Tecentriq Drug Information

Generic name: ATEZOLIZUMAB

Programmed Death Receptor-1 Blocking Antibody [EPC]

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Uses of Tecentriq

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 non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-authorized test. 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 or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area ), as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations. TECENTRIQ, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.

TECENTRIQ, in combination with paclitaxel protein-bound and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. TECENTRIQ, as a single-agent, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ.

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.

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.

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 .

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).

Muscle Invasive Bladder Cancer

TECENTRIQ, as a single agent, is indicated as adjuvant treatment of adult patients with muscle invasive bladder cancer (MIBC) after cystectomy who have circulating tumor DNA molecular residual disease (ctDNA MRD) as determined by an FDA-authorized test .

Dosage & Administration of Tecentriq

Metastatic NSCLC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks
Adjuvant Treatment of NSCLC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks
ASPS (adult)	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks
ASPS (pediatric, 2 years of age and older)	15 mg/kg (up to a maximum 1200 mg) every 3 weeks
MIBC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks

Side Effects of Tecentriq

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 . 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

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

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

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

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 . IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells or PD-L1 stained tumor-infiltrating immune cells 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

Constipation 12 1.0 22 0.8 Diarrhea 11 0 12 0.8 General Fatigue/asthenia

25 1.4 34

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

Hyponatremia 44 9 36 7 Increased

ALT 38 3.2 32

Increased

AST 36 3.2 32

Hyperkalemia 29 3.9 36 2.7 Hypocalcemia 24 1.4 24 2.7 Increased blood

creatinine 24 0.7 33

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 . 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

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

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

Constipation 30 0.3 23 0.3 Vomiting 19 2 18 1 Metabolism and

Nutrition Decreased appetite 29 4 21

Vascular Hypertension 25 9 22 8 Respiratory Cough 20 0.8 19 0.3

Epistaxis 17 1 22

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

Hyponatremia 38 10 36 9 Increased Alkaline Phosphatase 37 2 32 1

Increased ALT 37 6 28

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. 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

Diarrhea Includes diarrhea, colitis, and gastroenteritis 43 6 32 6 Constipation 36

1.1 31 0 Vomiting 27 2.7 19

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

Nervous System Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia

polyneuropathy 33 2.5 28

Respiratory, Thoracic and Mediastinal Dyspnea Includes dyspnea, dyspnea exertional and wheezing 32

4.9 25

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

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

Hyponatremia 37 9 28 7 Hypoalbuminemia 35 1.3 31 0 Increased

ALT 31 2.8 24

Hypocalcemia 31 2.6 27 1.8 Hypophosphatemia 29 6 20 3.2 Increased

AST 28 2.2 24

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

Increased Alkaline Phosphatase 25 2.6 22 1.3 Increased Blood Creatinine 23 2.8

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 . 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

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

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

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

Increased

ALT 27 3 14

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 . 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 . 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 . 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

Investigations Weight Decreased 11 0 10 0 Skin and Subcutaneous Tissue Disorders

Pruritus 19 0 10 0 Rash 12 0 17

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

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

Increased

ALT 62 8 70

Decreased Albumin 60 1.5 54 0.7 Decreased Sodium 54 13 49 9

Increased Glucose 48 9 43

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

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

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 . 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

General Disorders and

Administration Site Conditions Fatigue Includes fatigue, asthenia and malaise 51 3 45

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

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

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

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

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

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

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

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. 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 Muscle Invasive Bladder Cancer (MIBC) IMvigor011 The safety of TECENTRIQ was evaluated in IMvigor011, a multi-center, randomized, double-blind, placebo-controlled trial in 248 patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD) . Patients received TECENTRIQ 1680 mg (n=165) or placebo (n=83) intravenously every 4 weeks for up to 12 cycles or 1 year (whichever occurred first) unless either unacceptable toxicity or disease recurrence occurred. The median duration of exposure to TECENTRIQ was 6.5 months (0 to 11.8 months). Serious adverse reactions occurred in 27% of patients who received TECENTRIQ. Serious adverse reactions in ≥ 2% of patients included urinary tract infection (9%), and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3% of patients who received TECENTRIQ including septic shock, skin infection, death of unknown cause, interstitial lung disease, and congestive cardiac failure (1 patient each). Permanent discontinuation of TECENTRIQ due to adverse reactions occurred in 9% of patients.

Adverse reactions which resulted in permanent discontinuation of TECENTRIQ in ≥1% of patients included pneumonitis (1.8%). Dosage interruptions of TECENTRIQ due to adverse reactions occurred in 24% of patients. Adverse reactions which required dosage interruptions in ≥1% of patients included urinary tract infection (4.8%), COVID-19 (3.6%), increased blood creatinine, atrial fibrillation, abnormal hepatic function, pneumonitis, rash, hyperthyroidism, and hypothyroidism (1.2% each). Tables 24 and 25 summarize the adverse reactions and laboratory abnormalities in patients receiving TECENTRIQ in IMvigor011. Table 24: Adverse Reactions Occurring in ≥10% of Patients with MIBC Who Received TECENTRIQ in IMvigor011 Adverse Reaction Graded per NCI-CTCAE v5.0 TECENTRIQ N = 165 Placebo N=83 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Renal and Urinary Disorders Urinary tract infection Includes multiple related terms 22 8.5 18

Skin and Subcutaneous Tissue Pruritus 18 0 11 0 Rash 13 0.6

3.6 0 Endocrine Disorders Hypothyroidism 13 0 4.8 0 Gastrointestinal Constipation 11 0 7 0 Table 25: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with MIBC Who Received TECENTRIQ in IMvigor011 Laboratory Abnormality TECENTRIQ N=165 Placebo N=83 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Graded per NCI-CTCAE v5.0 Denominator is based on patients with at least one post-baseline assessment. For each parameter, the denominator includes patients with baseline Grade 0-2 in the specified direction of abnormality or patients with missing baseline values Hematology Decreased hemoglobin 30 1.8 24 0 Decreased lymphocytes 26 3.1 15 0 Chemistry Increased alanine aminotransferase 23 2.5 10 0 Increased alkaline phosphatase 23 1.2 15 0

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

Warnings & Cautions for Tecentriq

Severe and Fatal Immune-Mediated Adverse Reactions

TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (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 a 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. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less.

Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 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 Pneumonitis TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. TECENTRIQ as a Single Agent: Immune-mediated pneumonitis occurred in 3% (83/2616) of patients receiving TECENTRIQ as a single agent, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.8%), and Grade 2 (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 a single agent, including fatal (0.2%), Grade 4 (0.2%), and Grade 3 (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 3 (1.3%) and Grade 2 (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 Colitis TECENTRIQ 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 a Single Agent: Immune-mediated colitis occurred in 1% (26/2616) of patients receiving TECENTRIQ as a single agent, including Grade 3 (0.5%) and Grade 2 (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, 8 reinitiated treatment with TECENTRIQ after symptom improvement; of these, 25% had recurrence of colitis. Immune-Mediated Hepatitis TECENTRIQ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.8% (48/2616) of patients receiving TECENTRIQ as a single agent, including fatal (<0.1%), Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (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 6 patients in whom TECENTRIQ was withheld for hepatitis, 4 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 4 (1.3%), Grade 3 (1.7%) and Grade 2 (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 4 patients in whom TECENTRIQ was withheld for hepatitis, 3 reinitiated TECENTRIQ after symptom improvement; of these, 33% had recurrence of hepatitis.

Immune-Mediated Endocrinopathies Adrenal Insufficiency TECENTRIQ can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ depending on severity . Adrenal insufficiency occurred in 0.4% (11/2616) of patients receiving TECENTRIQ as a single agent, including Grade 3 (<0.1%) and Grade 2 (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, 3 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 a single agent, including Grade 3 (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, 4 patients remained on systemic corticosteroids. Hypophysitis TECENTRIQ 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 . Hypophysitis occurred in <0.1% (2/2616) of patients receiving TECENTRIQ as a single agent, including Grade 2 (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 2 patients.

Thyroid disorders TECENTRIQ 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 . Thyroiditis: Thyroiditis occurred in 0.2% (4/2616) of patients receiving TECENTRIQ as a single agent, including Grade 2 (<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 a single agent, including Grade 2 (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 a Single Agent: Hyperthyroidism occurred in 0.8% (21/2616) of patients receiving TECENTRIQ as a single agent, including Grade 2 (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 6 patients, the majority remained on antithyroid treatment. Of the 3 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 a single agent, including Grade 3 (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, 9 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 3 (0.9%) and Grade 2 (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 a Single Agent: Hypothyroidism occurred in 4.9% (128/2616) of patients receiving TECENTRIQ as a single agent, including Grade 3 (0.2%) and Grade 2 (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, 8 reinitiated TECENTRIQ after symptom improvement. In IMpower010 hypothyroidism occurred in 17% (86/495) of patients receiving TECENTRIQ as a 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 8 patients in whom TECENTRIQ was withheld for hypothyroidism, 3 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 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (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, 9 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 2 (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 6 patients in whom TECENTRIQ was withheld for hypothyroidism, 4 reinitiated TECENTRIQ after symptom improvement. The majority of patients with hypothyroidism required long term thyroid replacement. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes.

Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TECENTRIQ depending on severity . Type 1 diabetes mellitus occurred in 0.3% (7/2616) of patients receiving TECENTRIQ, including Grade 3 (0.2%) and Grade 2 (<0.1%) adverse reactions. Type 1 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 1 diabetes mellitus and insulin therapy was continued long-term. Of the 2 patients in whom TECENTRIQ was withheld for Type 1 diabetes mellitus, both re-initiated TECENTRIQ treatment. Immune-Mediated Nephritis with Renal Dysfunction TECENTRIQ can cause immune-mediated nephritis.

TECENTRIQ as a Single Agent: Immune-mediated nephritis with renal dysfunction occurred in <0.1% (1/2616) of patients receiving TECENTRIQ as a single agent, and this adverse reaction was a Grade 3 (<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 2 (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 3 of these patients. Of the 2 patients in whom TECENTRIQ was withheld for nephritis, both reinitiated TECENTRIQ after symptom improvement and neither had recurrence of nephritis.

Immune-Mediated Dermatologic Adverse Reactions TECENTRIQ 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 . Immune-mediated dermatologic adverse reactions occurred in 0.6% (15/2616) of patients receiving TECENTRIQ as a single agent, including Grade 3 (<0.1%) and Grade 2 (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 4 patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none re-initiated TECENTRIQ. Other Immune-Mediated Adverse Reactions The 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-Barré 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 a 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.

Hematologic/Immune : Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Other : Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurence of either two or all three adverse reactions.

Infusion-Related Reactions

TECENTRIQ can cause severe or life-threatening infusion-related reactions, including anaphylaxis. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity . For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

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

Complications 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 a 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 a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

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

Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose.

Pregnancy Safety for Tecentriq

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

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus.

Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Pediatric Use of Tecentriq

Pediatric Use Alveolar Soft Part Sarcoma The safety and effectiveness of TECENTRIQ for unresectable or metastatic ASPS have been established in pediatric patients aged 2 years and older. Use of TECENTRIQ for this indication is supported by evidence from an adequate and well controlled study of TECENTRIQ in adults and 2 adolescent pediatric patients (≥12 years of age) with ASPS with additional pharmacokinetic and safety data in pediatric patients 2 years to <17 years. These data suggest that atezolizumab exposure in pediatric patients aged 2 years and older is comparable with that of adults and is expected to result in similar safety and efficacy to that of adults . The course of unresectable or metastatic ASPS is sufficiently similar between pediatric patients 2 to 11 years old and that of adults and adolescent patients to allow extrapolation of efficacy and safety to pediatric patients 2 years and older.

