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Description for Tecentriq

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

TECENTRIQ Injection for intravenous use is a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials. Each mL of TECENTRIQ contains 60 mg of atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), sucrose (821.6 mg), polysorbate 20 (8 mg), pH 5.8.

ADVERSE REACTIONS

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

• Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
• Infusion-Related Reactions [see Warnings and Precautions (5.2)]
• Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors [see Warnings and Precautions (5.3)]

Clinical Trials Experience

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

The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as a single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and three open-label, single arm studies (PCD4989g, BIRCH, FIR) which enrolled 1636 patients with metastatic NSCLC, and 980 patients with other tumor types. TECENTRIQ was administered at a dose of 1200 mg intravenously every 3 weeks in all studies except PCD4989g. Among the 2616 patients who received a single-agent TECENTRIQ, 36% were exposed for longer than 6 months and 20% were exposed for longer than 12 months. Using the dataset described for patients who received TECENTRIQ as a single-agent, the most common adverse reactions in ≥ 20% of patients were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%). In addition, the data reflect exposure to TECENTRIQ as a single agent as adjuvant therapy in 495 patients with early stage NSCLC enrolled in a randomized study (IMpower010).

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

The data also reflect exposure to TECENTRIQ administered in combination with cobimetinib and vemurafenib in 230 patients enrolled in IMspire150. Among the 230 patients, 62% were exposed to TECENTRIQ for longer than 6 months and 42% were exposed to TECENTRIQ for longer than 12 months.

Non-Small Cell Lung Cancer (NSCLC)

Adjuvant Treatment of Early-stage NSCLC

IMpower010

The safety of TECENTRIQ was evaluated in IMpower010, a multicenter, open-label, randomized trial for the adjuvant treatment of patients with stage IB (tumors ≥ 4 cm) - IIIA NSCLC who had complete tumor resection and received up to 4 cycles of cisplatin-based adjuvant chemotherapy. Patients received TECENTRIQ 1200 mg every 3 weeks (n=495) for 1 year (16 cycles), unless disease progression or unacceptable toxicity occurred, or best supportive care [see Clinical Studies (14.1)]. The median number of cycles received was 16 (range: 1, 16).

Fatal adverse reactions occurred in 1.8% of patients receiving TECENTRIQ; these included multiple organ dysfunction syndrome, pneumothorax, interstitial lung disease, arrhythmia, acute cardiac failure, myocarditis, cerebrovascular accident, death of unknown cause, and acute myeloid leukemia (1 patient each).

Serious adverse reactions occurred in 18% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>1%) were pneumonia (1.8%), pneumonitis (1.6%), and pyrexia (1.2%).

TECENTRIQ was discontinued due to adverse reactions in 18% of patients; the most common adverse reactions (≥1%) leading to TECENTRIQ discontinuation were pneumonitis (2.2%), hypothyroidism (1.6%), increased aspartate aminotransferase (1.4%), arthralgia (1.0%), and increased alanine aminotransferase (1.0%).

Adverse reactions leading to interruption of TECENTRIQ occurred in 29% of patients; the most common (>1%) were rash (3.0%), hyperthyroidism (2.8%), hypothyroidism (1.6%), increased AST (1.6%), pyrexia (1.6%), increased ALT (1.4%), upper respiratory tract infection (1.4%), headache (1.2%), peripheral neuropathy (1.2%), and pneumonia (1.2%).

Tables 4 and 5 summarize adverse reactions and selected laboratory abnormalities in patients receiving TECENTRIQ in IMpower010.

Table 4: Adverse Reactions Occurring in ≥10% of Patients with Early Stage
NSCLC Receiving TECENTRIQ in IMpower010

Adverse Reaction*	TECENTRIQ N = 495		Best Supportive Care N = 495
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Skin and Subcutaneous Tissue
Rash1	17	1.2	1.4	0
Pruritus	10	0	0.6	0
Endocrine Disorders
Hypothyroidism2	14	0	0.6	0
Respiratory, Thoracic and Mediastinal
Cough3	16	0	11	0
General
Pyrexia4	14	0.8	2.2	0.2
Fatigue5	14	0.6	5	0.2
Nervous System Disorders
Peripheral neuropathy6	12	0.4	7	0.2
Musculoskeletal and Connective Tissue
Musculoskeletal pain7	14	0.8	9	0.2
Arthralgia8	11	0.6	6	0
*Graded per NCI CTCAE v4.0 1 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 2 Includes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased 3 Productive cough, upper airway cough syndrome, cough 4 Includes pyrexia, body temperature increased, hyperthermia 5 Includes fatigue, asthenia 6 Includes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy 7 Includes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, noncardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain 8 Includes arthralgia, arthritis

Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of
Patients with Early Stage NSCLC Receiving TECENTRIQ in IMpower010

Laboratory Abnormality1	TECENTRIQ2		Best Supportive Care2
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Chemistry
Increased aspartate aminotransferase	34	2.5	18	0
Increased alanine aminotransferase	30	3.3	19	0.4
Hyperkalemia	24	3.5	15	2.5
Increased blood creatinine	31	0.2	23	0.2
1Graded 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). 2The 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.

