ADVERSE REACTIONS SECTION.

6ADVERSE 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 (>= 20%) with TECENTRIQ as single-agent were fatigue/asthenia, decreased appetite, nausea, cough, and dyspnea. (6.1)Most common adverse reactions (>= 20%) with TECENTRIQ in combination with other antineoplastic drugs in patients with NSCLC and SCLC were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. (6.1)The most common adverse reactions (>= 20%) with TECENTRIQ in combination with bevacizumab in patients with HCC were hypertension, fatigue and proteinuria. (6.1)The most common adverse reactions (>= 20%) with TECENTRIQ in combination with cobimetinib and vemurafenib in patients with melanoma were rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions (>= 20%) with TECENTRIQ as single-agent were fatigue/asthenia, decreased appetite, nausea, cough, and dyspnea. (6.1). Most common adverse reactions (>= 20%) with TECENTRIQ in combination with other antineoplastic drugs in patients with NSCLC and SCLC were fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. (6.1). The most common adverse reactions (>= 20%) with TECENTRIQ in combination with bevacizumab in patients with HCC were hypertension, fatigue and proteinuria. (6.1). The most common adverse reactions (>= 20%) with TECENTRIQ in combination with cobimetinib and vemurafenib in patients with melanoma were rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction. (6.1). 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.The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and four open-label, single arm studies (PCD4989g, IMvigor210, BIRCH, FIR) which enrolled 524 patients with metastatic urothelial carcinoma, 1636 patients with metastatic NSCLC, and 456 patients with other tumor types. TECENTRIQ was administered at dose of 1200 mg intravenously every weeks in all studies except PCD4989g. Among the 2616 patients who received single-agent TECENTRIQ, 36% were exposed for longer than months and 20% were exposed for longer than 12 months. Using the dataset described for patients who received TECENTRIQ as single-agent, the most common adverse reactions in >= 20% of patients were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%). In addition, the data reflect exposure to TECENTRIQ as single agent as adjuvant therapy in 495 patients with early stage NSCLC enrolled in randomized study (IMpower010).In addition, the data reflect exposure to TECENTRIQ in combination with other antineoplastic drugs in 2421 patients with NSCLC (N 2223) or SCLC (N 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133. Among the 2421 patients, 53% were exposed to TECENTRIQ for longer than months and 29% were exposed to TECENTRIQ for longer than 12 months. Among the 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with other antineoplastic drugs, the most common adverse reactions in >=20% of patients were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%) and decreased appetite (27%).The data also reflect exposure to TECENTRIQ administered in combination with cobimetinib and vemurafenib in 230 patients enrolled in IMspire150. Among the 230 patients, 62% were exposed to TECENTRIQ for longer than months and 42% were exposed to TECENTRIQ for longer than 12 months.. Urothelial Carcinoma. Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial CarcinomaThe safety of TECENTRIQ was evaluated in IMvigor210 (Cohort 1), multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients received TECENTRIQ 1200 mg intravenously every weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15 weeks (0 to 87 weeks).Five patients (4.2%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. One additional patient (0.8%) was experiencing herpetic meningoencephalitis and disease progression at the time of death.Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (>= 2%) were diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure.TECENTRIQ was discontinued for adverse reactions in 4.2% of patients. The adverse reactions leading to discontinuation were diarrhea/colitis (1.7%), fatigue (0.8%), hypersensitivity (0.8%), and dyspnea (0.8%).Adverse reactions leading to interruption occurred in 35% of patients; the most common (>= 1%) were intestinal obstruction, fatigue, diarrhea, urinary tract infection, infusion-related reaction, cough, abdominal pain, peripheral edema, pyrexia, respiratory tract infection, upper respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, pruritus, and venous thromboembolism.Tables and summarize the adverse reactions and Grades 3-4 selected laboratory abnormalities, respectively, in patients who received TECENTRIQ in IMvigor210 (Cohort 1).Table 4: Adverse Reactions in >= 10% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)Adverse ReactionTECENTRIQ = 119All Grades(%)Grades 3-4(%)GeneralFatigueIncludes fatigue, asthenia, lethargy, and malaise 528Peripheral edemaIncludes edema peripheral, scrotal edema, lymphedema, and edema 172Pyrexia140.8GastrointestinalDiarrheaIncludes diarrhea, colitis, frequent bowel movements, autoimmune colitis 245Nausea222Vomiting160.8Constipation152Abdominal painIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and flank pain 150.8Metabolism and NutritionDecreased appetiteIncludes decreased appetite and early satiety 243Musculoskeletal and Connective TissueBack/Neck pain183Arthralgia130Skin and Subcutaneous TissuePruritus180.8RashIncludes rash, dermatitis, dermatitis acneiform, rash maculo-papular, rash erythematous, rash pruritic, rash macular, and rash papular 170.8InfectionsUrinary tract infectionIncludes urinary tract infection, urinary tract infection bacterial, cystitis, and urosepsis 175Respiratory, Thoracic, and MediastinalCoughIncludes cough and productive cough 140DyspneaIncludes dyspnea and exertional dyspnea 120Table 5: Grades 3-4 Laboratory Abnormalities in >= 1% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)Laboratory AbnormalityGrades 3-4 (%)Graded per NCI CTCAE v4.0.ChemistryHyponatremia15Hyperglycemia10Increased Alkaline Phosphatase7Increased Creatinine5Hypophosphatemia4Increased ALT4Increased AST4Hyperkalemia3Hypermagnesemia3Hyperbilirubinemia3HematologyLymphopenia9Anemia7. Non-Small Cell Lung Cancer (NSCLC). Adjuvant Treatment of Early-stage NSCLC. IMpower010The safety of TECENTRIQ 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 TECENTRIQ 1200 mg every weeks (n=495) for year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.2)]. The median number of cycles received was 16 (range: 1, 16).Fatal adverse reactions occurred in 1.8% of patients receiving TECENTRIQ; 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 TECENTRIQ. The most frequent serious adverse reactions (>1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%).TECENTRIQ was discontinued due to adverse reactions in 18% of patients; the most common adverse reactions (>=1%) leading to TECENTRIQ discontinuation were pneumonitis (2.2%), hypothyroidism (1.6%), increased aspartate aminotranferase (1.4%), arthralgia (1.0%), and increased alanine aminotransferase (1.0%). Adverse reactions leading to interruption of TECENTRIQ 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 TECENTRIQ in IMpower010.Table 6: Adverse Reactions Occurring in >=10% of Patients with Early Stage NSCLC Receiving TECENTRIQ in IMpower010Adverse ReactionGraded per NCI CTCAE v4.0 TECENTRIQN 495Best Supportive Care = 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 7: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with Early Stage NSCLC Receiving TECENTRIQ 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). TECENTRIQThe denominators used to calculate the rate varied from 78-480 for BSC arm and 483 for 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 TECENTRIQ 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 TECENTRIQ 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 (14.2)]. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained >= 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 1% of the tumor area). The median duration of exposure to TECENTRIQ was 5.3 months (0 to 33 months).Fatal adverse reactions occurred in 3.8% of patients receiving TECENTRIQ; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each).Serious adverse reactions occurred in 28% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%).TECENTRIQ was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (>=2 patients) leading to TECENTRIQ discontinuation were peripheral neuropathy and pneumonitis.Adverse reactions leading to interruption of TECENTRIQ occurred in 26% of patients; the most common (>1%) were ALT increased (2.1%), AST increased (2.1%), pneumonitis (2.1%), pyrexia (1.4%), pneumonia (1.4%) and upper respiratory tract infection (1.4%).Tables and summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower110.Table 8: Adverse Reactions Occurring in >=10% of Patients with NSCLC Receiving TECENTRIQ in IMpower110Adverse ReactionTECENTRIQN 286Platinum-Based Chemotherapy = 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 9: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients Receiving TECENTRIQ in IMpower110Laboratory AbnormalityTECENTRIQPlatinum-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: TECENTRIQ (range: 278-281); platinum-based chemotherapy (range: 256-260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range.HematologyAnemia691.89420Lymphopenia4795917ChemistryHypoalbuminemia480.4392Increased alkaline phosphatase462.5421.2Hyponatremia449367Increased ALT383.2320.8Increased AST363.2320.8Hyperkalemia293.9362.7Hypocalcemia241.4242.7Increased blood creatinine240.7331.5Hypophosphatemia233.6212. IMpower150The safety of TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ 1200 mg with bevacizumab 15 mg/kg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. The median duration of exposure to TECENTRIQ was 8.3 months in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin.Fatal adverse reactions occurred in 6% of patients receiving TECENTRIQ; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection.Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (>2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis.TECENTRIQ was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%).Adverse reactions leading to interruption of TECENTRIQ occurred in 48%; the most common (>1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria.Tables 10 and 11 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin in IMpower150.Table 10: Adverse Reactions Occurring in >=15% of Patients with NSCLC Receiving TECENTRIQ in IMpower150Adverse ReactionTECENTRIQ with Bevacizumab, Paclitaxel, and CarboplatinN 393Bevacizumab, Paclitaxel and Carboplatin = 394All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Graded per NCI CTCAE v4.0Nervous SystemNeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paraesthesia, 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 423342Arthralgia261221GastrointestinalNausea394322DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 336250.5Constipation300.3230.3Vomiting192181Metabolism and NutritionDecreased appetite294210.8VascularHypertension259228RespiratoryCough200.8190.3Epistaxis171220.3RenalProteinuriaData based on Preferred Terms since laboratory data for proteinuria were not systematically collected 163153Table 11: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with NSCLC Receiving TECENTRIQ in IMpower150Laboratory AbnormalityTECENTRIQ 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: TECENTRIQ with bevacizumab, paclitaxel, and carboplatin range: 337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0HematologyAnemia8310839Neutropenia52314526Lymphopenia48173813ChemistryHyperglycemia610600Increased BUN52NANA 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 TECENTRIQ 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 TECENTRIQ 1200 mg and carboplatin AUC mg/mL/min intravenously on Day and paclitaxel protein-bound 100 mg/m2 intravenously on Day 1, 8, and 15 of each 21-day cycle for maximum of or cycles, followed by TECENTRIQ 1200 mg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. Among patients receiving TECENTRIQ, 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 TECENTRIQ; 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 TECENTRIQ. 