The safety and effectiveness of TECENTRIQ for ASPS have not been established in pediatric patients younger than 2 years of age. Solid Tumors and Lymphomas The safety and effectiveness of TECENTRIQ in pediatric patients have not been established in non-small cell lung cancer, small-cell lung cancer, hepatocellular carcinoma, melanoma, or muscle invasive bladder cancer. The safety and effectiveness of TECENTRIQ were assessed, but not established in a single-arm, multi-center, multi-cohort trial (NCT02541604) in 60 pediatric patients aged 7 months to <17 years with relapsed or progressive solid tumors and lymphomas.

No new safety signals were observed in pediatric patients in this study.

Clinical Studies of Tecentriq

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), a 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 ≥ 4 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 a history of autoimmune disease; a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis; administration of a live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 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 3 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 4 months for the first year following Cycle 1, Day 1 and then every 6 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 Eastern Cooperative Oncology Group (ECOG) performance status in patients was 0 (55%) or 1 (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.

A 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 a statistically significant improvement in DFS in the PD-L1 ≥ 1% TC, Stage II – IIIA patient population. Efficacy results are presented in Table 26 and Figure 1. Table 26: Efficacy Results from IMpower010 in Patients with Stage II - IIIA NSCLC with PD-L1 expression ≥ 1% TC Arm A: TECENTRIQ N = 248 Arm B: Best Supportive Care N = 228 CI = Confidence interval, NE = Not estimable, NR = Not reached Disease-Free Survival Number of events (%) 88 105 Median, months NR 35.3 (95% CI) (36.1, NE) (29.0, NE) Hazard ratio Stratified by stage, sex, and histology (95% CI) 0.66 p-value 0.004 In a 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 a 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 a 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% TC At 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 a stratified HR of 0.77 (95% CI: 0.51, 1.17). Figure 1 Metastatic Chemotherapy-Naïve NSCLC with High PD-L1 Expression The efficacy of TECENTRIQ was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in patients with stage IV NSCLC whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 1% of the tumor area ), who had received no prior chemotherapy for metastatic disease. PD-L1 tumor status was determined based on immunohistochemistry (IHC) testing using the VENTANA PD-L1 (SP142) Assay. The evaluation of efficacy is based on the subgroup of patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), excluding those with EGFR or ALK genomic tumor aberrations.

The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization. Randomization was stratified by sex, ECOG performance status, histology (non-squamous vs. squamous) and PD-L1 expression (TC ≥ 1% and any IC vs. TC < 1% and IC ≥ 1%). Patients were randomized (1:1) to receive one of the following treatment arms: Arm A: TECENTRIQ 1200 mg every 3 weeks until disease progression or unacceptable toxicity Arm B: Platinum-based chemotherapy Arm B platinum-based chemotherapy regimens for non-squamous NSCLC consisted of cisplatin (75 mg/m 2 ) and pemetrexed (500 mg/m 2 ) OR carboplatin (AUC 6 mg/mL/min) and pemetrexed (500 mg/m 2 ) on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by pemetrexed (500 mg/m 2 ) until disease progression or unacceptable toxicity.

Arm B platinum-based chemotherapy regimens for squamous NSCLC consisted of cisplatin (75 mg/m 2 ) on Day 1 with gemcitabine (1250 mg/m 2 ) on Days 1 and 8 of each 21-day cycle OR carboplatin (AUC 5 mg/mL/min) on Day 1 with gemcitabine (1000 mg/m 2 ) on Days 1 and 8 of each 21-day cycle for a maximum of 4 or 6 cycles followed by best supportive care until disease progression or unacceptable toxicity. Administration of TECENTRIQ was permitted beyond RECIST-defined disease progression. Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter.

Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. The major efficacy outcome measure was overall survival (OS) sequentially tested in the following subgroups of patients, excluding those with EGFR or ALK genomic tumor aberrations: TC ≥50% or IC ≥10%; TC ≥5% or IC ≥5%; and TC ≥1% or IC ≥1%. Among the 205 chemotherapy-naïve patients with stage IV NSCLC with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%) excluding those with EGFR or ALK genomic tumor aberrations, the median age was 65.0 years (range: 33 to 87), and 70% of patients were male. The majority of patients were White (82%) and Asian (17%). Baseline ECOG performance status was 0 (36%) or 1 (64%); 88% were current or previous smokers; and 76% of patients had non-squamous disease while 24% of patients had squamous disease.

The trial demonstrated a statistically significant improvement in OS for patients with high PD-L1 expression (TC ≥50% or IC ≥10%) at the time of the OS interim analysis. There was no statistically significant difference in OS for the other two PD-L1 subgroups (TC ≥5% or IC ≥5%; and TC ≥1% or IC ≥1%) at the interim or final analyses. Efficacy results for patients with NSCLC with high PD-L1 expression are presented in Table 27 and Figure 2. Table 27: Efficacy Results from IMpower110 in Patients with NSCLC with High PD-L1 Expression (TC ≥ 50% or IC ≥ 10%) and without EGFR or ALK Genomic Tumor Aberrations Arm A: TECENTRIQ N = 107 Arm B: Platinum-Based Chemotherapy N = 98 CI=confidence interval; NE=not estimable Overall Survival Based on OS interim analysis.

The median survival follow-up time in patients was 15.7 months. Deaths (%) 44 (41%) 57 (58%) Median, months 20.2 13.1 (95% CI) (16.5, NE) Hazard ratio Stratified by sex and ECOG performance status (95% CI) 0.59 p-value Based on the stratified log-rank test compared to Arm A 0.0106 Compared 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 Aberrations Investigator-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 5 months (95% CI: 4.2, 5.7) in the platinum-based chemotherapy arm.

The investigator-assessed confirmed ORR was 38% (95% CI: 29%, 48%) in the TECENTRIQ arm and 29% (95% CI: 20%, 39%) in the platinum-based chemotherapy arm. Figure 2 Metastatic Chemotherapy-Naive Non-Squamous NSCLC IMpower150 The efficacy of TECENTRIQ with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), a multicenter, international, randomized (1:1:1), open-label trial in patients with metastatic non-squamous NSCLC. Patients with stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease but could have received prior EGFR or ALK kinase inhibitor if appropriate, regardless of PD-L1 or T-effector gene (tGE) status and ECOG performance status 0 or 1 were eligible. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization, or clear tumor infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions as seen on imaging.

