
    Progression-Free Survival,(n=185)(n=184)
      Events (%)136 (74)151 (82)
      Median, months7.4 (6.6, 9.2)4.8 (3.8, 5.5)
      Stratified Hazard ratio (95% CI)§0.60 (0.48, 0.77)
      p-value<0.0001
    Objective Response Rate,,,#n=185n=183
      Number of responders (%)98 (53)60 (33)
      (95% CI)(45.5, 60.3)(26.0, 40.1)
      Complete Response (%)17 (9)1 (<1)
      Partial Response (%)81 (44)59 (32)
    Duration of Response,,#n=98n=60
      Median, months9.26.2
      (95% CI)(7.5, 11.9)(5.5, 8.8)

    Figure 5: Kaplan-Meier Plot of Progression-Free-Survival in IMpassion130 in Patients with PD-L1 Expression ≥1%

    Figure 5

    14.4 Small Cell Lung Cancer

    The efficacy of TECENTRIQ with carboplatin and etoposide was investigated in IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC. IMpower133 enrolled patients with ES-SCLC who had received no prior chemotherapy for extensive stage disease and ECOG performance status 0 or 1. The trial excluded patients with active or untreated CNS metastases, history of autoimmune disease, administration of a live, attenuated vaccine within 4 weeks prior to randomization, or administration of systemic immunosuppressive medications within 1 week prior to randomization. Randomization was stratified by sex, ECOG performance status, and presence of brain metastases. Patients were randomized to receive one of the following two treatment arms:

    • TECENTRIQ 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles followed by TECENTRIQ 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or
    • placebo and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles followed by placebo once every 3 weeks until disease progression or unacceptable toxicity.

    Administration of TECENTRIQ was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Patients treated beyond disease progression had tumor assessment conducted every 6 weeks until treatment discontinuation.

    Major efficacy outcome measures were OS and PFS as assessed by investigator per RECIST v1.1 in the intent-to-treat population. Additional efficacy outcome measures included ORR and DoR as assessed by investigator per RECIST v1.1.

    A total of 403 patients were randomized, including 201 to the TECENTRIQ arm and 202 to the chemotherapy alone arm. The median age was 64 years (range 26 to 90) and 65% were male. The majority of patients were White (80%); 17% were Asian, 4% were Hispanic and 1% were Black. Baseline ECOG performance status was 0 (35%) or 1 (65%); 9% of patients had a history of brain metastases, and 97% were current or previous smokers.

    Efficacy results are presented in Table 27 and Figure 6.

    Table 27: Efficacy Results from IMpower133
     TECENTRIQ with Carboplatin and EtoposidePlacebo with Carboplatin and Etoposide
    CI=confidence interval
    *
    Stratified by sex and ECOG performance status
    Based on the stratified log-rank test
    Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary
    §
    As determined by investigator assessment
    per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
    #
    Compared to the allocated α of 0.05 for this analysis.
    Þ
    Confirmed response
    Overall SurvivalN=201N=202
      Deaths (%)104 (52%)134 (66%)
      Median, months12.310.3
      (95% CI)(10.8, 15.9)(9.3, 11.3)
      Hazard ratio* (95% CI)0.70 (0.54, 0.91)
      p-value, 0.0069
    Progression-Free Survival§,N=201N=202
      Number of events (%)171 (85%)189 (94%)
      Median, months5.24.3
      (95% CI)(4.4, 5.6)(4.2, 4.5)
      Hazard ratio* (95% CI)0.77 (0.62, 0.96)
      p-value, #0.0170
    Objective Response Rate§,,ÞN=201N=202
      Number of responders (%)121 (60%)130 (64%)
      (95% CI)(53, 67)(57, 71)
      Complete Response (%)5 (2%)2 (1%)
      Partial Response (%)116 (58%)128 (63%)
    Duration of Response§,,ÞN=121N=130
      Median, months4.23.9
      (95% CI)(4.1, 4.5)(3.1, 4.2)

    Figure 6: Kaplan-Meier Plot of Overall Survival in IMpower133

    Figure 6

    14.5 Hepatocellular Carcinoma

    The efficacy of TECENTRIQ in combination with bevacizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (<400 vs. ≥400 ng/mL), and by ECOG performance status (0 vs. 1).