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%).TECENTRIQ was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia (0.8%), pulmonary embolism (0.8%), fatigue (0.6%), dyspnea (0.6%), pneumonitis (0.6%), neutropenia (0.4%), nausea (0.4%), renal failure (0.4%), cardiac arrest (0.4%), and septic shock (0.4%).Adverse reactions leading to interruption of TECENTRIQ occurred in 62% of patients; the most common (>1%) were neutropenia, thrombocytopenia, anemia, diarrhea, fatigue/asthenia, pneumonia, dyspnea, pneumonitis, pyrexia, nausea, acute kidney injury, vomiting, pulmonary embolism, arthralgia, infusion-related reaction, abdominal pain, chronic obstructive pulmonary disease exacerbation, dehydration, and hypokalemia.Tables 12 and 13 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with paclitaxel protein-bound and carboplatin in IMpower130.Table 12: Adverse Reactions Occurring in >=20% of Patients with NSCLC Receiving TECENTRIQ in IMpower130Adverse ReactionTECENTRIQ 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/Asthenia6111608GastrointestinalNausea503.4462.2Diarrhea Includes diarrhea, colitis, and gastroenteritis 436326Constipation361.1310Vomiting272.7192.2Musculoskeletal and Connective TissueMyalgia/Pain Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 383220.4Nervous SystemNeuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 332.5282.2Respiratory, Thoracic and MediastinalDyspnea Includes dyspnea, dyspnea exertional and wheezing 324.9251.3Cough270.6170Skin and Subcutaneous TissueAlopecia320270Rash Includes 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 13: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients Receiving TECENTRIQ in IMpower130Laboratory AbnormalityTECENTRIQ with Paclitaxel Protein-Bound and CarboplatinN 473Paclitaxel Protein-Boundand 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: TECENTRIQ 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 NSCLCThe safety of TECENTRIQ 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 (14.2)]. total of 609 patients received TECENTRIQ 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 TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had ECOG performance status of 1.Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure.Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (>1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection.TECENTRIQ was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to TECENTRIQ discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of TECENTRIQ occurred in 25% of patients; the most common (>1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain.Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.Table 14: Adverse Reactions Occurring in >=10% of Patients with NSCLC Receiving TECENTRIQ in OAKAdverse ReactionTECENTRIQN 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 NutritionDecreased 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 15: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with NSCLC Receiving TECENTRIQ in OAK Laboratory AbnormalityTECENTRIQDocetaxelAll Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4 (%)Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546-585) and docetaxel (range: 532-560). Graded according to NCI CTCAE version 4.0HematologyAnemia673827Lymphocytopenia49146021ChemistryHypoalbuminemia484503Hyponatremia427316Increased Alkaline Phosphatase392251Increased AST313160.5Increased ALT273140.5Hypophosphatemia275234Hypomagnesemia261211Increased Creatinine232161. Small Cell Lung Cancer (SCLC)The safety of TECENTRIQ with carboplatin and etoposide was evaluated in IMpower133, randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received TECENTRIQ 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 TECENTRIQ 1200 mg every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.3)]. Among 198 patients receiving TECENTRIQ, 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 TECENTRIQ. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).Serious adverse reactions occurred in 37% of patients receiving TECENTRIQ. Serious adverse reactions in >2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%).TECENTRIQ was discontinued due to adverse reactions in 11% of patients. The most frequent adverse reaction requiring permanent discontinuation in >2% of patients was infusion-related reactions (2.5%).Adverse reactions leading to interruption of TECENTRIQ occurred in 59% of patients; the most common (>1%) were neutropenia (22%), anemia (9%), leukopenia (7%), thrombocytopenia (5%), fatigue (4.0%), infusion-related reaction (3.5%), pneumonia (2.0%), febrile neutropenia (1.5%), increased ALT (1.5%), and nausea (1.5%).Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower133.Table 16: Adverse Reactions Occurring in >=20% of Patients with SCLC Receiving TECENTRIQ in IMpower133Adverse ReactionTECENTRIQ 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 17: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with SCLC Receiving TECENTRIQ in IMpower133Laboratory AbnormalityTECENTRIQ 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: TECENTRIQ (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 Hepatocellular Carcinoma (HCC)The safety of TECENTRIQ 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 (14.4)]. Patients received 1,200 mg of TECENTRIQ 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 TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months).Fatal adverse reactions occurred in 4.6% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).Serious adverse reactions occurred in 38% of patients in the TECENTRIQ and bevacizumab arm. The most frequent serious adverse reactions (>= 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%).Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to TECENTRIQ discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%).Adverse reactions leading to interruption of TECENTRIQ occurred in 41% of patients in the TECENTRIQ and bevacizumab arm; the most common (>= 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline 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 TECENTRIQ and bevacizumab arm.Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ and bevacizumab in IMbrave150.Table 18: Adverse Reactions Occurring in >=10% of Patients with HCC Receiving TECENTRIQ in IMbrave150Adverse ReactionTECENTRIQ 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 19: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with HCC Receiving TECENTRIQ in IMbrave150Laboratory AbnormalityTECENTRIQ 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: TECENTRIQ 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. MelanomaThe safety of TECENTRIQ, 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 (14.5)]. Patients received TECENTRIQ with cobimetinib and vemurafenib (N=230) or placebo with cobimetinib and vemurafenib (n=281).Among the 230 patients who received TECENTRIQ administered with cobimetinib and vemurafenib, the median duration of exposure to TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ occurred in 21% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to TECENTRIQ discontinuation were increased ALT (2.2%) and pneumonitis (2.6%).Adverse reactions leading to interruption of TECENTRIQ occurred in 68% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to TECENTRIQ 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 20 and 21 summarize the incidence of adverse reactions and laboratory abnormalities in Study IMspire150.Table 20: Adverse Reactions Occurring in >=10% of Patients on the TECENTRIQ 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 TECENTRIQ in IMspire150)Adverse ReactionTECENTRIQ in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib(n=281)All Grades(%)Grade 3-4(%)All Grades(%)Grade 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 ConditionsFatigue Includes fatigue, asthenia and malaise 513451.8Pyrexia Includes pyrexia and hyperpyrexia 491.7352.1Edema Includes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema 26<1210Gastrointestinal DisordersHepatotoxicity Includes 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<1322.5Stomatitis Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 231.315<1Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain Includes 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 DisordersHypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased 220100Hyperthyroidism18<180Injury, Poisoning and Procedural ComplicationsInfusion-related reaction Includes infusion related reaction and hypersensitivity 102.68<1Respiratory, Thoracic and Mediastinal DisordersPneumonitis Includes pneumonitis and interstitial lung disease 121.36<1Vascular DisordersHypertension Includes hypertension, blood pressure increased, hypertensive crisis 1710187Clinically important adverse reactions in 10% of patients who received TECENTRIQ 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 21: Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving TECENTRIQ 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 AbnormalityTECENTRIQ in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib (n=281)All Grades(%)Grade 3-4(%)All Grades(%)Grade 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: TECENTRIQ 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 Hormone Increased Thyroid Stimulating Hormone has difference <5% (All Grades) between arms and is included for clinical completeness. 37NA 33NA Decreased Potassium365224.3Increased Triiodothyronine33NA 8NA Increased Free Thyroxine32NA 21NA Decreased Total Triiodothyronine32NA 8NA Increased Potassium291.3191.4Decreased Triiodothyronine27NA 21NA Increased Sodium200130.4. 6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to atezolizumab in the studies described above with the incidence of antibodies in other studies or to other products may be misleading.Among 111 patients in IMvigor210 (Cohort 1), 48% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposures. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions. Among 565 patients with NSCLC in OAK, 30% tested positive for treatment-emergent anti-drug antibodies (ADA) at one or more post-dose time points. The median onset time to ADA formation was weeks. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposure [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA positive by week (21%; 118/560) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week [see Clinical Studies (14.2)]. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions.Among 487 ADA-evaluable patients with NSCLC who received atezolizumab in IMpower010, 31% (n=152) tested positive for treatment-emergent ADA at one or more post-dose time points. Among 241 patients in the PD-L1 SP263 >=1% TC Stage II-IIIA population, 28% (n=67) tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative [see Clinical Pharmacology (12.3)]. There were insufficient numbers of patients and DFS events in the ADA-positive subgroup (19%; 39/207 by week 7) to determine whether ADA alters the efficacy of atezolizumab. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions.Among 364 ADA-evaluable patients with NSCLC who received TECENTRIQ with bevacizumab, paclitaxel and carboplatin in IMpower150, 36% (n=132) tested positive for treatment-emergent ADA at one or more post-dose time points and 83% of these 132 patients tested ADA positive prior to receiving the second dose of atezolizumab. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA negative [see Clinical Pharmacology (12.3)]. The presence of ADA did not increase the incidence or severity of adverse reactions [see Clinical Studies (14.2)]. Among 315 ADA-evaluable patients with HCC who received TECENTRIQ and bevacizumab in IMbrave150, 28% (n=88) tested positive for treatment-emergent ADA at one or more post-dose time points and 66% (58/88) of these 88 patients tested ADA-positive prior to receiving the third dose of TECENTRIQ. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA-positive by week (20%; 58/288) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 6; [see Clinical Studies (14.4)]. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions.Among 218 ADA-evaluable patients with melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib in IMspire150, 13% (n=29) tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had decreased systemic atezolizumab exposure [see Clinical Pharmacology (12.3)]. There are insufficient numbers of patients with positive ADA to determine whether ADA alters the efficacy or incidence or severity of adverse reactions.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. 14.1Urothelial Carcinoma. Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial CarcinomaThe efficacy of TECENTRIQ was investigated in IMvigor210 (Cohort 1) (NCT02951767), multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. Patients were considered cisplatin-ineligible if they met any one of the following criteria at study entry: impaired renal function [creatinine clearance (CLcr) of 30 to 59 mL/min], Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, hearing loss of >= 25 decibels (dB) at two contiguous frequencies, or Grades 2-4 peripheral neuropathy. This study excluded patients who had: history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of live, attenuated vaccine within 28 days prior to enrollment; or administration of systemic immunostimulatory agents within weeks or systemic immunosuppressive medications within weeks prior to enrollment. Patients received TECENTRIQ 1200 mg as an intravenous infusion every weeks until unacceptable toxicity or disease progression. Tumor response assessments were conducted every weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed overall response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), duration of response (DoR) and overall survival (OS).In this study, the median age was 73 years, 81% were male, and 91% were White. Thirty-five percent of patients had non-bladder urothelial carcinoma and 66% had visceral metastases. Eighty percent of patients had an ECOG PS of or 1. Reasons for ineligibility for cisplatin-containing chemotherapy were: 70% had impaired renal function, 20% had an ECOG PS of 2, 14% had hearing loss of >= 25dB, and 6% had Grades 2-4 peripheral neuropathy at baseline. Twenty percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at central laboratory, and the results were used to define subgroups for pre-specified analyses. Of the 119 patients, 27% were classified as having PD-L1 expression of >= 5% (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area). The remaining 73% of patients were classified as having PD-L1 expression of 5% (PD-L1 stained tumor-infiltrating IC covering 5% of the tumor area).Among the 32 patients with PD-L1 expression of >= 5%, median age was 67 years, 81% were male, 19% female, and 88% were White. Twenty-eight percent of patients had non-bladder urothelial carcinoma and 56% had visceral metastases. Seventy-two percent of patients had an ECOG PS of or 1. Reasons for ineligibility for cisplatin-containing chemotherapy were: 66% had impaired renal function, 28% had an ECOG PS of 2, 16% had hearing loss >= 25 dB, and 9% had Grades 2-4 peripheral neuropathy at baseline. Thirty-one percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 22. The median follow-up time for this study was 14.4 months. In 24 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 33% (95% CI: 16%, 55%).Table 22: Efficacy Results in IMvigor210 (Cohort 1)All PatientsPD-L1 Expression SubgroupsN 119PD-L1 Expression of 5% in ICsPD-L1 expression in tumor-infiltrating immune cells (ICs) = 87PD-L1 Expression of >= 5% in ICs = 32NR Not reachedNumber of IRF-assessed Confirmed Responders28 19 9ORR (95% CI)23.5% (16.2, 32.2)21.8% (13.7, 32)28.1% (13.8, 46.8)Complete Response6.7%6.9%6.3%Partial Response16.8%14.9%21.9%Median DoR, months(range) NR(3.7, 16.6Denotes censored value)NR(3.7, 16.6)NR(8.1, 15.6)IMvigor130 (NCT02807636) is an ongoing multicenter, randomized study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study contains three arms: TECENTRIQ monotherapy, TECENTRIQ with platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine), and platinum-based chemotherapy alone (comparator). Both cisplatin-eligible and cisplatin-ineligible patients are included in the study. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at central laboratory. The independent Data Monitoring Committee (iDMC) for the study conducted review of early data and found that patients classified as having PD-L1 expression of <5% when treated with TECENTRIQ monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended closure of the monotherapy arm to further accrual of patients with low PD-L1 expression, however, no other changes were recommended for the study, including any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm.. 14.2 Non-Small Cell Lung Cancer. Adjuvant Treatment of Stage II-IIIA NSCLC with PD-L1 Expression >= 1%The efficacy of TECENTRIQ 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 TECENTRIQ 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:TECENTRIQN 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 TECENTRIQ 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 TECENTRIQ 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).. Figure 1. Metastatic Chemotherapy-Naive NSCLC with High PD-L1 ExpressionThe efficacy of TECENTRIQ 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: TECENTRIQ 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 TECENTRIQ 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: TECENTRIQN 107Arm B: Platinum-Based ChemotherapyN 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 TECENTRIQ 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 TECENTRIQ arm and 29% (95% CI: 20%, 39%) in the platinum-based chemotherapy arm.. Arm A: TECENTRIQ 1200 mg every weeks until disease progression or unacceptable toxicity. Arm B: Platinum-based chemotherapy. Figure 2. Metastatic Chemotherapy-Naive Non-Squamous NSCLC. IMpower150The efficacy of TECENTRIQ 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: TECENTRIQ 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: TECENTRIQ 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: TECENTRIQ 1200 mg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicityArm B: TECENTRIQ 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: TECENTRIQ with Bevacizumab, Paclitaxel, and CarboplatinArm A: TECENTRIQ 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 Responsen 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 Adverse Reactions (6.2), Clinical Pharmacology (12.3)]. In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm with matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly ADA negative patients in the TECENTRIQ, 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: TECENTRIQ 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: TECENTRIQ 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: TECENTRIQ 1200 mg intravenously on Day of each 21-day cycle until disease progression or unacceptable toxicity. Arm B: TECENTRIQ 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. Figure 3. IMpower130The efficacy of TECENTRIQ 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:TECENTRIQ 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 TECENTRIQ 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 IMpower130TECENTRIQ with Paclitaxel Protein-Bound and CarboplatinPaclitaxel Protein-Bound and CarboplatinCI=confidence intervalOverall SurvivalBased on OS interim analysis n=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)n=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 responsen=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. TECENTRIQ 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 TECENTRIQ 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.. Figure 4. Previously Treated Metastatic NSCLCThe efficacy of TECENTRIQ 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 TECENTRIQ 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 5.Table 27: Efficacy Results in OAKTECENTRIQDocetaxelCI=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 ResponseN=58N=57 Median, months16.36.2 (95% CI)(10.0, NE)(4.9, 7.6)Overall Survival in all 1225 patients Number of patientsN=613N=612 Deaths (%)384 (63%)409 (67%) Median, months13.39.8 (95% CI)(11.3, 14.9)(8.9, 11.3) Hazard ratio (95% CI)0.79 (0.69, 0.91) p-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 Adverse Reactions (6.2), Clinical Pharmacology (12.3)]. 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 atezolizumab arm with matched population in the docetaxel arm and ADA negative patients in the 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 5. 14.3 Small Cell Lung Cancer. The efficacy of TECENTRIQ 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:TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ arm and 202 to the chemotherapy alone arm. The median age was 64 years (range 26 to 90) and 65% were male. The majority of patients were White (80%); 17% were Asian, 4% were Hispanic and 1% were Black. Baseline ECOG performance status was (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 IMpower133TECENTRIQ 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)N=201N=202 Number of events (%)171 (85%)189 (94%) Median, months5.24.3 (95% CI)(4.4, 5.6)(4.2, 4.5) Hazard ratio (95% CI)0.77 (0.62, 0.96) p-value Compared to the allocated of 0.05 for this analysis 0.0170Objective Response Rate,,Confirmed responseN=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,,N=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. TECENTRIQ 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 TECENTRIQ 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. 14.4 Hepatocellular Carcinoma. The efficacy of TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ or bevacizumab (e.g., due to adverse events) and continue on single-agent therapy until disease progression or unacceptable toxicity associated with the single-agent.The study enrolled patients who were ECOG performance score 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 IMbrave150TECENTRIQ in combination with Bevacizumab(N= 336)Sorafenib(N=165)CI=confidence interval; HCC mRECIST=Modified RECIST Assessment for Hepatocellular Carcinoma; NE=not estimable; RECIST 1.1=Response Evaluation Criteria in Solid Tumors v1.1 Overall SurvivalNumber of deaths (%)96 (29)65 (39)Median OS in months (95% CI)NE(NE, NE)13.2 (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 1.1Number of responders (%)93 (28)19 (12)(95% CI)(23, 33)(7,17)p-valueBased on two-sided Cochran-Mantel-Haesnszel test <0.0001Complete responses, (%)22 (7)0Partial responses, (%)71 (21)19 (12)Duration of Response (DOR) RECIST 1.1(n=93)(n=19)Median DOR in months (95% CI)NE(NE, NE)6.3(4.7, NE)Range (months)(1.3Denotes censored value, 13.4)(1.4, 9.1)Overall Response Rate (ORR), HCC mRECISTNumber of responders (%)112 (33)21 (13)(95% CI)(28, 39)(8, 19)p-value <0.0001Complete 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 months(95% CI)NE(NE, NE)6.3(4.9, NE)Range (months)(1.3, 13.4)(1.4, 9.1)Figure 7: Kaplan-Meier Plot of Overall Survival in 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 Adverse Reactions (6.2), Clinical Pharmacology (12.3)]. 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 TECENTRIQ and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (<400 ng/mL vs >=400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology (HBV vs. HCV vs. non-viral) and Child-Pugh Score (A5 vs. A6). The OS hazard ratio comparing the ADA-positive subgroup of the TECENTRIQ and bevacizumab arm to sorafenib was 0.93 (95% CI: 0.57, 1.53). The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was 0.39 (95% CI: 0.26, 0.60).. Figure 7. 14.5 Melanoma. The efficacy of TECENTRIQ 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.TECENTRIQ 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 TECENTRIQ 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 IMspire150TECENTRIQ 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 TECENTRIQ 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.