Randomization was stratified by sex, presence of liver metastases, and PD-L1 expression status on tumor cells (TC) and tumor-infiltrating immune cells (IC) as follows: TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Patients were randomized to one of the following three treatment arms: Arm A: TECENTRIQ 1200 mg, paclitaxel 175 mg/m 2 or 200 mg/m 2 and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles Arm B: TECENTRIQ 1200 mg, bevacizumab 15 mg/kg, paclitaxel 175 mg/m 2 or 200 mg/m 2, and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles Arm C: bevacizumab 15 mg/kg, paclitaxel 175 mg/m 2 or 200 mg/m 2, and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles Patients who had not experienced disease progression following the completion or cessation of platinum-based chemotherapy, received: Arm A: TECENTRIQ 1200 mg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity Arm B: TECENTRIQ 1200 mg and bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity Arm C: bevacizumab 15 mg/kg intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity Tumor assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter.

Tumor specimens were evaluated prior to randomization for PD-L1 tumor expression using the VENTANA PD-L1 (SP142) assay at a central laboratory. Tumor tissue was collected at baseline for expression of tGE signature and evaluation was performed using a clinical trial assay in a central laboratory prior to the analysis of efficacy outcome measures. Major efficacy outcome measures for comparison of Arms B and C were progression free survival (PFS) by RECIST v1.1 in the tGE-WT (patients with high expression of T-effector gene signature, excluding those with EGFR- and ALK-positive NSCLC ) and in the ITT-WT subpopulations and overall survival (OS) in the ITT-WT subpopulation.

Additional efficacy outcome measures for comparison of Arms B and C or Arms A and C were PFS and OS in the ITT population, OS in the tGE-WT subpopulation, and ORR/DoR in the tGE-WT and ITT-WT subpopulations. A total of 1202 patients were enrolled across the three arms of whom 1045 were in the ITT-WT subpopulation and 447 were in the tGE-WT subpopulation. The demographic information is limited to the 800 patients enrolled in Arms B and C where efficacy has been demonstrated.

The median age was 63 years (range: 31 to 90), and 60% of patients were male. The majority of patients were White (82%), 13% of patients were Asian, 10% were Hispanic, and 2% of patients were Black. Clinical sites in Asia (enrolling 13% of the study population) received paclitaxel at a dose of 175 mg/m 2 while the remaining 87% received paclitaxel at a dose of 200 mg/m 2. Approximately 14% of patients had liver metastases at baseline, and most patients were current or previous smokers (80%). Baseline ECOG performance status was 0 (43%) or 1 (57%). PD-L1 was TC3 and any IC in 12%, TC0/1/2 and IC2/3 in 13%, and TC0/1/2 and IC0/1 in 75%. The demographics for the 696 patients in the ITT-WT subpopulation were similar to the ITT population except for the absence of patients with EGFR- or ALK- positive NSCLC. The trial demonstrated a statistically significant improvement in PFS between Arms B and C in both the tGE-WT and ITT-WT subpopulations, but did not demonstrate a significant difference for either subpopulation between Arms A and C based on the final PFS analyses.

In the interim analysis of OS, a statistically significant improvement was observed for Arm B compared to Arm C, but not for Arm A compared to Arm C. Efficacy results for the ITT-WT subpopulation are presented in Table 28 and Figure 3. Table 28: Efficacy Results in ITT-WT Population in IMpower150 Arm C: Bevacizumab, Paclitaxel and Carboplatin Arm B: TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin Arm A: TECENTRIQ with Paclitaxel, and Carboplatin N = 337 N = 359 N = 349 CI=confidence interval Overall Survival Based on OS interim analysis Deaths (%) 197 (59%) 179 (50%) 179 (51%) Median, months 14.7 19.2 19.4 (95% CI) Hazard ratio Stratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC (95% CI) --- 0.78 0.84 p-value Based on the stratified log-rank test compared to Arm C --- 0.016 Compared to the allocated α=0.0174 (two sided) for this interim analysis 0.204 Compared to the allocated α=0.0128 (two sided) for this interim analysis Progression-Free Survival As 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, months 7.0 8.5 6.7 (95% CI) Hazard ratio (95% CI) --- 0.71 0.94 p-value --- 0.0002 Compared to the allocated α=0.006 (two sided) for the final PFS analysis 0.5219 Objective Response Rate Number of responders (%) 142 (42%) 196 (55%) 150 (43%) (95% CI) Complete Response 3 (1%) 14 (4%) 9 (3%) Partial Response 139 (41%) 182 (51%) 141 (40%) Duration of Response n = 142 n = 196 n = 150 Median, months 6.5 10.8 9.5 (95% CI) Figure 3: Kaplan-Meier Curves for Overall Survival in ITT-WT Population in IMpower150 Exploratory analyses showed that the subset of patients in the four drug regimen arm who were ADA positive by week 4 (30%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (70%) . In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly ADA negative patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm were compared with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, tobacco history, metastatic site, TC level, and IC level.

The hazard ratio comparing the ADA-positive subgroup with its matched control was 0.69 (95% CI: 0.44, 1.07). The hazard ratio comparing the ADA-negative subgroup with its matched control was 0.64 (95% CI: 0.46, 0.90). Figure 3 IMpower130 The efficacy of TECENTRIQ with paclitaxel protein-bound and carboplatin was evaluated in IMpower130 (NCT02367781), a multicenter, randomized (2:1), open-label trial in patients with stage IV non-squamous NSCLC. Patients with Stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease, but could have received prior EGFR or ALK kinase inhibitor, if appropriate, were eligible. The trial excluded patients with history of autoimmune disease, administration of live attenuated vaccine within 28 days prior to randomization, administration of immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization, and active or untreated CNS metastases. Randomization was stratified by sex, presence of liver metastases, and PD-L1 tumor expression according to the VENTANA PD-L1 (SP142) assay as follows: TC3 and any IC vs.

TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Patients were randomized to one of the following treatment regimens: TECENTRIQ 1200 mg on Day 1, paclitaxel protein-bound 100 mg/m 2 on Days 1, 8, and 15, and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by TECENTRIQ 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or Paclitaxel protein-bound 100 mg/m 2 on Days 1, 8 and 15 and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for a maximum of 4 or 6 cycles followed by best supportive care or pemetrexed. Tumor assessments were conducted every 6 weeks for the first 48 weeks, then every 9 weeks thereafter.

Major efficacy outcome measures were PFS by RECIST v1.1 and OS in the subpopulation of patients evaluated for and documented to have no EGFR or ALK genomic tumor aberrations (ITT-WT). A total of 724 patients were enrolled; of these, 681 (94%) were in the ITT-WT population. The median age was 64 years (range: 18 to 86) and 59% were male. The majority of patients were white (90%), 2% of patients were Asian, 5% were Hispanic, and 4% were Black.

Baseline ECOG performance status was 0 (41%) or 1 (58%). Most patients were current or previous smokers (90%). PD-L1 tumor expression was TC0/1/2 and IC0/1 in 73%; TC3 and any IC in 14%; and TC0/1/2 and IC2/3 in 13%. Efficacy results for the ITT-WT population are presented in Table 29 and Figure 4. Table 29: Efficacy Results from IMpower130 TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin Paclitaxel Protein-Bound and Carboplatin CI=confidence interval Overall Survival Based on OS interim analysis n=453 n=228 Deaths (%) 228 (50%) 131 (57%) Median, months 18.6 13.9 (95% CI) Hazard ratio Stratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC) (95% CI) 0.80 p-value Based on the stratified log-rank test 0.0384 Compared to the allocated α=0.0428 (two sided) for this interim analysis Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) n=453 n=228 Number of events (%) 330 (73%) 177 (78%) Median, months 7.2 6.5 (95% CI) Hazard ratio (95% CI) 0.75 p-value 0.0024 Compared to the allocated α=0.006 (two sided) for the final PFS analysis Overall Response Rate, Confirmed response n=453 n=228 Number of responders (%) 207 (46%) 74 (32%) (95% CI) Complete Response 22 (5%) 2 (1%) Partial Response 185 (41%) 72 (32%) Duration of Response, n=207 n=74 Median, months 10.8 7.8 (95% CI) Figure 4: Kaplan-Meier Curves for Overall Survival in IMpower130 Figure 4 Previously Treated Metastatic NSCLC OAK The efficacy of TECENTRIQ was evaluated in a multicenter, international, randomized (1:1), open-label study (OAK; NCT02008227) conducted in patients with locally advanced or metastatic NSCLC whose disease progressed during or following a platinum-containing regimen. Patients with a history of autoimmune disease, symptomatic or corticosteroid-dependent brain metastases, or requiring systemic immunosuppression within 2 weeks prior to enrollment were ineligible. Randomization was stratified by PD-L1 expression tumor-infiltrating immune cells (IC), the number of prior chemotherapy regimens (1 vs. 2), and histology (squamous vs. non-squamous). Patients were randomized to receive TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel 75 mg/m 2 intravenously every 3 weeks until unacceptable toxicity or disease progression.

Tumor assessments were conducted every 6 weeks for the first 36 weeks and every 9 weeks thereafter. Major efficacy outcome measure was overall survival (OS) in the first 850 randomized patients and OS in the subgroup of patients with PD-L1-expressing tumors (defined as ≥ 1% PD-L1 expression on tumor cells or immune cells ). 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 performance status (PS) of 0 and 63% had a baseline ECOG PS of 1. Nearly all (94%) had metastatic disease, 74% had non-squamous histology, 75% had received only one prior platinum-based chemotherapy regimen, and 55% of patients had PD-L1-expressing tumors. Efficacy results are presented in Table 30 and Figure 5. Table 30: Efficacy Results in OAK TECENTRIQ Docetaxel CI=confidence interval; NE=not estimable Overall Survival in first 850 patients Number of patients N=425 N=425 Deaths (%) 271 (64%) 298 (70%) Median, months 13.8 9.6 (95% CI) Hazard ratio Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology (95% CI) 0.74 p-value Based on the stratified log-rank test 0.0004 Compared to the pre-specified allocated α of 0.03 for this analysis Progression-Free Survival Number of Patients N=425 N=425 Events (%) 380 (89%) 375 (88%) Progression (%) 332 (78%) 290 (68%) Deaths (%) 48 (11%) 85 (20%) Median, months 2.8 4.0 (95% CI) Hazard ratio (95% CI) 0.95 Overall Response Rate Per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) Number of Patients N=425 N=425 ORR, n (%) 58 (14%) 57 (13%) (95% CI) (11%, 17%) (10%, 17%) Complete Response 6 (1%) 1 (0.2%) Partial Response 52 (12%) 56 (13%) Duration of Response N=58 N=57 Median, months 16.3 6.2 (95% CI) (10.0, NE) Overall Survival in all 1225 patients Number of patients N=613 N=612 Deaths (%) 384 (63%) 409 (67%) Median, months 13.3 9.8 (95% CI) Hazard ratio (95% CI) 0.79 p-value 0.0013 Compared to the allocated α of 0.0177 for this interim analysis based on 86% information using O'Brien-Fleming boundary Figure 5: Kaplan-Meier Curves of Overall Survival in the First 850 Patients Randomized in OAK Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define the PD-L1 expression subgroups for pre-specified analyses.

