ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Infusion-Related Reactions [see Warnings and Precautions (5.2)] Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors [see Warnings and Precautions (5.3)] Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Infusion-Related Reactions [see Warnings and Precautions (5.2)] Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors [see Warnings and Precautions (5.3)] Most common adverse reactions (AR) (>= 10%) with TECENTRIQ HYBREZA as monotherapy in patients with NSCLC were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. (6.1)Safety of TECENTRIQ HYBREZA for the approved NSCLC, EC-SCLC, HCC, melanoma and ASPS indications is based on safety of intravenous atezolizumab in these populations. Most common AR with intravenous atezolizumab are presented below by indication and regimen (6.1):Most common AR (>= 20%) as monotherapy were:First-line NSCLC: fatigue/asthenia.Metastatic NSCLC: fatigue/asthenia, cough, decreased appetite, dyspnea, and myalgia/pain.ASPS: musculoskeletal pain, fatigue, rash, cough, headache, nausea, hypertension, vomiting, constipation, dyspnea, dizziness, hemorrhage, diarrhea, insomnia, abdominal pain hypothyroidism, pyrexia, anxiety, arrhythmia and decreased appetite. Most common AR (>= 20%) in combination with other antineoplastic drugs were:NSCLC (with bevacizumab, paclitaxel, and carboplatin): neuropathy fatigue/asthenia, alopecia, myalgia, nausea, diarrhea, constipation, decreased appetite, arthralgia, hypertension, rash, cough.Non-squamous NSCLC (with paclitaxel protein-bound and carboplatin): fatigue/asthenia, nausea, diarrhea, myalgia/pain, constipation, neuropathy, alopecia, dyspnea, decreased appetite, cough, vomiting and rash.SCLC (with carboplatin and etoposide): fatigue/asthenia, nausea, alopecia, decreased appetite, constipation and vomiting.HCC (with bevacizumab): hypertension, fatigue and proteinuria.Melanoma (with cobimetinib and vemurafenib): rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction. To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions (AR) (>= 10%) with TECENTRIQ HYBREZA as monotherapy in patients with NSCLC were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. (6.1). Safety of TECENTRIQ HYBREZA for the approved NSCLC, EC-SCLC, HCC, melanoma and ASPS indications is based on safety of intravenous atezolizumab in these populations. Most common AR with intravenous atezolizumab are presented below by indication and regimen (6.1):. Most common AR (>= 20%) as monotherapy were:First-line NSCLC: fatigue/asthenia.Metastatic NSCLC: fatigue/asthenia, cough, decreased appetite, dyspnea, and myalgia/pain.ASPS: musculoskeletal pain, fatigue, rash, cough, headache, nausea, hypertension, vomiting, constipation, dyspnea, dizziness, hemorrhage, diarrhea, insomnia, abdominal pain hypothyroidism, pyrexia, anxiety, arrhythmia and decreased appetite. First-line NSCLC: fatigue/asthenia.. Metastatic NSCLC: fatigue/asthenia, cough, decreased appetite, dyspnea, and myalgia/pain.. ASPS: musculoskeletal pain, fatigue, rash, cough, headache, nausea, hypertension, vomiting, constipation, dyspnea, dizziness, hemorrhage, diarrhea, insomnia, abdominal pain hypothyroidism, pyrexia, anxiety, arrhythmia and decreased appetite.. Most common AR (>= 20%) in combination with other antineoplastic drugs were:NSCLC (with bevacizumab, paclitaxel, and carboplatin): neuropathy fatigue/asthenia, alopecia, myalgia, nausea, diarrhea, constipation, decreased appetite, arthralgia, hypertension, rash, cough.Non-squamous NSCLC (with paclitaxel protein-bound and carboplatin): fatigue/asthenia, nausea, diarrhea, myalgia/pain, constipation, neuropathy, alopecia, dyspnea, decreased appetite, cough, vomiting and rash.SCLC (with carboplatin and etoposide): fatigue/asthenia, nausea, alopecia, decreased appetite, constipation and vomiting.HCC (with bevacizumab): hypertension, fatigue and proteinuria.Melanoma (with cobimetinib and vemurafenib): rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction. NSCLC (with bevacizumab, paclitaxel, and carboplatin): neuropathy fatigue/asthenia, alopecia, myalgia, nausea, diarrhea, constipation, decreased appetite, arthralgia, hypertension, rash, cough.. Non-squamous NSCLC (with paclitaxel protein-bound and carboplatin): fatigue/asthenia, nausea, diarrhea, myalgia/pain, constipation, neuropathy, alopecia, dyspnea, decreased appetite, cough, vomiting and rash.. SCLC (with carboplatin and etoposide): fatigue/asthenia, nausea, alopecia, decreased appetite, constipation and vomiting.. HCC (with bevacizumab): hypertension, fatigue and proteinuria.. Melanoma (with cobimetinib and vemurafenib): rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions of TECENTRIQ HYBREZA in Adult Patients with NSCLCThe safety of TECENTRIQ HYBREZA was evaluated in IMscin001, open-label, multi-center, international, randomized trial for patients with locally advanced or metastatic NSCLC who have not been exposed to cancer immunotherapy and who have had disease progression on prior platinum-based therapy [see Clinical Studies (14.1)]. Patients with previously treated metastatic non-small cell lung cancer (NSCLC) either received TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously into the thigh over approximately minutes every weeks or intravenous atezolizumab every weeks until disease progression or unacceptable toxicity. Among 247 patients who received TECENTRIQ HYBREZA, 32% were exposed for months or longer and 8% were exposed for greater than one year.The median age was 64 years (range: 27 to 85); 69% male; 67% White, 22% Asian, 0.8% Black or African American; 74% were non-Hispanic or Latino; 26% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 74% had an ECOG PS of 1; and 70% of patients were current or previous smokers.Serious adverse reactions occurred in 19% of patients who received TECENTRIQ HYBREZA. Serious adverse reactions (> 1%) included pneumonia, myocardial infarction, and pleural effusion. Fatal adverse reactions occurred in 6% of patients who received TECENTRIQ HYBREZA, including pneumonia (2.4%), myocardial infarction (1.2%), head injury (0.4%), ischemic stroke (0.4%), pleural effusion (0.4%), pulmonary embolism (0.4%), respiratory tract infection (0.4%), sepsis (0.4%), and toxic epidermal necrolysis (0.4%).Permanent discontinuation of TECENTRIQ HYBREZA due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of TECENTRIQ HYBREZA in 1% of patients included pneumonia (2%).Dosage interruptions of TECENTRIQ HYBREZA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in 1% of patients were COVID-19 (4.9%), increased aspartate aminotransferase (2.8%), increased alanine aminotransferase (2.4%), pneumonia (2.4%), anemia (1.6%), dyspnea (1.6%), fatigue (1.2%), and viral respiratory tract infection (1.2%). The most common adverse reactions of any grade (occurring in >= 10% of patients) were fatigue (19%), musculoskeletal pain (15%), cough (13%), dyspnea (12%), and decreased appetite (11%).Tables and summarize adverse reactions and selected laboratory abnormalities, respectively in TECENTRIQ HYBREZA-treated patients in IMscin001.Table 3:Adverse Reactions (>= 10%) in Adult Patients with Locally Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001Adverse ReactionGraded per NCI CTCAE v5.0 TECENTRIQ HYBREZA = 247Intravenous Atezolizumab = 124All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Disorder and Administration Site ConditionsFatigueComposite term includes fatigue, asthenia 190.8180Musculoskeletal and Connective Tissue disordersMusculoskeletal PainComposite term includes back pain, myalgia, bone pain, musculoskeletal chest pain, neck pain, spinal pain, non-cardiac chest pain 150.4133.2Respiratory, Thoracic and MediastinalCoughComposite term includes cough, productive cough 13070DyspneaComposite term includes dyspnea, dyspnea at rest, dyspnea exertional 121.2151.6Metabolism and Nutrition DisordersDecreased appetite110110Clinically relevant adverse reactions in 10% of patients who received TECENTRIQ HYBREZA were local injection site reactions (4.5%) and pyrexia (1.2%).Table 4:Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Adult Patients with Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001Laboratory AbnormalityGraded per NCI CTCAE v5.0 TECENTRIQ HYBREZA (n 247)Intravenous Atezolizumab (n 124)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 HYBREZA (48-233) and intravenous atezolizumab (19-117)HematologyDecreased Hemoglobin 676635Decreased lymphocytes3794515ChemistryDecreased Sodium463.9475Decreased Albumin342.2270Increased Alkaline Phosphatase331.3270Increased AST282.6322.6Increased ALT282.6231.7Decreased calcium222.6230.9Increased calcium202.6241.7Increased potassium211.7221.7Increased INR202230Increased Creatinine191.7260.9. Adverse Reactions in Adult Patients with NSCLC Treated with Intravenous AtezolizumabThe safety of TECENTRIQ HYBREZA for its approved NSCLC indications [see Indications and Usage (1.1)] has been established in adequate and well-controlled studies of intravenous atezolizumab for the:adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells (IMpower010 study).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%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study).first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study).first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study).first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).Below is description of adverse reactions of intravenous atezolizumab in these adequate and well-controlled NSCLC studies.. adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells (IMpower010 study).. 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%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study).. first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study).. first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study).. first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).. Non-Small Cell Lung Cancer (NSCLC). Adjuvant Treatment of Early-stage NSCLC. IMpower010The safety of intravenous atezolizumab was evaluated in IMpower010, multicenter, open-label, randomized trial for the adjuvant treatment of patients with stage IB (tumors >= cm) -IIIA NSCLC who had complete tumor resection and received up to cycles of cisplatin-based adjuvant chemotherapy. Patients received intravenous atezolizumab 1200 mg every weeks (n 495) for year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.1)]. The median number of cycles received was 16 (range: 1, 16).Fatal adverse reactions occurred in 1.8% of patients receiving intravenous atezolizumab; these included multiple organ dysfunction syndrome, pneumothorax, interstitial lung disease, arrhythmia, acute cardiac failure, myocarditis, cerebrovascular accident, death of unknown cause, and acute myeloid leukemia (1 patient each).Serious adverse reactions occurred in 18% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%).Intravenous atezolizumab was discontinued due to adverse reactions in 18% of patients; the most common adverse reactions (>= 1%) leading to intravenous atezolizumab discontinuation were pneumonitis (2.2%), hypothyroidism (1.6%), increased aspartate aminotransferase (1.4%), arthralgia (1.0%), and increased alanine aminotransferase (1.0%).Adverse reactions leading to interruption of intravenous atezolizumab occurred in 29% of patients; the most common (> 1%) were rash (3.0%), hyperthyroidism (2.8%), hypothyroidism (1.6%), increased AST (1.6%), pyrexia (1.6%), increased ALT (1.4%), upper respiratory tract infection (1.4%), headache (1.2%), peripheral neuropathy (1.2%), and pneumonia (1.2%).Tables and summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower010.Table 5:Adverse Reactions Occurring in >= 10% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010Adverse ReactionGraded per NCI CTCAE v4.0 Intravenous Atezolizumab = 495Best Supportive CareN 495All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous TissueRashIncludes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform 171.21.40Pruritus1000.60Endocrine DisordersHypothyroidismIncludes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased 1400.60Respiratory, Thoracic and MediastinalCoughProductive cough, upper airway cough syndrome, cough 160110GeneralPyrexiaIncludes pyrexia, body temperature increased, hyperthermia 140.82.20.2FatigueIncludes fatigue, asthenia 140.650.2Nervous System DisordersPeripheral neuropathyIncludes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy 120.470.2Musculoskeletal and Connective TissueMusculoskeletal painIncludes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain 140.890.2ArthralgiaIncludes arthralgia, arthritis 110.660Table 6:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010Laboratory AbnormalityGraded 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 events (NCI CTCAE v5.0). Intravenous AtezolizumabThe denominators used to calculate the rate varied from 78-480 for BSC arm and 483 for intravenous atezolizumab are for all tests of interest based on the number of patients with baseline value and at least one post-treatment value. Best Supportive Care All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)ChemistryIncreased aspartate aminotransferase342.5180Increased alanine aminotransferase303.3190.4Hyperkalemia243.5152.5Increased blood creatinine310.2230.2. Metastatic Chemotherapy-Naive NSCLC. IMpower110The safety of intravenous atezolizumab was evaluated in IMpower110, multicenter, international, randomized, open-label study in 549 chemotherapy-naive patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received intravenous atezolizumab 1200 mg every 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 (14.1)]. 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 intravenous atezolizumab was 5.3 months (0 to 33 months).Fatal adverse reactions occurred in 3.8% of patients receiving intravenous atezolizumab; 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 infarction, and device occlusion (1 patient each).Serious adverse reactions occurred in 28% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%).Intravenous atezolizumab was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (>= patients) leading to intravenous atezolizumab discontinuation were peripheral neuropathy and pneumonitis.Adverse reactions leading to interruption of intravenous atezolizumab 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 and summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower110.Table 7:Adverse Reactions Occurring in >= 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower110Adverse ReactionIntravenous Atezolizumab = 286Platinum-Based ChemotherapyN 263All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GastrointestinalNausea140.3341.9Constipation121.0220.8Diarrhea110120.8GeneralFatigue/Asthenia251.4344.2Pyrexia14090.4Metabolism and NutritionDecreased appetite150.7190Respiratory, Thoracic and MediastinalDyspnea140.7100Cough120.3100Table 8:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving Intravenous Atezolizumab in IMpower110Laboratory AbnormalityIntravenous AtezolizumabPlatinum-Based ChemotherapyAll 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: intravenous atezolizumab (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.HematologyAnemia691.89420Lymphopenia4795917ChemistryHypoalbuminemia480.4392Increased alkaline phosphatase462.5421.2Hyponatremia449367Increased ALT383.2320.8Increased AST363.2320.8Hyperkalemia293.9362.7Hypocalcemia241.4242.7Increased blood creatinine240.7331.5Hypophosphatemia233.6212. First-Line Metastatic Non-squamous NSCLC. IMpower150The safety of intravenous atezolizumab with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, multicenter, international, randomized, open-label trial in which 393 chemotherapy-naive patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC mg/mL/min intravenously every weeks for maximum of or cycles, followed by intravenous atezolizumab 1200 mg with bevacizumab 15 mg/kg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. The median duration of exposure to intravenous atezolizumab was 8.3 months in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin.Fatal adverse reactions occurred in 6% of patients receiving intravenous atezolizumab; 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.Intravenous atezolizumab 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 intravenous atezolizumab 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 and 10 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin in IMpower150.Table 9:Adverse Reactions Occurring in >= 15% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150Adverse ReactionIntravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin = 393Bevacizumab, Paclitaxel and CarboplatinN 394All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0Nervous SystemNeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 563473Headache160.8130GeneralFatigue/Asthenia506466Pyrexia190.390.5Skin and Subcutaneous TissueAlopecia480460RashIncludes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform 232100.3Musculoskeletal and Connective TissueMyalgia/PainIncludes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain 423342Arthralgia261221Gastrointestinal Nausea394322DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 336250.5Constipation300.3230.3Vomiting192181Metabolism and NutritionDecreased appetite294210.8VascularHypertension259228RespiratoryCough200.8190.3Epistaxis171220.3RenalProteinuriaBased on adverse reaction terms since laboratory data for proteinuria was not systematically collected 163153Table 10:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150Laboratory AbnormalityIntravenous Atezolizumab with Bevacizumab, Paclitaxel, and CarboplatinBevacizumab, Paclitaxel and CarboplatinAll 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: Intravenous Atezolizumab with bevacizumab, paclitaxel, and carboplatin range: (337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0HematologyAnemia8310839Neutropenia52314526Lymphopenia48173813ChemistryHyperglycemia610600Increased BUN 52NANA Not applicable. NCI CTCAE does not provide Grades 3-4 definition for these laboratory abnormalities 44NA Hypomagnesemia422361Hypoalbuminemia403312Increased AST404280.8Hyponatremia3810369Increased Alkaline Phosphatase372321Increased ALT376280.5Increased TSH30NA 20NA Hyperkalemia283252Increased Creatinine281192Hypocalcemia263213Hypophosphatemia254184Hypokalemia237144Hyperphosphatemia25NA 19NA IMpower130The safety of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, multicenter, international, randomized, open-label trial in which 473 chemotherapy-naive patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg and carboplatin AUC mg/mL/min intravenously on Day and paclitaxel protein-bound 100 mg/m2 intravenously on Days 1, 8, and 15 of each 21-day cycle for maximum of or cycles, followed by intravenous atezolizumab 1200 mg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among patients receiving intravenous atezolizumab, 55% were exposed for months or longer and 3.5% were exposed for greater than one year.Fatal adverse reactions occurred in 5.3% of patients receiving intravenous atezolizumab; these included pneumonia (1.1%), pulmonary embolism (0.8%), myocardial infarction (0.6%), cardiac arrest (0.4%), 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 intravenous atezolizumab. The most frequent serious adverse reactions (>= 2%) were pneumonia (6%), diarrhea (3%), lung infection (3%), pulmonary embolism (3%), chronic obstructive pulmonary disease exacerbation (2.5%), dyspnea (2.3%), and febrile neutropenia (1.9%).Intravenous atezolizumab 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 intravenous atezolizumab 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 11 and 12 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with paclitaxel protein-bound and carboplatin in IMpower130.Table 11:Adverse Reactions Occurring in >= 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower130Adverse ReactionIntravenous Atezolizumab with Paclitaxel Protein-Bound and CarboplatinN 473Paclitaxel Protein-Bound and CarboplatinN 232All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GeneralFatigue/Asthenia6111608GastrointestinalNausea503.4462.2DiarrheaIncludes diarrhea, colitis, and gastroenteritis 436326Constipation361.1310Vomiting272.7192.2Musculoskeletal and Connective TissueMyalgia/PainIncludes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 383220.4Nervous SystemNeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 332.5282.2Respiratory, Thoracic and MediastinalDyspneaIncludes dyspnea, dyspnea exertional and wheezing 324.9251.3Cough270.6170Skin and Subcutaneous TissueAlopecia320270RashIncludes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular 200.6110.9Metabolism and NutritionDecreased appetite302.1262.2Table 12:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving Intravenous Atezolizumab in IMpower130Laboratory AbnormalityIntravenous Atezolizumab with Paclitaxel Protein-Bound and CarboplatinN 473Paclitaxel Protein-Bound and CarboplatinN 232All 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: intravenous atezolizumab with paclitaxel protein-bound and carboplatin (range: 423-467); paclitaxel protein-bound and carboplatin (range: 218-229). Graded per NCI CTCAE v4.0.HematologyAnemia92338725Neutropenia75506739Thrombocytopenia73195913Lymphopenia71236116ChemistryHyperglycemia758668Hypomagnesemia503.4423.2Hyponatremia379287Hypoalbuminemia351.3310Increased ALT312.8243.9Hypocalcemia312.6271.8Hypophosphatemia296203.2Increased AST282.2241.8Increased TSH26NANA Not applicable. NCI CTCAE does not provide Grades 3-4 definition for these laboratory abnormalities 5NA Hypokalemia266244.4Increased Alkaline Phosphatase252.6221.3Increased Blood Creatinine232.8160.4Hyperphosphatemia21NA 13NA Previously Treated Metastatic NSCLC. OAKThe safety of intravenous atezolizumab was evaluated in OAK, multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.1)]. total of 609 patients received intravenous atezolizumab 1200 mg intravenously every weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n 578) 75 mg/m2 intravenously every 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 intravenous atezolizumab-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.Intravenous atezolizumab was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to intravenous atezolizumab discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of intravenous atezolizumab occurred in 25% of patients; the most common (> 1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain.Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.Table 13:Adverse Reactions Occurring in >= 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAKAdverse ReactionIntravenous AtezolizumabN 609DocetaxelN 578All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GeneralFatigue/AstheniaIncludes fatigue and asthenia 444536Pyrexia18< 113< 1RespiratoryCoughIncludes cough and exertional cough 26< 121< 1Dyspnea222.8212.6Metabolism and Nutrition Decreased appetite23< 1241.6MusculoskeletalMyalgia/PainIncludes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia 201.320< 1Arthralgia120.5100.2GastrointestinalNausea18< 123< 1Constipation18< 114< 1Diarrhea16< 1242SkinRashIncludes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid 12< 1100Table 14:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAKLaboratory AbnormalityIntravenous AtezolizumabDocetaxelAll 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: intravenous atezolizumab (range: 546-585) and docetaxel (range: 532-560). Graded according to NCI CTCAE version 4.0HematologyAnemia673827Lymphocytopenia49146021ChemistryHypoalbuminemia484503Hyponatremia427316Increased Alkaline Phosphatase392251Increased AST313160.5Increased ALT273140.5Hypophosphatemia275234Hypomagnesemia261211Increased Creatinine232161. Adverse Reactions in Adult Patients with Small Cell Lung CancerThe safety of TECENTRIQ HYBREZA for its approved Small Cell Lung Cancer (SCLC) indication [see Indications and Usage (1.2)] has been established in adequate and well-controlled studies of intravenous atezolizumab for SCLC (IMpower133 study).. Small Cell Lung Cancer (SCLC). IMpower133The safety of intravenous atezolizumab with carboplatin and etoposide was evaluated in IMpower133, randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received intravenous atezolizumab 1200 mg and carboplatin AUC mg/mL/min on Day and etoposide 100 mg/m2 intravenously on Days 1, and of each 21-day cycle for maximum of cycles, followed by intravenous atezolizumab 1200 mg every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. Among 198 patients receiving intravenous atezolizumab, 32% were exposed for months or longer and 12% were exposed for 12 months or longer.Fatal adverse reactions occurred in 2% of patients receiving intravenous atezolizumab. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).Serious adverse reactions occurred in 37% of patients receiving intravenous atezolizumab. Serious adverse reactions in 2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%).Intravenous atezolizumab 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 intravenous atezolizumab 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 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with carboplatin and etoposide in IMpower133.Table 15:Adverse Reactions Occurring in >= 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133Adverse ReactionIntravenous Atezolizumab with Carboplatin and EtoposideN 198Placebo with Carboplatin and EtoposideN 196All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GeneralFatigue/Asthenia395333GastrointestinalNausea381331Constipation261301Vomiting202173Skin and Subcutaneous TissueAlopecia370350Metabolism and NutritionDecreased appetite271180Table 16:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133Laboratory AbnormalityIntravenous Atezolizumab with Carboplatin and EtoposidePlacebo with Carboplatin and EtoposideAll 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: Intravenous Atezolizumab (range: 181-193); Placebo (range: 181-196). Graded per NCI CTCAE v4.0HematologyAnemia94179319Neutropenia73457648Thrombocytopenia58205317Lymphopenia46143811ChemistryHyperglycemia6710658Increased Alkaline Phosphatase381352Hyponatremia34153311Hypoalbuminemia321300Decreased TSHTSH thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories. 28NANA Not applicable 15NA Hypomagnesemia315356Hypocalcemia263285Increased ALT263311Increased AST221212Increased Blood Creatinine224151Hyperphosphatemia21NA 23NA Increased TSH 21NA 7NA Adverse Reactions in Adult Patients with Hepatocellular CarcinomaThe safety of TECENTRIQ HYBREZA for its approved indication hepatocellular carcinoma [see Indications and Usage (1.3)] has been established in adequate and well-controlled studies of intravenous atezolizumab for hepatocellular carcinoma (IMbrave150 study).. Hepatocellular Carcinoma. IMbrave150The safety of intravenous atezolizumab in combination with bevacizumab was evaluated in IMbrave150, multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.3)]. Patients received 1,200 mg of intravenous atezolizumab intravenously followed by 15 mg/kg bevacizumab (n 329) every weeks, or 400 mg of sorafenib (n 156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab occurred in 9% of patients in the intravenous atezolizumab and bevacizumab arm. The most common adverse reactions leading to intravenous atezolizumab 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 intravenous atezolizumab occurred in 41% of patients in the intravenous atezolizumab and bevacizumab arm; the most common (>= 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatase (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 intravenous atezolizumab and bevacizumab arm.Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab and bevacizumab in IMbrave150.Table 17:Adverse Reactions Occurring in >= 10% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150Adverse ReactionIntravenous Atezolizumab in combination with Bevacizumab(n 329)Sorafenib(n 156)All GradesGraded per NCI CTCAE v4.0 (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Vascular DisordersHypertension30152412General Disorders and Administration Site ConditionsFatigue/AstheniaIncludes fatigue and asthenia 262326Pyrexia180100Renal and Urinary DisordersProteinuria20370.6InvestigationsWeight Decreased110100Skin and Subcutaneous Tissue DisordersPruritus190100Rash120172.6Gastrointestinal DisordersDiarrhea191.8495Constipation130140Abdominal Pain120170Nausea120160Vomiting10080Metabolism and Nutrition DisordersDecreased Appetite181.2243.8Respiratory, Thoracic and Mediastinal DisordersCough120100Epistaxis1004.50Injury, Poisoning and Procedural ComplicationsInfusion-Related Reaction112.400Table 18:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150Laboratory AbnormalityIntravenous Atezolizumab in combination with Bevacizumab(n 329)Sorafenib(n 156)All GradesGraded per NCI CTCAE v4.0 (%)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: intravenous atezolizumab plus bevacizumab (222-323) and sorafenib (90-153)ChemistryIncreased AST86169016Increased Alkaline Phosphatase704764.6Increased ALT628704.6Decreased Albumin601.5540.7Decreased Sodium5413499Increased Glucose489434.6Decreased Calcium300.3351.3Decreased Phosphorus264.75816Increased Potassium231.9162Hypomagnesemia220220HematologyDecreased Platelet687634.6Decreased Lymphocytes62135811Decreased Hemoglobin583.1623.9Increased Bilirubin5785914Decreased Leukocyte323.4291.3Decreased Neutrophil232.3161.1. Adverse Reactions in Adult Patients with MelanomaThe safety of TECENTRIQ HYBREZA for its approved melanoma indication [see Indications and Usage (1.4)] has been established in adequate and well-controlled studies of intravenous atezolizumab for melanoma (IMspire150 study).. Metastatic Melanoma. IMspire150The safety of intravenous atezolizumab, administered with cobimetinib and vemurafenib, was evaluated in IMspire150, double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma [see Clinical Studies (14.4)]. Patients received intravenous atezolizumab with cobimetinib and vemurafenib (n 230) or placebo with cobimetinib and vemurafenib (n 281).Among the 230 patients who received intravenous atezolizumab administered with cobimetinib and vemurafenib, the median duration of exposure to intravenous atezolizumab was 9.2 months (range: 0-30 months), to cobimetinib was 10.0 months (range: 1-31 months) and to vemurafenib was 9.8 months (range: 1-31 months).Fatal adverse reactions occurred in 3% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. Adverse reactions leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest.Serious adverse reactions occurred in 45% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) serious adverse reactions were hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%).Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 21% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to intravenous atezolizumab discontinuation were increased ALT (2.2%) and pneumonitis (2.6%).Adverse reactions leading to interruption of intravenous atezolizumab occurred in 68% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to intravenous atezolizumab interruption were pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased AST (10%), increased lipase (9%), increased amylase (7%), pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%), rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%), peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and respiratory tract infection (2.2%).Tables 19 and 20 summarize the incidence of adverse reactions and laboratory abnormalities in IMspire150.Table 19:Adverse Reactions Occurring in >= 10% of Patients on the Intravenous Atezolizumab plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at Higher Incidence (Between Arm Difference of >= 5% All Grades or >= 2% Grades 3-4 Intravenous Atezolizumab in IMspire150)Adverse ReactionIntravenous Atezolizumab in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib(n=281)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue DisordersRashIncludes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysaesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalised and rash morbilliform 75277223Pruritus26< 117< 1Photosensitivity reaction21< 1253.2General Disorders and Administration Site ConditionsFatigueIncludes fatigue, asthenia and malaise 513451.8PyrexiaIncludes pyrexia and hyperpyrexia 491.7352.1EdemaIncludes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema 26< 1210Gastrointestinal Disorders HepatotoxicityIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasaemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinaemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal 50213613Nausea30< 1322.5StomatitisIncludes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 231.315< 1Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncludes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain 624.3483.2Endocrine DisordersHypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased 220100Hyperthyroidism18< 180Injury, Poisoning and Procedural ComplicationsInfusion-related reactionIncludes infusion related reaction and hypersensitivity 102.68< 1Respiratory, Thoracic and Mediastinal DisordersPneumonitisIncludes pneumonitis and interstitial lung disease 121.36< 1Vascular DisordersHypertensionIncludes hypertension, blood pressure increased, hypertensive crisis 1710187Clinically important adverse reactions in 10% of patients who received intravenous atezolizumab plus cobimetinib and vemurafenib were:Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolongedEye Disorders: UveitisGastrointestinal disorders: PancreatitisInfections and infestations: Pneumonia, urinary tract infectionMetabolism and nutrition disorders: HyperglycemiaNervous system Disorders: Dizziness, dysgeusia, syncopeRespiratory, thoracic and mediastinal disorders: Dyspnea, oropharyngeal painSkin and Subcutaneous Tissue Disorders: VitiligoTable 20:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving Intravenous Atezolizumab Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at Higher Incidence (Between Arm Difference of >= 5% All Grades or >= 2% Grades 3-4) in IMspire150Laboratory AbnormalityIntravenous Atezolizumab in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib(n=281)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Graded per NCI CTCAE v4.0.Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230).HematologyDecreased Lymphocytes80247217Decreased Hemoglobin772.6722.2Decreased Platelet341.3240.4Decreased Neutrophils262.2191.5ChemistryIncreased Creatine Kinase88228118Increased AST8013686Increased ALT79186212Increased Triacylglycerol Lipase75466235Increased Alkaline Phosphatase736632.9Decreased Phosphorus67226414Increased Amylase51134513Increased Blood Urea Nitrogen47NANA Not applicable. NCI CTCAE v4.0 does not include these laboratories 37NA Decreased Albumin430.9341.5Increased Bilirubin423.1330.7Decreased Calcium411.3280Decreased Sodium405347Decreased Thyroid-Stimulating Hormone38NA 23NA Increased Thyroid-Stimulating HormoneIncreased Thyroid Stimulating Hormone has difference 5% (All Grades) between arms and is included for clinical completeness 37NA 33NA Decreased Potassium365224.3Increased Triiodothyronine33NA 18NA Increased Free Thyroxine32NA 21NA Decreased Total Triiodothyronine32NA 8NA Increased Potassium291.3191.4Decreased Triiodothyronine27NA 21NA Increased Sodium200130.4. Adverse Reactions in Adults with Alveolar Soft Part SarcomaThe safety of TECENTRIQ HYBREZA for its approved alveolar soft part sarcoma (ASPS) indication [see Indications and Usage (1.5)] has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS (ML39345 study).. Alveolar Soft Part Sarcoma. ML39345 StudyThe safety of intravenous atezolizumab was evaluated in 47 adult and pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5)]. Adult patients received intravenous atezolizumab 1200 mg every weeks and pediatric patients received 15 mg/kg up to maximum 1200 mg every weeks until disease progression or unacceptable toxicity. The median duration of exposure to intravenous atezolizumab was 8.9 months (1 to 40 months).Serious adverse reactions occurred in 41% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each).Dosage interruptions of intravenous atezolizumab due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (>= 3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each).Tables 21 and 22 summarize adverse reactions and laboratory abnormalities in Study ML39345.Table 21:Adverse Reactions Occurring in >= 15% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345Adverse ReactionIntravenous AtezolizumabN 49All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0General disorders and administration site conditionsFatigue552Pyrexia252Influenza like illness180Gastrointestinal disordersNausea430Vomiting370Constipation330Diarrhea272Abdominal painIncludes abdominal pain and abdominal pain upper 250Metabolism and nutrition disordersDecreased appetite222Respiratory, Thoracic and MediastinalCoughIncludes cough, upper-airway cough syndrome, and productive cough 450Dyspnea330Rhinitis allergic160Musculoskeletal and connective tissue disordersMusculoskeletal painIncludes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain 678Skin and subcutaneous tissue disordersRashIncludes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption 472Nervous system disordersHeadache434DizzinessIncludes vertigo and dizziness 294Vascular disordersHypertension436HemorrhageIncludes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage 292Psychiatric disordersInsomnia270Anxiety250Cardiac DisordersArrhythmiaIncludes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia 222Endocrine disordersHypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased 250InvestigationsWeight decreased180Weight increased166Table 22:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345Laboratory AbnormalityLaboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges Intravenous AtezolizumabThe denominators used to calculate the rate varied from 4-49 for all tests of interest based on the number of patients with baseline value and at least one on-study laboratory measurement available All Grades (%)Grades 3-4 (%)HematologyDecreased Hemoglobin 630Decreased Platelets270Increased Platelets290ChemistryIncreased Alkaline Phosphatase290Decreased Amylase400Increased Amylase2020Decreased Bilirubin490Decreased Calcium470Increased Calcium2514Decreased Glucose 330Increased Glucose780Decreased Glucose (fasting)250Decreased Magnesium210Increased Magnesium2626Increased AST392Increased ALT332Decreased Sodium430Increased Lipase2525. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of intravenous atezolizumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiac: pericarditis, pericardial effusion, cardiac tamponade. Cardiac: pericarditis, pericardial effusion, cardiac tamponade.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Non-Small Cell Lung Cancer. NSCLC TECENTRIQ HYBREZAIMscin001 (NCT03735121) was an open-label, multi-center, international, randomized study conducted in adult patients with locally advanced or metastatic NSCLC who were not exposed to cancer immunotherapy and who have disease progression following platinum-based chemotherapy. Patients were excluded if they had history of autoimmune disease; active or corticosteroid-dependent brain metastases; received live, attenuated vaccine within weeks prior to randomization; or received systemic immunostimulatory agents within weeks or systemic immunosuppressive drugs within weeks prior to randomization. total of 371 patients were randomized 2:1 to receive either TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously in the thigh every weeks (n 247) or intravenous atezolizumab 1,200 mg every weeks (n 124) until disease progression or unacceptable toxicity.The primary outcome measure was atezolizumab exposure (Ctrough and AUC0-21days) of subcutaneous TECENTRIQ HYBREZA as compared to intravenous atezolizumab [see Clinical Pharmacology (12.3)]. Additional descriptive efficacy outcome measures were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).The median age was 64 years (range: 27 to 85); 69% were male; 67% were White, 22% were Asian, and 0.8% were Black or African American; 74% were non-Hispanic or Latino; 26% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 74% had an ECOG PS of 1; and 70% of patients were current or previous smokers. Sixty-five percent of patients had non-squamous histology, 5% had known EGFR mutations, 1.6% had known ALK rearrangements, 36% had known PD-L1 positive tumors, 16% had asymptomatic CNS metastases at baseline. Eighty percent of patients had received only one prior therapeutic regimen for NSCLC.At the primary analysis, the confirmed ORR was 9% (95% CI: 5, 13) in the subcutaneous TECENTRIQ HYBREZA arm and 8% (95% CI: 4, 14) in the intravenous atezolizumab arm. After further follow up, no notable differences in PFS and OS were observed between patients who received subcutaneous TECENTRIQ HYBREZA and patients who received intravenous atezolizumab.. NSCLC Trials Intravenous AtezolizumabThe effectiveness of TECENTRIQ HYBREZA has been established for:adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells (IMpower010 study).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%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study).first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study).first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study).first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).Use of TECENTRIQ HYBREZA for these NSCLC indications is supported by evidence from the adequate and well-controlled studies conducted with intravenous atezolizumab in these NSCLC populations and pharmacokinetics data that demonstrated comparable exposures to atezolizumab between TECENTRIQ HYBREZA and intravenous atezolizumab in the IMscin001 trial [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Below is description of the efficacy results of these adequate and well-controlled studies of intravenous atezolizumab in these NSCLC populations.. adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells (IMpower010 study).. 