TECENTRIQ

Atezolizumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa. TECENTRIQ (atezolizumab) injection for intravenous use is a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials. Each 20 mL vial contains 1200 mg of atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 mg), with a pH of 5.8. Each 14 mL vial contains 840 mg of atezolizumab and is formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) with a pH of 5.8.

TECENTRIQ is a programmed death-ligand 1 (PD-L1) blocking antibody indicated: Non-Small Cell Lung Cancer (NSCLC) as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-approved test. ( 1.1 , 14.1 ) for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%] ), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations ( 1.1 ) for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ. ( 1.1 ) Small Cell Lung Cancer (SCLC) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). ( 1.2 ) in combination with lurbinectedin, for the maintenance treatment of adult patients with ES-SCLC whose disease has not progressed after first-line induction therapy with TECENTRIQ or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide. ( 1.2 ) Hepatocellular Carcinoma (HCC) in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic HCC who have not received prior systemic therapy. ( 1.3 ) Melanoma in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. ( 1.4 ) Alveolar Soft Part Sarcoma (ASPS) for the treatment of adult and pediatric patients 2 years of age and older with unresectable or metastatic ASPS. ( 1.5 ) 1.1 Non-Small Cell Lung Cancer TECENTRIQ, as a single-agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1) ] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-approved test [see Dosage and Administration (2.1) ]. TECENTRIQ, as a single agent, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [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 a single-agent, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ. 1.2 Small Cell Lung Cancer TECENTRIQ, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). TECENTRIQ, in combination with lurbinectedin, is indicated for the maintenance treatment of adult patients with ES-SCLC whose disease has not progressed after first-line induction therapy with TECENTRIQ or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide. 1.3 Hepatocellular Carcinoma TECENTRIQ, in combination with bevacizumab, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy. 1.4 Melanoma TECENTRIQ, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma [see Dosage and Administration (2.1) ] . 1.5 Alveolar Soft Part Sarcoma TECENTRIQ, as a single agent, is indicated for the treatment of adult and pediatric patients 2 years of age and older with unresectable or metastatic alveolar soft part sarcoma (ASPS).

Administer TECENTRIQ intravenously over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. NSCLC In the adjuvant setting, administer TECENTRIQ following resection and up to 4 cycles of platinum-based chemotherapy as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. ( 2.2 ) In the metastatic setting, administer TECENTRIQ as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 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 Cancer Administer TECENTRIQ as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. Administer TECENTRIQ prior to chemotherapy when given on the same day. ( 2.2 ) Hepatocellular Carcinoma Administer TECENTRIQ as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. Administer TECENTRIQ prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every 3 weeks. ( 2.2 ) Melanoma Following completion of a 28-day cycle of cobimetinib and vemurafenib, administer TECENTRIQ 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily. ( 2.2 ) ASPS Adults: Administer TECENTRIQ as 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. ( 2.2 ) Pediatric patients 2 years of age and older: 15 mg/kg (up to a maximum of 1200 mg), every 3 weeks ( 2.2 ) 2.1 Patient Selection for Treatment of Non-Small Cell Lung Cancer and Melanoma Select patients with Stage II to IIIA non-small cell lung cancer for treatment with TECENTRIQ as a single agent based on PD-L1 expression on tumor cells [see Clinical Studies (14.1) ]. Select patients with first-line metastatic non-small cell lung cancer for treatment with TECENTRIQ as a single agent based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells [see Clinical Studies (14.1) ]. Information on FDA-approved tests for the determination of PD-L1 expression in metastatic 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 a BRAF V600 mutation [see Clinical Studies (14.4) ]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosages of TECENTRIQ are presented in Table 1 . Administer TECENTRIQ as an intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Table 