    A total of 501 patients were randomized (2:1) to receive either TECENTRIQ as an intravenous infusion of 1200 mg, followed by 15 mg/kg bevacizumab, on the same day every 3 weeks or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. Patients could discontinue either TECENTRIQ or bevacizumab (e.g., due to adverse events) and continue on single-agent therapy until disease progression or unacceptable toxicity associated with the single-agent.

    The study enrolled patients who were ECOG performance score 0 or 1 and who had not received prior systemic treatment. Patients were required to be evaluated for the presence of varices within 6 months prior to treatment, and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients with Child-Pugh B or C cirrhosis, moderate or severe ascites; history of hepatic encephalopathy; a history of autoimmune disease; administration of a live, attenuated vaccine within 4 weeks prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases were excluded. Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter.

    The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The median age was 65 years (range: 26 to 88) and 83% of patients were male. The majority of patients were Asian (57%) or White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥400 ng/mL. Baseline ECOG performance status was 0 (62%) or 1 (38%). HCC risk factors were Hepatitis B in 48% of patients, Hepatitis C in 22%, and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage C (82%) disease at baseline, while 16% had stage B, and 3% had stage A.

    The major efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression free survival (PFS) per RECIST v1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST.

    Efficacy results are presented in Table 28 and Figure 7.

    Table 28: Efficacy Results from IMbrave150
    TECENTRIQ in combination with Bevacizumab
    (N= 336)
    Sorafenib
    (N=165)
    + Denotes a censored value
    CI=confidence interval; HCC mRECIST= Modified RECIST Assessment for Hepatocellular Carcinoma; NE=not estimable; N/A=not applicable; RECIST 1.1= Response Evaluation Criteria in Solid Tumors v1.1
    *
    Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. ≥400 ng/mL)
    Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method
    Per independent radiology review
    §
    Confirmed responses
    Based on two-sided Cochran-Mantel-Haesnszel test
    Overall Survival
    Number of deaths (%)96 (29)65 (39)
    Median OS in months
    (95% CI)
    NE
    (NE, NE)
    13.2
    (10.4, NE)
    Hazard ratio* (95% CI)0.58 (0.42, 0.79)
    p-value0.0006
    Progression-Free Survival
    Number of events(%)197 (59)109 (66)
    Median PFS in months (95% CI)6.8 (5.8, 8.3)4.3 (4.0, 5.6)
    Hazard ratio* (95% CI)0.59 (0.47, 0.76)
    p-value<0.0001
    Overall Response Rate,§(ORR), RECIST 1.1
    Number of responders (%)93 (28)19 (12)
    (95% CI)(23, 33)(7,17)
    p-value<0.0001
    Complete responses, n (%)22 (7)0
    Partial responses, n (%)71 (21)19 (12)
    Duration of Response,§ (DOR) RECIST 1.1
    (n=93)(n=19)
    Median DOR in months
    (95% CI)
    NE
    (NE, NE)
    6.3
    (4.7, NE)
    Range (months)(1.3+, 13.4+)(1.4+, 9.1+)
    Overall Response Rate,§ (ORR), HCC mRECIST
    Number of responders (%)112 (33)21 (13)
    (95% CI)(28, 39)(8, 19)
    p-value<0.0001
    Complete responses, n (%)37 (11)3 (1.8)
    Partial responses, n (%)75 (22)18 (11)
    Duration of Response,§ (DOR) HCC mRECIST
    (n=112)(n=21)
    Median DOR in months
    (95% CI)
    NE
    (NE, NE)
    6.3
    (4.9, NE)
    Range (months)(1.3+, 13.4+)(1.4+, 9.1+)

    Figure 7: Kaplan-Meier Plot of Overall Survival in IMbrave150

    Figure 7

    Exploratory analyses showed that the subset of patients (20%) who were ADA-positive by week 6 appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week 6 [see Adverse Reactions (6.2), Clinical Pharmacology (12.3)]. ADA-positive patients by week 6 appeared to have similar overall survival compared to sorafenib-treated patients. In an exploratory analysis, inverse probability weighting was conducted to compare ADA-positive patients and ADA-negative patients in the TECENTRIQ and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (<400 ng/mL vs ≥400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology (HBV vs. HCV vs. non-viral) and Child-Pugh Score (A5 VS. A6). The OS hazard ratio comparing the ADA-positive subgroup of the TECENTRIQ and bevacizumab arm to sorafenib was 0.93 (95% CI: 0.57, 1.53). The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was 0.39 (95% CI: 0.26, 0.60).