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%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study).. first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study).. first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study).. first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).. Adjuvant Treatment of Early-stage NSCLC. IMpower010The efficacy of intravenous atezolizumab was evaluated in IMpower010 (NCT02486718), multi-center, randomized, open-label trial for the adjuvant treatment of patients with NSCLC who had complete tumor resection and were eligible to receive cisplatin-based adjuvant chemotherapy. Eligible patients were required to have Stage IB (tumors >= cm) Stage IIIA NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system, 7th edition. Patients were excluded if they had history of autoimmune disease; history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis; administration of live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within weeks or systemic immunosuppressive medications within weeks prior to randomization.A total of 1005 patients who had complete tumor resection and received cisplatin-based adjuvant chemotherapy were randomized (1:1) to receive intravenous atezolizumab 1200 mg intravenous infusion every weeks for 16 cycles, unless disease recurrence or unacceptable toxicity occurred, or best supportive care (BSC). Randomization was stratified by sex, stage of disease, histology, and PD-L1 expression.Tumor assessments were conducted at baseline of the randomization phase and every months for the first year following Cycle 1, Day and then every months until year five, then annually thereafter.The median age was 62 years (range: 26 to 84), and 67% of patients were male. The majority of patients were White (73%) and Asian (24%). Most patients were current or previous smokers (78%) and baseline ECOG performance status in patients was (55%) or (44%). Overall, 12% of patients had Stage IB, 47% had Stage II and 41% had Stage IIIA disease. PD-L1 expression, defined as the percentage of tumor cells expressing PD-L1 as measured by the VENTANA PD-L1 (SP263) assay, was >= 1% in 53% of patients, 1% in 44% and unknown in 2.6%.The primary efficacy outcome measure was disease-free survival (DFS) as assessed by the investigator. The primary efficacy analysis population (n 476) was patients with Stage II IIIA NSCLC with PD-L1 expression on >= 1% of tumor cells (PD-L1 >= 1% TC). DFS was defined as the time from the date of randomization to the date of occurrence of any of the following: first documented recurrence of disease, new primary NSCLC, or death due to any cause, whichever occurred first. key secondary efficacy outcome measure was overall survival (OS) in the intent-to-treat population.At the time of the interim DFS analysis, the study demonstrated statistically significant improvement in DFS in the PD-L1 >= 1% TC, Stage II IIIA patient population.Efficacy results are presented in Table 23 and Figure 1.Table 23:Efficacy Results from IMpower010 in Patients with Stage II IIIA NSCLC with PD-L1 expression >= 1% TCArm A: Intravenous AtezolizumabN 248Arm B: Best Supportive CareN 228CI Confidence interval, NE Not estimable, NR Not reachedDisease-Free Survival Number of events (%)88 (35)105 (46) Median, monthsNR35.3 (95% CI)(36.1, NE)(29.0, NE) Hazard ratioStratified by stage, sex, and histology (95% CI)0.66 (0.50, 0.88) p-value0.004In pre-specified secondary subgroup analysis of patients with PD-L1 TC >= 50% Stage II IIIA NSCLC (n 229), the median DFS was not reached (95% CI: 42.3 months, NE) for patients in the intravenous atezolizumab arm and was 35.7 months (95% CI: 29.7, NE) for patients in the best supportive care arm, with HR of 0.43 (95% CI: 0.27, 0.68). In an exploratory subgroup analysis of patients with PD-L1 TC 1-49% Stage II IIIA NSCLC (n 247), the median DFS was 32.8 months (95% CI:29.4, NE) for patients in the intravenous atezolizumab arm and 31.4 months (95% CI: 24.0, NE) for patients in the best supportive care arm, with HR of 0.87 (95% CI: 0.60, 1.26).Figure 1:Kaplan-Meier Plot of Disease-Free Survival in IMpower010 in Patients with Stage II IIIA NSCLC with PD-L1 expression >= 1% TCAt the time of the DFS interim analysis, 19% of patients in the PD-L1 >=1% TC Stage II IIIA patient population had died. An exploratory analysis of OS in this population resulted in stratified HR of 0.77 (95% CI: 0.51, 1.17).. Metastatic Chemotherapy-Naive NSCLC. IMpower110The efficacy of intravenous atezolizumab was evaluated in IMpower110 (NCT02409342), 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 history of autoimmune disease, administration of live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within weeks or systemic immunosuppressive medications within 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: Intravenous atezolizumab 1200 mg every weeks until disease progression or unacceptable toxicityArm B: Platinum-based chemotherapyArm platinum-based chemotherapy regimens for non-squamous NSCLC consisted of cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) OR carboplatin (AUC mg/mL/min) and pemetrexed (500 mg/m2) on Day of each 21-day cycle for maximum of or cycles followed by pemetrexed (500 mg/m2) until disease progression or unacceptable toxicity.Arm platinum-based chemotherapy regimens for squamous NSCLC consisted of cisplatin (75 mg/m2) on Day with gemcitabine (1250 mg/m2) on Days and of each 21-day cycle OR carboplatin (AUC mg/mL/min) on Day with gemcitabine (1000 mg/m2) on Days and of each 21-day cycle for maximum of or cycles followed by best supportive care until disease progression or unacceptable toxicity.Administration of intravenous atezolizumab was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every weeks for the first 48 weeks following Cycle 1, Day and then every weeks thereafter. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at 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-naive 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 (36%) or (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 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 24 and Figure 2.Table 24: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 AberrationsArm A: Intravenous AtezolizumabArm B: Platinum-Based ChemotherapyN 107N 98CI confidence interval; NE not estimableOverall SurvivalBased on OS interim analysis. The median survival follow-up time in patients was 15.7 months Deaths (%)44 (41%)57 (58%) Median, months20.213.1 (95% CI)(16.5, NE)(7.4, 16.5) Hazard ratioStratified by sex and ECOG performance status (95% CI)0.59 (0.40, 0.89) p-valueBased on the stratified log-rank test compared to Arm 0.0106Compared to the allocated alpha of 0.0413 (two-sided) for this interim analysis Figure 2: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 AberrationsInvestigator-assessed PFS showed an 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 intravenous atezolizumab arm and 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 intravenous atezolizumab arm and 29% (95% CI: 20%, 39%) in the platinum-based chemotherapy arm.. Arm A: Intravenous atezolizumab 1200 mg every weeks until disease progression or unacceptable toxicity. Arm B: Platinum-based chemotherapy. First-Line Metastatic Non-squamous NSCLC. IMpower150The efficacy of intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), 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 or were eligible. The trial excluded patients with history of autoimmune disease, administration of live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within weeks or systemic immunosuppressive medications within 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: intravenous atezolizumab 1200 mg, paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cyclesArm B: intravenous atezolizumab 1200 mg, bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cyclesArm C: bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cyclesPatients who had not experienced disease progression following the completion or cessation of platinum-based chemotherapy, received:Arm A: intravenous atezolizumab 1200 mg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicityArm B: intravenous atezolizumab 1200 mg and bevacizumab 15 mg/kg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicityArm C: bevacizumab 15 mg/kg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicityTumor assessments were conducted every weeks for the first 48 weeks following Cycle 1, Day and then every weeks thereafter. Tumor specimens were evaluated prior to randomization for PD-L1 tumor expression using the VENTANA PD-L1 (SP142) assay at central laboratory. Tumor tissue was collected at baseline for expression of tGE signature and evaluation was performed using clinical trial assay in central laboratory prior to the analysis of efficacy outcome measures.Major efficacy outcome measures for comparison of Arms and 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 and or Arms and 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 and 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 dose of 175 mg/m2 while the remaining 87% received paclitaxel at 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 (43%) or (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 statistically significant improvement in PFS between Arms and in both the tGE-WT and ITT-WT subpopulations, but did not demonstrate significant difference for either subpopulation between Arms and based on the final PFS analyses. In the interim analysis of OS, statistically significant improvement was observed for Arm compared to Arm C, but not for Arm compared to Arm C. Efficacy results for the ITT-WT subpopulation are presented in Table 25 and Figure 3.Table 25:Efficacy Results in ITT-WT Population in IMpower150Arm C: Bevacizumab, Paclitaxel and CarboplatinArm B: Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and CarboplatinArm A: Intravenous Atezolizumab with Paclitaxel, and CarboplatinN 337N 359N 349CI confidence intervalOverall SurvivalBased on OS interim analysis 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 ratioStratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC (95% CI)---0.78 (0.64, 0.96)0.84 (0.72, 1.08) p-valueBased on the stratified log-rank test compared to Arm ---0.016Compared to the allocated =0.0174 (two sided) for this interim analysis 0.204Compared to the allocated =0.0128 (two sided) for this interim analysis Progression-Free SurvivalAs determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) 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 ---0.0002Compared to the allocated =0.006 (two sided) for the final PFS analysis 0.5219Objective 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 = 142n 196n 150 Median, months6.510.89.5 (95% CI)(5.6, 7.6)(8.4, 13.9)(7.0, 13.0)Figure 3:Kaplan-Meier Curves for Overall Survival in ITT-WT Population in IMpower150Exploratory analyses showed that the subset of patients in the four drug regimen arm who were ADA positive by week (30%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week (70%) [see, Clinical Pharmacology (12.6)]. In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the intravenous atezolizumab, bevacizumab, paclitaxel, and carboplatin arm with matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly, ADA negative patients in the intravenous atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were compared with 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).. Arm A: intravenous atezolizumab 1200 mg, paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles. Arm B: intravenous atezolizumab 1200 mg, bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles. Arm C: bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles. Arm A: intravenous atezolizumab 1200 mg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicity. Arm B: intravenous atezolizumab 1200 mg and bevacizumab 15 mg/kg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicity. Arm C: bevacizumab 15 mg/kg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicity. IMpower130The efficacy of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130 (NCT02367781), 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 weeks or systemic immunosuppressive medications within 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:Intravenous atezolizumab 1200 mg on Day 1, paclitaxel protein-bound 100 mg/m2 on Days 1, 8, and 15, and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles followed by intravenous atezolizumab 1200 mg once every weeks until disease progression or unacceptable toxicity, orPaclitaxel protein-bound 100 mg/m2 on Days 1, and 15 and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles followed by best supportive care or pemetrexed.Tumor assessments were conducted every weeks for the first 48 weeks, then every 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 (41%) or (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 26 and Figure 4.Table 26:Efficacy Results from IMpower130Intravenous Atezolizumab with Paclitaxel Protein-Bound and CarboplatinPaclitaxel Protein-Bound and CarboplatinCI confidence intervalOverall SurvivalBased on OS interim analysis = 453n 228 Deaths (%)228 (50%)131 (57%) Median, months18.613.9 (95% CI)(15.7, 21.1)(12.0, 18.7) Hazard ratioStratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC) (95% CI)0.80 (0.64, 0.99) p-valueBased on the stratified log-rank test 0.0384Compared to the allocated =0.0428 (two sided) for this interim analysis Progression-Free SurvivalAs determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) = 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-value 0.0024Compared to the allocated =0.006 (two sided) for the final PFS analysis Overall Response Rate Confirmed response = 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 n 207n 74 Median, months10.87.8 (95% CI)(9.0, 14.4)(6.8, 10.9)Figure 4:Kaplan-Meier Curves for Overall Survival in IMpower130. Intravenous atezolizumab 1200 mg on Day 1, paclitaxel protein-bound 100 mg/m2 on Days 1, 8, and 15, and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles followed by intravenous atezolizumab 1200 mg once every weeks until disease progression or unacceptable toxicity, or. Paclitaxel protein-bound 100 mg/m2 on Days 1, and 15 and carboplatin AUC mg/mL/min on Day of each 21-day cycle for maximum of or cycles followed by best supportive care or pemetrexed.. Previously Treated Metastatic NSCLC. OAKThe efficacy of intravenous atezolizumab was evaluated in 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 platinum-containing regimen. Patients with history of autoimmune disease, symptomatic or corticosteroid-dependent brain metastases, or requiring systemic immunosuppression within 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 intravenous atezolizumab 1200 mg intravenously every weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel 75 mg/m2 intravenously every weeks until unacceptable toxicity or disease progression. Tumor assessments were conducted every weeks for the first 36 weeks and every 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 and 63% had 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 27 and Figure Table 27:Efficacy Results in OAKIntravenous AtezolizumabDocetaxelCI confidence interval; NE not estimableOverall 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 ratioStratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology (95% CI)0.74 (0.63, 0.87) p-valueBased on the stratified log-rank test 0.0004Compared to the pre-specified allocated of 0.03 for this analysis 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 RatePer RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) Number of PatientsN 425N 425 ORR, (%)58 (14%)57 (13%) (95% CI)(11%, 17%)(10%, 17%) Complete Response6 (1%)1 (0.2%) Partial Response52 (12%)56 (13%)Duration of Response = 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-value 0.0013Compared to the allocated of 0.0177 for this interim analysis based on 86% information using OBrien-Fleming boundary Figure 5:Kaplan-Meier Curves of Overall Survival in the First 850 Patients Randomized in OAKTumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at 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 (21%) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week (79%) [see Clinical Pharmacology (12.6)]. ADA positive patients by week 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 intravenous atezolizumab arm with matched population in the docetaxel arm and ADA negative patients in the intravenous atezolizumab arm with 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).. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. 14.2 Small Cell Lung Cancer. The efficacy of TECENTRIQ HYBREZA in combination with carboplatin and etoposide for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with carboplatin and etoposide for ES-SCLC. Below is description of the efficacy results of intravenous atezolizumab in combination with carboplatin and etoposide in this adequate and well-controlled ES-SCLC trial.. Small Cell Lung Cancer (SCLC). IMpower133The efficacy of intravenous atezolizumab with carboplatin and etoposide was investigated in IMpower133 (NCT02763579), 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 or 1. The trial excluded patients with active or untreated CNS metastases, history of autoimmune disease, administration of live, attenuated vaccine within weeks prior to randomization, or administration of systemic immunosuppressive medications within 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:intravenous atezolizumab 1200 mg and carboplatin AUC mg/mL/min on Day and etoposide 100 mg/m2 intravenously on Days 1, and of each 21-day cycle for maximum of cycles followed by intravenous atezolizumab 1200 mg once every weeks until disease progression or unacceptable toxicity, orplacebo and carboplatin AUC mg/mL/min on Day and etoposide 100 mg/m2 intravenously on Days 1, 2, and of each 21-day cycle for maximum of cycles followed by placebo once every weeks until disease progression or unacceptable toxicity.Administration of intravenous atezolizumab was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every weeks for the first 48 weeks following Cycle 1, Day and then every weeks thereafter. Patients treated beyond disease progression had tumor assessment conducted every 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 intravenous atezolizumab 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 (35%) or (65%); 9% of patients had history of brain metastases, and 97% were current or previous smokers. Efficacy results are presented in Table 28 and Figure 6.Table 28:Efficacy Results from IMpower133Intravenous Atezolizumab with Carboplatin and EtoposidePlacebo with Carboplatin and EtoposideCI confidence intervalOverall SurvivalN 201N 202 Deaths (%)104 (52%)134 (66%) Median, months12.310.3 (95% CI)(10.8, 15.9)(9.3, 11.3) Hazard ratioStratified by sex and ECOG performance status (95% CI)0.70 (0.54, 0.91) p-valueBased on the stratified log-rank test Compared to the allocated of 0.0193 for this interim analysis based on 78% information using OBrien-Fleming boundary 0.0069Progression-Free SurvivalAs determined by investigator assessment per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) = 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 Compared to the allocated of 0.05 for this analysis 0.0170Objective Response Rate , Confirmed response = 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 , = 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. intravenous atezolizumab 1200 mg and carboplatin AUC mg/mL/min on Day and etoposide 100 mg/m2 intravenously on Days 1, and of each 21-day cycle for maximum of cycles followed by intravenous atezolizumab 1200 mg once every weeks until disease progression or unacceptable toxicity, or. placebo and carboplatin AUC mg/mL/min on Day and etoposide 100 mg/m2 intravenously on Days 1, 2, and of each 21-day cycle for maximum of cycles followed by placebo once every weeks until disease progression or unacceptable toxicity.. Figure 6. 14.3Hepatocellular Carcinoma. The efficacy of TECENTRIQ HYBREZA in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with bevacizumab for HCC. Below is description of efficacy results of intravenous atezolizumab in combination with bevacizumab in this adequate and well-controlled HCC trial.. Hepatocellular Carcinoma. IMbrave150The efficacy of intravenous atezolizumab in combination with bevacizumab was investigated in IMbrave150 (NCT03434379), 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 intravenous atezolizumab as an intravenous infusion of 1200 mg, followed by 15 mg/kg bevacizumab, on the same day every weeks or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. Patients could discontinue either intravenous atezolizumab or bevacizumab (e.g., due to adverse events) and continue on monotherapy until disease progression or unacceptable toxicity associated with the monotherapy.The study enrolled patients who were ECOG performance score or and who had not received prior systemic treatment. Patients were required to be evaluated for the presence of varices within months prior to treatment, and were excluded if they had variceal bleeding within months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients with Child-Pugh or cirrhosis, moderate or severe ascites; history of hepatic encephalopathy; history of autoimmune disease; administration of live, attenuated vaccine within weeks prior to randomization; administration of systemic immunostimulatory agents within weeks or systemic immunosuppressive medications within weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases were excluded. Tumor assessments were performed every weeks for the first 54 weeks and every 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 baseline AFP >= 400 ng/mL. Baseline ECOG performance status was (62%) or (38%). HCC risk factors were Hepatitis in 48% of patients, Hepatitis in 22%, and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage (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 29 and Figure 7.Table 29:Efficacy Results from IMbrave150Intravenous Atezolizumab in combination with Bevacizumab(N= 336)Sorafenib(N=165)+Denotes censored value CI confidence interval; HCC mRECIST Modified RECIST Assessment for Hepatocellular Carcinoma; NE not estimable; RECIST 1.1 Response Evaluation Criteria in Solid Tumors v1.1Overall Survival Number of deaths (%)96 (29)65 (39) Median OS in monthsNE13.2 (95% CI)(NE, NE)(10.4, NE) Hazard ratioStratified 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) (95% CI)0.58 (0.42, 0.79) p-valueBased 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 0.0006 Progression-Free SurvivalPer independent radiology review 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< 0.0001Overall Response Rate Confirmed responses (ORR), RECIST 1.1 Number of responders (%)93 (28)19 (12) (95% CI)(23, 33)(7,17) p-valueBased on two-sided Cochran-Mantel-Haesnszel test 0.0001 Complete responses, (%)22 (7)0 Partial responses, (%)71 (21)19 (12)Duration of Response (DOR) RECIST 1.1(n=93)(n=19) Median DOR in monthsNE6.3 (95% CI)(NE, NE)(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, (%)37 (11)3 (1.8) Partial responses, (%)75 (22)18 (11)Duration of Response (DOR) HCC mRECIST(n=112)(n=21) Median DOR in monthsNE6.3 (95% CI)(NE, NE)(4.9, NE) Range (months)(1.3+, 13.4+)(1.4+, 9.1+)Figure 7:Kaplan-Meier Plot of Overall Survival in IMbrave150Exploratory analyses showed that the subset of patients (20%) who were ADA-positive by week appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week [see Clinical Pharmacology (12.6)]. ADA-positive patients by week 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 intravenous atezolizumab 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 intravenous atezolizumab 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).. Figure 7. 