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.The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and four open-label, single arm studies (PCD4989g, IMvigor210, BIRCH, FIR) which enrolled 524 patients with metastatic urothelial carcinoma, 1636 patients with metastatic NSCLC, and 456 patients with other tumor types. TECENTRIQ was administered at dose of 1200 mg intravenously every weeks in all studies except PCD4989g. Among the 2616 patients who received single-agent TECENTRIQ, 36% were exposed for longer than months and 20% were exposed for longer than 12 months. Using the dataset described for patients who received TECENTRIQ as single-agent, the most common adverse reactions in >= 20% of patients were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%). In addition, the data reflect exposure to TECENTRIQ as single agent as adjuvant therapy in 495 patients with early stage NSCLC enrolled in randomized study (IMpower010).In addition, the data reflect exposure to TECENTRIQ in combination with other antineoplastic drugs in 2421 patients with NSCLC (N 2223) or SCLC (N 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133. Among the 2421 patients, 53% were exposed to TECENTRIQ for longer than months and 29% were exposed to TECENTRIQ for longer than 12 months. Among the 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with other antineoplastic drugs, the most common adverse reactions in >=20% of patients were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%) and decreased appetite (27%).The data also reflect exposure to TECENTRIQ administered in combination with cobimetinib and vemurafenib in 230 patients enrolled in IMspire150. Among the 230 patients, 62% were exposed to TECENTRIQ for longer than months and 42% were exposed to TECENTRIQ for longer than 12 months.. Urothelial Carcinoma. Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial CarcinomaThe safety of TECENTRIQ was evaluated in IMvigor210 (Cohort 1), multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients received TECENTRIQ 1200 mg intravenously every weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15 weeks (0 to 87 weeks).Five patients (4.2%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. One additional patient (0.8%) was experiencing herpetic meningoencephalitis and disease progression at the time of death.Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (>= 2%) were diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure.TECENTRIQ was discontinued for adverse reactions in 4.2% of patients. The adverse reactions leading to discontinuation were diarrhea/colitis (1.7%), fatigue (0.8%), hypersensitivity (0.8%), and dyspnea (0.8%).Adverse reactions leading to interruption occurred in 35% of patients; the most common (>= 1%) were intestinal obstruction, fatigue, diarrhea, urinary tract infection, infusion-related reaction, cough, abdominal pain, peripheral edema, pyrexia, respiratory tract infection, upper respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, pruritus, and venous thromboembolism.Tables and summarize the adverse reactions and Grades 3-4 selected laboratory abnormalities, respectively, in patients who received TECENTRIQ in IMvigor210 (Cohort 1).Table 4: Adverse Reactions in >= 10% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)Adverse ReactionTECENTRIQ = 119All Grades(%)Grades 3-4(%)GeneralFatigueIncludes fatigue, asthenia, lethargy, and malaise 528Peripheral edemaIncludes edema peripheral, scrotal edema, lymphedema, and edema 172Pyrexia140.8GastrointestinalDiarrheaIncludes diarrhea, colitis, frequent bowel movements, autoimmune colitis 245Nausea222Vomiting160.8Constipation152Abdominal painIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and flank pain 150.8Metabolism and NutritionDecreased appetiteIncludes decreased appetite and early satiety 243Musculoskeletal and Connective TissueBack/Neck pain183Arthralgia130Skin and Subcutaneous TissuePruritus180.8RashIncludes rash, dermatitis, dermatitis acneiform, rash maculo-papular, rash erythematous, rash pruritic, rash macular, and rash papular 170.8InfectionsUrinary tract infectionIncludes urinary tract infection, urinary tract infection bacterial, cystitis, and urosepsis 175Respiratory, Thoracic, and MediastinalCoughIncludes cough and productive cough 140DyspneaIncludes dyspnea and exertional dyspnea 120Table 5: Grades 3-4 Laboratory Abnormalities in >= 1% of Patients with Urothelial Carcinoma in IMvigor210 (Cohort 1)Laboratory AbnormalityGrades 3-4 (%)Graded per NCI CTCAE v4.0.ChemistryHyponatremia15Hyperglycemia10Increased Alkaline Phosphatase7Increased Creatinine5Hypophosphatemia4Increased ALT4Increased AST4Hyperkalemia3Hypermagnesemia3Hyperbilirubinemia3HematologyLymphopenia9Anemia7. Non-Small Cell Lung Cancer (NSCLC). Adjuvant Treatment of Early-stage NSCLC. IMpower010The safety of TECENTRIQ 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 TECENTRIQ 1200 mg every weeks (n=495) for year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.2)]. The median number of cycles received was 16 (range: 1, 16).Fatal adverse reactions occurred in 1.8% of patients receiving TECENTRIQ; 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 TECENTRIQ. The most frequent serious adverse reactions (>1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%).TECENTRIQ was discontinued due to adverse reactions in 18% of patients; the most common adverse reactions (>=1%) leading to TECENTRIQ discontinuation were pneumonitis (2.2%), hypothyroidism (1.6%), increased aspartate aminotranferase (1.4%), arthralgia (1.0%), and increased alanine aminotransferase (1.0%). Adverse reactions leading to interruption of TECENTRIQ 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 TECENTRIQ in IMpower010.Table 6: Adverse Reactions Occurring in >=10% of Patients with Early Stage NSCLC Receiving TECENTRIQ in IMpower010Adverse ReactionGraded per NCI CTCAE v4.0 TECENTRIQN 495Best Supportive Care = 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 7: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with Early Stage NSCLC Receiving TECENTRIQ 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). TECENTRIQThe denominators used to calculate the rate varied from 78-480 for BSC arm and 483 for 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 TECENTRIQ 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 TECENTRIQ 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 (14.2)]. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained >= 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 1% of the tumor area). The median duration of exposure to TECENTRIQ was 5.3 months (0 to 33 months).Fatal adverse reactions occurred in 3.8% of patients receiving TECENTRIQ; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each).Serious adverse reactions occurred in 28% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%).TECENTRIQ was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (>=2 patients) leading to TECENTRIQ discontinuation were peripheral neuropathy and pneumonitis.Adverse reactions leading to interruption of TECENTRIQ occurred in 26% of patients; the most common (>1%) were ALT increased (2.1%), AST increased (2.1%), pneumonitis (2.1%), pyrexia (1.4%), pneumonia (1.4%) and upper respiratory tract infection (1.4%).Tables and summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower110.Table 8: Adverse Reactions Occurring in >=10% of Patients with NSCLC Receiving TECENTRIQ in IMpower110Adverse ReactionTECENTRIQN 286Platinum-Based Chemotherapy = 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 9: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients Receiving TECENTRIQ in IMpower110Laboratory AbnormalityTECENTRIQPlatinum-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: TECENTRIQ (range: 278-281); platinum-based chemotherapy (range: 256-260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range.HematologyAnemia691.89420Lymphopenia4795917ChemistryHypoalbuminemia480.4392Increased alkaline phosphatase462.5421.2Hyponatremia449367Increased ALT383.2320.8Increased AST363.2320.8Hyperkalemia293.9362.7Hypocalcemia241.4242.7Increased blood creatinine240.7331.5Hypophosphatemia233.6212. IMpower150The safety of TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ 1200 mg with bevacizumab 15 mg/kg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. The median duration of exposure to TECENTRIQ was 8.3 months in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin.Fatal adverse reactions occurred in 6% of patients receiving TECENTRIQ; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection.Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (>2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis.TECENTRIQ was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%).Adverse reactions leading to interruption of TECENTRIQ occurred in 48%; the most common (>1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria.Tables 10 and 11 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin in IMpower150.Table 10: Adverse Reactions Occurring in >=15% of Patients with NSCLC Receiving TECENTRIQ in IMpower150Adverse ReactionTECENTRIQ with Bevacizumab, Paclitaxel, and CarboplatinN 393Bevacizumab, Paclitaxel and Carboplatin = 394All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Graded per NCI CTCAE v4.0Nervous SystemNeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paraesthesia, 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 423342Arthralgia261221GastrointestinalNausea394322DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis 336250.5Constipation300.3230.3Vomiting192181Metabolism and NutritionDecreased appetite294210.8VascularHypertension259228RespiratoryCough200.8190.3Epistaxis171220.3RenalProteinuriaData based on Preferred Terms since laboratory data for proteinuria were not systematically collected 163153Table 11: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with NSCLC Receiving TECENTRIQ in IMpower150Laboratory AbnormalityTECENTRIQ 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: TECENTRIQ with bevacizumab, paclitaxel, and carboplatin range: 337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0HematologyAnemia8310839Neutropenia52314526Lymphopenia48173813ChemistryHyperglycemia610600Increased BUN52NANA 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 TECENTRIQ 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 TECENTRIQ 1200 mg and carboplatin AUC mg/mL/min intravenously on Day and paclitaxel protein-bound 100 mg/m2 intravenously on Day 1, 8, and 15 of each 21-day cycle for maximum of or cycles, followed by TECENTRIQ 1200 mg intravenously every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. Among patients receiving TECENTRIQ, 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 TECENTRIQ; 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 TECENTRIQ. 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%).TECENTRIQ was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia (0.8%), pulmonary embolism (0.8%), fatigue (0.6%), dyspnea (0.6%), pneumonitis (0.6%), neutropenia (0.4%), nausea (0.4%), renal failure (0.4%), cardiac arrest (0.4%), and septic shock (0.4%).Adverse reactions leading to interruption of TECENTRIQ occurred in 62% of patients; the most common (>1%) were neutropenia, thrombocytopenia, anemia, diarrhea, fatigue/asthenia, pneumonia, dyspnea, pneumonitis, pyrexia, nausea, acute kidney injury, vomiting, pulmonary embolism, arthralgia, infusion-related reaction, abdominal pain, chronic obstructive pulmonary disease exacerbation, dehydration, and hypokalemia.Tables 12 and 13 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with paclitaxel protein-bound and carboplatin in IMpower130.Table 12: Adverse Reactions Occurring in >=20% of Patients with NSCLC Receiving TECENTRIQ in IMpower130Adverse ReactionTECENTRIQ 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/Asthenia6111608GastrointestinalNausea503.4462.2Diarrhea Includes diarrhea, colitis, and gastroenteritis 436326Constipation361.1310Vomiting272.7192.2Musculoskeletal and Connective TissueMyalgia/Pain Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 383220.4Nervous SystemNeuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 332.5282.2Respiratory, Thoracic and MediastinalDyspnea Includes dyspnea, dyspnea exertional and wheezing 324.9251.3Cough270.6170Skin and Subcutaneous TissueAlopecia320270Rash Includes 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 13: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients Receiving TECENTRIQ in IMpower130Laboratory AbnormalityTECENTRIQ with Paclitaxel Protein-Bound and CarboplatinN 473Paclitaxel Protein-Boundand 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: TECENTRIQ 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 NSCLCThe safety of TECENTRIQ 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 (14.2)]. total of 609 patients received TECENTRIQ 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 TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had ECOG performance status of 1.Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure.Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (>1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection.TECENTRIQ was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to TECENTRIQ discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of TECENTRIQ occurred in 25% of patients; the most common (>1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain.Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.Table 14: Adverse Reactions Occurring in >=10% of Patients with NSCLC Receiving TECENTRIQ in OAKAdverse ReactionTECENTRIQN 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 NutritionDecreased 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 15: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with NSCLC Receiving TECENTRIQ in OAK Laboratory AbnormalityTECENTRIQDocetaxelAll Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4 (%)Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546-585) and docetaxel (range: 532-560). Graded according to NCI CTCAE version 4.0HematologyAnemia673827Lymphocytopenia49146021ChemistryHypoalbuminemia484503Hyponatremia427316Increased Alkaline Phosphatase392251Increased AST313160.5Increased ALT273140.5Hypophosphatemia275234Hypomagnesemia261211Increased Creatinine232161. Small Cell Lung Cancer (SCLC)The safety of TECENTRIQ with carboplatin and etoposide was evaluated in IMpower133, randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received TECENTRIQ 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 TECENTRIQ 1200 mg every weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.3)]. Among 198 patients receiving TECENTRIQ, 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 TECENTRIQ. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).Serious adverse reactions occurred in 37% of patients receiving TECENTRIQ. Serious adverse reactions in >2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%).TECENTRIQ was discontinued due to adverse reactions in 11% of patients. The most frequent adverse reaction requiring permanent discontinuation in >2% of patients was infusion-related reactions (2.5%).Adverse reactions leading to interruption of TECENTRIQ occurred in 59% of patients; the most common (>1%) were neutropenia (22%), anemia (9%), leukopenia (7%), thrombocytopenia (5%), fatigue (4.0%), infusion-related reaction (3.5%), pneumonia (2.0%), febrile neutropenia (1.5%), increased ALT (1.5%), and nausea (1.5%).Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower133.Table 16: Adverse Reactions Occurring in >=20% of Patients with SCLC Receiving TECENTRIQ in IMpower133Adverse ReactionTECENTRIQ 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 17: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with SCLC Receiving TECENTRIQ in IMpower133Laboratory AbnormalityTECENTRIQ 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: TECENTRIQ (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 Hepatocellular Carcinoma (HCC)The safety of TECENTRIQ 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 (14.4)]. Patients received 1,200 mg of TECENTRIQ 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 TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months).Fatal adverse reactions occurred in 4.6% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%).Serious adverse reactions occurred in 38% of patients in the TECENTRIQ and bevacizumab arm. The most frequent serious adverse reactions (>= 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%).Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to TECENTRIQ discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%).Adverse reactions leading to interruption of TECENTRIQ occurred in 41% of patients in the TECENTRIQ and bevacizumab arm; the most common (>= 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline 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 TECENTRIQ and bevacizumab arm.Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ and bevacizumab in IMbrave150.Table 18: Adverse Reactions Occurring in >=10% of Patients with HCC Receiving TECENTRIQ in IMbrave150Adverse ReactionTECENTRIQ 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 19: Laboratory Abnormalities Worsening from Baseline Occurring in >=20% of Patients with HCC Receiving TECENTRIQ in IMbrave150Laboratory AbnormalityTECENTRIQ 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: TECENTRIQ 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. MelanomaThe safety of TECENTRIQ, 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 (14.5)]. Patients received TECENTRIQ with cobimetinib and vemurafenib (N=230) or placebo with cobimetinib and vemurafenib (n=281).Among the 230 patients who received TECENTRIQ administered with cobimetinib and vemurafenib, the median duration of exposure to TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ 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 TECENTRIQ occurred in 21% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to TECENTRIQ discontinuation were increased ALT (2.2%) and pneumonitis (2.6%).Adverse reactions leading to interruption of TECENTRIQ occurred in 68% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (>= 2%) adverse reactions leading to TECENTRIQ 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 20 and 21 summarize the incidence of adverse reactions and laboratory abnormalities in Study IMspire150.Table 20: Adverse Reactions Occurring in >=10% of Patients on the TECENTRIQ 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 TECENTRIQ in IMspire150)Adverse ReactionTECENTRIQ in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib(n=281)All Grades(%)Grade 3-4(%)All Grades(%)Grade 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 ConditionsFatigue Includes fatigue, asthenia and malaise 513451.8Pyrexia Includes pyrexia and hyperpyrexia 491.7352.1Edema Includes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema 26<1210Gastrointestinal DisordersHepatotoxicity Includes 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<1322.5Stomatitis Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 231.315<1Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain Includes 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 DisordersHypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased 220100Hyperthyroidism18<180Injury, Poisoning and Procedural ComplicationsInfusion-related reaction Includes infusion related reaction and hypersensitivity 102.68<1Respiratory, Thoracic and Mediastinal DisordersPneumonitis Includes pneumonitis and interstitial lung disease 121.36<1Vascular DisordersHypertension Includes hypertension, blood pressure increased, hypertensive crisis 1710187Clinically important adverse reactions in 10% of patients who received TECENTRIQ 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 21: Laboratory Abnormalities Worsening from Baseline Occurring in >= 20% of Patients Receiving TECENTRIQ 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 AbnormalityTECENTRIQ in combination with Cobimetinib and Vemurafenib(n=230)Placebo with Cobimetinib and Vemurafenib (n=281)All Grades(%)Grade 3-4(%)All Grades(%)Grade 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: TECENTRIQ 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 Hormone Increased Thyroid Stimulating Hormone has difference <5% (All Grades) between arms and is included for clinical completeness. 37NA 33NA Decreased Potassium365224.3Increased Triiodothyronine33NA 8NA Increased Free Thyroxine32NA 21NA Decreased Total Triiodothyronine32NA 8NA Increased Potassium291.3191.4Decreased Triiodothyronine27NA 21NA Increased Sodium200130.4.