1: Recommended Dosage of TECENTRIQ as a Single Agent Indication Recommended Dosage of TECENTRIQ Duration of Therapy Metastatic NSCLC 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Until disease progression or unacceptable toxicity Adjuvant Treatment of NSCLC 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Up to one year, unless there is disease recurrence or unacceptable toxicity ASPS (adult) 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Until disease progression or unacceptable toxicity ASPS (pediatric, 2 years of age and older) 15 mg/kg (up to a maximum 1200 mg) every 3 weeks The 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 Agents Indication Recommended Dosage of TECENTRIQ Duration of Therapy NSCLC 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day. Until disease progression or unacceptable toxicity SCLC 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ prior to chemotherapy when given on the same day. HCC 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every 3 weeks. Melanoma 840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ with cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 720 mg orally twice daily. Prior to initiating TECENTRIQ, patients should receive a 28-day treatment cycle of cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 960 mg orally twice daily from Days 1-21 and vemurafenib 720 mg orally twice daily from Days 22-28. 2.3 Dosage 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 Reactions Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4 Dosage Modification ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic epidermal necrolysis Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grade 0 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 3 or 4 Permanently discontinue Colitis Grades 2 or 3 Withhold Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If 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 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grades 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grades 2 or 3 increased blood creatinine Withhold Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis or Pericarditis Grades 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grades 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Grades 1 or 2 Interrupt or slow the rate of infusion Grades 3 or 4 Permanently discontinue 2.4 Preparation and Administration Preparation Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial. Prepare the solution for infusion as follows: Select the appropriate vial(s) based on the prescribed dose. Withdraw the required volume of TECENTRIQ from the vial(s) using sterile needle and syringe. Dilute to a final concentration between 3.2 mg/mL and 16.8 mg/mL in a polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection, USP. Dilute with only 0.9% Sodium Chloride Injection, USP. Mix diluted solution by gentle inversion. Do not shake. Discard used or empty vials of TECENTRIQ. Storage of Infusion Solution This product does not contain a preservative. Administer immediately once prepared. If diluted TECENTRIQ infusion solution is not used immediately, store solution either: At room temperature for no more than 6 hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration of the infusion, or Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of preparation. Do not freeze. Do not shake. Administration Administer the initial infusion over 60 minutes through an intravenous line with or without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron). If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Do not coadminister other drugs through the same intravenous line. Do not administer as an intravenous push or bolus.

None. None. ( 4 )

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) ] TECENTRIQ as a single-agent Most common adverse reactions (≥ 20%) with TECENTRIQ as a single-agent are fatigue/asthenia, decreased appetite, nausea, cough, and dyspnea. ( 6.1 ) TECENTRIQ in combination with other antineoplastic drugs Most common adverse reactions (≥ 20%) in patients with NSCLC and SCLC are fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. ( 6.1 ) TECENTRIQ in combination with bevacizumab Most common adverse reactions (≥ 20%) in patients with HCC are hypertension, fatigue and proteinuria. ( 6.1 ) TECENTRIQ in combination with cobimetinib and vemurafenib Most common adverse reactions (≥ 20%) with TECENTRIQ in patients with melanoma are 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as a single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and three open-label, single arm studies (PCD4989g, BIRCH, FIR) which enrolled 1636 patients with metastatic NSCLC, and 980 patients with other tumor types. TECENTRIQ was administered at a dose of 1200 mg intravenously every 3 weeks