14.4Melanoma. The efficacy of TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with bevacizumab for BRAF V600 mutation-positive unresectable or metastatic melanoma. Below is description of the efficacy results of intravenous atezolizumab in combination with cobimetinib and vemurafenib in this adequate and well-controlled melanoma trial.. Metastatic Melanoma. IMspire150The efficacy of intravenous atezolizumab in combination with cobimetinib and vemurafenib was evaluated in double-blind, randomized (1:1), placebo-controlled, multicenter trial (IMspire150; NCT02908672) conducted in 514 patients. Randomization was stratified by geographic location (North America vs. Europe vs. Australia, New Zealand, and others) and baseline lactate dehydrogenase (LDH) [less than or equal to upper limit of normal (ULN) vs. greater than ULN].Eligible patients were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma as detected by locally available test and centrally confirmed with the FoundationOne(TM) assay. Patients were excluded if they had history of autoimmune disease; administration of live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within weeks or systemic immunosuppressive medications within weeks prior to randomization; and active or untreated CNS metastases.Intravenous atezolizumab was initiated after patients received 28-day treatment cycle of cobimetinib 60 mg orally once daily (21 days on/7 days off) and vemurafenib 960 mg orally twice daily Days 1-21 and 720 mg orally twice daily Days 22-28. Patients received intravenous atezolizumab 840 mg intravenous infusion over 60 minutes every weeks in combination with cobimetinib 60 mg orally once daily and vemurafenib 720 mg orally twice daily, or placebo in combination with cobimetinib 60 mg orally once daily and vemurafenib 960 mg orally twice daily. Treatment continued until disease progression or unacceptable toxicity. There was no crossover at the time of disease progression. Tumor assessments were performed every weeks (+- week) for the first 24 months and every 12 weeks (+- week) thereafter.The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes included PFS assessed by an independent central review, investigator-assessed ORR, OS, and DOR.The median age of the study population was 54 years (range: 22-88), 58% of patients were male, 95% were White, baseline ECOG performance status of (77%) or (23%), 33% had elevated LDH, 94% had metastatic disease, 60% were Stage IV (M1C), 56% had less than three metastatic sites at baseline, 3% had prior treatment for brain metastases, 30% had liver metastases at baseline, and 14% had received prior adjuvant systemic therapy. Based on central testing, 74% were identified as having V600E mutation, 11% as having V600K mutation, and 1% as having V600D or V600R mutations.Efficacy results are summarized in Table 30 and Figure 8. Patients had median survival follow up time of 18.9 months.Table 30:Efficacy Results from IMspire150Intravenous Atezolizumab Cobimetinib VemurafenibN 256Placebo Cobimetinib VemurafenibN 258Progression-Free SurvivalAs determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI confidence interval Number of events (%)148 (58)179 (69) Median, months15.110.6 (95% CI)(11.4, 18.4)(9.3, 12.7) Hazard ratioStratified by baseline LDH (95% CI)0.78 (0.63, 0.97) p-valueBased on the stratified log-rank test 0.0249Overall Response Rate Confirmed responses Number of responders (%)170 (66)168 (65) (95% CI)(60, 72)(59, 71) Complete responses, (%)41 (16)46 (18) Partial response, (%)129 (50)122 (47)Duration of Response n 170n 168 Median, months20.412.5 (95% CI)(15.1, NE)(10.7, 16.6)Figure 8:Kaplan-Meier Plot for Progression-Free Survival in IMspire150At pre-specified analysis at the time of the primary analysis of PFS, the OS data were not mature. The median OS was 28.8 months with 93 (36%) deaths in the intravenous atezolizumab plus cobimetinib and vemurafenib arm, and 25.1 months with 112 (43%) deaths in the placebo plus cobimetinib and vemurafenib arm. The hazard ratio for OS was 0.85 (95% CI: 0.64, 1.11) and the p-value was 0.2310.. Figure 8. 14.5Alveolar Soft Part Sarcoma. The efficacy of TECENTRIQ HYBREZA as monotherapy for the treatment of adult patients with unresectable or metastatic alveolar soft part sarcoma (ASPS) has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS. TECENTRIQ HYBREZA is not indicated for the treatment of pediatric patients. Below is description of the efficacy results of intravenous atezolizumab in this adequate and well-controlled ASPS trial.The efficacy of intravenous atezolizumab was evaluated in study ML39345 (NCT03141684), an open-label, single-arm study, in 49 adult and pediatric patients aged years and older with unresectable or metastatic ASPS. Although this study enrolled pediatric patients, TECENTRIC HYBREZA is not indicated for use in pediatric patients. Eligible patients were required to have histologically or cytologically confirmed ASPS that was not curable by surgery, and an ECOG performance status of <= 2.Patients were excluded if they had known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, known clinically significant liver disease, or history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.Adult patients received 1200 mg intravenously and pediatric patients received 15 mg/kg (up to maximum of 1200 mg) intravenously once every 21 days until disease progression or unacceptable toxicity.The major efficacy outcomes were Overall Response Rate (ORR) and Duration of Response (DOR) by Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.A total of 49 patients were enrolled. The median age of patients was 31 years (range: 12-70); 2% of adult patients (n 47) were >= 65 years of age and the pediatric patients (n 2) were >= 12 years of age; 51% of patients were female, 55% White, 29% Black or African American, 10% Asian; 53% had an ECOG performance status of and 45% had an ECOG performance status of 1. All patients had prior surgery for ASPS and 55% received at least one prior line of treatment for ASPS; 55% received radiotherapy and 53% received chemotherapy. Of the patients who reported staging at initial diagnosis, all were Stage IV.Efficacy results of this study are summarized in Table 31.Table 31:Efficacy Results from Study ML39345EndpointAll Patients(N=49)CI: confidence interval; N: number of patients; +: CensoredOverall Response Rate (95% CI)95% CI based on Clopper-Pearson exact method. 24% (13, 39) Complete responses, n0 Partial responses, (%)12 (24)Duration of Response Median, monthNE (95% CI)(17.0, NE) Range1+, 41+ Durability of response >= months, (%)8 (67%) >= 12 months, (%)5 (42%). 14.6Patient Experience. The IMscin002 study (NCT03735121) was randomized, multi-center, open-label cross-over trial conducted in 179 patients with either PD-L1-positive early-stage NSCLC receiving adjuvant treatment or were chemotherapy-naive with high PD-L1 stage IV NSCLC. Patients were randomized (1:1) to receive cycles of TECENTRIQ HYBREZA followed by cycles of intravenous atezolizumab (Arm A) or cycles of intravenous atezolizumab followed by cycles of TECENTRIQ HYBREZA (Arm B).Of the 126 eligible patients, 123 (98%) completed the patient preference questionnaire at the beginning of cycle or after at least two consecutive cycles of each treatment method was administered in case of treatment discontinuation prior to cycle 6. Eighty-seven of 123 patients (71%) reported preferring subcutaneous administration of TECENTRIQ HYBREZA over intravenous atezolizumab and the most common reason was that administration required less time in the clinic; 26 out of 123 patients (21%) reported preferring intravenous atezolizumab over TECENTRIQ HYBREZA and the most common reason was that it felt more comfortable during administration; and 10 out of 123 patients (8%) had no preference for the route of administration.Patients in both arms could continue to receive treatment after the crossover period for up to 16 cycles (patients with early-stage NSCLC) or until disease progression or unacceptable toxicity (patients with stage IV NSCLC). Of the 107 patients who reached the treatment continuation period, 85 (79%) patients (42 from IV/SC and 43 from SC/IV) chose to continue treatment with the SC route of administration.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions of TECENTRIQ HYBREZA in Adult Patients with NSCLCThe safety of TECENTRIQ HYBREZA was evaluated in IMscin001, open-label, multi-center, international, randomized trial for patients with locally advanced or metastatic NSCLC who have not been exposed to cancer immunotherapy and who have had disease progression on prior platinum-based therapy [see Clinical Studies (14.1)]. Patients with previously treated metastatic non-small cell lung cancer (NSCLC) either received TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously into the thigh over approximately minutes every weeks or intravenous atezolizumab every weeks until disease progression or unacceptable toxicity. Among 247 patients who received TECENTRIQ HYBREZA, 32% were exposed for months or longer and 8% were exposed for greater than one year.The median age was 64 years (range: 27 to 85); 69% male; 67% White, 22% Asian, 0.8% Black or African American; 74% were non-Hispanic or Latino; 26% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 74% had an ECOG PS of 1; and 70% of patients were current or previous smokers.Serious adverse reactions occurred in 19% of patients who received TECENTRIQ HYBREZA. Serious adverse reactions (> 1%) included pneumonia, myocardial infarction, and pleural effusion. Fatal adverse reactions occurred in 6% of patients who received TECENTRIQ HYBREZA, including pneumonia (2.4%), myocardial infarction (1.2%), head injury (0.4%), ischemic stroke (0.4%), pleural effusion (0.4%), pulmonary embolism (0.4%), respiratory tract infection (0.4%), sepsis (0.4%), and toxic epidermal necrolysis (0.4%).Permanent discontinuation of TECENTRIQ HYBREZA due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of TECENTRIQ HYBREZA in 1% of patients included pneumonia (2%).Dosage interruptions of TECENTRIQ HYBREZA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in 1% of patients were COVID-19 (4.9%), increased aspartate aminotransferase (2.8%), increased alanine aminotransferase (2.4%), pneumonia (2.4%), anemia (1.6%), dyspnea (1.6%), fatigue (1.2%), and viral respiratory tract infection (1.2%). The most common adverse reactions of any grade (occurring in >= 10% of patients) were fatigue (19%), musculoskeletal pain (15%), cough (13%), dyspnea (12%), and decreased appetite (11%).Tables and summarize adverse reactions and selected laboratory abnormalities, respectively in TECENTRIQ HYBREZA-treated patients in IMscin001.Table 3:Adverse Reactions (>= 10%) in Adult Patients with Locally Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001Adverse ReactionGraded per NCI CTCAE v5.0 TECENTRIQ HYBREZA = 247Intravenous Atezolizumab = 124All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)General Disorder and Administration Site ConditionsFatigueComposite term includes fatigue, asthenia 190.8180Musculoskeletal and Connective Tissue disordersMusculoskeletal PainComposite term includes back pain, myalgia, bone pain, musculoskeletal chest pain, neck pain, spinal pain, non-cardiac chest pain 150.4133.2Respiratory, Thoracic and MediastinalCoughComposite term includes cough, productive cough 13070DyspneaComposite term includes dyspnea, dyspnea at rest, dyspnea exertional 121.2151.6Metabolism and Nutrition DisordersDecreased appetite110110Clinically relevant adverse reactions in 10% of patients who received TECENTRIQ HYBREZA were local injection site reactions (4.5%) and pyrexia (1.2%).Table 4:Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Adult Patients with Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001Laboratory AbnormalityGraded per NCI CTCAE v5.0 TECENTRIQ HYBREZA (n 247)Intravenous Atezolizumab (n 124)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 HYBREZA (48-233) and intravenous atezolizumab (19-117)HematologyDecreased Hemoglobin 676635Decreased lymphocytes3794515ChemistryDecreased Sodium463.9475Decreased Albumin342.2270Increased Alkaline Phosphatase331.3270Increased AST282.6322.6Increased ALT282.6231.7Decreased calcium222.6230.9Increased calcium202.6241.7Increased potassium211.7221.7Increased INR202230Increased Creatinine191.7260.9. Adverse Reactions in Adult Patients with NSCLC Treated with Intravenous AtezolizumabThe safety of TECENTRIQ HYBREZA for its approved NSCLC indications [see Indications and Usage (1.1)] has been established in adequate and well-controlled studies of intravenous atezolizumab for the:adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells (IMpower010 study).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%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study).first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study).first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study).first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).Below is description of adverse reactions of intravenous atezolizumab in these adequate and well-controlled NSCLC studies.. adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells (IMpower010 study).. 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%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study).. first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study).. first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study).. first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).. Non-Small Cell Lung Cancer (NSCLC). Adjuvant Treatment of Early-stage NSCLC. IMpower010The safety of intravenous atezolizumab was evaluated in IMpower010, multicenter, open-label, randomized trial for the adjuvant treatment of patients with stage IB (tumors >= cm) -IIIA NSCLC who had complete tumor resection and received up to cycles of cisplatin-based adjuvant chemotherapy. Patients received intravenous atezolizumab 1200 mg every weeks (n 495) for year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.1)]. The median number of cycles received was 16 (range: 1, 16).Fatal adverse reactions occurred in 1.8% of patients receiving intravenous atezolizumab; these included multiple organ dysfunction syndrome, pneumothorax, interstitial lung disease, arrhythmia, acute cardiac failure, myocarditis, cerebrovascular accident, death of unknown cause, and acute myeloid leukemia (1 patient each).Serious adverse reactions occurred in 18% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%).Intravenous atezolizumab was discontinued due to adverse reactions in 18% of patients; the most common adverse reactions (>= 1%) leading to intravenous atezolizumab discontinuation were pneumonitis (2.2%), hypothyroidism (1.6%), increased aspartate aminotransferase (1.4%), arthralgia (1.0%), and increased alanine aminotransferase (1.0%).Adverse reactions leading to interruption of intravenous atezolizumab occurred in 29% of patients; the most common (> 1%) were rash (3.0%), hyperthyroidism (2.8%), hypothyroidism (1.6%), increased AST (1.6%), pyrexia (1.6%), increased ALT (1.4%), upper respiratory tract infection (1.4%), headache (1.2%), peripheral neuropathy (1.2%), and pneumonia (1.2%).Tables and summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower010.Table 5:Adverse Reactions Occurring in >= 10% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010Adverse ReactionGraded per NCI CTCAE v4.0 Intravenous Atezolizumab = 495Best Supportive CareN 495All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous TissueRashIncludes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform 171.21.40Pruritus1000.60Endocrine DisordersHypothyroidismIncludes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased 1400.60Respiratory, Thoracic and MediastinalCoughProductive cough, upper airway cough syndrome, cough 160110GeneralPyrexiaIncludes pyrexia, body temperature increased, hyperthermia 140.82.20.2FatigueIncludes fatigue, asthenia 140.650.2Nervous System DisordersPeripheral neuropathyIncludes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy 120.470.2Musculoskeletal and Connective TissueMusculoskeletal painIncludes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain 140.890.2ArthralgiaIncludes arthralgia, arthritis 110.660Table 6:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010Laboratory AbnormalityGraded 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 events (NCI CTCAE v5.0). Intravenous AtezolizumabThe denominators used to calculate the rate varied from 78-480 for BSC arm and 483 for intravenous atezolizumab are for all tests of interest based on the number of patients with baseline value and at least one post-treatment value. Best Supportive Care All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)ChemistryIncreased aspartate aminotransferase342.5180Increased alanine aminotransferase303.3190.4Hyperkalemia243.5152.5Increased blood creatinine310.2230.2. Metastatic Chemotherapy-Naive NSCLC. IMpower110The safety of intravenous atezolizumab was evaluated in IMpower110, multicenter, international, randomized, open-label study in 549 chemotherapy-naive patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received intravenous atezolizumab 1200 mg every 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 (14.1)]. 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 intravenous atezolizumab was 5.3 months (0 to 33 months).Fatal adverse reactions occurred in 3.8% of patients receiving intravenous atezolizumab; 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 infarction, and device occlusion (1 patient each).Serious adverse reactions occurred in 28% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%).Intravenous atezolizumab was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (>= patients) leading to intravenous atezolizumab discontinuation were peripheral neuropathy and pneumonitis.Adverse reactions leading to interruption of intravenous atezolizumab 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 and summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower110.Table 7:Adverse Reactions Occurring in >= 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower110Adverse ReactionIntravenous Atezolizumab = 286Platinum-Based ChemotherapyN 263All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GastrointestinalNausea140.3341.9Constipation121.0220.8Diarrhea110120.8GeneralFatigue/Asthenia251.4344.2Pyrexia14090.4Metabolism and NutritionDecreased appetite150.7190Respiratory, Thoracic and MediastinalDyspnea140.7100Cough120.3100Table 8:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving Intravenous Atezolizumab in IMpower110Laboratory AbnormalityIntravenous AtezolizumabPlatinum-Based ChemotherapyAll 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: intravenous atezolizumab (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.HematologyAnemia691.89420Lymphopenia4795917ChemistryHypoalbuminemia480.4392Increased alkaline phosphatase462.5421.2Hyponatremia449367Increased ALT383.2320.8Increased AST363.2320.8Hyperkalemia293.9362.7Hypocalcemia241.4242.7Increased blood creatinine240.7331.5Hypophosphatemia233.6212. First-Line Metastatic Non-squamous NSCLC. IMpower150The safety of intravenous atezolizumab with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, multicenter, international, randomized, open-label trial in which 393 chemotherapy-naive patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC mg/mL/min intravenously every weeks for maximum of or cycles, followed by intravenous atezolizumab 1200 mg with bevacizumab 15 mg/kg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. The median duration of exposure to intravenous atezolizumab was 8.3 months in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin.Fatal adverse reactions occurred in 6% of patients receiving intravenous atezolizumab; 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.Intravenous atezolizumab 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 intravenous atezolizumab 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 and 10 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin in IMpower150.Table 9:Adverse Reactions Occurring in >= 15% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150Adverse ReactionIntravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin = 393Bevacizumab, Paclitaxel and CarboplatinN 394All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0Nervous SystemNeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 563473Headache160.8130GeneralFatigue/Asthenia506466Pyrexia190.390.5Skin and Subcutaneous TissueAlopecia480460RashIncludes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform 232100.3Musculoskeletal and Connective TissueMyalgia/PainIncludes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain 423342Arthralgia261221Gastrointestinal Nausea394322DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 336250.5Constipation300.3230.3Vomiting192181Metabolism and NutritionDecreased appetite294210.8VascularHypertension259228RespiratoryCough200.8190.3Epistaxis171220.3RenalProteinuriaBased on adverse reaction terms since laboratory data for proteinuria was not systematically collected 163153Table 10:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150Laboratory AbnormalityIntravenous Atezolizumab with Bevacizumab, Paclitaxel, and CarboplatinBevacizumab, Paclitaxel and CarboplatinAll 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: Intravenous Atezolizumab with bevacizumab, paclitaxel, and carboplatin range: (337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0HematologyAnemia8310839Neutropenia52314526Lymphopenia48173813ChemistryHyperglycemia610600Increased BUN 52NANA Not applicable. NCI CTCAE does not provide Grades 3-4 definition for these laboratory abnormalities 44NA Hypomagnesemia422361Hypoalbuminemia403312Increased AST404280.8Hyponatremia3810369Increased Alkaline Phosphatase372321Increased ALT376280.5Increased TSH30NA 20NA Hyperkalemia283252Increased Creatinine281192Hypocalcemia263213Hypophosphatemia254184Hypokalemia237144Hyperphosphatemia25NA 19NA IMpower130The safety of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, multicenter, international, randomized, open-label trial in which 473 chemotherapy-naive patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg and carboplatin AUC mg/mL/min intravenously on Day and paclitaxel protein-bound 100 mg/m2 intravenously on Days 1, 8, and 15 of each 21-day cycle for maximum of or cycles, followed by intravenous atezolizumab 1200 mg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among patients receiving intravenous atezolizumab, 55% were exposed for months or longer and 3.5% were exposed for greater than one year.Fatal adverse reactions occurred in 5.3% of patients receiving intravenous atezolizumab; these included pneumonia (1.1%), pulmonary embolism (0.8%), myocardial infarction (0.6%), cardiac arrest (0.4%), 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 intravenous atezolizumab. The most frequent serious adverse reactions (>= 2%) were pneumonia (6%), diarrhea (3%), lung infection (3%), pulmonary embolism (3%), chronic obstructive pulmonary disease exacerbation (2.5%), dyspnea (2.3%), and febrile neutropenia (1.9%).Intravenous atezolizumab 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 intravenous atezolizumab 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 11 and 12 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with paclitaxel protein-bound and carboplatin in IMpower130.Table 11:Adverse Reactions Occurring in >= 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower130Adverse ReactionIntravenous Atezolizumab with Paclitaxel Protein-Bound and CarboplatinN 473Paclitaxel Protein-Bound and CarboplatinN 232All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GeneralFatigue/Asthenia6111608GastrointestinalNausea503.4462.2DiarrheaIncludes diarrhea, colitis, and gastroenteritis 436326Constipation361.1310Vomiting272.7192.2Musculoskeletal and Connective TissueMyalgia/PainIncludes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 383220.4Nervous SystemNeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 332.5282.2Respiratory, Thoracic and MediastinalDyspneaIncludes dyspnea, dyspnea exertional and wheezing 324.9251.3Cough270.6170Skin and Subcutaneous TissueAlopecia320270RashIncludes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular 200.6110.9Metabolism and NutritionDecreased appetite302.1262.2Table 12:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving Intravenous Atezolizumab in IMpower130Laboratory AbnormalityIntravenous Atezolizumab with Paclitaxel Protein-Bound and CarboplatinN 473Paclitaxel Protein-Bound and CarboplatinN 232All 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: intravenous atezolizumab with paclitaxel protein-bound and carboplatin (range: 423-467); paclitaxel protein-bound and carboplatin (range: 218-229). Graded per NCI CTCAE v4.0.HematologyAnemia92338725Neutropenia75506739Thrombocytopenia73195913Lymphopenia71236116ChemistryHyperglycemia758668Hypomagnesemia503.4423.2Hyponatremia379287Hypoalbuminemia351.3310Increased ALT312.8243.9Hypocalcemia312.6271.8Hypophosphatemia296203.2Increased AST282.2241.8Increased TSH26NANA Not applicable. NCI CTCAE does not provide Grades 3-4 definition for these laboratory abnormalities 5NA Hypokalemia266244.4Increased Alkaline Phosphatase252.6221.3Increased Blood Creatinine232.8160.4Hyperphosphatemia21NA 13NA Previously Treated Metastatic NSCLC. OAKThe safety of intravenous atezolizumab was evaluated in OAK, multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.1)]. total of 609 patients received intravenous atezolizumab 1200 mg intravenously every weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n 578) 75 mg/m2 intravenously every 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 intravenous atezolizumab-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.Intravenous atezolizumab was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to intravenous atezolizumab discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of intravenous atezolizumab occurred in 25% of patients; the most common (> 1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain.Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.Table 13:Adverse Reactions Occurring in >= 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAKAdverse ReactionIntravenous AtezolizumabN 609DocetaxelN 578All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GeneralFatigue/AstheniaIncludes fatigue and asthenia 444536Pyrexia18< 113< 1RespiratoryCoughIncludes cough and exertional cough 26< 121< 1Dyspnea222.8212.6Metabolism and Nutrition Decreased appetite23< 1241.6MusculoskeletalMyalgia/PainIncludes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia 201.320< 1Arthralgia120.5100.2GastrointestinalNausea18< 123< 1Constipation18< 114< 1Diarrhea16< 1242SkinRashIncludes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid 12< 1100Table 14:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAKLaboratory AbnormalityIntravenous AtezolizumabDocetaxelAll 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: intravenous atezolizumab (range: 546-585) and docetaxel (range: 532-560). Graded according to NCI CTCAE version 4.0HematologyAnemia673827Lymphocytopenia49146021ChemistryHypoalbuminemia484503Hyponatremia427316Increased Alkaline Phosphatase392251Increased AST313160.5Increased ALT273140.5Hypophosphatemia275234Hypomagnesemia261211Increased Creatinine232161. Adverse Reactions in Adult Patients with Small Cell Lung CancerThe safety of TECENTRIQ HYBREZA for its approved Small Cell Lung Cancer (SCLC) indication [see Indications and Usage (1.2)] has been established in adequate and well-controlled studies of intravenous atezolizumab for SCLC (IMpower133 study).. Small Cell Lung Cancer (SCLC). IMpower133The safety of intravenous atezolizumab with carboplatin and etoposide was evaluated in IMpower133, randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received intravenous atezolizumab 1200 mg and carboplatin AUC mg/mL/min on Day and etoposide 100 mg/m2 intravenously on Days 1, and of each 21-day cycle for maximum of cycles, followed by intravenous atezolizumab 1200 mg every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. Among 198 patients receiving intravenous atezolizumab, 32% were exposed for months or longer and 12% were exposed for 12 months or longer.Fatal adverse reactions occurred in 2% of patients receiving intravenous atezolizumab. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).Serious adverse reactions occurred in 37% of patients receiving intravenous atezolizumab. Serious adverse reactions in 2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%).Intravenous atezolizumab 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 intravenous atezolizumab 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 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with carboplatin and etoposide in IMpower133.Table 15:Adverse Reactions Occurring in >= 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133Adverse ReactionIntravenous Atezolizumab with Carboplatin and EtoposideN 198Placebo with Carboplatin and EtoposideN 196All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0GeneralFatigue/Asthenia395333GastrointestinalNausea381331Constipation261301Vomiting202173Skin and Subcutaneous TissueAlopecia370350Metabolism and NutritionDecreased appetite271180Table 16:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133Laboratory AbnormalityIntravenous Atezolizumab with Carboplatin and EtoposidePlacebo with Carboplatin and EtoposideAll 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: Intravenous Atezolizumab (range: 181-193); Placebo (range: 181-196). Graded per NCI CTCAE v4.0HematologyAnemia94179319Neutropenia73457648Thrombocytopenia58205317Lymphopenia46143811ChemistryHyperglycemia6710658Increased Alkaline Phosphatase381352Hyponatremia34153311Hypoalbuminemia321300Decreased TSHTSH thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories. 28NANA Not applicable 15NA Hypomagnesemia315356Hypocalcemia263285Increased ALT263311Increased AST221212Increased Blood Creatinine224151Hyperphosphatemia21NA 23NA Increased TSH 21NA 7NA Adverse Reactions in Adult Patients with Hepatocellular CarcinomaThe safety of TECENTRIQ HYBREZA for its approved indication hepatocellular carcinoma [see Indications and Usage (1.3)] has been established in adequate and well-controlled studies of intravenous atezolizumab for hepatocellular carcinoma (IMbrave150 study).. Hepatocellular Carcinoma. IMbrave150The safety of intravenous atezolizumab in combination with bevacizumab was evaluated in IMbrave150, multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.3)]. Patients received 1,200 mg of intravenous atezolizumab intravenously followed by 15 mg/kg bevacizumab (n 329) every weeks, or 400 mg of sorafenib (n 156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab occurred in 9% of patients in the intravenous atezolizumab and bevacizumab arm. The most common adverse reactions leading to intravenous atezolizumab 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 intravenous atezolizumab occurred in 41% of patients in the intravenous atezolizumab and bevacizumab arm; the most common (>= 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatase (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 intravenous atezolizumab and bevacizumab arm.Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab and bevacizumab in IMbrave150.Table 17:Adverse Reactions Occurring in >= 10% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150Adverse ReactionIntravenous Atezolizumab in combination with Bevacizumab(n 329)Sorafenib(n 156)All GradesGraded per NCI CTCAE v4.0 (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Vascular DisordersHypertension30152412General Disorders and Administration Site ConditionsFatigue/AstheniaIncludes fatigue and asthenia 262326Pyrexia180100Renal and Urinary DisordersProteinuria20370.6InvestigationsWeight Decreased110100Skin and Subcutaneous Tissue DisordersPruritus190100Rash120172.6Gastrointestinal DisordersDiarrhea191.8495Constipation130140Abdominal Pain120170Nausea120160Vomiting10080Metabolism and Nutrition DisordersDecreased Appetite181.2243.8Respiratory, Thoracic and Mediastinal DisordersCough120100Epistaxis1004.50Injury, Poisoning and Procedural ComplicationsInfusion-Related Reaction112.400Table 18:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150Laboratory AbnormalityIntravenous Atezolizumab in combination with Bevacizumab(n 329)Sorafenib(n 156)All GradesGraded per NCI CTCAE v4.0 (%)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: intravenous atezolizumab plus bevacizumab (222-323) and sorafenib (90-153)ChemistryIncreased AST86169016Increased Alkaline Phosphatase704764.6Increased ALT628704.6Decreased Albumin601.5540.7Decreased Sodium5413499Increased Glucose489434.6Decreased Calcium300.3351.3Decreased Phosphorus264.75816Increased Potassium231.9162Hypomagnesemia220220HematologyDecreased Platelet687634.6Decreased Lymphocytes62135811Decreased Hemoglobin583.1623.9Increased Bilirubin5785914Decreased Leukocyte323.4291.3Decreased Neutrophil232.3161.1. Adverse Reactions in Adult Patients with MelanomaThe safety of TECENTRIQ HYBREZA for its approved melanoma indication [see Indications and Usage (1.4)] has been established in adequate and well-controlled studies of intravenous atezolizumab for melanoma (IMspire150 study).. Metastatic Melanoma. IMspire150The safety of intravenous atezolizumab, administered with cobimetinib and vemurafenib, was evaluated in IMspire150, double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma [see Clinical Studies (14.4)]. Patients received intravenous atezolizumab with cobimetinib and vemurafenib (n 230) or placebo with cobimetinib and vemurafenib (n 281).Among the 230 patients who received intravenous atezolizumab administered with cobimetinib and vemurafenib, the median duration of exposure to intravenous atezolizumab was 9.2 months (range: 0-30 months), to cobimetinib was 10.0 months (range: 1-31 months) and to vemurafenib was 9.8 months (range: 1-31 months).Fatal adverse reactions occurred in 3% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. Adverse reactions leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest.Serious adverse reactions occurred in 45% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) serious adverse reactions were hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%).Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 21% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to intravenous atezolizumab discontinuation were increased ALT (2.2%) and pneumonitis (2.6%).Adverse reactions leading to interruption of intravenous atezolizumab occurred in 68% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to intravenous atezolizumab interruption were pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased AST (10%), increased lipase (9%), increased amylase (7%), pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%), rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%), peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and respiratory tract infection (2.2%).Tables 19 and 20 summarize the incidence of adverse reactions and laboratory abnormalities in IMspire150.Table 19:Adverse Reactions Occurring in >= 10% of Patients on the Intravenous Atezolizumab plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at Higher Incidence (Between Arm Difference of >= 5% All Grades or >= 2% Grades 3-4 Intravenous Atezolizumab in IMspire150)Adverse ReactionIntravenous Atezolizumab in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib(n=281)All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Skin and Subcutaneous Tissue DisordersRashIncludes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysaesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalised and rash morbilliform 75277223Pruritus26< 117< 1Photosensitivity reaction21< 1253.2General Disorders and Administration Site ConditionsFatigueIncludes fatigue, asthenia and malaise 513451.8PyrexiaIncludes pyrexia and hyperpyrexia 491.7352.1EdemaIncludes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema 26< 1210Gastrointestinal Disorders HepatotoxicityIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasaemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinaemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal 50213613Nausea30< 1322.5StomatitisIncludes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 231.315< 1Musculoskeletal and Connective Tissue DisordersMusculoskeletal painIncludes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain 624.3483.2Endocrine DisordersHypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased 220100Hyperthyroidism18< 180Injury, Poisoning and Procedural ComplicationsInfusion-related reactionIncludes infusion related reaction and hypersensitivity 102.68< 1Respiratory, Thoracic and Mediastinal DisordersPneumonitisIncludes pneumonitis and interstitial lung disease 121.36< 1Vascular DisordersHypertensionIncludes hypertension, blood pressure increased, hypertensive crisis 1710187Clinically important adverse reactions in 10% of patients who received intravenous atezolizumab plus cobimetinib and vemurafenib were:Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolongedEye Disorders: UveitisGastrointestinal disorders: PancreatitisInfections and infestations: Pneumonia, urinary tract infectionMetabolism and nutrition disorders: HyperglycemiaNervous system Disorders: Dizziness, dysgeusia, syncopeRespiratory, thoracic and mediastinal disorders: Dyspnea, oropharyngeal painSkin and Subcutaneous Tissue Disorders: VitiligoTable 20:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving Intravenous Atezolizumab Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at Higher Incidence (Between Arm Difference of >= 5% All Grades or >= 2% Grades 3-4) in IMspire150Laboratory AbnormalityIntravenous Atezolizumab in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib(n=281)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Graded per NCI CTCAE v4.0.Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230).HematologyDecreased Lymphocytes80247217Decreased Hemoglobin772.6722.2Decreased Platelet341.3240.4Decreased Neutrophils262.2191.5ChemistryIncreased Creatine Kinase88228118Increased AST8013686Increased ALT79186212Increased Triacylglycerol Lipase75466235Increased Alkaline Phosphatase736632.9Decreased Phosphorus67226414Increased Amylase51134513Increased Blood Urea Nitrogen47NANA Not applicable. NCI CTCAE v4.0 does not include these laboratories 37NA Decreased Albumin430.9341.5Increased Bilirubin423.1330.7Decreased Calcium411.3280Decreased Sodium405347Decreased Thyroid-Stimulating Hormone38NA 23NA Increased Thyroid-Stimulating HormoneIncreased Thyroid Stimulating Hormone has difference 5% (All Grades) between arms and is included for clinical completeness 37NA 33NA Decreased Potassium365224.3Increased Triiodothyronine33NA 18NA Increased Free Thyroxine32NA 21NA Decreased Total Triiodothyronine32NA 8NA Increased Potassium291.3191.4Decreased Triiodothyronine27NA 21NA Increased Sodium200130.4. Adverse Reactions in Adults with Alveolar Soft Part SarcomaThe safety of TECENTRIQ HYBREZA for its approved alveolar soft part sarcoma (ASPS) indication [see Indications and Usage (1.5)] has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS (ML39345 study).. Alveolar Soft Part Sarcoma. ML39345 StudyThe safety of intravenous atezolizumab was evaluated in 47 adult and pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5)]. Adult patients received intravenous atezolizumab 1200 mg every weeks and pediatric patients received 15 mg/kg up to maximum 1200 mg every weeks until disease progression or unacceptable toxicity. The median duration of exposure to intravenous atezolizumab was 8.9 months (1 to 40 months).Serious adverse reactions occurred in 41% of patients receiving intravenous atezolizumab. The most frequent serious adverse reactions (> 2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each).Dosage interruptions of intravenous atezolizumab due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (>= 3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each).Tables 21 and 22 summarize adverse reactions and laboratory abnormalities in Study ML39345.Table 21:Adverse Reactions Occurring in >= 15% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345Adverse ReactionIntravenous AtezolizumabN 49All Grades (%)Grades 3-4 (%)Graded per NCI CTCAE v4.0General disorders and administration site conditionsFatigue552Pyrexia252Influenza like illness180Gastrointestinal disordersNausea430Vomiting370Constipation330Diarrhea272Abdominal painIncludes abdominal pain and abdominal pain upper 250Metabolism and nutrition disordersDecreased appetite222Respiratory, Thoracic and MediastinalCoughIncludes cough, upper-airway cough syndrome, and productive cough 450Dyspnea330Rhinitis allergic160Musculoskeletal and connective tissue disordersMusculoskeletal painIncludes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain 678Skin and subcutaneous tissue disordersRashIncludes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption 472Nervous system disordersHeadache434DizzinessIncludes vertigo and dizziness 294Vascular disordersHypertension436HemorrhageIncludes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage 292Psychiatric disordersInsomnia270Anxiety250Cardiac DisordersArrhythmiaIncludes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia 222Endocrine disordersHypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased 250InvestigationsWeight decreased180Weight increased166Table 22:Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345Laboratory AbnormalityLaboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges Intravenous AtezolizumabThe denominators used to calculate the rate varied from 4-49 for all tests of interest based on the number of patients with baseline value and at least one on-study laboratory measurement available All Grades (%)Grades 3-4 (%)HematologyDecreased Hemoglobin 630Decreased Platelets270Increased Platelets290ChemistryIncreased Alkaline Phosphatase290Decreased Amylase400Increased Amylase2020Decreased Bilirubin490Decreased Calcium470Increased Calcium2514Decreased Glucose 330Increased Glucose780Decreased Glucose (fasting)250Decreased Magnesium210Increased Magnesium2626Increased AST392Increased ALT332Decreased Sodium430Increased Lipase2525.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential. Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating TECENTRIQ HYBREZA [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].. ContraceptionFemales: Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ HYBREZA and for months following the last dose.. InfertilityFemales: Based on animal studies, TECENTRIQ HYBREZA may impair fertility in females of reproductive potential while receiving TECENTRIQ HYBREZA treatment [see Nonclinical Toxicology (13.1)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal Toxicology and/or Pharmacology. In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, 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 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 lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately times the AUC in patients receiving the recommended intravenous atezolizumab dose and was reversible. There was no effect on the male monkey reproductive organs.Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when up to 220,000 units/kg of subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks, which is 223 times higher than the human recommended dose for hyaluronidase, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters (e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism 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 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.In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared to targeted therapy alone.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days.Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in TECENTRIQ HYBREZA acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.. 12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of atezolizumab and hyaluronidase have not been fully characterized.. 12.3 Pharmacokinetics. When comparing atezolizumab exposure following subcutaneous TECENTRIQ HYBREZA to that of intravenous atezolizumab in Study IMscin001 [see Clinical Studies (14.1)], the geometric mean ratio (GMR) (90% CI) for Cycle Ctrough was 1.05 (0.88, 1.24) and AUC0-21days was 0.87 (0.83, 0.92); the steady state Ctrough was 1.15 (1.05, 1.26) and AUC was 1.01 (0.94, 1.08). Steady-state was achieved to weeks. The systemic accumulation ratio following administration of the approved recommended dosage of TECENTRIQ HYBREZA was 2.2.. AbsorptionThe mean absolute bioavailability (CV%) of atezolizumab was 72% (83%) and the median time (range) to reach maximum atezolizumab concentration (Tmax) was 4.5 (2.2, 9) days.. DistributionThe volume of distribution of atezolizumab at steady state was 6.9 L.. EliminationThe atezolizumab clearance (CV%) was 0.2 L/day (29%) and the terminal half-life was 27 days. Atezolizumab clearance decreased over time, with mean maximal reduction (CV%) from baseline value of 17% (41%); this decrease in clearance is not considered clinically significant.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of atezolizumab were observed based on age, body weight, sex, albumin levels, tumor burden, region, race, mild or moderate renal impairment (estimated glomerular filtration rate 30 to 89 mL/minute/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 3x ULN and any AST), level of PD-L1 expression, and performance status.. 