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    TECENTRIQ injection is a sterile, preservative-free, and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 840 mg/14 mL single-dose vial (NDC 50242-918-01) or 1,200 mg/20 mL single-dose vial (NDC 50242-917-01).

    Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Immune-Mediated Adverse Reactions

    Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ, including:

    • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
    • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2)].
    • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [see Warnings and Precautions (5.3)].
    • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.4)].
    • Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of other potential immune-mediated adverse reactions [see Warnings and Precautions (5.5)].

    Infections

    Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)].

    Infusion-Related Reactions

    Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)].

    Embryo-Fetal Toxicity

    Advise females of reproductive potential that TECENTRIQ can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].

    Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of TECENTRIQ [see Use in Specific Populations (8.3)].

    Lactation

    Advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.2)].

  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    Genentech, Inc.
    A Member of the Roche Group
    1 DNA Way
    South San Francisco, CA 94080-4990

    U.S. License No. 1048

    TECENTRIQ is a registered trademark of Genentech, Inc.
    ©2020 Genentech, Inc.

  • MEDICATION GUIDE

    This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 05/2020                        
    MEDICATION GUIDE
    TECENTRIQ® (te-SEN-trik)
    (atezolizumab)
    injection
    What is the most important information I should know about TECENTRIQ?
    TECENTRIQ is a medicine that may treat certain cancers by working with your immune system. TECENTRIQ can cause your immune system to attack normal organs and tissues and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.
    Call or see your healthcare provider right away if you get any symptoms of the following problems or these symptoms get worse:
    Lung problems (pneumonitis). Signs and symptoms of pneumonitis may include:
    • new or worsening cough
    • shortness of breath
    • chest pain
    Liver problems (hepatitis). Signs and symptoms of hepatitis may include:
    • yellowing of your skin or the whites of your eyes
    • severe nausea or vomiting
    • pain on the right side of your stomach area (abdomen)
    • drowsiness
    • dark urine (tea colored)
    • bleeding or bruising more easily than normal
    • feeling less hungry than usual
    Intestinal problems (colitis). Signs and symptoms of colitis may include:
    • diarrhea (loose stools) or more bowel movements than usual
    • blood or mucus in your stools or dark, tarry, sticky stools
    • severe stomach area (abdomen) pain or tenderness
    Hormone gland problems (especially the thyroid, adrenal glands, pancreas, and pituitary). Signs and symptoms that your hormone glands are not working properly may include:
    • headaches that will not go away or unusual headaches
    • extreme tiredness
    • weight gain or weight loss
    • dizziness or fainting
    • feeling more hungry or thirsty than usual
    • hair loss
    • changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
    • feeling cold
    • constipation
    • your voice gets deeper
    • urinating more often than usual
    • nausea or vomiting
    • stomach area (abdomen) pain
    Problems in other organs. Signs and symptoms may include:
    • severe muscle weakness
    • numbness or tingling in hands or feet
    • confusion
    • blurry vision, double vision, or other vision problems
    • changes in mood or behavior
    • extreme sensitivity to light
    • neck stiffness
    • eye pain or redness
    • skin blisters or peeling
    • chest pain, irregular heartbeat, shortness of breath or swelling of the ankles
    Severe infections. Signs and symptoms of infection may include:
    • fever
    • cough
    • flu-like symptoms
    • pain when urinating, frequent urination or back pain
    Severe infusion reactions. Signs and symptoms of infusion reactions may include:
    • chills or shaking
    • itching or rash
    • flushing
    • shortness of breath or wheezing
    • swelling of your face or lips
    • dizziness
    • fever
    • feeling like passing out
    • back or neck pain
    Getting medical treatment right away may help keep these problems from becoming more serious.
    Your healthcare provider will check you for these problems during your treatment with TECENTRIQ. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may delay or completely stop treatment with TECENTRIQ if you have severe side effects.
    What is TECENTRIQ?
    TECENTRIQ is a prescription medicine used to treat adults with:
    • a type of bladder and urinary tract cancer called urothelial carcinoma. TECENTRIQ may be used when your bladder cancer has spread or cannot be removed by surgery, and if you have any one of the following conditions:
      • you are not able to take chemotherapy that contains a medicine called cisplatin, and your cancer tests positive for "PD-L1", or