in all studies except PCD4989g. Among the 2616 patients who received a single-agent TECENTRIQ, 36% were exposed for longer than 6 months and 20% were exposed for longer than 12 months. Using the dataset described for patients who received TECENTRIQ as a single-agent, the most common adverse reactions in ≥ 20% of patients were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%). In addition, the data reflect exposure to TECENTRIQ as a single agent as adjuvant therapy in 495 patients with early-stage NSCLC enrolled in a 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 6 months and 29% were exposed to TECENTRIQ for longer than 12 months. Among the 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with other antineoplastic drugs, the most common adverse reactions in ≥20% of patients were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%) and decreased appetite (27%). 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 6 months and 42% were exposed to TECENTRIQ for longer than 12 months. Non-Small Cell Lung Cancer (NSCLC) Adjuvant Treatment of Early-stage NSCLC IMpower010 The safety of TECENTRIQ was evaluated in IMpower010, a multicenter, open-label, randomized trial for the adjuvant treatment of patients with stage IB (tumors ≥ 4 cm) - IIIA NSCLC who had complete tumor resection and received up to 4 cycles of cisplatin-based adjuvant chemotherapy. Patients received TECENTRIQ 1200 mg every 3 weeks (n=495) for 1 year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.1) ] . The median number of cycles received was 16 (range: 1, 16). Fatal adverse reactions occurred in 1.8% of patients receiving 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 aminotransferase (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 4 and 5 summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower010. Table 4: Adverse Reactions Occurring in ≥10% of Patients with Early-Stage NSCLC Receiving TECENTRIQ in IMpower010 Adverse Reaction Graded per NCI CTCAE v4.0 TECENTRIQ N = 495 Best Supportive Care N = 495 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Skin and Subcutaneous Tissue Rash Includes 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 17 1.2 1.4 0 Pruritus 10 0 0.6 0 Endocrine Disorders Hypothyroidism Includes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased 14 0 0.6 0 Respiratory, Thoracic and Mediastinal Cough Productive cough, upper airway cough syndrome, cough 16 0 11 0 General Pyrexia Includes pyrexia, body temperature increased, hyperthermia 14 0.8 2.2 0.2 Fatigue Includes fatigue, asthenia 14 0.6 5 0.2 Nervous System Disorders Peripheral neuropathy Includes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy 12 0.4 7 0.2 Musculoskeletal and Connective Tissue Musculoskeletal pain Includes 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 14 0.8 9 0.2 Arthralgia Includes arthralgia, arthritis 11 0.6 6 0 Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with Early-Stage NSCLC Receiving TECENTRIQ in IMpower010 Laboratory Abnormality Graded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0). TECENTRIQ The denominators used to calculate the rate varied from 78-480 for BSC arm and 483 for TECENTRIQ are for all tests of interest based on the number of patients with a baseline value and at least one post-treatment value. Best Supportive Care All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Chemistry Increased aspartate aminotransferase 34 2.5 18 0 Increased alanine aminotransferase 30 3.3 19 0.4 Hyperkalemia 24 3.5 15 2.5 Increased blood creatinine 31 0.2 23 0.2 Metastatic Chemotherapy-Naïve NSCLC IMpower110 The safety of TECENTRIQ was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received TECENTRIQ 1200 mg every 3 weeks (n=286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n=263) until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ] . IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area). The median duration of exposure to 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 6 and 7 summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower110. Table 6: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving TECENTRIQ in IMpower110 Adverse Reaction TECENTRIQ N = 286 Platinum-Based Chemotherapy N = 263 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 Gastrointestinal Nausea 14 0.3 34 1.9 Constipation 12 1.0 22 0.8 Diarrhea 11 0 12 0.8 General Fatigue/asthenia 25 1.4 34 4.2 Pyrexia 14 0 9 0.4 Metabolism and Nutrition Decreased appetite 15 0.7 19 0 Respiratory, Thoracic and Mediastinal Dyspnea 14 0.7 10 0 Cough 12 0.3 10 0 Table 7: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower110 Laboratory Abnormality TECENTRIQ Platinum-Based Chemotherapy All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: TECENTRIQ (range: 278-281); platinum-based chemotherapy (range: 256-260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range. Hematology Anemia 69 1.8 94 20 Lymphopenia 47 9 59 17 Chemistry Hypoalbuminemia 48 0.4 39 2 Increased alkaline phosphatase 46 2.5 42 1.2 Hyponatremia 44 9 36 7 Increased ALT 38 3.2 32 0.8 Increased AST 36 3.2 32 0.8 Hyperkalemia 29 3.9 36 2.7 Hypocalcemia 24 1.4 24 2.7 Increased blood creatinine 24 0.7 33 1.5 Hypophosphatemia 23 3.6 21 2 IMpower150 The safety of TECENTRIQ with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, a multicenter, international, randomized, open-label trial in which 393 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m 2 or 200 mg/m 2 , and carboplatin AUC 6 mg/mL/min intravenously every 3 weeks for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg with bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ] . The median duration of exposure to TECENTRIQ was 8.3 months in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin. Fatal adverse reactions occurred in 6% of patients receiving TECENTRIQ; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection. Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (>2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis. TECENTRIQ was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%). Adverse reactions leading to interruption of TECENTRIQ occurred in 48%; the most common (>1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria. Tables 8 and 9 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin in IMpower150. Table 8: Adverse Reactions Occurring in ≥15% of Patients with NSCLC Receiving TECENTRIQ in IMpower150 Adverse Reaction TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin N = 393 Bevacizumab, Paclitaxel and Carboplatin N = 394 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 Nervous System Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paraesthesia, dysesthesia, polyneuropathy 56 3 47 3 Headache 16 0.8 13 0 General Fatigue/Asthenia 50 6 46 6 Pyrexia 19 0.3 9 0.5 Skin and Subcutaneous Tissue Alopecia 48 0 46 0 Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform 23 2 10 0.3 Musculoskeletal and Connective Tissue Myalgia/Pain Includes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain 42 3 34 2 Arthralgia 26 1 22 1 Gastrointestinal Nausea 39 4 32 2 Diarrhea Includes diarrhea, gastroenteritis, colitis, enterocolitis 33 6 25 0.5 Constipation 30 0.3 23 0.3 Vomiting 19 2 18 1 Metabolism and Nutrition Decreased appetite 29 4 21 0.8 Vascular Hypertension 25 9 22 8 Respiratory Cough 20 0.8 19 0.3 Epistaxis 17 1 22 0.3 Renal Proteinuria Data based on Preferred Terms since laboratory data for proteinuria were not systematically collected 16 3 15 3 Table 9: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower150 Laboratory Abnormality TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin Bevacizumab, Paclitaxel and Carboplatin All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with bevacizumab, paclitaxel, and carboplatin range: 337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0 Hematology Anemia 83 10 83 9 Neutropenia 52 31 45 26 Lymphopenia 48 17 38 13 Chemistry Hyperglycemia 61 0 60 0 Increased BUN 52 NA NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities 44 NA Hypomagnesemia 42 2 36 1 Hypoalbuminemia 40 3 31 2 Increased AST 40 4 28 0.8 Hyponatremia 38 10 36 9 Increased Alkaline Phosphatase 37 2 32 1 Increased ALT 37 6 28 0.5 Increased TSH 30 NA 20 NA Hyperkalemia 28 3 25 2 Increased Creatinine 28 1 19 2 Hypocalcemia 26 3 21 3 Hypophosphatemia 25 4 18 4 Hypokalemia 23 7 14 4 Hyperphosphatemia 25 NA 19 NA IMpower130 The safety of TECENTRIQ with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, a multicenter, international, randomized, open-label trial in which 473 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m 2 intravenously on Day 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ] . Among patients receiving TECENTRIQ, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. Fatal adverse reactions occurred in 5.3% of patients receiving TECENTRIQ; these included 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 10 and 11 summarize adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ with paclitaxel protein-bound and carboplatin in IMpower130. Table 10: Adverse Reactions Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower130 Adverse Reaction TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin N = 473 Paclitaxel Protein-Bound and Carboplatin N = 232 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General Fatigue/Asthenia 61 11 60 8 Gastrointestinal Nausea 50 3.4 46 2.2 Diarrhea Includes diarrhea, colitis, and gastroenteritis 43 6 32 6 Constipation 36 1.1 31 0 Vomiting 27 2.7 19 2.2 Musculoskeletal and Connective Tissue Myalgia/Pain Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 38 3 22 