12.6Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of TECENTRIQ HYBREZA or of other atezolizumab products or hyaluronidase products.During the first year of treatment in the Study IMscin001 [see Clinical Studies (14.1)], the incidence of anti-atezolizumab antibodies was 20% (43/221) and the incidence of neutralizing antibodies (NAb) in ADA-positive patients was 54% (21/39) for TECENTRIQ HYBREZA. The corresponding incidence of ADA was 14% (15/108) and NAb was 60% (9/15) for intravenous atezolizumab.In Study IMscin001, atezolizumab clearance increased by 29% in patients who received TECENTRIQ HYBREZA and who tested positive for ADA, compared to patients who tested negative for ADA; this change in clearance is not expected to be clinically significant. Because of limited immunogenicity data the effect of anti-atezolizumab antibodies on the effectiveness of TECENTRIQ HYBREZA is unknown. There was no identified clinically significant effect of anti-atezolizumab antibodies on the safety of TECENTRIQ HYBREZA during the first months of treatment.In Study IMscin001, the incidence of anti-rHuPH20 antibodies was 5.4% (12/224) and the incidence of NAb was 0% (0/12). Because of the low occurrence of anti-rHuPH20 antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics and/or safety of hyaluronidase in TECENTRIQ HYBREZA is unknown.. Immunogenicity with Other Clinical Trials with Intravenous Atezolizumab:During the first year of treatment with intravenous atezolizumab across clinical studies of patients with NSCLC, SCLC, HCC, and melanoma 13% to 36% of patients developed anti-atezolizumab antibodies. Across clinical studies, the NAb incidence in ADA-positive patients was 24% to 83%.In OAK and IMbrave150, exploratory analyses showed that the subset of patients who were ADA-positive appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for ADA [see Clinical Studies (14.1, 14.3)]. In study IMpower150, the impact of ADA on efficacy did not appear to be clinically significant [see Clinical Studies (14.1)]. In the remaining studies, there is insufficient information to characterize the effect of ADA on efficacy.Median atezolizumab clearance in patients who tested positive for anti-atezolizumab antibodies (ADA) was 19% (range of 18% to 49%) higher as compared to atezolizumab clearance in patients who tested negative for ADA; this change in clearance is not expected to be clinically significant. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions. The effect of NAb on atezolizumab exposure and safety did not appear to be clinically significant. The effect of NAb on key efficacy endpoints is uncertain due to small sample sizes.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TECENTRIQ HYBREZA is contraindicated in patients with known hypersensitivity to hyaluronidase or to any of its excipients.. TECENTRIQ HYBREZA is contraindicated in patients with known hypersensitivity to hyaluronidase or any of its excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. TECENTRIQ HYBREZA is fixed-combination drug product containing atezolizumab and hyaluronidase (human recombinant).Atezolizumab is programmed cell death ligand (PD-L1) blocking antibody. Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin that has calculated molecular mass of 145 kDa.Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs administered subcutaneously. It is glycosylated single-chain protein produced by mammalian (Chinese Hamster Ovary) cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has molecular weight of approximately 61 kDa.TECENTRIQ HYBREZA (atezolizumab and hyaluronidase-tqjs) injection for subcutaneous use is sterile, preservative-free, clear and slightly opalescent, and colorless to slightly yellow solution in single-dose vials. Each 15 mL single-dose vial contains 1,875 mg of atezolizumab, 30,000 units of hyaluronidase, histidine (46.5 mg), methionine (22.4 mg), polysorbate 20 (9 mg), sucrose (1,232 mg), and water for injection, adjusted to pH 5.8 with acetic acid.. Atezolizumab is programmed cell death ligand (PD-L1) blocking antibody. Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin that has calculated molecular mass of 145 kDa.. Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs administered subcutaneously. It is glycosylated single-chain protein produced by mammalian (Chinese Hamster Ovary) cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has molecular weight of approximately 61 kDa.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products. (2.2)TECENTRIQ HYBREZA is not indicated for use in pediatric patients. (2.2)TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. (2.2)Do not administer TECENTRIQ HYBREZA intravenously. (2.2)Recommended dosage: TECENTRIQ HYBREZA 15 mL (1,875 mg atezolizumab and 30,000 units hyaluronidase) subcutaneously into the thigh over approximately minutes every weeks. (2.2)TECENTRIQ HYBREZA must be administered by healthcare professional. (2.2)NSCLC DosageIn the adjuvant setting, administer TECENTRIQ HYBREZA following resection and up to cycles of platinum-based chemotherapy every weeks for up to year. (2.2)In the metastatic setting, administer TECENTRIQ HYBREZA every weeks. (2.2)When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day. (2.2)SCLC DosageAdminister TECENTRIQ HYBREZA every weeks. When administering with carboplatin and etoposide, administer TECENTRIQ HYBREZA prior to chemotherapy when given on the same day. (2.2)HCC DosageAdminister TECENTRIQ HYBREZA every weeks.Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every weeks. (2.2)Melanoma DosageFollowing completion of 28-day cycle of cobimetinib and vemurafenib, administer TECENTRIQ HYBREZA every weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily. (2.2)ASPS DosageAdminister TECENTRIQ HYBREZA every weeks. (2.2). TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products. (2.2). TECENTRIQ HYBREZA is not indicated for use in pediatric patients. (2.2). TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. (2.2). Do not administer TECENTRIQ HYBREZA intravenously. (2.2). Recommended dosage: TECENTRIQ HYBREZA 15 mL (1,875 mg atezolizumab and 30,000 units hyaluronidase) subcutaneously into the thigh over approximately minutes every weeks. (2.2). TECENTRIQ HYBREZA must be administered by healthcare professional. (2.2). In the adjuvant setting, administer TECENTRIQ HYBREZA following resection and up to cycles of platinum-based chemotherapy every weeks for up to year. (2.2). In the metastatic setting, administer TECENTRIQ HYBREZA every weeks. (2.2). When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day. (2.2). Administer TECENTRIQ HYBREZA every weeks.. Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every weeks. (2.2). Following completion of 28-day cycle of cobimetinib and vemurafenib, administer TECENTRIQ HYBREZA every weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily. (2.2). Administer TECENTRIQ HYBREZA every weeks. (2.2). 2.1 Patient Selection for Treatment of Non-Small Cell Lung Cancer and Melanoma. Select adult patients with:Stage II to IIIA NSCLC for adjuvant treatment with TECENTRIQ HYBREZA as monotherapy (following tumor resection and platinum-based chemotherapy) based on PD-L1 expression on tumor cells [see Clinical Studies (14.2)]. Metastatic NSCLC for first-line treatment with TECENTRIQ HYBREZA as monotherapy based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells [see Clinical Studies (14.2)]. Unresectable or metastatic melanoma for treatment with TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib after confirming the presence of BRAF V600 mutation [see Clinical Studies (14.5)]. Information on FDA-approved tests for the determination of PD-L1 expression in metastatic NSCLC or for detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.. Stage II to IIIA NSCLC for adjuvant treatment with TECENTRIQ HYBREZA as monotherapy (following tumor resection and platinum-based chemotherapy) based on PD-L1 expression on tumor cells [see Clinical Studies (14.2)]. Metastatic NSCLC for first-line treatment with TECENTRIQ HYBREZA as monotherapy based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells [see Clinical Studies (14.2)]. Unresectable or metastatic melanoma for treatment with TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib after confirming the presence of BRAF V600 mutation [see Clinical Studies (14.5)]. 2.2Important Dosage and Administration Information. TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products.To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared is subcutaneously administered TECENTRIQ HYBREZA and not intravenously administered atezolizumab.Do not substitute TECENTRIQ HYBREZA for or with intravenous atezolizumab products because they have different recommended dosages.Adult patients who are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose.Adult patients who are treated with TECENTRIQ HYBREZA can switch to intravenous atezolizumab at their next scheduled dose. TECENTRIQ HYBREZA is not indicated for use in pediatric patients.TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. Administer over approximately minutes. Inject in healthy skin and never into areas where the skin is red, bruised, tender, or hard.When possible, alternate injections between the left and right thigh. Ensure the injection site is at least 2.5 cm from the previous site.Do not administer TECENTRIQ HYBREZA intravenously.TECENTRIQ HYBREZA must be administered by healthcare professional.Do not administer the remaining volume in the tubing to the patient.If using concomitant subcutaneous drugs, administer at sites other than the thighs.. TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products.To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared is subcutaneously administered TECENTRIQ HYBREZA and not intravenously administered atezolizumab.Do not substitute TECENTRIQ HYBREZA for or with intravenous atezolizumab products because they have different recommended dosages.Adult patients who are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose.Adult patients who are treated with TECENTRIQ HYBREZA can switch to intravenous atezolizumab at their next scheduled dose. To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared is subcutaneously administered TECENTRIQ HYBREZA and not intravenously administered atezolizumab.. Do not substitute TECENTRIQ HYBREZA for or with intravenous atezolizumab products because they have different recommended dosages.. Adult patients who are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose.. Adult patients who are treated with TECENTRIQ HYBREZA can switch to intravenous atezolizumab at their next scheduled dose.. TECENTRIQ HYBREZA is not indicated for use in pediatric patients.. TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. Administer over approximately minutes. Inject in healthy skin and never into areas where the skin is red, bruised, tender, or hard.. When possible, alternate injections between the left and right thigh. Ensure the injection site is at least 2.5 cm from the previous site.. Do not administer TECENTRIQ HYBREZA intravenously.. TECENTRIQ HYBREZA must be administered by healthcare professional.. Do not administer the remaining volume in the tubing to the patient.. If using concomitant subcutaneous drugs, administer at sites other than the thighs.. 2.3Recommended Dosage and Administration Instructions. The recommended dosage of TECENTRIQ HYBREZA is one 15 mL injection (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase, referred to as TECENTRIQ HYBREZA) administered subcutaneously in the thigh over approximately minutes every weeks.Administration instructions for TECENTRIQ HYBREZA as monotherapy and in combination with other therapeutic agents are presented in Table 1. For the recommended dosage of each therapeutic agent administered in combination with TECENTRIQ HYBREZA refer to the products respective Prescribing Information.Table 1:TECENTRIQ HYBREZA Administration Instructions and Duration of TherapyIndicationAdministration Instructions for TECENTRIQ HYBREZADuration of TherapyAdjuvant Treatment of Non-Small Cell Lung CancerAdminister TECENTRIQ HYBREZA as monotherapyUp to one year, unless there is disease recurrence or unacceptable toxicityMetastatic Non-Small Cell Lung CancerUntil disease progression or unacceptable toxicityNon-Small Cell Lung CancerAdminister TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day.Until disease progression or unacceptable toxicitySmall Cell Lung CancerAdminister TECENTRIQ HYBREZA prior to chemotherapy when given on the same day.Hepatocellular CarcinomaAdminister TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every weeks.MelanomaPrior to initiating TECENTRIQ HYBREZA, patients should receive the following 28-day treatment cycle of cobimetinib and vemurafenib:Days to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice dailyDays 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily Alveolar Soft Part SarcomaAdminister TECENTRIQ HYBREZA as monotherapyUntil disease progression or unacceptable toxicity. Days to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice daily. Days 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily. 2.4Dosage Modifications for Adverse Reactions. No dose reduction for TECENTRIQ HYBREZA is recommended. In general, withhold TECENTRIQ HYBREZA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue TECENTRIQ HYBREZA for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the daily corticosteroid dosage to 10 mg or less of prednisone or equivalent corticosteroid dosage within 12 weeks of initiating corticosteroids.Dosage modifications for TECENTRIQ HYBREZA for adverse reactions that require management different from these general guidelines are summarized in Table 2.Table 2:Recommended Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityBased on Common Terminology Criteria for Adverse Events (CTCAE), version Dosage ModificationALT alanine aminotransferase, AST aspartate aminotransferase, ULN upper limit normal, DRESS Drug Rash with Eosinophilia and Systemic Symptoms, SJS Stevens Johnson syndrome, TEN toxic epidermal necrolysisImmune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]PneumonitisGrade 2WithholdResume in patients with complete or partial resolution (Grade to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids Grades or 4Permanently discontinue ColitisGrades or 3Withhold Grade 4Permanently discontinueHepatitis with no tumor involvement of the liverAST or ALT increases to more than and up to times ULN or Total bilirubin increases to more than 1.5 and up to times ULN Withhold AST or ALT increases to more than times ULN or Total bilirubin increases to more than times ULN Permanently discontinueHepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ HYBREZA based on recommendations for hepatitis with no liver involvement Baseline AST or ALT is more than and up to times ULN and increases to more than and up to 10 times ULN or Baseline AST or ALT is more than and up to times ULN and increases to more than and up to 10 times ULNWithhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than times ULNPermanently discontinueEndocrinopathiesGrades or 4Withhold until clinically stable or permanently discontinue depending on severityNephritis with Renal DysfunctionGrades or increased blood creatinineWithhold Grade increased blood creatininePermanently discontinueExfoliative Dermatologic ConditionsSuspected SJS, TEN, or DRESSWithholdConfirmed SJS, TEN, or DRESSPermanently discontinueMyocarditis or pericarditisGrades 2, 3, or 4Permanently discontinueNeurological ToxicitiesGrade 2Withhold Grades or 4Permanently discontinueOther Adverse ReactionsInfusion-Related Reactions [see Warnings and Precautions (5.2)] Grades or 2Pause or slow the rate of injection Premedication with antipyretic and antihistamines may be considered for subsequent doses.Grades or 4Permanently discontinue. 2.5Preparation Instructions. TECENTRIQ HYBREZA does not contain any antimicrobial preservative. If the TECENTRIQ HYBREZA dose is not administered immediately, refer to Storage Instructions [see Dosage and Administration (2.6)]. Remove the vial from the refrigerator and allow the solution to acclimate to room temperature. Visually inspect for particulate matter and discoloration prior to administration. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.Do not shake, freeze, or dilute.The unpunctured vial may be stored at room temperature in ambient light for maximum of hours prior to the preparation for administration.Use an 18-gauge transfer needle and syringe to withdraw the entire contents of the TECENTRIQ HYBREZA solution from the vial. Discard the vial and any residual drug remaining.TECENTRIQ HYBREZA is compatible with stainless steel transfer and injection needles, and polypropylene, polycarbonate, polyvinyl chloride, and polyurethane syringe material and subcutaneous administration sets.Remove the transfer needle from the syringe and replace it with subcutaneous administration set (e.g. winged/butterfly) containing 23-gauge, 24-gauge, or 25-gauge hypodermic needle and with priming volume that does not exceed 0.5 mL for administration.Prime the subcutaneous administration line with TECENTRIQ HYBREZA to eliminate the air in the line and stop when the fluid reaches the needle.Ensure the syringe contains exactly 15 mL of TECENTRIQ HYBREZA after priming the administration line by expelling any excess volume from the syringe.Administer immediately to avoid needle clogging.Discard any unused portion remaining.. Remove the vial from the refrigerator and allow the solution to acclimate to room temperature. Visually inspect for particulate matter and discoloration prior to administration. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.. Do not shake, freeze, or dilute.. The unpunctured vial may be stored at room temperature in ambient light for maximum of hours prior to the preparation for administration.. Use an 18-gauge transfer needle and syringe to withdraw the entire contents of the TECENTRIQ HYBREZA solution from the vial. Discard the vial and any residual drug remaining.. TECENTRIQ HYBREZA is compatible with stainless steel transfer and injection needles, and polypropylene, polycarbonate, polyvinyl chloride, and polyurethane syringe material and subcutaneous administration sets.. Remove the transfer needle from the syringe and replace it with subcutaneous administration set (e.g. winged/butterfly) containing 23-gauge, 24-gauge, or 25-gauge hypodermic needle and with priming volume that does not exceed 0.5 mL for administration.. Prime the subcutaneous administration line with TECENTRIQ HYBREZA to eliminate the air in the line and stop when the fluid reaches the needle.. Ensure the syringe contains exactly 15 mL of TECENTRIQ HYBREZA after priming the administration line by expelling any excess volume from the syringe.. Administer immediately to avoid needle clogging.. Discard any unused portion remaining.. 2.6Storage Instructions. Do not store the prepared syringe that has been attached to the already-primed subcutaneous administration set.If the prepared syringe containing TECENTRIQ HYBREZA is not for immediate use, do not attach subcutaneous administration set. The capped syringe may be stored at room temperature [at up to 25C (77F)] in ambient room lighting for up to hours and in the refrigerator [2C to 8C (36F to 46F)] for up to 72 hours. Do not shake or freeze.If the prepared syringe is stored at 2C to 8C (36F to 46F), allow the syringe to acclimate to room temperature prior to administration.. Do not store the prepared syringe that has been attached to the already-primed subcutaneous administration set.. If the prepared syringe containing TECENTRIQ HYBREZA is not for immediate use, do not attach subcutaneous administration set. The capped syringe may be stored at room temperature [at up to 25C (77F)] in ambient room lighting for up to hours and in the refrigerator [2C to 8C (36F to 46F)] for up to 72 hours. Do not shake or freeze.. If the prepared syringe is stored at 2C to 8C (36F to 46F), allow the syringe to acclimate to room temperature prior to administration.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 1,875 mg atezolizumab and 30,000 units hyaluronidase per 15 mL (125 mg and 2,000 units per mL) clear to slightly opalescent, and colorless to slightly yellow solution in single-dose vial.. Injection: 1,875 mg atezolizumab and 30,000 units hyaluronidase per 15 mL (125 mg/2,000 units per mL) solution in single-dose vial. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of 247 adult patients treated with TECENTRIQ HYBREZA as monotherapy in IMscin001, 45% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness of TECENTRIQ HYBREZA have been observed between patients aged 65 years or older and younger adult patients.The safety of TECENTRIQ HYBREZA as monotherapy or in combination with other antineoplastic drugs for its approved indications [see Indications and Usage (1.1, 1.2, 1.3, 1.4, 1.5)] has been established in adequate and well-controlled studies of intravenous atezolizumab as single agent and in combination with other antineoplastic drugs. Below is description of geriatric use information from the intravenous atezolizumab studies.Of 2,616 adult patients with metastatic NSCLC and other tumor types treated with monotherapy intravenous atezolizumab in clinical studies, 49% were 65 years and over and 15% were 75 years and over.Of 2,421 adult patients with NSCLC and EC-SCLC treated with intravenous atezolizumab in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over.No overall differences in safety or effectiveness were observed between intravenous atezolizumab-treated patients aged 65 years or older and younger adult patients.. Of 2,616 adult patients with metastatic NSCLC and other tumor types treated with monotherapy intravenous atezolizumab in clinical studies, 49% were 65 years and over and 15% were 75 years and over.. Of 2,421 adult patients with NSCLC and EC-SCLC treated with intravenous atezolizumab in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. TECENTRIQ HYBREZA (atezolizumab and hyaluronidase-tqjs) injection for subcutaneous use is sterile, preservative-free, clear to slightly opalescent, and colorless to slightly yellow solution. It is supplied in carton containing:1,875 mg and 30,000 units/15 mL (125 mg and 2,000 units/mL) in single-dose vial (NDC 50242-933-01).. Store vials under refrigeration at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not freeze. Do not shake.