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. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

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 dose and was reversible. There was no effect on the male monkey reproductive organs.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL 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 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 cell infiltration and activation compared to targeted therapy alone.. 12.3Pharmacokinetics. Patients exposure to atezolizumab increased dose proportionally over the dose range of mg/kg to 20 mg/kg, including dose of 1200 mg administered every weeks. The clearance (CV%) was 0.20 L/day (29%), the volume of distribution at steady state was 6.9 L, and the terminal half-life was 27 days. Steady state was achieved after to weeks following multiple doses. The systemic accumulation ratio for every weeks administration and every weeks administration was 3.3- and 1.9- fold, respectively. Atezolizumab clearance was found to decrease over time, with mean maximal reduction (CV%) from baseline value of approximately 17% (41%); however, the decrease in clearance was not considered clinically relevant.. Specific PopulationsAge (21 to 89 years), body weight, sex, albumin levels, tumor burden, region or race, mild or moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2], mild hepatic impairment (bilirubin <= ULN and AST ULN or bilirubin 1 to 1.5 ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3x ULN and any AST), level of PD-L1 expression, or performance status had no clinically significant effect on the systemic exposure of atezolizumab. Across clinical trials with TECENTRIQ, median atezolizumab clearance in patients who tested positive for treatment-emergent anti-drug antibodies (ADA) was 19% (range: 18% to 49%) higher as compared to atezolizumab clearance in patients who tested negative for treatment-emergent ADA.. Drug Interaction StudiesThe drug interaction potential of atezolizumab is unknown.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

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

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. Administer TECENTRIQ intravenously over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.Urothelial CarcinomaAdminister TECENTRIQ as single agent as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. (2.2)NSCLCIn the adjuvant setting, administer TECENTRIQ following resection and up to cycles of platinum-based chemotherapy as 840 mg every weeks, 1200 mg every weeks or 1680 mg every weeks for up to year. (2.2)In the metastatic setting, administer TECENTRIQ as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. (2.2)When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day. (2.2)Small Cell Lung CancerAdminister TECENTRIQ as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. When administering with carboplatin and etoposide, administer TECENTRIQ prior to chemotherapy when given on the same day. (2.2)Hepatocellular CarcinomaAdminister TECENTRIQ as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. Administer TECENTRIQ prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every weeks. (2.2)MelanomaFollowing completion of 28 day cycle of cobimetinib and vemurafenib, administer TECENTRIQ 840 mg every weeks, 1200 mg every weeks, or 1680 mg 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 as single agent as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. (2.2). In the adjuvant setting, administer TECENTRIQ following resection and up to cycles of platinum-based chemotherapy as 840 mg every weeks, 1200 mg every weeks or 1680 mg every weeks for up to year. (2.2). In the metastatic setting, administer TECENTRIQ as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. (2.2). When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day. (2.2). Administer TECENTRIQ as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. When administering with carboplatin and etoposide, administer TECENTRIQ prior to chemotherapy when given on the same day. (2.2). Administer TECENTRIQ as 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks. Administer TECENTRIQ prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every weeks. (2.2). Following completion of 28 day cycle of cobimetinib and vemurafenib, administer TECENTRIQ 840 mg every weeks, 1200 mg every weeks, or 1680 mg every weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily. (2.2). 2.1Patient Selection for Treatment of Urothelial Carcinoma, Non-Small Cell Lung Cancer and Melanoma. Select cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma for treatment with TECENTRIQ based on the PD-L1 expression on tumor-infiltrating immune cells [see Clinical Studies (14.1)].Select patients with Stage II to IIIA non-small cell lung cancer for treatment with TECENTRIQ as single agent based on PD-L1 expression on tumor cells [see Clinical Studies (14.2)]. Select patients with first-line metastatic non-small cell lung cancer for treatment with TECENTRIQ as single agent based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells [see Clinical Studies (14.2)]. Information on FDA-approved tests for the determination of PD-L1 expression in locally advanced or metastatic urothelial carcinoma or non-small cell lung cancer are available at: http://www.fda.gov/CompanionDiagnostics.Select patients with unresectable or metastatic melanoma for treatment with TECENTRIQ 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 detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Dosage. The recommended dosages of TECENTRIQ administered intravenously as single agent are presented in Table 1.Table 1: Recommended Dosage of TECENTRIQ as Single AgentIndicationRecommended Dosage of TECENTRIQ60-minute intravenous infusion. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Duration of TherapyUrothelial Carcinoma840 mg every weeks or1200 mg every weeks or1680 mg every weeksUntil disease progression or unacceptable toxicityMetastatic NSCLCAdjuvant Treatment of NSCLC840 mg every weeks or1200 mg every weeks or1680 mg every weeksUp to one year, unless there is disease recurrence or unacceptable toxicityThe recommended intravenous dosages of TECENTRIQ in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with TECENTRIQ for the recommended dosage information, as appropriate.Table 2: Recommended Dosage of TECENTRIQ in Combination with Other Therapeutic AgentsIndicationRecommended Dosage of TECENTRIQ60-minute intravenous infusion. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Duration of TherapyNSCLC840 mg every weeks or1200 mg every weeks or1680 mg every weeksAdminister TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day.Until disease progression or unacceptable toxicitySCLC840 mg every weeks or1200 mg every weeks or1680 mg every weeksAdminister TECENTRIQ prior to chemotherapy when given on the same day.HCC840 mg every weeks or1200 mg every weeks or1680 mg every weeksAdminister TECENTRIQ prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every weeks.Melanoma840 mg every weeks or1200 mg every weeks or1680 mg every weeksAdminister TECENTRIQ with cobimetinib 60 mg orally once daily (21 days on and days off) and vemurafenib 720 mg orally twice daily.Prior to initiating TECENTRIQ, patients should receive 28 day treatment cycle of cobimetinib 60 mg orally once daily (21 days on and days off) and vemurafenib 960 mg orally twice daily from Days 1-21 and vemurafenib 720 mg orally twice daily from Days 22-28.. 840 mg every weeks or. 1200 mg every weeks or. 1680 mg every weeks. 840 mg every weeks or. 1200 mg every weeks or. 1680 mg every weeks. 840 mg every weeks or. 1200 mg every weeks or. 1680 mg every weeks. 840 mg every weeks or. 1200 mg every weeks or. 1680 mg every weeks. 840 mg every weeks or. 1200 mg every weeks or. 1680 mg every weeks. 840 mg every weeks or. 1200 mg every weeks or. 1680 mg every weeks. 2.3Dosage Modifications for Adverse Reactions. No dose reduction for TECENTRIQ is recommended. In general, withhold TECENTRIQ for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue TECENTRIQ 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 corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.Dosage modifications for TECENTRIQ for adverse reactions that require management different from these general guidelines are summarized in Table 3.Table 3: 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 discontinueColitisGrades or 3Withhold Grade 4Permanently discontinueHepatitis with no tumor involvement of the liverAST or ALT increases to more than and up to times ULNorTotal bilirubin increases to more than 1.5 and up to times ULN Withhold AST or ALT increases to more than times ULNor Total bilirubin increases to more than times ULNPermanently discontinueHepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ 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 orBaseline 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 orTotal 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 discontinueMyocarditisGrades 2, 3, or 4Permanently discontinueNeurological ToxicitiesGrade 2Withhold Grades or 4Permanently discontinueOther Adverse ReactionsInfusion-Related Reactions [see Warnings and Precautions (5.2)] Grades or 2Interrupt or slow the rate of infusionGrades or 4Permanently discontinue. 2.4Preparation and Administration. PreparationVisually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial.Prepare the solution for infusion as follows:Select the appropriate vial(s) based on the prescribed dose.Withdraw the required volume of TECENTRIQ from the vial(s) using sterile needle and syringe.Dilute to final concentration between 3.2 mg/mL and 16.8 mg/mL in polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection, USP.Dilute with only 0.9% Sodium Chloride Injection, USP.Mix diluted solution by gentle inversion. Do not shake.Discard used or empty vials of TECENTRIQ.. Select the appropriate vial(s) based on the prescribed dose.. Withdraw the required volume of TECENTRIQ from the vial(s) using sterile needle and syringe.. Dilute to final concentration between 3.2 mg/mL and 16.8 mg/mL in polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection, USP.. Dilute with only 0.9% Sodium Chloride Injection, USP.. Mix diluted solution by gentle inversion. Do not shake.. Discard used or empty vials of TECENTRIQ.. Storage of Infusion SolutionThis product does not contain preservative.Administer immediately once prepared. If diluted TECENTRIQ infusion solution is not used immediately, store solution either:At room temperature for no more than hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration of the infusion, orUnder refrigeration at 2C to 8C (36F to 46F) for no more than 24 hours from time of preparation.Do not freeze.Do not shake.. At room temperature for no more than hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration of the infusion, or. Under refrigeration at 2C to 8C (36F to 46F) for no more than 24 hours from time of preparation.. AdministrationAdminister the initial infusion over 60 minutes through an intravenous line with or without sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2-0.22 micron). If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.Do not coadminister other drugs through the same intravenous line.Do not administer as an intravenous push or bolus.