Of the 850 patients, 16% were classified as having high PD-L1 expression, defined as having PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was 0.41 (95% CI: 0.27, 0.64) in the high PD-L1 expression subgroup and 0.82 (95% CI: 0.68, 0.98) in patients who did not have high PD-L1 expression. Exploratory analyses showed that the subset of patients who were ADA positive by week 4 (21%) appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (79%) . ADA positive patients by week 4 appeared to have similar OS compared to docetaxel-treated patients. In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the TECENTRIQ arm with a matched population in the docetaxel arm and ADA negative patients in the TECENTRIQ arm with a matched population in the docetaxel arm.

Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, histology (squamous vs. non-squamous), baseline albumin, baseline LDH, gender, tobacco history, metastases status (advanced or local), metastatic site, TC level, and IC level. The hazard ratio comparing the ADA positive subgroup with its matched control was 0.89 (95% CI: 0.61, 1.3). The hazard ratio comparing the ADA negative subgroup with its matched control was 0.68 (95% CI: 0.55, 0.83). Figure 5

Small Cell Lung Cancer IMpower133

The efficacy of TECENTRIQ with carboplatin and etoposide was investigated in IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC. IMpower133 enrolled patients with ES-SCLC who had received no prior chemotherapy for extensive stage disease and ECOG performance status 0 or 1. The trial excluded patients with active or untreated CNS metastases, history of autoimmune disease, administration of a live, attenuated vaccine within 4 weeks prior to randomization, or administration of systemic immunosuppressive medications within 1 week prior to randomization. Randomization was stratified by sex, ECOG performance status, and presence of brain metastases. Patients were randomized to receive one of the following two treatment arms: TECENTRIQ 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/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 once every 3 weeks until disease progression or unacceptable toxicity, or placebo and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m 2 intravenously on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles followed by placebo once every 3 weeks until disease progression or unacceptable toxicity.

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

Major efficacy outcome measures were OS and PFS as assessed by investigator per RECIST v1.1 in the intent-to-treat population. Additional efficacy outcome measures included ORR and DoR as assessed by investigator per RECIST v1.1. A total of 403 patients were randomized, including 201 to the TECENTRIQ arm and 202 to the chemotherapy alone arm. The median age was 64 years (range 26 to 90) and 65% were male.

The majority of patients were White (80%); 17% were Asian, 4% were Hispanic and 1% were Black. Baseline ECOG performance status was 0 (35%) or 1 (65%); 9% of patients had a history of brain metastases, and 97% were current or previous smokers. Efficacy results are presented in Table 31 and Figure 6. Table 31: Efficacy Results from IMpower133 TECENTRIQ with Carboplatin and Etoposide Placebo with Carboplatin and Etoposide CI=confidence interval Overall Survival N=201 N=202 Deaths (%) 104 (52%) 134 (66%) Median, months 12.3 10.3 (95% CI) Hazard ratio Stratified by sex and ECOG performance status (95% CI) 0.70 p-value Based on the stratified log-rank test, Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary 0.0069 Progression-Free Survival As determined by investigator assessment, per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) N=201 N=202 Number of events (%) 171 (85%) 189 (94%) Median, months 5.2 4.3 (95% CI) Hazard ratio (95% CI) 0.77 p-value, Compared to the allocated α of 0.05 for this analysis 0.0170 Objective Response Rate,, Confirmed response N=201 N=202 Number of responders (%) 121 (60%) 130 (64%) (95% CI) Complete Response (%) 5 (2%) 2 (1%) Partial Response (%) 116 (58%) 128 (63%) Duration of Response,, N=121 N=130 Median, months 4.2 3.9 (95% CI) Figure 6: Kaplan-Meier Plot of Overall Survival in IMpower133 Figure 6 IMforte The efficacy of TECENTRIQ in combination with lurbinectedin as maintenance treatment was evaluated in IMforte (NCT05091567), a randomized, multicenter, open-label study in patients with ES-SCLC. Patients were eligible if their disease had not progressed after completion of four cycles of TECENTRIQ, carboplatin and etoposide (induction treatment) and they had an ECOG performance status of 0 or 1. The trial excluded patients with CNS metastases, history of autoimmune disease, or administration of systemic immunosuppressive medications within 1 week prior to enrollment.

Unless contraindicated, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was mandated for patients assigned to the TECENTRIQ with lurbinectedin arm. The trial randomized 483 patients who had not experienced disease progression following the completion of four cycles of TECENTRIQ with carboplatin and etoposide to one of the following two treatment arms: TECENTRIQ 1200 mg IV in combination with lurbinectedin 3.2 mg/m 2 IV once every 3 weeks until disease progression or unacceptable toxicity, or TECENTRIQ 1200 mg IV once every 3 weeks until disease progression or unacceptable toxicity Randomization was stratified by ECOG performance status prior to randomization (0 vs. 1), lactate dehydrogenase (LDH) (≤ ULN vs. > ULN) prior to randomization, presence of liver metastases prior to initial study enrollment (yes vs. no), and prior receipt of prophylactic cranial irradiation (yes vs. no). The major efficacy outcome measures were OS and PFS by Independent Review Facility (IRF) per RECIST v1.1. A total of 483 patients were randomized, including 242 to the TECENTRIQ with lurbinectedin arm and 241 to the TECENTRIQ arm. The median age was 66 years (range 35 to 85 years); 63% male; 82% White; 13% Asian; 0.8% were Black or African American; 7% were of Hispanic or Latino ethnicity and 98% were current or previous smokers.