IMMUNOGENICITY.

12.6Immunogenicity. The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of TECENTRIQ HYBREZA or of other atezolizumab products or hyaluronidase products.During the first year of treatment in the Study IMscin001 [see Clinical Studies (14.1)], the incidence of anti-atezolizumab antibodies was 20% (43/221) and the incidence of neutralizing antibodies (NAb) in ADA-positive patients was 54% (21/39) for TECENTRIQ HYBREZA. The corresponding incidence of ADA was 14% (15/108) and NAb was 60% (9/15) for intravenous atezolizumab.In Study IMscin001, atezolizumab clearance increased by 29% in patients who received TECENTRIQ HYBREZA and who tested positive for ADA, compared to patients who tested negative for ADA; this change in clearance is not expected to be clinically significant. Because of limited immunogenicity data the effect of anti-atezolizumab antibodies on the effectiveness of TECENTRIQ HYBREZA is unknown. There was no identified clinically significant effect of anti-atezolizumab antibodies on the safety of TECENTRIQ HYBREZA during the first months of treatment.In Study IMscin001, the incidence of anti-rHuPH20 antibodies was 5.4% (12/224) and the incidence of NAb was 0% (0/12). Because of the low occurrence of anti-rHuPH20 antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics and/or safety of hyaluronidase in TECENTRIQ HYBREZA is unknown.. Immunogenicity with Other Clinical Trials with Intravenous Atezolizumab:During the first year of treatment with intravenous atezolizumab across clinical studies of patients with NSCLC, SCLC, HCC, and melanoma 13% to 36% of patients developed anti-atezolizumab antibodies. Across clinical studies, the NAb incidence in ADA-positive patients was 24% to 83%.In OAK and IMbrave150, exploratory analyses showed that the subset of patients who were ADA-positive appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for ADA [see Clinical Studies (14.1, 14.3)]. In study IMpower150, the impact of ADA on efficacy did not appear to be clinically significant [see Clinical Studies (14.1)]. In the remaining studies, there is insufficient information to characterize the effect of ADA on efficacy.Median atezolizumab clearance in patients who tested positive for anti-atezolizumab antibodies (ADA) was 19% (range of 18% to 49%) higher as compared to atezolizumab clearance in patients who tested negative for ADA; this change in clearance is not expected to be clinically significant. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions. The effect of NAb on atezolizumab exposure and safety did not appear to be clinically significant. The effect of NAb on key efficacy endpoints is uncertain due to small sample sizes.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TECENTRIQ HYBREZA is combination of atezolizumab, programmed death-ligand (PD-L1) blocking antibody, and hyaluronidase, an endoglycosidase indicated:Non-Small Cell Lung Cancer (NSCLC)as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells, as determined by an FDA-approved test. (1.1)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. (1.1)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. (1.1)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. (1.1)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 HYBREZA. (1.1)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). (1.2)Hepatocellular Carcinoma (HCC)in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic HCC who have not received prior systemic therapy. (1.3)Melanomain combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test. (1.4)Alveolar Soft Part Sarcoma (ASPS)for the treatment of adult patients with unresectable or metastatic ASPS. (1.5). as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on >= 1% of tumor cells, as determined by an FDA-approved test. (1.1). 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. (1.1). 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. (1.1). 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. (1.1). 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 HYBREZA. (1.1). in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.2). in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic HCC who have not received prior systemic therapy. (1.3). in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test. (1.4). for the treatment of adult patients with unresectable or metastatic ASPS. (1.5). 1.1Non-Small Cell Lung Cancer. TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1)] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on >= 1% of tumor cells, as determined by an FDA-approved test [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, as monotherapy, 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 [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, 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 HYBREZA, 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 HYBREZA, as monotherapy, 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 HYBREZA.. TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1)] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on >= 1% of tumor cells, as determined by an FDA-approved test [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, as monotherapy, 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 [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, 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 HYBREZA, 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 HYBREZA, as monotherapy, 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 HYBREZA.. 1.2Small Cell Lung Cancer. TECENTRIQ HYBREZA, 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).. 1.3Hepatocellular Carcinoma. TECENTRIQ HYBREZA, in combination with bevacizumab, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.. 1.4Melanoma. TECENTRIQ HYBREZA, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test [see Dosage and Administration (2.1)].. 1.5Alveolar Soft Part Sarcoma. TECENTRIQ HYBREZA, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic alveolar soft part sarcoma (ASPS).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Immune-Mediated Adverse ReactionsInform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ HYBREZA, 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)].Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [see Warnings and Precautions (5.1)].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 (5.1)].Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].Nephritis: Advise patients to contact their healthcare provider immediately for pelvic pain, frequent urination, or unusual swelling [see Warnings and Precautions (5.1)].Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately for generalized rash, skin eruption, or painful skin and mucous membrane lesions [see Warnings and Precautions (5.1)].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 (5.1)].. 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)].. Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [see Warnings and Precautions (5.1)].. 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 (5.1)].. Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].. Nephritis: Advise patients to contact their healthcare provider immediately for pelvic pain, frequent urination, or unusual swelling [see Warnings and Precautions (5.1)].. Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately for generalized rash, skin eruption, or painful skin and mucous membrane lesions [see Warnings and Precautions (5.1)].. 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 (5.1)].. Infusion-Related ReactionsAdvise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].. Complications of Allogeneic HSCT after PD-1/PD-L1 InhibitorsFollow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT [see Warnings and Precautions (5.3)].. Embryo-Fetal ToxicityAdvise females of reproductive potential that TECENTRIQ HYBREZA can cause harm to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].Advise females of reproductive potential to use effective contraception during treatment and for months after the last dose of TECENTRIQ HYBREZA [see Use in Specific Populations (8.3)].. LactationAdvise female patients not to breastfeed while taking TECENTRIQ HYBREZA and for months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of atezolizumab or hyaluronidase in human milk or its effects on the breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to TECENTRIQ HYBREZA are unknown. Because of the potential for serious adverse reactions in breastfed children from TECENTRIQ HYBREZA, advise women not to breastfeed during treatment with TECENTRIQ HYBREZA and for months after the last dose.

MECHANISM OF ACTION SECTION.

12.1Mechanism 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 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.In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared to targeted therapy alone.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days.Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in TECENTRIQ HYBREZA acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, 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 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 lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately times the AUC in patients receiving the recommended intravenous atezolizumab dose and was reversible. There was no effect on the male monkey reproductive organs.Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when up to 220,000 units/kg of subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks, which is 223 times higher than the human recommended dose for hyaluronidase, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters (e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data).. 13.2Animal Toxicology and/or Pharmacology. In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 15 mL Vial Box. NDC 50242-933-01Tecentriq Hybreza(TM) (atezolizumab and hyaluronidase-tqjs) Injection1,875 mg and 30,000 units/15 mL (125 mg and 2,000 units/mL)For subcutaneous use onlySingle-Dose Vial Discard Unused PortionAttention Pharmacist: Dispense the accompanying Medication Guide to each patient.1 vialRx only Genentech11001667. PRINCIPAL DISPLAY PANEL 15 mL Vial Box.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of TECENTRIQ HYBREZA have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of atezolizumab and hyaluronidase have not been fully characterized.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. When comparing atezolizumab exposure following subcutaneous TECENTRIQ HYBREZA to that of intravenous atezolizumab in Study IMscin001 [see Clinical Studies (14.1)], the geometric mean ratio (GMR) (90% CI) for Cycle Ctrough was 1.05 (0.88, 1.24) and AUC0-21days was 0.87 (0.83, 0.92); the steady state Ctrough was 1.15 (1.05, 1.26) and AUC was 1.01 (0.94, 1.08). Steady-state was achieved to weeks. The systemic accumulation ratio following administration of the approved recommended dosage of TECENTRIQ HYBREZA was 2.2.. AbsorptionThe mean absolute bioavailability (CV%) of atezolizumab was 72% (83%) and the median time (range) to reach maximum atezolizumab concentration (Tmax) was 4.5 (2.2, 9) days.. DistributionThe volume of distribution of atezolizumab at steady state was 6.9 L.. EliminationThe atezolizumab clearance (CV%) was 0.2 L/day (29%) and the terminal half-life was 27 days. Atezolizumab clearance decreased over time, with mean maximal reduction (CV%) from baseline value of 17% (41%); this decrease in clearance is not considered clinically significant.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of atezolizumab were observed based on age, body weight, sex, albumin levels, tumor burden, region, race, mild or moderate renal impairment (estimated glomerular filtration rate 30 to 89 mL/minute/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 3x ULN and any AST), level of PD-L1 expression, and performance status.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of intravenous atezolizumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiac: pericarditis, pericardial effusion, cardiac tamponade. Cardiac: pericarditis, pericardial effusion, cardiac tamponade.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)], TECENTRIQ HYBREZA can cause fetal harm when administered to pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA 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 fetus [see Warnings and Precautions (5.4)].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:TECENTRIQ HYBREZA for subcutaneous injection contains atezolizumab and hyaluronidase [see Description (11)].Atezolizumab: Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. literature-based assessment of the effects on reproduction demonstrated that central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to fetus and to result in an increase in fetal loss; therefore, potential risks of administering atezolizumab 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.Hyaluronidase: In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is 2,400 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is 400 times higher than the human dose.In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is 1,200 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions (5.2)08/2025.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: 9/2024MEDICATION GUIDETECENTRIQ HYBREZA(TM) (te-SEN-trik hye-BREEZE-uh)(atezolizumab and hyaluronidase-tqjs)injection, for subcutaneous useWhat is the most important information should know about TECENTRIQ HYBREZATECENTRIQ HYBREZA is medicine that may treat certain cancers by working with your immune system. TECENTRIQ HYBREZA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during your treatment or even after your treatment has ended.Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:Lung problems.coughshortness of breathchest painIntestinal problems.diarrhea (loose stools) or more frequent bowel movements than usualstools that are black, tarry, sticky, or have blood or mucussevere stomach-area (abdomen) pain or tendernessLiver problems.yellowing of your skin or the whites of your eyessevere nausea or vomitingpain on the right side of your stomach area (abdomen)dark urine (tea colored)bleeding or bruising more easily than normalHormone gland problems.headaches that will not go away or unusual headacheseye sensitivity to lighteye problemsrapid heartbeatincreased sweatingextreme tirednessweight gain or weight lossfeeling more hungry or thirsty than usualurinating more often than usualhair lossfeeling coldconstipationyour voice gets deeperdizziness or faintingchanges in mood or behavior, such as decreased sex drive, irritability, or forgetfulnessKidney problems.decrease in your amount of urineblood in your urineswelling of your anklesloss of appetiteSkin problems.rashitchingskin blistering or peelingpainful sores or ulcers in mouth or nose, throat, or genital areafever or flu-like symptomsswollen lymph nodesProblems can also happen in other organs. These are not all of the signs and symptoms of immune system problems that can happen with TECENTRIQ HYBREZA. Call or see your healthcare provider right away for any new or worse signs or symptoms, including:chest pain, irregular heartbeat, shortness of breath, or swelling of anklesconfusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legsdouble vision, blurry vision, sensitivity to light, eye pain, changes in eye sightpersistent or severe muscle pain or weakness, muscle crampslow red blood cells, bruisingInfusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:chills or shakingitching or rashflushingshortness of breath or wheezingdizzinessfeeling like passing outfeverback or neck painComplications, including graft-versus-host disease (GVHD), in people who have received bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with TECENTRIQ HYBREZA. Your healthcare provider will monitor you for these complications.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 HYBREZA. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with TECENTRIQ HYBREZA if you have severe side effects.What is TECENTRIQ HYBREZATECENTRIQ HYBREZA is prescription medicine used to treat adults with:a type of lung cancer called non-small cell lung cancer (NSCLC).TECENTRIQ HYBREZA may be used alone as treatment for your lung cancer:to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and you have stage to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and your cancer tests positive for PD-L1.TECENTRIQ HYBREZA 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 HYBREZA may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ HYBREZA 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 type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ HYBREZA 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 lung cancer called small cell lung cancer (SCLC). TECENTRIQ HYBREZA may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer is type called extensive-stage SCLC, which means that it has spread or grown.a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ HYBREZA 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.a type of skin cancer called melanoma. TECENTRIQ HYBREZA may be used with the medicines cobimetinib and vemurafenib when your melanoma:has spread to other parts of the body or cannot be removed by surgery, and has certain type of abnormal BRAF gene. Your healthcare provider will perform test to make sure this TECENTRIQ HYBREZA combination is right for you.a type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ HYBREZA may be used alone when your sarcoma has spread to other parts of the body or cannot be removed by surgery. It is not known if TECENTRIQ HYBREZA is safe and effective in children.Do not receive TECENTRIQ HYBREZA if you are allergic to hyaluronidase or any of the ingredients in TECENTRIQ HYBREZA. See the end of this Medication Guide for complete list of ingredients in TECENTRIQ HYBREZA.Before receiving TECENTRIQ HYBREZA, tell your healthcare provider about all of your medical conditions, including if you:have immune system problems such as Crohns disease, ulcerative colitis, or lupushave received an organ transplanthave received or plan to receive stem cell transplant that uses donor stem cells (allogeneic)have received radiation treatment to your chest areahave condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndromeare pregnant or plan to become pregnant. TECENTRIQ HYBREZA 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 HYBREZA. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with TECENTRIQ HYBREZA.You should use an effective method of birth control during your treatment and for months after the last dose of TECENTRIQ HYBREZA. are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ HYBREZA passes into your breast milk. Do not breastfeed during treatment and for months after the last dose of TECENTRIQ HYBREZA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive TECENTRIQ HYBREZAYour healthcare provider will give you TECENTRIQ HYBREZA as an injection under the skin in the thigh over about minutes.TECENTRIQ HYBREZA is given every 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.For treatment of type of skin cancer called melanoma, your healthcare provider will also prescribe you cobimetinib and vemurafenib. Take cobimetinib and vemurafenib exactly as your healthcare provider tells you.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 HYBREZATECENTRIQ HYBREZA can cause serious side effects, including:See What is the most important information should know about TECENTRIQ HYBREZAThe most common side effects of TECENTRIQ HYBREZA when used alone in NSCLC include:feeling tired or weakmuscle or bone paincough shortness of breathdecreased appetiteThe most common side effects observed with intravenous TECENTRIQ, which may be experienced with TECENTRIQ HYBREZA are shown below.The most common side effects of TECENTRIQ when used alone as the first treatment for NSCLC include:feeling tired or weakThe most common side effects of TECENTRIQ when used alone in NSCLC that has spread or grown include:feeling tired or weakcoughdecreased appetiteshortness of breathmuscle or bone painThe most common side effects of TECENTRIQ when used alone in ASPS include:muscle or bone painfeeling tiredrashcoughheadachenauseahigh blood pressurevomitingconstipationshortness of breathdizzinessbleedingdiarrheatrouble sleepingstomach-area (abdominal) painlow thyroid hormone levelsfeveranxietyirregular heartbeat (arrhythmia)decreased appetiteThe most common side effects of TECENTRIQ when used in NSCLC with bevacizumab, paclitaxel, and carboplatin include:numbness, pain, tingling, or burning in your hands or feetfeeling tired or weakhair lossmuscle or bone painnauseadiarrheaconstipationdecreased appetitejoint painhigh blood pressurerashcoughThe most common side effects of TECENTRIQ when used in non-squamous NSCLC with paclitaxel protein-bound and carboplatin include:feeling tired or weaknauseadiarrheamuscle or bone painconstipationnumbness, pain, tingling, or burning in your hands or feethair lossshortness of breathdecreased appetitecoughvomitingrashThe most common side effects of TECENTRIQ when used in SCLC with carboplatin and etoposide include:feeling tired or weaknauseahair lossdecreased appetiteconstipationvomitingThe most common side effects of TECENTRIQ when used in HCC with bevacizumab include:high blood pressurefeeling tired or weaktoo much protein in the urineThe most common side effects of TECENTRIQ when used in melanoma with cobimetinib and vemurafenib include:skin rashjoint, muscle or bone painfeeling tired or weakliver injuryfevernauseaitchingswelling of legs or armsmouth swelling (sometimes with sores)low thyroid hormone levelssunburn or sun sensitivityTECENTRIQ HYBREZA 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 HYBREZA.