      • you are not able to take chemotherapy that contains any platinum regardless of "PD-L1" status, or
      • you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
    • a type of lung cancer called non-small cell lung cancer (NSCLC).
      • TECENTRIQ may be used alone as your first treatment when your lung cancer:
        • has spread or grown, and
        • your cancer tests positive for "high PD-L1", and
        • your tumor does not have an abnormal "EGFR" or "ALK" gene.
      • TECENTRIQ may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:
        • has spread or grown, and
        • is a type called "non-squamous NSCLC", and
        • your tumor does not have an abnormal "EGFR" or "ALK" gene.
      • TECENTRIQ may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:
        • has spread or grown, and
        • is a type called "non-squamous NSCLC", and
        • your tumor does not have an abnormal "EGFR" or "ALK" gene.
      • TECENTRIQ may also be used alone when your lung cancer:
        • has spread or grown, and
        • you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
        • if your tumor has an abnormal "EGFR" or "ALK" gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.
    • a type of breast cancer called triple-negative breast cancer (TNBC). TECENTRIQ may be used with the medicine paclitaxel protein-bound when your breast cancer:
      • has spread or cannot be removed by surgery, and
      • your cancer tests positive for "PD-L1".
    • a type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer
      • is a type called "extensive-stage SCLC," which means that it has spread or grown.
    • a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:
      • has spread or cannot be removed by surgery, and
      • you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.
    It is not known if TECENTRIQ is safe and effective in children.
    Before you receive TECENTRIQ, tell your healthcare provider about all of your medical conditions, including if you:
    • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus
    • have had an organ transplant
    • have lung or breathing problems
    • have liver problems
    • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
    • are being treated for an infection
    • are pregnant or plan to become pregnant. TECENTRIQ can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ.
      Females who are able to become pregnant:
      • Your healthcare provider should do a pregnancy test before you start treatment with TECENTRIQ.
      • You should use an effective method of birth control during your treatment and for at least 5 months after the last dose of TECENTRIQ.
    • are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ passes into your breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of TECENTRIQ.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    How will I receive TECENTRIQ?
    • Your healthcare provider will give you TECENTRIQ into your vein through an intravenous (IV) line over 30 to 60 minutes.
    • TECENTRIQ is usually given every 2, 3, or 4 weeks.
    • Your healthcare provider will decide how many treatments you need.
    • Your healthcare provider will test your blood to check you for certain side effects.
    • If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
    What are the possible side effects of TECENTRIQ?
    TECENTRIQ can cause serious side effects, including:
    The most common side effects of TECENTRIQ when used alone include:
    • feeling tired or weak
    • nausea
    • cough
    • shortness of breath
    • decreased appetite
    The most common side effects of TECENTRIQ when used in lung cancer with other anti-cancer medicines include:
    • feeling tired or weak
    • nausea
    • hair loss
    • constipation
    • diarrhea
    • decreased appetite
    The most common side effects of TECENTRIQ when used in triple-negative breast cancer with paclitaxel protein-bound include:
    • hair loss
    • tingling or numbness in hands or feet
    • feeling tired
    • nausea
    • diarrhea
    • low red blood cells (anemia)
    • constipation
    • cough
    • headache
    • low white blood cells
    • vomiting
    • decreased appetite
    The most common side effects of TECENTRIQ when used in hepatocellular carcinoma with bevacizumab include:
    • high blood pressure
    • feeling tired or weak
    • too much protein in the urine
    TECENTRIQ may cause fertility problems in females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility.
    These are not all the possible side effects of TECENTRIQ. Ask your healthcare provider or pharmacist for more information.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
    General information about the safe and effective use of TECENTRIQ.
    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about TECENTRIQ, talk with your healthcare provider. You can ask your healthcare provider for information about TECENTRIQ that is written for health professionals.
    What are the ingredients in TECENTRIQ?
    Active ingredient: atezolizumab
    Inactive ingredients: glacial acetic acid, L-histidine, polysorbate 20 and sucrose
    Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 USA
    U.S. License No. 1048 TECENTRIQ is a registered trademark of Genentech, Inc.
    For more information, call 1-844-832-3687 or go to www.TECENTRIQ.com.
  • SPL UNCLASSIFIED SECTION

    Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

  • PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton

    NDC 50242-917-01

    Tecentriq®
    (atezolizumab)
    Injection

    1200 mg/20 mL
    (60 mg/mL)

    For Intravenous Infusion After Dilution
    Single-Dose Vial
    Discard Unused Portion
    No preservative.

    Attention Pharmacist: Dispense the
    accompanying Medication Guide
    to each patient.

    1 vial

    Rx only

    Genentech

    10199144

    PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton
  • PRINCIPAL DISPLAY PANEL - 14 mL Vial Carton

    NDC 50242-918-01

    Tecentriq®
    (atezolizumab)
    Injection

    840 mg/14 mL
    (60 mg/mL)

    For Intravenous Infusion After Dilution
    Single-Dose Vial
    Discard Unused Portion
    No preservative.

    Attention Pharmacist: Dispense the
    accompanying Medication Guide
    to each patient.

    1 vial

    Rx only
    Genentech

    10198487

    PRINCIPAL DISPLAY PANEL - 14 mL Vial Carton
  • INGREDIENTS AND APPEARANCE
    TECENTRIQ 
    atezolizumab injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:50242-917
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    atezolizumab (UNII: 52CMI0WC3Y) (atezolizumab - UNII:52CMI0WC3Y) atezolizumab1200 mg  in 20 mL
    Inactive Ingredients
    Ingredient NameStrength
    histidine (UNII: 4QD397987E) 62 mg  in 20 mL
    acetic acid (UNII: Q40Q9N063P) 16.5 mg  in 20 mL
    sucrose (UNII: C151H8M554) 821.6 mg  in 20 mL
    polysorbate 20 (UNII: 7T1F30V5YH) 8 mg  in 20 mL
    water (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:50242-917-011 in 1 CARTON05/18/2016
    120 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    2NDC:50242-917-861 in 1 CARTON08/11/2016
    220 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA76103405/18/2016
    TECENTRIQ 
    atezolizumab injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:50242-918
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    atezolizumab (UNII: 52CMI0WC3Y) (atezolizumab - UNII:52CMI0WC3Y) atezolizumab840 mg  in 14 mL
    Inactive Ingredients
    Ingredient NameStrength
    histidine (UNII: 4QD397987E) 43.4 mg  in 14 mL
    acetic acid (UNII: Q40Q9N063P) 11.5 mg  in 14 mL
    sucrose (UNII: C151H8M554) 575.1 mg  in 14 mL
    polysorbate 20 (UNII: 7T1F30V5YH) 5.6 mg  in 14 mL
    water (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:50242-918-011 in 1 CARTON03/08/2019
    114 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    2NDC:50242-918-861 in 1 CARTON03/08/2019
    214 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    BLABLA76103403/08/2019
    Labeler - Genentech, Inc. (080129000)
    Establishment
    NameAddressID/FEIBusiness Operations
    Roche Diagnostics GmbH315028860MANUFACTURE(50242-917) , ANALYSIS(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    F. Hoffmann-La Roche Ltd485244961ANALYSIS(50242-917, 50242-918) , LABEL(50242-917, 50242-918) , MANUFACTURE(50242-917, 50242-918) , PACK(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    Genentech, Inc.833220176LABEL(50242-917, 50242-918) , PACK(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    F. Hoffmann-La Roche Ltd482242971API MANUFACTURE(50242-917, 50242-918) , ANALYSIS(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    Genentech, Inc.080129000ANALYSIS(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    Genentech, Inc.146373191ANALYSIS(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    Roche Singapore Technical Operation, Pte. Ltd. (RSTO)937189173ANALYSIS(50242-917, 50242-918)
    Establishment
    NameAddressID/FEIBusiness Operations
    Roche Diagnostics GmbH323105205ANALYSIS(50242-917, 50242-918)