0.4 Nervous System Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 33 2.5 28 2.2 Respiratory, Thoracic and Mediastinal Dyspnea Includes dyspnea, dyspnea exertional and wheezing 32 4.9 25 1.3 Cough 27 0.6 17 0 Skin and Subcutaneous Tissue Alopecia 32 0 27 0 Rash Includes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular. 20 0.6 11 0.9 Metabolism and Nutrition Decreased appetite 30 2.1 26 2.2 Table 11: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower130 Laboratory Abnormality TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin N = 473 Paclitaxel Protein-Bound and Carboplatin N = 232 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with paclitaxel protein-bound and carboplatin (range: 423 - 467); paclitaxel protein-bound and carboplatin (range: 218 - 229). Graded per NCI CTCAE v4.0. Hematology Anemia 92 33 87 25 Neutropenia 75 50 67 39 Thrombocytopenia 73 19 59 13 Lymphopenia 71 23 61 16 Chemistry Hyperglycemia 75 8 66 8 Hypomagnesemia 50 3.4 42 3.2 Hyponatremia 37 9 28 7 Hypoalbuminemia 35 1.3 31 0 Increased ALT 31 2.8 24 3.9 Hypocalcemia 31 2.6 27 1.8 Hypophosphatemia 29 6 20 3.2 Increased AST 28 2.2 24 1.8 Increased TSH 26 NA NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities 5 NA Hypokalemia 26 6 24 4.4 Increased Alkaline Phosphatase 25 2.6 22 1.3 Increased Blood Creatinine 23 2.8 16 0.4 Hyperphosphatemia 21 NA 13 NA Previously Treated Metastatic NSCLC OAK The safety of TECENTRIQ was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.1) ] . A total of 609 patients received TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n=578) 75 mg/m 2 intravenously every 3 weeks until unacceptable toxicity or disease progression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The median duration of exposure was 3.4 months (0 to 26 months) in TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients. The study population characteristics were: median age of 63 years (25 to 85 years), 46% age 65 years or older, 62% male, 71% White, 20% Asian, 68% former smoker, 16% current smoker, and 63% had Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure. Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (>1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection. TECENTRIQ was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions leading to TECENTRIQ discontinuation were fatigue, infections and dyspnea. Adverse reactions leading to interruption of TECENTRIQ occurred in 25% of patients; the most common (>1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain. Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in OAK. Table 12: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving TECENTRIQ in OAK Adverse Reaction TECENTRIQ N = 609 Docetaxel N = 578 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General Fatigue/Asthenia Includes fatigue and asthenia 44 4 53 6 Pyrexia 18 <1 13 <1 Respiratory Cough Includes cough and exertional cough 26 <1 21 <1 Dyspnea 22 2.8 21 2.6 Metabolism and Nutrition Decreased appetite 23 <1 24 1.6 Musculoskeletal Myalgia/Pain Includes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia 20 1.3 20 <1 Arthralgia 12 0.5 10 0.2 Gastrointestinal Nausea 18 <1 23 <1 Constipation 18 <1 14 <1 Diarrhea 16 <1 24 2 Skin Rash Includes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid 12 <1 10 0 Table 13: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in OAK Laboratory Abnormality TECENTRIQ Docetaxel All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0 Hematology Anemia 67 3 82 7 Lymphocytopenia 49 14 60 21 Chemistry Hypoalbuminemia 48 4 50 3 Hyponatremia 42 7 31 6 Increased Alkaline Phosphatase 39 2 25 1 Increased AST 31 3 16 0.5 Increased ALT 27 3 14 0.5 Hypophosphatemia 27 5 23 4 Hypomagnesemia 26 1 21 1 Increased Creatinine 23 2 16 1 Small Cell Lung Cancer (SCLC) IMpower133 The safety of TECENTRIQ with carboplatin and etoposide was evaluated in IMpower133, a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received TECENTRIQ 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m 2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by TECENTRIQ 1200 mg every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2) ] . Among 198 patients receiving TECENTRIQ, 32% were exposed for 6 months or longer and 12% were exposed for 12 months or longer. Fatal adverse reactions occurred in 2% of patients receiving TECENTRIQ. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each). Serious adverse reactions occurred in 37% of patients receiving TECENTRIQ. Serious adverse reactions in >2% were pneumonia (4.5%), neutropenia (3.5%), febrile neutropenia (2.5%), and thrombocytopenia (2.5%). TECENTRIQ was discontinued due to adverse reactions in 11% of patients. The most frequent adverse reaction requiring permanent discontinuation in >2% of patients was infusion-related reactions (2.5%). Adverse reactions leading to interruption of TECENTRIQ occurred in 59% of patients; the most common (>1%) were neutropenia (22%), anemia (9%), leukopenia (7%), thrombocytopenia (5%), fatigue (4.0%), infusion-related reaction (3.5%), pneumonia (2.0%), febrile neutropenia (1.5%), increased ALT (1.5%), and nausea (1.5%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower133. Table 14: Adverse Reactions Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133 Adverse Reaction TECENTRIQ with Carboplatin and Etoposide N = 198 Placebo with Carboplatin and Etoposide N = 196 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General Fatigue/asthenia 39 5 33 3 Gastrointestinal Nausea 38 1 33 1 Constipation 26 1 30 1 Vomiting 20 2 17 3 Skin and Subcutaneous Tissue Alopecia 37 0 35 0 Metabolism and Nutrition Decreased appetite 27 1 18 0 Table 15: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133 Laboratory Abnormality TECENTRIQ with Carboplatin and Etoposide Placebo with Carboplatin and Etoposide All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 181-193); Placebo (range: 181-196). Graded per NCI CTCAE v4.0 Hematology Anemia 94 17 93 19 Neutropenia 73 45 76 48 Thrombocytopenia 58 20 53 17 Lymphopenia 46 14 38 11 Chemistry Hyperglycemia 67 10 65 8 Increased Alkaline Phosphatase 38 1 35 2 Hyponatremia 34 15 33 11 Hypoalbuminemia 32 1 30 0 Decreased TSH TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories. 28 NA NA = Not applicable. 15 NA Hypomagnesemia 31 5 35 6 Hypocalcemia 26 3 28 5 Increased ALT 26 3 31 1 Increased AST 22 1 21 2 Increased Blood Creatinine 22 4 15 1 Hyperphosphatemia 21 NA 23 NA Increased TSH 21 NA 7 NA IMforte The safety of TECENTRIQ in combination with lurbinectedin was evaluated in IMforte [see Clinical Studies (14.2) ]. Patients received TECENTRIQ 1200 mg IV and lurbinectedin 3.2 mg/m 2 IV, on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Primary prophylaxis of G-CSF was administered to 84% of patients. Among 242 patients receiving TECENTRIQ with lurbinectedin, the median duration of exposure to TECENTRIQ was 4.2 months, with 34% of patients exposed for 6 months or longer and 8% of patients exposed for 12 months or longer. Serious adverse reactions occurred in 31% of patients receiving TECENTRIQ with lurbinectedin. Serious adverse reactions in >2% of patients were pneumonia (2.5%), respiratory tract infection (2.1%), dyspnea (2.1%), and decreased platelet count (2.1%). Fatal adverse reactions occurred in 5% of patients receiving TECENTRIQ with lurbinectedin including pneumonia (3 patients), sepsis (3 patients), cardio-respiratory arrest (2 patients), myocardial infarction (2 patients) and febrile neutropenia (1 patient). Permanent discontinuation of TECENTRIQ due to an adverse reaction occurred in 2.5% of patients. The adverse reactions requiring permanent discontinuation in ≥ 1% of patients who received TECENTRIQ were immune-mediated nephritis, peripheral neuropathy, nephropathy, pneumonitis, anemia, neutropenia, and thrombocytopenia. Dosage interruptions of TECENTRIQ due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia, fatigue, decreased neutrophil count, pneumonitis, and decreased platelet count. Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with lurbinectedin in IMforte. Table 16: Adverse Reactions (≥10%) in Patients with ES-SCLC Who Received TECENTRIQ with Lurbinectedin in IMforte Adverse Reaction TECENTRIQ with Lurbinectedin N = 242 TECENTRIQ N = 240 All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Graded per NCI CTCAE v5.0 Gastrointestinal Nausea 36 3 4 1 Diarrhea Includes diarrhea and colitis. 15 0 8 0 Vomiting 14 1 3 0 Constipation 12 0 6 1 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 32 5 13 2 Musculoskeletal and connective tissue disorders Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. 19 2 16 1 Metabolism and Nutrition Decreased appetite 17 0 7 0 Respiratory, thoracic and mediastinal disorders Cough Includes cough, productive cough, and upper-airway cough syndrome. 12 0 8 0 Dyspnea Includes dyspnea and dyspnea exertional. 11 2 10 2 Clinically relevant adverse reactions in < 10% of patients who received TECENTRIQ in combination with lurbinectedin included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity and increased creatine phosphokinase. Table 17: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES-SCLC Who Received TECENTRIQ in Combination with Lurbinectedin in IMforte Laboratory Abnormality TECENTRIQ with Lurbinectedin N = 242 TECENTRIQ N = 240 All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Graded per NCI CTCAE v5.0 Hematology Lymphopenia 55 17 31 11 Thrombocytopenia 54 15 15 3 Anemia 51 13 12 3 Neutropenia 36 18 7 4 Chemistry Increased alkaline phosphatase 29 1 14 0 Decreased sodium 27 4 30 5 Increased ALT 25 3 18 2 Increased AST 24 3 22 1 Decreased calcium 24 3 8 1 Increased creatinine 21 3 14 0 Hepatocellular Carcinoma (HCC) IMbrave150 The safety of TECENTRIQ in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.3) ] . Patients received 1,200 mg of TECENTRIQ intravenously followed by 15 mg/kg bevacizumab (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months). Fatal adverse reactions occurred in 4.6% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%). Serious adverse reactions occurred in 38% of patients in the TECENTRIQ and bevacizumab arm. The most frequent serious adverse reactions (≥ 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%). Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. The most common adverse reactions leading to TECENTRIQ discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%). Adverse reactions leading to interruption of TECENTRIQ occurred in 41% of patients in the TECENTRIQ and bevacizumab arm; the most common (≥ 2%) were liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline 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 IMbrave150 Adverse Reaction TECENTRIQ in combination with Bevacizumab (n = 329) Sorafenib (n=156) All Grades Graded per NCI CTCAE v4.0 (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Vascular Disorders Hypertension 30 15 24 12 General Disorders and Administration Site Conditions Fatigue/asthenia Includes fatigue and asthenia 26 2 32 6 Pyrexia 18 0 10 0 Renal and Urinary Disorders Proteinuria 20 3 7 0.6 Investigations Weight Decreased 11 0 10 0 Skin and Subcutaneous Tissue Disorders Pruritus 19 0 10 0 Rash 12 0 17 2.6 Gastrointestinal Disorders Diarrhea 19 1.8 49 5 Constipation 13 0 14 0 Abdominal Pain 12 0 17 0 Nausea 12 0 16 0 Vomiting 10 0 8 0 Metabolism and Nutrition Disorders Decreased Appetite 18 1.2 24 3.8 Respiratory, Thoracic and Mediastinal Disorders Cough 12 0 10 0 Epistaxis 10 0 4.5 0 Injury, Poisoning and Procedural Complications Infusion-Related Reaction 11 2.4 0 0 Table 19: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with HCC Receiving TECENTRIQ in IMbrave150 Laboratory Abnormality TECENTRIQ in combination with Bevacizumab (n = 329) Sorafenib (n=156) All Grades Graded 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) Chemistry Increased AST 86 16 90 16 Increased Alkaline Phosphatase 70 4 76 4.6 Increased ALT 62 8 70 4.6 Decreased Albumin 60 1.5 54 0.7 Decreased Sodium 54 13 49 9 Increased Glucose 48 9 43 4.6 Decreased Calcium 30 0.3 35 1.3 Decreased Phosphorus 26 4.7 58 16 Increased Potassium 23 1.9 16 2 Hypomagnesemia 22 0 22 0 Hematology Decreased Platelet 68 7 63 4.6 Decreased Lymphocytes 62 13 58 11 Decreased Hemoglobin 58 3.1 62 3.9 Increased Bilirubin 57 8 59 14 Decreased Leukocyte 32 3.4 29 1.3 Decreased Neutrophil 23 2.3 16 1.1 Melanoma IMspire150 The safety of TECENTRIQ, administered with cobimetinib and vemurafenib was evaluated in IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma [see Clinical Studies (14.4) ] . Patients received 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 a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 TECENTRIQ in IMspire150) Adverse Reaction TECENTRIQ 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 Disorders Rash Includes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalized and rash morbilliform 75 27 72 23 Pruritus 26 <1 17 <1 Photosensitivity reaction 21 <1 25 3.2 General Disorders and Administration Site Conditions Fatigue Includes fatigue, asthenia and malaise 51 3 45 1.8 Pyrexia Includes pyrexia and hyperpyrexia 49 1.7 35 2.1 Edema Includes edema peripheral, lymphoedema, edema, face edema, eyelid edema, periorbital edema, lip edema and generalized edema 26 <1 21 0 Gastrointestinal Disorders Hepatotoxicity Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal 50 21 36 13 Nausea 30 <1 32 2.5 Stomatitis Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 23 1.3 15 <1 Musculoskeletal and Connective Tissue Disorders Musculoskeletal 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 62 4.3 48 3.2 Endocrine Disorders Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased 22 0 10 0 Hyperthyroidism 18 <1 8 0 Injury, Poisoning and Procedural Complications Infusion-related reaction Includes infusion related reaction and hypersensitivity 10 2.6 8 <1 Respiratory, Thoracic and Mediastinal Disorders Pneumonitis Includes pneumonitis and interstitial lung disease 12 1.3 6 <1 Vascular Disorders Hypertension Includes hypertension, blood pressure increased, hypertensive crisis 17 10 18 7 Clinically important adverse reactions in < 10% of patients who received TECENTRIQ plus cobimetinib and vemurafenib were: Cardiac Disorders : Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged Eye Disorders : Uveitis Gastrointestinal disorders : Pancreatitis Infections and infestations: Pneumonia, urinary tract infection Metabolism and nutrition disorders: Hyperglycemia Nervous system Disorders : Dizziness, dysgeusia, syncope Respiratory, thoracic and mediastinal disorders : Dyspnea, oropharyngeal pain Skin and Subcutaneous Tissue Disorders : Vitiligo Table 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 a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4) in IMspire150 Laboratory Abnormality TECENTRIQ 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). Hematology Decreased Lymphocytes 80 24 72 17 Decreased Hemoglobin 77 2.6 72 2.2 Decreased Platelet 34 1.3 24 0.4 Decreased Neutrophils 26 2.2 19 1.5 Chemistry Increased Creatine Kinase 88 22 81 18 Increased AST 80 13 68 6 Increased ALT 79 18 62 12 Increased Triacylglycerol Lipase 75 46 62 35 Increased Alkaline Phosphatase 73 6 63 2.9 Decreased Phosphorus 67 22 64 14 Increased Amylase 51 13 45 13 Increased Blood Urea Nitrogen 47 NA NA= Not applicable. NCI CTCAE v4.0 does not include these laboratories. 37 NA Decreased Albumin 43 0.9 34 1.5 Increased Bilirubin 42 3.1 33 0.7 Decreased Calcium 41 1.3 28 0 Decreased Sodium 40 5 34 7 Decreased Thyroid-Stimulating Hormone 38 NA 23 NA Increased Thyroid-Stimulating Hormone Increased Thyroid Stimulating Hormone has a difference <5% (All Grades) between arms and is included for clinical completeness. 37 NA 33 NA Decreased Potassium 36 5 22 4.3 Increased Triiodothyronine 33 NA 18 NA Increased Free Thyroxine 32 NA 21 NA Decreased Total Triiodothyronine 32 NA 8 NA Increased Potassium 29 1.3 19 1.4 Decreased Triiodothyronine 27 NA 21 NA Increased Sodium 20 0 13 0.4 Unresectable or Metastatic Alveolar Soft Part Sarcoma (ASPS) ML39345 Study The safety of TECENTRIQ was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5) ]. Adult patients received TECENTRIQ 1200 mg every 3 weeks and pediatric patients received 15 mg/kg up to a maximum 1200 mg every 3 weeks until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 8.9 months (1 to 40 months). Serious adverse reactions occurred in 41% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each). Dosage interruptions of TECENTRIQ due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (≥3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each). Tables 22 and 23 summarize adverse reactions and laboratory abnormalities in Study ML39345. Table 22: Adverse Reactions Occurring in ≥15% of Patients with ASPS Receiving TECENTRIQ in ML39345 Adverse Reaction TECENTRIQ N = 49 All Grades (%) Grades 3–4 (%) Graded per NCI CTCAE v4.0 General disorders and administration site conditions Fatigue 55 2 Pyrexia 25 2 Influenza like illness 18 0 Gastrointestinal disorders Nausea 43 0 Vomiting 37 0 Constipation 33 0 Diarrhea 27 2 Abdominal pain Includes abdominal pain and abdominal pain upper 25 0 Metabolism and nutrition disorders Decreased appetite 22 2 Respiratory, Thoracic and Mediastinal Cough Includes cough, upper-airway cough syndrome, and productive cough 45 0 Dyspnea 33 0 Rhinitis allergic 16 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain 67 8 Skin and subcutaneous tissue disorders Rash Includes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption 47 2 Nervous system disorders Headache 43 4 Dizziness Includes vertigo and dizziness 29 4 Vascular disorders Hypertension 43 6 Hemorrhage Includes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage 29 2 Psychiatric disorders Insomnia 27 0 Anxiety 25 0 Cardiac Disorders Arrhythmia Includes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia 22 2 Endocrine disorders Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased 25 0 Investigations Weight decreased 18 0 Weight increased 16 6 Table 23: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with ASPS Receiving TECENTRIQ in ML39345 Laboratory Abnormality Laboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges. TECENTRIQ The denominators used to calculate the rate varied from 4-49 for all tests of interest based on the number of patients with a baseline value and at least one on-study laboratory measurement available. All Grades (%) Grades 3–4 (%) Hematology Decreased Hemoglobin 63 0 Decreased Platelets 27 0 Increased Platelets 29 0 Chemistry Increased Alkaline Phosphatase 29 0 Decreased Amylase 40 0 Increased Amylase 20 20 Decreased Bilirubin 49 0 Decreased Calcium 47 0 Increased Calcium 25 14 Decreased Glucose 33 0 Increased Glucose 78 0 Decreased Glucose (fasting) 25 0 Decreased Magnesium 21 0 Increased Magnesium 26 26 Increased AST 39 2 Increased ALT 33 2 Decreased Sodium 43 0 Increased Lipase 25 25 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TECENTRIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: pericarditis, pericardial effusion, cardiac tamponade Musculoskeletal and Connective Tissue: tenosynovitis

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