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 HYBREZA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about TECENTRIQ HYBREZA that is written for health professionals.What are the ingredients in TECENTRIQ HYBREZAActive ingredients: atezolizumab and hyaluronidase-tqjsInactive ingredients: acetic acid, histidine, methionine, polysorbate 20, sucrose, water for injection. Manufactured by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990 USA U.S. License No.: 1048 TECENTRIQ HYBREZA is trademark of Genentech, Inc. For more information, call 1-877-436-3683 or go to www.TECENTRIQHYBREZA.com.. cough. shortness of breath. chest pain. diarrhea (loose stools) or more frequent bowel movements than usual. stools that are black, tarry, sticky, or have blood or mucus. severe stomach-area (abdomen) pain or tenderness. yellowing of your skin or the whites of your eyes. severe nausea or vomiting. pain on the right side of your stomach area (abdomen). dark urine (tea colored). bleeding or bruising more easily than normal. headaches that will not go away or unusual headaches. eye sensitivity to light. eye problems. rapid heartbeat. increased sweating. extreme tiredness. weight gain or weight loss. feeling more hungry or thirsty than usual. urinating more often than usual. hair loss. feeling cold. constipation. your voice gets deeper. dizziness or fainting. changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness. decrease in your amount of urine. blood in your urine. swelling of your ankles. loss of appetite. rash. itching. skin blistering or peeling. painful sores or ulcers in mouth or nose, throat, or genital area. fever or flu-like symptoms. swollen lymph nodes. chest pain, irregular heartbeat, shortness of breath, or swelling of ankles. confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs. double vision, blurry vision, sensitivity to light, eye pain, changes in eye sight. persistent or severe muscle pain or weakness, muscle cramps. low red blood cells, bruising. chills or shaking. itching or rash. flushing. shortness of breath or wheezing. dizziness. feeling like passing out. fever. back or neck pain. type of lung cancer called non-small cell lung cancer (NSCLC).TECENTRIQ HYBREZA may be used alone as treatment for your lung cancer:to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and you have stage to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and your cancer tests positive for PD-L1.TECENTRIQ HYBREZA 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 HYBREZA may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ HYBREZA 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 type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ HYBREZA 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.. TECENTRIQ HYBREZA may be used alone as treatment for your lung cancer:to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and you have stage to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and your cancer tests positive for PD-L1.. to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and you have stage to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and your cancer tests positive for PD-L1.. TECENTRIQ HYBREZA 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.. 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 HYBREZA may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.. has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.. TECENTRIQ HYBREZA 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 type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.. has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.. TECENTRIQ HYBREZA 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.. 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.. type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ HYBREZA may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer is type called extensive-stage SCLC, which means that it has spread or grown.. type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ HYBREZA 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.. 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.. type of skin cancer called melanoma. TECENTRIQ HYBREZA may be used with the medicines cobimetinib and vemurafenib when your melanoma:has spread to other parts of the body or cannot be removed by surgery, and has certain type of abnormal BRAF gene. Your healthcare provider will perform test to make sure this TECENTRIQ HYBREZA combination is right for you.. has spread to other parts of the body or cannot be removed by surgery, and has certain type of abnormal BRAF gene. Your healthcare provider will perform test to make sure this TECENTRIQ HYBREZA combination is right for you.. type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ HYBREZA may be used alone when your sarcoma has spread to other parts of the body or cannot be removed by surgery.. have immune system problems such as Crohns disease, ulcerative colitis, or lupus. have received an organ transplant. have received or plan to receive stem cell transplant that uses donor stem cells (allogeneic). have received radiation treatment to your chest area. have condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndrome. are pregnant or plan to become pregnant. TECENTRIQ HYBREZA 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 HYBREZA. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with TECENTRIQ HYBREZA.You should use an effective method of birth control during your treatment and for months after the last dose of TECENTRIQ HYBREZA. Your healthcare provider should do pregnancy test before you start treatment with TECENTRIQ HYBREZA.. You should use an effective method of birth control during your treatment and for months after the last dose of TECENTRIQ HYBREZA.. are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ HYBREZA passes into your breast milk. Do not breastfeed during treatment and for months after the last dose of TECENTRIQ HYBREZA.. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.. Your healthcare provider will give you TECENTRIQ HYBREZA as an injection under the skin in the thigh over about minutes.. TECENTRIQ HYBREZA is given every 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.. For treatment of type of skin cancer called melanoma, your healthcare provider will also prescribe you cobimetinib and vemurafenib. Take cobimetinib and vemurafenib exactly as your healthcare provider tells you.. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.. See What is the most important information should know about TECENTRIQ HYBREZA. feeling tired or weak. muscle or bone pain. cough shortness of breath. decreased appetite. feeling tired or weak. feeling tired or weak. cough. decreased appetite. shortness of breath. muscle or bone pain. muscle or bone pain. feeling tired. rash. cough. headache. nausea. high blood pressure. vomiting. constipation. shortness of breath. dizziness. bleeding. diarrhea. trouble sleeping. stomach-area (abdominal) pain. low thyroid hormone levels. fever. anxiety. irregular heartbeat (arrhythmia). decreased appetite. numbness, pain, tingling, or burning in your hands or feet. feeling tired or weak. hair loss. muscle or bone pain. nausea. diarrhea. constipation. decreased appetite. joint pain. high blood pressure. rash. cough. feeling tired or weak. nausea. diarrhea. muscle or bone pain. constipation. numbness, pain, tingling, or burning in your hands or feet. hair loss. shortness of breath. decreased appetite. cough. vomiting. rash. feeling tired or weak. nausea. hair loss. decreased appetite. constipation. vomiting. high blood pressure. feeling tired or weak. too much protein in the urine. skin rash. joint, muscle or bone pain. feeling tired or weak. liver injury. fever. nausea. itching. swelling of legs or arms. mouth swelling (sometimes with sores). low thyroid hormone levels. sunburn or sun sensitivity.

SPL UNCLASSIFIED SECTION.

1.1Non-Small Cell Lung Cancer. TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1)] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on >= 1% of tumor cells, as determined by an FDA-approved test [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, as monotherapy, 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 [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, 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 HYBREZA, 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 HYBREZA, as monotherapy, 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 HYBREZA.. TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1)] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on >= 1% of tumor cells, as determined by an FDA-approved test [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, as monotherapy, 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 [see Dosage and Administration (2.1)]. TECENTRIQ HYBREZA, 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 HYBREZA, 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 HYBREZA, as monotherapy, 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 HYBREZA.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)], TECENTRIQ HYBREZA can cause fetal harm when administered to pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA 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 fetus [see Warnings and Precautions (5.4)].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:TECENTRIQ HYBREZA for subcutaneous injection contains atezolizumab and hyaluronidase [see Description (11)].Atezolizumab: Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. literature-based assessment of the effects on reproduction demonstrated that central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to fetus and to result in an increase in fetal loss; therefore, potential risks of administering atezolizumab 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.Hyaluronidase: In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is 2,400 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is 400 times higher than the human dose.In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is 1,200 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of atezolizumab or hyaluronidase in human milk or its effects on the breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to TECENTRIQ HYBREZA are unknown. Because of the potential for serious adverse reactions in breastfed children from TECENTRIQ HYBREZA, advise women not to breastfeed during treatment with TECENTRIQ HYBREZA and for months after the last dose.. 8.3Females and Males of Reproductive Potential. Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating TECENTRIQ HYBREZA [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].. ContraceptionFemales: Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ HYBREZA and for months following the last dose.. InfertilityFemales: Based on animal studies, TECENTRIQ HYBREZA may impair fertility in females of reproductive potential while receiving TECENTRIQ HYBREZA treatment [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of TECENTRIQ HYBREZA have not been established in pediatric patients.. 8.5 Geriatric Use. Of 247 adult patients treated with TECENTRIQ HYBREZA as monotherapy in IMscin001, 45% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness of TECENTRIQ HYBREZA have been observed between patients aged 65 years or older and younger adult patients.The safety of TECENTRIQ HYBREZA as monotherapy or in combination with other antineoplastic drugs for its approved indications [see Indications and Usage (1.1, 1.2, 1.3, 1.4, 1.5)] has been established in adequate and well-controlled studies of intravenous atezolizumab as single agent and in combination with other antineoplastic drugs. Below is description of geriatric use information from the intravenous atezolizumab studies.Of 2,616 adult patients with metastatic NSCLC and other tumor types treated with monotherapy intravenous atezolizumab in clinical studies, 49% were 65 years and over and 15% were 75 years and over.Of 2,421 adult patients with NSCLC and EC-SCLC treated with intravenous atezolizumab in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over.No overall differences in safety or effectiveness were observed between intravenous atezolizumab-treated patients aged 65 years or older and younger adult patients.. Of 2,616 adult patients with metastatic NSCLC and other tumor types treated with monotherapy intravenous atezolizumab in clinical studies, 49% were 65 years and over and 15% were 75 years and over.. Of 2,421 adult patients with NSCLC and EC-SCLC treated with intravenous atezolizumab in combination with other antineoplastic drugs in clinical studies, 48% were 65 years and over and 10% were 75 years and over.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Immune-Mediated Adverse ReactionsImmune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. (5.1)Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.Withhold or permanently discontinue based on severity and type of reaction.Infusion-Related Reactions: Pause or slow the rate of injection, or permanently discontinue based on severity of the reaction. (5.2)Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. (5.3)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception. (5.4, 8.1, 8.3). Immune-Mediated Adverse ReactionsImmune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. (5.1)Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.Withhold or permanently discontinue based on severity and type of reaction.. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. (5.1). Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.. Withhold or permanently discontinue based on severity and type of reaction.. Infusion-Related Reactions: Pause or slow the rate of injection, or permanently discontinue based on severity of the reaction. (5.2). Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with PD-1/PD-L1 blocking antibody. Follow patients closely for evidence of transplant-related complications and intervene promptly. (5.3). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and use of effective contraception. (5.4, 8.1, 8.3). 5.1Severe and Fatal Immune-Mediated Adverse Reactions. TECENTRIQ HYBREZA is monoclonal antibody that belongs to class of drugs that bind to either the programmed death-receptor (PD-1) or the PD-ligand (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)]. In general, if TECENTRIQ HYBREZA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to mg/kg/day prednisone or equivalent) until improvement to Grade or less. Upon improvement to Grade or less, initiate corticosteroid taper and continue to taper over at least month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.. Immune-Mediated PneumonitisTECENTRIQ HYBREZA can cause immune-mediated pneumonitis, including fatal adverse reactions. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.Immune-mediated pneumonitis occurred in 2% (5/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade (0.8%), and Grade (1.2%) events. Pneumonitis led to the withholding of TECENTRIQ HYBREZA in one patient.Systemic corticosteroids were required in 40% (2/5) patients with pneumonitis who received TECENTRIQ HYBREZA as monotherapy. Pneumonitis resolved in both patients. The single patient in whom TECENTRIQ HYBREZA was withheld for pneumonitis reinitiated TECENTRIQ HYBREZA after symptom improvement.. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade (1.3%) and Grade (7%) adverse reactions. Pneumonitis led to permanent discontinuation of intravenous atezolizumab in 2.6% of patients and withholding of intravenous atezolizumab in 7.4% of patients.Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients. Of the 17 patients in whom intravenous atezolizumab was withheld for pneumonitis, 10 reinitiated intravenous atezolizumab after symptom improvement; of these, 50% had recurrence of pneumonitis.. Immune-Mediated ColitisTECENTRIQ HYBREZA can cause immune-mediated colitis, including Grade adverse reactions. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal bleeding. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.. Immune-Mediated HepatitisTECENTRIQ HYBREZA can cause immune-mediated hepatitis, including fatal adverse reactions.Immune-mediated hepatitis occurred in 1.2% (3/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade (0.4%) and Grade (0.8%) events. Hepatitis led to the withholding of TECENTRIQ HYBREZA in 0.4% of patients.Systemic corticosteroids were required in 67% (2/3) of patients with hepatitis who received TECENTRIQ HYBREZA as monotherapy. Hepatitis resolved in of the patients.. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade (1.3%), Grade (1.7%) and Grade (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of intravenous atezolizumab in 2.2% and withholding of intravenous atezolizumab in 1.7% of patients.Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the patients in whom intravenous atezolizumab was withheld for hepatitis, reinitiated intravenous atezolizumab after symptom improvement; of these, 33% had recurrence of hepatitis.. Immune-Mediated Endocrinopathies. Adrenal Insufficiency:TECENTRIQ HYBREZA can cause primary or secondary adrenal insufficiency, including Grade adverse reactions. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].Immune-mediated adrenal insufficiency occurred in 0.8% (2/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade (0.4%) adverse reactions. Adrenal insufficiency led to the withholding of TECENTRIQ HYBREZA in both patients. Systemic corticosteroids were required in 50% (1/2) of patients with adrenal insufficiency who received TECENTRIQ HYBREZA as monotherapy; this single patient remained on systemic corticosteroids.. Hypophysitis:TECENTRIQ HYBREZA can cause immune-mediated hypophysitis, including Grade adverse reactions. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].Immune-mediated hypophysitis occurred in 0.4% (1/247) of patients with locally advanced or metastatic NSCLC in the IMscin001 trial [see Adverse Reactions (6.1)] receiving TECENTRIQ HYBREZA as monotherapy, including Grade (0.4%) adverse reactions. Hypophysitis led to the withholding of TECENTRIQ HYBREZA in this patient.. Thyroid Disorders:TECENTRIQ HYBREZA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].. Thyroiditis:Immune-mediated thyroiditis occurred in 0.8% (2/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade (0.4%) adverse reactions. Thyroiditis resolved in 50% of patients.. Hyperthyroidism:Immune-mediated hyperthyroidism occurred in 2% (5/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade (1.2%) adverse reactions. Hyperthyroidism led to withholding of TECENTRIQ HYBREZA in 0.8% of patients.Anti-thyroid therapy was required in 40% (2/5) of patients with hyperthyroidism who received TECENTRIQ HYBREZA as monotherapy. Of these patients, one remained on anti-thyroid treatment. Of the patients in whom TECENTRIQ HYBREZA was withheld for hyperthyroidism, patient reinitiated TECENTRIQ HYBREZA; this patient did not have recurrence of hyperthyroidism.. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:Hyperthyroidism occurred in 19% (43/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade (0.9%) and Grade (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 10% of patients. Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom intravenous atezolizumab was withheld for hyperthyroidism, 18 patients reinitiated intravenous atezolizumab; of these, 28% had recurrence of hyperthyroidism.. Hypothyroidism:TECENTRIQ HYBREZA can cause immune-mediated hypothyroidism, including Grade adverse reactions. Immune-mediated hypothyroidism occurred in 10% (25/247) of patients with locally advanced or metastatic NSCLC who received TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)].Hormone replacement was required in 68% (17/25) of patients with hypothyroidism who received TECENTRIQ HYBREZA as monotherapy. Two patients with hypothyroidism remained on thyroid hormone replacement.. Intravenous Atezolizumab in Combination with Platinum-based Chemotherapy:Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC (N 2223) or SCLC (N 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133 receiving intravenous atezolizumab in combination with platinum-based chemotherapy, including Grade (< 0.1%), Grade (0.3%), and Grade (5.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of intravenous atezolizumab in 0.1% and withholding of intravenous atezolizumab in 1.6% of patients.Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 39 patients in whom intravenous atezolizumab was withheld for hypothyroidism, reinitiated intravenous atezolizumab after symptom improvement.. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:Hypothyroidism occurred in 26% (60/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade (9.1%) adverse reactions. Hypothyroidism led to withholding of intravenous atezolizumab in 2.6% of patients. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the patients in whom intravenous atezolizumab was withheld for hypothyroidism, reinitiated intravenous atezolizumab after symptom improvement. The majority of patients with hypothyroidism required long term thyroid replacement.. Type Diabetes Mellitus, which can present with Diabetic Ketoacidosis:TECENTRIQ HYBREZA can cause type diabetes mellitus, including Grade adverse reactions and diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].. Immune-Mediated Nephritis with Renal DysfunctionTECENTRIQ HYBREZA can cause immune-mediated nephritis, including Grade adverse reactions.. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade (1.3%) adverse reactions. Nephritis led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 0.9% of patients.Systemic corticosteroids were required in 67% (2/3) of patients with nephritis. Nephritis resolved in all of these patients. Of the patients in whom intravenous atezolizumab was withheld for nephritis, both reinitiated intravenous atezolizumab after symptom improvement and neither had recurrence of nephritis.. Immune-Mediated Dermatologic Adverse ReactionsTECENTRIQ HYBREZA can cause immune-mediated rash or dermatitis, including Grade and fatal adverse reactions. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].One fatal case of an immune-mediated dermatologic adverse reaction, due to TEN, occurred (0.4%, 1/247) in patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)].. Other Immune-Mediated Adverse ReactionsThe following clinically significant immune-mediated adverse reactions occurred at an incidence of 1% (unless otherwise noted) in patients receiving intravenous atezolizumab or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy.Ocular: Uveitis, iritis, and other ocular inflammatory toxicities occurred. Some cases were associated with retinal detachment. Various grades of visual impairment, including blindness, occurred. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.Endocrine: Hypoparathyroidism.Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.. Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy.. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities occurred. Some cases were associated with retinal detachment. Various grades of visual impairment, including blindness, occurred. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.. Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.. Endocrine: Hypoparathyroidism.. Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.. 5.2Infusion-Related Reactions. TECENTRIQ HYBREZA can cause severe or life-threatening infusion-related reactions, including Grade adverse reactions and anaphylaxis. Monitor for signs and symptoms of infusion-related reactions. Pause, slow the rate of, or permanently discontinue TECENTRIQ HYBREZA based on the severity [see Dosage and Administration (2.3)]. For Grade or infusion-related reactions, consider using pre-medications with subsequent doses.. 5.3Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors. Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockage and allogeneic HSCT.Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.. 5.4Embryo-Fetal Toxicity. Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA 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 HYBREZA. Advise females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ HYBREZA and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].