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. Injection: 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in single-dose vial.. Injection: 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) solution in single-dose vial. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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

GERIATRIC USE SECTION.

8.5Geriatric Use. Of 2616 patients with metastatic urothelial carcinoma, metastatic NSCLC, and other tumor types treated with single agent TECENTRIQ in clinical studies, 49% were 65 years and over and 15% were 75 years and over. Of 2421 patients with NSCLC and SCLC treated with TECENTRIQ 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 patients aged 65 years or older and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. TECENTRIQ injection is sterile, preservative-free, and colorless to slightly yellow solution for intravenous infusion supplied as carton containing one 840 mg/14 mL single-dose vial (NDC 50242-918-01) or 1,200 mg/20 mL single-dose vial (NDC 50242-917-01).. Store vials under refrigeration at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze. Do not shake.

IMMUNOGENICITY.

6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to atezolizumab in the studies described above with the incidence of antibodies in other studies or to other products may be misleading.Among 111 patients in IMvigor210 (Cohort 1), 48% tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposures. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions. Among 565 patients with NSCLC in OAK, 30% tested positive for treatment-emergent anti-drug antibodies (ADA) at one or more post-dose time points. The median onset time to ADA formation was weeks. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA also had decreased systemic atezolizumab exposure [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA positive by week (21%; 118/560) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week [see Clinical Studies (14.2)]. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions.Among 487 ADA-evaluable patients with NSCLC who received atezolizumab in IMpower010, 31% (n=152) tested positive for treatment-emergent ADA at one or more post-dose time points. Among 241 patients in the PD-L1 SP263 >=1% TC Stage II-IIIA population, 28% (n=67) tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative [see Clinical Pharmacology (12.3)]. There were insufficient numbers of patients and DFS events in the ADA-positive subgroup (19%; 39/207 by week 7) to determine whether ADA alters the efficacy of atezolizumab. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions.Among 364 ADA-evaluable patients with NSCLC who received TECENTRIQ with bevacizumab, paclitaxel and carboplatin in IMpower150, 36% (n=132) tested positive for treatment-emergent ADA at one or more post-dose time points and 83% of these 132 patients tested ADA positive prior to receiving the second dose of atezolizumab. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA negative [see Clinical Pharmacology (12.3)]. The presence of ADA did not increase the incidence or severity of adverse reactions [see Clinical Studies (14.2)]. Among 315 ADA-evaluable patients with HCC who received TECENTRIQ and bevacizumab in IMbrave150, 28% (n=88) tested positive for treatment-emergent ADA at one or more post-dose time points and 66% (58/88) of these 88 patients tested ADA-positive prior to receiving the third dose of TECENTRIQ. The ability of these binding ADA to neutralize atezolizumab is unknown. Patients who tested positive for treatment-emergent ADA had lower systemic atezolizumab exposure as compared to patients who were ADA-negative [see Clinical Pharmacology (12.3)]. Exploratory analyses showed that the subset of patients who were ADA-positive by week (20%; 58/288) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 6; [see Clinical Studies (14.4)]. The presence of ADA did not have clinically significant effect on the incidence or severity of adverse reactions.Among 218 ADA-evaluable patients with melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib in IMspire150, 13% (n=29) tested positive for treatment-emergent ADA at one or more post-dose time points. Patients who tested positive for treatment-emergent ADA had decreased systemic atezolizumab exposure [see Clinical Pharmacology (12.3)]. There are insufficient numbers of patients with positive ADA to determine whether ADA alters the efficacy or incidence or severity of adverse reactions.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. TECENTRIQ is programmed death-ligand (PD-L1) blocking antibody indicated:Urothelial Carcinomafor the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test, orare not eligible for any platinum-containing chemotherapy regardless of PD-L1 status This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1.1)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. (1.2, 14.2)for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained >= 50% of tumor cells [TC >= 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 10% of the tumor area [IC >= 10%] ), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. (1.2)in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. (1.2)in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (1.2)for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ. (1.2)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). (1.3)Hepatocellular Carcinoma (HCC)in combination with bevacizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy. (1.4 Melanomain combination with cobimetinib and vemurafenib for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. (1.5). for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test, orare not eligible for any platinum-containing chemotherapy regardless of PD-L1 status are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test, or. are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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. (1.2, 14.2). for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained >= 50% of tumor cells [TC >= 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 10% of the tumor area [IC >= 10%] ), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. (1.2). in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. (1.2). in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (1.2). for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ. (1.2). in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.3). in combination with bevacizumab for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy. (1.4 . in combination with cobimetinib and vemurafenib for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. (1.5). 1.1Urothelial Carcinoma. TECENTRIQ is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test [see Dosage and Administration (2.1)], orare not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).. are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test [see Dosage and Administration (2.1)], or. are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.. 1.2Non-Small Cell Lung Cancer. TECENTRIQ, as single-agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.2)] 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, as single agent, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained >= 50% of tumor cells [TC >= 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 10% of the tumor area [IC >= 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [see Dosage and Administration (2.1)]. TECENTRIQ, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.TECENTRIQ, in combination with paclitaxel protein-bound and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.TECENTRIQ, as single-agent, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ.. TECENTRIQ, as single-agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.2)] 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, as single agent, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained >= 50% of tumor cells [TC >= 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 10% of the tumor area [IC >= 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [see Dosage and Administration (2.1)]. TECENTRIQ, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.. TECENTRIQ, in combination with paclitaxel protein-bound and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.. TECENTRIQ, as single-agent, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ.. 1.3Small Cell Lung Cancer. TECENTRIQ, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).. 1.4Hepatocellular Carcinoma. TECENTRIQ, in combination with bevacizumab, is indicated for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.. 1.5Melanoma. TECENTRIQ, in combination with cobimetinib and vemurafenib, is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma [see Dosage and Administration (2.1)].

INFORMATION FOR PATIENTS SECTION.

17PATIENT 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, 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 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 at least months after the last dose of TECENTRIQ [see Use in Specific Populations (8.3)].. LactationAdvise female patients not to breastfeed while taking TECENTRIQ and for at least months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2Lactation. Risk SummaryThere is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise women not to breastfeed during treatment and for at least 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 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 cell infiltration and activation compared to targeted therapy alone.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL 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 dose and was reversible. There was no effect on the male monkey reproductive organs.. 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. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 20 mL Vial Carton. NDC 50242-917-01Tecentriq(R) (atezolizumab)Injection1200 mg/20 mL(60 mg/mL)For Intravenous Infusion After DilutionSingle-Dose VialDiscard Unused PortionNo preservative.Attention Pharmacist: Dispense theaccompanying Medication Guideto each patient.1 vialRx onlyGenentech10199144. PRINCIPAL DISPLAY PANEL 20 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and effectiveness of TECENTRIQ have not been established in pediatric patients.The safety and antitumor activity of TECENTRIQ were assessed but not established in single-arm, multi-center, multi-cohort trial (NCT02541604) in 60 pediatric patients aged months to <17 years with relapsed or progressive solid tumors and lymphomas. No new safety signals were observed in pediatric patients in this study.In pediatric patients who received TECENTRIQ 15 mg/kg with maximum dose of 1200 mg every weeks, the steady-state exposure (AUC) of atezolizumab in pediatric patients aged 12 years or older was comparable to that in adult patients who received TECENTRIQ 1200 mg every weeks, while the exposure trended lower in pediatric patients less than 12 years old.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Patients exposure to atezolizumab increased dose proportionally over the dose range of mg/kg to 20 mg/kg, including dose of 1200 mg administered every weeks. The clearance (CV%) was 0.20 L/day (29%), the volume of distribution at steady state was 6.9 L, and the terminal half-life was 27 days. Steady state was achieved after to weeks following multiple doses. The systemic accumulation ratio for every weeks administration and every weeks administration was 3.3- and 1.9- fold, respectively. Atezolizumab clearance was found to decrease over time, with mean maximal reduction (CV%) from baseline value of approximately 17% (41%); however, the decrease in clearance was not considered clinically relevant.. Specific PopulationsAge (21 to 89 years), body weight, sex, albumin levels, tumor burden, region or race, mild or moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2], mild hepatic impairment (bilirubin <= ULN and AST ULN or bilirubin 1 to 1.5 ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3x ULN and any AST), level of PD-L1 expression, or performance status had no clinically significant effect on the systemic exposure of atezolizumab. Across clinical trials with TECENTRIQ, median atezolizumab clearance in patients who tested positive for treatment-emergent anti-drug antibodies (ADA) was 19% (range: 18% to 49%) higher as compared to atezolizumab clearance in patients who tested negative for treatment-emergent ADA.. Drug Interaction StudiesThe drug interaction potential of atezolizumab is unknown.