Baseline ECOG performance status was 0 (43%) or 1 (57%). Efficacy results are presented in Table 32 and Figures 7 and 8. Table 32: Efficacy Results from IMforte TECENTRIQ with Lurbinectedin N=242 TECENTRIQ N=241 CI=confidence interval Overall Survival Measured from the time of randomization Deaths (%) 113 (47%) 136 (56%) Median, months 13.2 10.6 (95% CI) Hazard ratio Stratified by ECOG performance status, LDH level, presence of liver metastases and prior receipt of prophylactic cranial irradiation (95% CI) 0.73 p-value Based on the stratified log-rank test, Compared to the allocated alpha of 0.0313 (two-sided) for this interim OS analysis. 0.0174 Progression-Free Survival, As determined by an IRF, per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) Number of events (%) 174 (72%) 202 (84%) Median, months 5.4 2.1 (95% CI) Hazard ratio (95% CI) 0.54 p-value, Compared to the allocated alpha of 0.001 (two- sided) for this final PFS analysis. <0.0001 Figure 7: Kaplan-Meier Plot of IRF-assessed Progression-Free Survival in IMforte Figure 8: Kaplan-Meier Plot of Overall Survival in IMforte Figure 7 Figure 8

Hepatocellular Carcinoma

The efficacy of TECENTRIQ in combination with bevacizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (<400 vs. ≥400 ng/mL), and by ECOG performance status (0 vs. 1). A total of 501 patients were randomized (2:1) to receive either TECENTRIQ as an intravenous infusion of 1200 mg, followed by 15 mg/kg bevacizumab, on the same day every 3 weeks or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. Patients could discontinue either TECENTRIQ or bevacizumab (e.g., due to adverse events) and continue on single-agent therapy until disease progression or unacceptable toxicity associated with the single-agent.

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

Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter. The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The median age was 65 years (range: 26 to 88) and 83% of patients were male.

The majority of patients were Asian (57%) or White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥400 ng/mL. Baseline ECOG performance status was 0 (62%) or 1 (38%). HCC risk factors were Hepatitis B in 48% of patients, Hepatitis C in 22%, and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage C (82%) disease at baseline, while 16% had stage B, and 3% had stage A. The major efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression free survival (PFS) per RECIST v1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST. Efficacy results are presented in Table 33 and Figure 9. Table 33: Efficacy Results from IMbrave150 TECENTRIQ 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 Survival Number of deaths (%) 96 65 Median OS in months (95% CI) NE (NE, NE) 13.2 (10.4, NE) Hazard ratio Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. ≥400 ng/mL) (95% CI) 0.58 p-value Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method 0.0006 Progression-Free Survival Per independent radiology review Number of events (%) 197 109 Median PFS in months (95% CI) 6.8

Hazard ratio (95% CI) 0.59 p-value <0.0001 Overall Response Rate, Confirmed responses

(ORR), RECIST

Number of responders (%) 93 19 (95% CI) p-value

Based on two-sided Cochran-Mantel-Haesnszel test <0.0001 Complete responses, n (%) 22 0 Partial responses, n (%) 71 19 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) (

Denotes a censored value, 13.4 ) Overall Response Rate, (ORR)

HCC mRECIST Number of responders (%) 112 21 (95% CI) p-value <0.0001 Complete responses, n (%) 37 3 Partial responses, n (%) 75 18 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) Figure 9: Kaplan-Meier Plot of Overall Survival in IMbrave150 Exploratory analyses showed that the subset of patients (20%) who were ADA-positive by week 6 appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week 6 . ADA-positive patients by week 6 appeared to have similar overall survival compared to sorafenib-treated patients. In an exploratory analysis, inverse probability weighting was conducted to compare ADA-positive patients and ADA-negative patients in the TECENTRIQ and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (<400 ng/mL vs ≥400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology (HBV vs.

HCV vs. non-viral) and Child-Pugh Score (A5 vs. A6). The OS hazard ratio comparing the ADA-positive subgroup of the TECENTRIQ and bevacizumab arm to sorafenib was 0.93 (95% CI: 0.57, 1.53). The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was 0.39 (95% CI: 0.26, 0.60). FIGURE 9

Melanoma

The efficacy of TECENTRIQ in combination with cobimetinib and vemurafenib was evaluated in a 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). Eligible patients were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma as detected by a locally available test and centrally confirmed with the FoundationOne™ assay. Patients were excluded if they had history of autoimmune disease; administration of a live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; and active or untreated CNS metastases. TECENTRIQ was initiated after patients received a 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 2 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 8 weeks (± 1 week) for the first 24 months and every 12 weeks (± 1 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, a baseline ECOG performance status of 0 (77%) or 1 (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 a V600E mutation, 11% as having V600K mutation, and 1% as having V600D or V600R mutations. Efficacy results are summarized in Table 34 and Figure 10. Patients had a median survival follow up time of 18.9 months.

Table 34: Efficacy Results from IMspire150 TECENTRIQ + Cobimetinib + Vemurafenib N=256 Placebo + Cobimetinib + Vemurafenib N=258 Progression-Free Survival As determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI=confidence interval Number of events (%) 148 179 Median, months 15.1 10.6 (95% CI) Hazard ratio Stratified by baseline LDH (95% CI) 0.78 p-value Based on the stratified log-rank test 0.0249 Overall Response Rate, Confirmed Responses Number of responders (%) 170 168 (95% CI) Complete responses, n (%) 41 46 Partial response, n (%) 129 122 Duration of Response, n=170 n=168 Median, months 20.4 12.5 (95% CI) (15.1, NE) Figure 10: Kaplan-Meier Plot for Progression-Free Survival in IMspire150 At a 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 10

Alveolar Soft Part Sarcoma

The efficacy of TECENTRIQ was evaluated in study ML39345 (NCT03141684), an open-label, single-arm study, in 49 adult and pediatric patients aged 2 years and older with unresectable or metastatic ASPS. Eligible patients were required to have histologically or cytologically confirmed ASPS that was not curable by surgery, and an ECOG performance status of ≤ 2. Patients were excluded if they had known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, known clinically significant liver disease, or history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. Adult patients received 1200 mg intravenously and pediatric patients received 15 mg/kg (up to a maximum of 1200 mg) intravenously once every 21 days until disease progression or unacceptable toxicity. The major efficacy outcomes were Overall Response Rate (ORR) and Duration of Response (DOR) by Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A total of 49 patients were enrolled.

The median age of patients was 31 years (range: 12-70); 2% of adult patients (n=47) were ≥65 years of age and the pediatric patients (n=2) were ≥12 years of age; 51% of patients were female, 55% White, 29% Black or African American, 10% Asian; 53% had an ECOG performance status of 0 and 45% had an ECOG performance status of 1. All patients had prior surgery for ASPS and 55% received at least one prior line of treatment for ASPS; 55% received radiotherapy and 53% received chemotherapy. Of the patients who reported staging at initial diagnosis, all were Stage IV. Efficacy results of this study are summarized in Table 35. Table 35: Efficacy Results from Study ML39345 Endpoint All Patients (N=49) CI: confidence interval; N: number of patients; +: Censored Overall response rate (95% CI) 95% CI based on Clopper–Pearson exact method. 24% Complete Responses, n 0 Partial Responses, n (%) 12 Duration of response Median, month NE (95% CI) (17.0, NE) Range 1+, 41+ Durability of Response ≥6 months, n (%) 8 (67%) ≥12 months, n (%) 5 (42%)

Muscle Invasive Bladder Cancer IMvigor011

The efficacy of TECENTRIQ was evaluated in IMvigor011 (NCT04660344), a multi-center, randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD). The trial enrolled patients with histologically confirmed MIBC who underwent radical cystectomy with lymph node dissection. Eligible patients had pathologic tumor staging of pT2-4a and/or positive lymph nodes following cystectomy, with no evidence of residual disease or metastasis on imaging, confirmed within 28 days before randomization. Patients were eligible regardless of whether they had received prior neoadjuvant chemotherapy (NAC) or not.

Patients were excluded if they had received any anti-cancer therapy within 3 weeks prior to trial enrollment or had a history of autoimmune disease. Serial ctDNA MRD testing was performed every 6 weeks for 9 months starting at least 6 weeks after cystectomy with a final test at one year. Patients who did not develop ctDNA MRD within the testing period were monitored without study treatment, while those who had ctDNA MRD were screened for the treatment phase by confirming that they remained free of radiographic disease.

The ctDNA MRD status was determined using either a Signatera™ clinical trial assay (whole exome-based tumor NGS sequencing and 16-plex NGS-based plasma sequencing) or a clinical trial assay performed locally in China. Randomization was stratified by nodal status (positive vs. negative), tumor stage (≤(y)pT2 vs. (y)pT3/pT4), PD-L1 immunohistochemistry (IHC) (IC <5% vs. IC ≥5%), and time from cystectomy to first ctDNA MRD positive sample (≤20 weeks vs. >20 weeks). A total of 250 patients were randomized 2:1 to receive either: Arm A: TECENTRIQ 1680 mg intravenously every 4 weeks on Day 1 of each 28-day cycle.

Arm B: Placebo intravenously every 4 weeks on Day 1 of each 28-day cycle Treatment continued for up to 12 cycles or 1 year (whichever occurred first) unless there was disease recurrence, or unacceptable toxicity. Tumor assessments were conducted every 9 weeks for the first two years, then every 12 weeks for year 3, and every 24 weeks thereafter. Among the 250 patients, the median age was 69 years (range: 42 to 87); 83% were male.

The majority of patients were White (62%), 32% Asian, 1.6% American Indian or Alaska Native, 0.8% Black or African American, and 4.4% unknown; 11% Hispanic or Latino ethnicity, 84% not Hispanic or Latino, and 4% not reported/unknown ethnicity. Baseline ECOG performance status was 0 in 66% of patients and 1 in 32%. A total of 48% of patients in the TECENTRIQ arm received prior platinum containing neoadjuvant chemotherapy. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). Overall Survival (OS) was an additional efficacy measure.

The study demonstrated statistically significant improvements in DFS and OS for patients randomized to the TECENTRIQ arm compared with placebo. Efficacy results are presented in Table 36 and Figures 11 and 12. Table 36: Efficacy Results from IMvigor011 TECENTRIQ N=167 Placebo N=83 CI=confidence interval; NE=not estimable Investigator - assessed DFS Number of events (%) 112 (67%) 66 (80%) Median Based on Kaplan-Meier estimates, months 9.9 4.8 (95% CI) Hazard ratio Based on stratified Cox proportional hazards model, Stratified by programmed death-ligand 1 (PD-L1) status, nodal status, tumor stage after cystectomy (95% CI) 0.64 p-value, Based on stratified log-rank test 0.0047 Overall survival Number of deaths (%) 60 (36%) 36 (43%) Median, months 32.8 21.1 (95% CI) (27.7, NE) (14.7, NE) Hazard ratio, (95% CI) 0.59 p-value, 0.0131 Figure 11: Kaplan-Meier Plot of Investigator-Assessed Disease-Free Survival in IMvigor011 Figure 12: Kaplan-Meier Plot of Overall Survival in IMvigor011 In a pre-specified exploratory analysis based on time from cystectomy to first ctDNA MRD positive sample, the unstratified hazard ratio (HR) for investigator-assessed DFS in the subgroup of patients who had ≤20 weeks to first ctDNA MRD positive sample (n=176), was 0.52 (95% CI: 0.37, 0.74), with median DFS of 8.3 months (95% CI: 6.2, 12.7) in the TECENTRIQ arm and 4.1 months (95% CI: 2.3, 6.2) in the placebo arm. The unstratified HR for OS was 0.63 (95% CI: 0.39, 1.00), with median OS of 32.8 months (95% CI: 24.4, not reached) in the TECENTRIQ arm and 18.2 months (95% CI: 13.1, not reached) in the placebo arm.

In the subgroup of patients who had >20 weeks to first ctDNA MRD positive sample (n=74), the unstratified HR for investigator-assessed DFS was 1.04 (95% CI: 0.54, 1.97), with median DFS of 10.5 months (95% CI: 6.9, 20.9) in the TECENTRIQ arm and 10.5 months (95% CI: 6.5, 20.5) in the placebo arm. The unstratified HR for OS was 0.77 (95% CI: 0.30, 1.96); median OS was not reached in either arm (95% CI: 21.1 months, not reached in the TECENTRIQ arm and 18.4 months, not reached in the placebo arm). Figure 11 Figure 12

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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