PREGNANCY SECTION.

8.1Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)], TECENTRIQ can cause fetal harm when administered to pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women.Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death (see Data). Advise females of reproductive potential of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataAnimal reproduction studies have not been conducted with TECENTRIQ 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 TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.

RECENT MAJOR CHANGES SECTION.

Indications and Usage, Triple-Negative Breast Cancer Accelerated Approval Indication Removed10/2021Indications and Usage, Urothelial Carcinoma Accelerated Approval Indication Removed (1.1)4/2021Indications and Usage, Non-Small Cell Lung Cancer (1.2)10/2021Dosage and Administration (2.1)1/2022Dosage and Administration (2.2)2/2021Warnings and Precautions (5.1)10/2021.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE TECENTRIQ(R) (te-SEN-trik) (atezolizumab) InjectionThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 10/2021 What is the most important information should know about TECENTRIQTECENTRIQ is medicine that may treat certain cancers by working with your immune system. TECENTRIQ 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 heart beatincreased 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. 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. 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. 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 if you have severe side effects.What is TECENTRIQTECENTRIQ is prescription medicine used to treat adults with:a type of bladder and urinary tract cancer called urothelial carcinoma. TECENTRIQ may be used when your bladder cancer has spread or cannot be removed by surgery, and if you have any one of the following conditions: you are not able to take chemotherapy that contains medicine called cisplatin, and your cancer tests positive for PD-L1, or you are not able to take chemotherapy that contains any platinum regardless of PD-L1 status. type of lung cancer called non-small cell lung cancer (NSCLC).TECENTRIQ 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 may be used alone as your first treatment when your lung cancer:has spread or grown, and your cancer tests positive for high PD-L1, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ may also be used alone when your lung cancer:has spread or grown, and you have tried chemotherapy that contains platinum, and it did not work or is no longer working.if your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.a type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung canceris type called extensive-stage SCLC, which means that it has spread or grown.a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:has spread or cannot be removed by surgery, and you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.a type of skin cancer called melanoma. TECENTRIQ 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 combination is right for you.It is not known if TECENTRIQ is safe and effective in children.Before receiving TECENTRIQ, 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 area have condition that affects your nervous system, such as myasthenia gravis or Guillain-Barre syndromeare pregnant or plan to become pregnant. TECENTRIQ can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with TECENTRIQ.You should use an effective method of birth control during your treatment and for at least months after the last dose of TECENTRIQ. are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ passes into your breast milk. Do not breastfeed during treatment and for at least months after the last dose of TECENTRIQ.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive TECENTRIQYour healthcare provider will give you TECENTRIQ into your vein through an intravenous (IV) line over 30 to 60 minutes.TECENTRIQ is usually given every 2, 3, or 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 TECENTRIQTECENTRIQ can cause serious side effects, including:See What is the most important information should know about TECENTRIQThe most common side effects of TECENTRIQ when used alone include:feeling tired or weakdecreased appetitenauseacoughshortness of breathThe most common side effects of TECENTRIQ when used in lung cancer with other anti-cancer medicines include:feeling tired or weaknauseahair lossconstipationdiarrheadecreased appetiteThe most common side effects of TECENTRIQ when used in hepatocellular carcinoma 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 injuryfever nauseaitchingswelling of legs or armsmouth swelling (sometimes with sores)low thyroid hormone levelssunburn or sun sensitivityTECENTRIQ 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.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of TECENTRIQ.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about TECENTRIQ that is written for health professionals.What are the ingredients in TECENTRIQActive ingredient: atezolizumabInactive ingredients: glacial acetic acid, L-histidine, polysorbate 20 and sucroseManufactured by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990 USAU.S. License No. 1048 TECENTRIQ is registered trademark of Genentech, Inc.For more information, call 1-844-832-3687 or go to www.TECENTRIQ.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 heart beat. 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 bladder and urinary tract cancer called urothelial carcinoma. TECENTRIQ may be used when your bladder cancer has spread or cannot be removed by surgery, and if you have any one of the following conditions: you are not able to take chemotherapy that contains medicine called cisplatin, and your cancer tests positive for PD-L1, or you are not able to take chemotherapy that contains any platinum regardless of PD-L1 status. you are not able to take chemotherapy that contains medicine called cisplatin, and your cancer tests positive for PD-L1, or you are not able to take chemotherapy that contains any platinum regardless of PD-L1 status.. type of lung cancer called non-small cell lung cancer (NSCLC).TECENTRIQ 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 may be used alone as your first treatment when your lung cancer:has spread or grown, and your cancer tests positive for high PD-L1, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:has spread or grown, and is type called non-squamous NSCLC, and your tumor does not have an abnormal EGFR or ALK gene.TECENTRIQ may also be used alone when your lung cancer:has spread or grown, and you have tried chemotherapy that contains platinum, and it did not work or is no longer working.if your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.. TECENTRIQ 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 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 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 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 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 may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung canceris type called extensive-stage SCLC, which means that it has spread or grown.. is type called extensive-stage SCLC, which means that it has spread or grown.. type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:has spread or cannot be removed by surgery, and you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.. 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 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 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 combination is right for you.. 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 can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with TECENTRIQ.You should use an effective method of birth control during your treatment and for at least months after the last dose of TECENTRIQ. Your healthcare provider should do pregnancy test before you start treatment with TECENTRIQ.. You should use an effective method of birth control during your treatment and for at least months after the last dose of TECENTRIQ.. are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ passes into your breast milk. Do not breastfeed during treatment and for at least months after the last dose of TECENTRIQ.. Your healthcare provider will give you TECENTRIQ into your vein through an intravenous (IV) line over 30 to 60 minutes.. TECENTRIQ is usually given every 2, 3, or 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. feeling tired or weak. decreased appetite. nausea. cough. shortness of breath. feeling tired or weak. nausea. hair loss. constipation. diarrhea. decreased appetite. 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.

1.1Urothelial Carcinoma. TECENTRIQ is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test [see Dosage and Administration (2.1)], orare not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).. are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >= 5% of the tumor area), as determined by an FDA-approved test [see Dosage and Administration (2.1)], or. are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)], TECENTRIQ can cause fetal harm when administered to pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women.Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death (see Data). Advise females of reproductive potential of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataAnimal reproduction studies have not been conducted with TECENTRIQ 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 TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.. 8.2Lactation. Risk SummaryThere is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise women not to breastfeed during treatment and for at least months after the last dose.. 8.3Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating TECENTRIQ [see Use in Specific Populations (8.1)].. Contraception. FemalesBased on its mechanism of action, TECENTRIQ can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least months following the last dose.. Infertility. FemalesBased on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].. 8.4Pediatric Use. The safety and effectiveness of TECENTRIQ have not been established in pediatric patients.The safety and antitumor activity of TECENTRIQ were assessed but not established in single-arm, multi-center, multi-cohort trial (NCT02541604) in 60 pediatric patients aged months to <17 years with relapsed or progressive solid tumors and lymphomas. No new safety signals were observed in pediatric patients in this study.In pediatric patients who received TECENTRIQ 15 mg/kg with maximum dose of 1200 mg every weeks, the steady-state exposure (AUC) of atezolizumab in pediatric patients aged 12 years or older was comparable to that in adult patients who received TECENTRIQ 1200 mg every weeks, while the exposure trended lower in pediatric patients less than 12 years old.. 8.5Geriatric Use. Of 2616 patients with metastatic urothelial carcinoma, metastatic NSCLC, and other tumor types treated with single agent TECENTRIQ in clinical studies, 49% were 65 years and over and 15% were 75 years and over. Of 2421 patients with NSCLC and SCLC treated with TECENTRIQ 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 patients aged 65 years or older and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Immune-Mediated Adverse Reactions (5.1)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.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: Interrupt, slow the rate of infusion, or permanently discontinue based on severity of infusion reactions. (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. (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 Reactions (5.1)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.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.. 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: Interrupt, slow the rate of infusion, or permanently discontinue based on severity of infusion reactions. (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. (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 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 depending on severity [see Dosage and Administration (2.3)]. In general, if TECENTRIQ 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 can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.. TECENTRIQ as Single Agent:Immune-mediated pneumonitis occurred in 3% (83/2616) of patients receiving TECENTRIQ as single agent, including fatal (<0.1%), Grade (0.2%), Grade (0.8%), and Grade (1.1%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 0.5% and withholding of TECENTRIQ in 1.5% of patients. Systemic corticosteroids were required in 55% (46/83) of patients with pneumonitis. Pneumonitis resolved in 69% of the 83 patients. Of the 39 patients in whom TECENTRIQ was withheld for pneumonitis, 25 reinitiated TECENTRIQ after symptom improvement; of these, 4% had recurrence of pneumonitis. In IMpower010 immune-mediated pneumonitis occurred in 3.8% (19/495) of patients receiving TECENTRIQ as single agent, including fatal (0.2%), Grade (0.2%), and Grade (0.6%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 2.2% and withholding of TECENTRIQ in 0.8% of patients.Systemic corticosteroids were required in 63% (12/19) of patients with pneumonitis. Pneumonitis resolved in 84% of the 19 patients. TECENTRIQ in Combination with Cobimetinib and Vemurafenib:Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade (1.3%) and Grade (7%) adverse reactions. Pneumonitis led to permanent discontinuation of TECENTRIQ in 2.6% and withholding of TECENTRIQ 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 TECENTRIQ was withheld for pneumonitis, 10 reinitiated TECENTRIQ after symptom improvement; of these, 50% had recurrence of pneumonitis.. Immune-Mediated ColitisTECENTRIQ can cause immune-mediated colitis. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal (GI) 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.. TECENTRIQ as Single Agent:Immune-mediated colitis occurred in 1% (26/2616) of patients receiving TECENTRIQ as single agent, including Grade (0.5%) and Grade (0.3%) adverse reactions. Colitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.5% of patients.Systemic corticosteroids were required in 50% (13/26) of patients with colitis. Colitis resolved in 73% of the 26 patients. Of the 12 patients in whom TECENTRIQ was withheld for colitis, reinitiated treatment with TECENTRIQ after symptom improvement; of these, 25% had recurrence of colitis.. Immune-Mediated HepatitisTECENTRIQ can cause immune-mediated hepatitis.Immune-mediated hepatitis occurred in 1.8% (48/2616) of patients receiving TECENTRIQ as single agent, including fatal (<0.1%), Grade (0.2%), Grade (0.5%), and Grade (0.5%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 0.2% and withholding of TECENTRIQ in 0.2% of patients.Systemic corticosteroids were required in 25% (12/48) of patients with hepatitis. Hepatitis resolved in 50% of the 48 patients. Of the patients in whom TECENTRIQ was withheld for hepatitis, reinitiated treatment with TECENTRIQ after symptom improvement; of these, none had recurrence of hepatitis.. TECENTRIQ in Combination with Cobimetinib and Vemurafenib:Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade (1.3%), Grade (1.7%) and Grade (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of TECENTRIQ in 2.2% and withholding of TECENTRIQ 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 TECENTRIQ was withheld for hepatitis, reinitiated TECENTRIQ after symptom improvement; of these, 33% had recurrence of hepatitis.. Immune-Mediated Endocrinopathies. Adrenal InsufficiencyTECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ depending on severity [see Dosage and Administration (2.3)].Adrenal insufficiency occurred in 0.4% (11/2616) of patients receiving TECENTRIQ as single agent, including Grade (<0.1%) and Grade (0.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in one patient and withholding of TECENTRIQ in one patient.Systemic corticosteroids were required in 82% (9/11) of patients with adrenal insufficiency; of these, patients remained on systemic corticosteroids. The single patient in whom TECENTRIQ was withheld for adrenal insufficiency did not reinitiate TECENTRIQ.In IMpower010 immune-mediated adrenal insufficiency occurred in 1.2% (6/495) of patients receiving TECENTRIQ as single agent, including Grade (0.4%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of TECENTRIQ in 0.6% and withholding of TECENTRIQ in 0.2% of patients.Systemic corticosteroids were required in 83% (5/6) of patients with adrenal insufficiency; of these, patients remained on systemic corticosteroids.. HypophysitisTECENTRIQ can cause immune-mediated hypophysitis. 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 depending on severity [see Dosage and Administration (2.3)].Hypophysitis occurred in <0.1% (2/2616) of patients receiving TECENTRIQ as single agent, including Grade (1 patient, <0.1%) adverse reactions. Hypophysitis led to permanent discontinuation of TECENTRIQ in one patient and no patients required withholding of TECENTRIQ.Systemic corticosteroids were required in 50% (1/2) of patients with hypophysitis. Hypophysitis did not resolve in these patients.. Thyroid disordersTECENTRIQ 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 depending on severity [see Dosage and Administration (2.3)].. Thyroiditis:Thyroiditis occurred in 0.2% (4/2616) of patients receiving TECENTRIQ as single agent, including Grade (<0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in one patient.Hormone replacement therapy was required in 75% (3/4) of patients with thyroiditis. Systemic corticosteroids were required in 25% (1/4) of patients with thyroiditis. Thyroiditis resolved in 50% of patients. The single patient in whom TECENTRIQ was withheld for thyroiditis reinitiated TECENTRIQ; this patient did not have recurrence of thyroiditis.In IMpower010, thyroiditis occurred in 1.2% (6/495) of patients receiving TECENTRIQ as single agent, including Grade (0.4%) adverse reactions. Thyroiditis led to withholding of TECENTRIQ in one patient.Hormone replacement therapy was required in 67% (4/6) of patients with thyroiditis. Systemic corticosteroids were required in 33% (2/6) of patients with thyroiditis. Thyroiditis resolved in 50% of patients.. Hyperthyroidism:. TECENTRIQ as Single Agent:Hyperthyroidism occurred in 0.8% (21/2616) of patients receiving TECENTRIQ as single agent, including Grade (0.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.1% of patients.Antithyroid therapy was required in 29% (6/21) of patients with hyperthyroidism. Of these patients, the majority remained on antithyroid treatment. Of the patients in whom TECENTRIQ was withheld for hyperthyroidism, one patient reinitiated TECENTRIQ; this patient did not have recurrence of hyperthyroidism.In IMpower010 hyperthyroidism occurred in 6% (32/495) of patients receiving TECENTRIQ as single agent, including Grade (0.4%) adverse reactions. Hyperthyroidism led to permanent discontinuation of TECENTRIQ in 0.8% and withholding of TECENTRIQ in 2.8% of patients.Antithyroid therapy was required in 38% (12/32) of patients with hyperthyroidism. Of these 12 patients, the majority remained on antithyroid treatment. Of the 14 patients in whom TECENTRIQ was withheld for hyperthyroidism, patients reinitiated TECENTRIQ.. TECENTRIQ in Combination with Cobimetinib and Vemurafenib:Hyperthyroidism occurred in 19% (43/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade (0.9%) and Grade (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of TECENTRIQ in 0.4% and withholding of TECENTRIQ 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 TECENTRIQ was withheld for hyperthyroidism, 18 patients reinitiated TECENTRIQ; of these, 28% had recurrence of hyperthyroidism.. Hypothyroidism:. TECENTRIQ as Single Agent: Hypothyroidism occurred in 4.9% (128/2616) of patients receiving TECENTRIQ as single agent, including Grade (0.2%) and Grade (3.4%) adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ in 0.6% of patients.Hormone replacement therapy was required in 81% (104/128) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 17 patients in whom TECENTRIQ was withheld for hypothyroidism, reinitiated TECENTRIQ after symptom improvement. In IMpower010 hypothyroidism occurred in 17% (86/495) of patients receiving TECENTRIQ as single agent. Hypothyroidism led to permanent discontinuation of TECENTRIQ in 1.6% and withholding of TECENTRIQ in 1.6% of patients.Hormone replacement was required in 57% (49/86) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the patients in whom TECENTRIQ was withheld for hypothyroidism, reinitiated TECENTRIQ after symptom improvement.. TECENTRIQ in Combination with Platinum-based Chemotherapy:Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC and SCLC receiving TECENTRIQ 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 TECENTRIQ in 0.1% and withholding of TECENTRIQ 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 TECENTRIQ was withheld for hypothyroidism, reinitiated TECENTRIQ after symptom improvement.. TECENTRIQ in Combination with Cobimetinib and Vemurafenib:Hypothyroidism occurred in 26% (60/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade (9.1%) adverse reactions. Hypothyroidism did not lead to permanent discontinuation of TECENTRIQ in any of these patients, but led to withholding of TECENTRIQ 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 TECENTRIQ was withheld for hypothyroidism, reinitiated TECENTRIQ after symptom improvement. The majority of patients with hypothyroidism required long term thyroid replacement.. Type Diabetes Mellitus, which can present with Diabetic KetoacidosisMonitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TECENTRIQ depending on severity [see Dosage and Administration (2.3)]. Type diabetes mellitus occurred in 0.3% (7/2616) of patients receiving TECENTRIQ, including Grade (0.2%) and Grade (<0.1%) adverse reactions. Type diabetes mellitus led to permanent discontinuation of TECENTRIQ in one patient and withholding of TECENTRIQ in two patients.Treatment with insulin was required for all patients with confirmed Type diabetes mellitus and insulin therapy was continued long-term. Of the patients in whom TECENTRIQ was withheld for Type diabetes mellitus, both re-initiated TECENTRIQ treatment.. Immune-Mediated Nephritis with Renal DysfunctionTECENTRIQ can cause immune-mediated nephritis.. TECENTRIQ as Single Agent:Immune-mediated nephritis with renal dysfunction occurred in <0.1% (1/2616) of patients receiving TECENTRIQ as single agent, and this adverse reaction was Grade (<0.1%) adverse reaction. Nephritis led to permanent discontinuation of TECENTRIQ in this patient.This patient required systemic corticosteroids. In this patient, nephritis did not resolve.. TECENTRIQ in Combination with Cobimetinib and Vemurafenib:Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving TECENTRIQ in combination with cobimetinib and vemurafenib, including Grade (1.3%) adverse reactions. Nephritis led to permanent discontinuation of TECENTRIQ in 0.4% and withholding of TECENTRIQ 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 TECENTRIQ was withheld for nephritis, both reinitiated TECENTRIQ after symptom improvement and neither had recurrence of nephritis.. Immune-Mediated Dermatologic Adverse ReactionsTECENTRIQ can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), 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 depending on severity [see Dosage and Administration (2.3)].Immune-mediated dermatologic adverse reactions occurred in 0.6% (15/2616) of patients receiving TECENTRIQ as single agent, including Grade (<0.1%) and Grade (0.2%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 0.2% of patients.Systemic corticosteroids were required in 20% (3/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87% of the 15 patients. Of the patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none re-initiated TECENTRIQ.. Other Immune-Mediated Adverse ReactionsThe following clinically significant immune-mediated adverse reactions occurred at an incidence of 1% (unless otherwise noted) in patients who received TECENTRIQ 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 can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. 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.. 5.2Infusion-Related Reactions. TECENTRIQ can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity [see Dosage and Administration (2.3)]. For Grade or infusion-related reactions, consider using pre-medications with subsequent doses.In clinical studies enrolling 2616 patients with various cancers who received TECENTRIQ as single-agent [see Adverse Reactions (6.1)], infusion-related reactions occurred in 1.3% of patients, including Grade (0.2%). The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as single-agent in patients with various cancers, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range (840 mg Q2W to 1680 mg Q4W).. 5.3Complications 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 (VOD) 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 can cause fetal harm when administered to pregnant woman. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death.Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least months after the last dose [see Use in Specific Populations (8.1, 8.3)].

PHARMACODYNAMICS SECTION.

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

POSTMARKETING EXPERIENCE SECTION.

6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of TECENTRIQ. 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.