Metastatic Chemotherapy-Naïve NSCLC

IMpower110

The safety of TECENTRIQ was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations. Patients received TECENTRIQ 1200 mg every 3 weeks (n=286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n=263) until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells [TC] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 1% of the tumor area). The median duration of exposure to TECENTRIQ was 5.3 months (0 to 33 months).

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

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

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

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

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

Table 6: Adverse Reactions Occurring in ≥10% of Patients with NSCLC
Receiving TECENTRIQ in IMpower110

Adverse Reaction	TECENTRIQ N = 286		Platinum-Based Chemotherapy N = 263
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Gastrointestinal
Nausea	14	0.3	34	1.9
Constipation	12	1.0	22	0.8
Diarrhea	11	0	12	0.8
General
Fatigue/asthenia	25	1.4	34	4.2
Pyrexia	14	0	9	0.4
Metabolism and Nutrition
Decreased appetite	15	0.7	19	0
Respiratory, Thoracic and Mediastinal
Dyspnea	14	0.7	10	0
Cough	12	0.3	10	0
Graded per NCI CTCAE v4.0

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 (%)
Hematology
Anemia	69	1.8	94	20
Lymphopenia	47	9	59	17
Chemistry
Hypoalbuminemia	48	0.4	39	2
Increased alkaline phosphatase	46	2.5	42	1.2
Hyponatremia	44	9	36	7
Increased ALT	38	3.2	32	0.8
Increased AST	36	3.2	32	0.8
Hyperkalemia	29	3.9	36	2.7
Hypocalcemia	24	1.4	24	2.7
Increased blood creatinine	24	0.7	33	1.5
Hypophosphatemia	23	3.6	21	2
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.

IMpower150

The safety of TECENTRIQ with bevacizumab, paclitaxel and carboplatin was evaluated in IMpower150, a multicenter, international, randomized, open-label trial in which 393 chemotherapy-naïve patients with metastatic non-squamous NSCLC received TECENTRIQ 1200 mg with bevacizumab 15 mg/kg, paclitaxel 175 mg/m2 or 200 mg/m2, and carboplatin AUC 6 mg/mL/min intravenously every 3 weeks for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg with bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. The median duration of exposure to TECENTRIQ was 8.3 months in patients receiving TECENTRIQ with bevacizumab, paclitaxel, and carboplatin.

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

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

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

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

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

Table 8: Adverse Reactions Occurring in ≥15% of Patients with NSCLC Receiving
TECENTRIQ in IMpower150

Adverse Reaction	TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin N = 393		Bevacizumab, Paclitaxel and Carboplatin N = 394
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Nervous System
Neuropathy1	56	3	47	3
Headache	16	0.8	13	0
General
Fatigue/Asthenia	50	6	46	6
Pyrexia	19	0.3	9	0.5
Skin and Subcutaneous Tissue
Alopecia	48	0	46	0
Rash2	23	2	10	0.3
Musculoskeletal and Connective Tissue
Myalgia/Pain3	42	3	34	2
Arthralgia	26	1	22	1
Gastrointestinal
Nausea	39	4	32	2
Diarrhea4	33	6	25	0.5
Constipation	30	0.3	23	0.3
Vomiting	19	2	18	1
Metabolism and Nutrition
Decreased appetite	29	4	21	0.8
Vascular
Hypertension	25	9	22	8
Respiratory
Cough	20	0.8	19	0.3
Epistaxis	17	1	22	0.3
Renal
Proteinuria5	16	3	15	3
Graded per NCI CTCAE v4.0 1Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paraesthesia, dysesthesia, polyneuropathy 2Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform 3Includes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain 4Includes diarrhea, gastroenteritis, colitis, enterocolitis 5Data based on Preferred Terms since laboratory data for proteinuria were not systematically collected

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 (%)
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	NA1	44	NA1
Hypomagnesemia	42	2	36	1
Hypoalbuminemia	40	3	31	2
Increased AST	40	4	28	0.8
Hyponatremia	38	10	36	9
Increased Alkaline Phosphatase	37	2	32	1
Increased ALT	37	6	28	0.5
Increased TSH	30	NA1	20	NA1
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	NA1	19	NA1
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 1 NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities

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 proteinbound 100 mg/m2 intravenously on Day 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by TECENTRIQ 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among patients receiving TECENTRIQ, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.

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

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

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

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

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

Table 10: Adverse Reactions Occurring in ≥20% of Patients with NSCLC Receiving
TECENTRIQ in IMpower130

Adverse Reaction	TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin N = 473		Paclitaxel Protein-Bound and Carboplatin N = 232
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
General
Fatigue/Asthenia	61	11	60	8
Gastrointestinal
Nausea	50	3.4	46	2.2
Diarrhea 1	43	6	32	6
Constipation	36	1.1	31	0
Vomiting	27	2.7	19	2.2
Musculoskeletal and Connective Tissue
Myalgia/Pain 2	38	3	22	0.4
Nervous System
Neuropathy 3	33	2.5	28	2.2
Respiratory, Thoracic and Mediastinal
Dyspnea 4	32	4.9	25	1.3
Cough	27	0.6	17	0
Skin and Subcutaneous Tissue
Alopecia	32	0	27	0
Rash 5	20	0.6	11	0.9
Metabolism and Nutrition
Decreased appetite	30	2.1	26	2.2
Graded per NCI CTCAE v4.0 1 Includes diarrhea, colitis, and gastroenteritis 2 Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort 3 Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy 4 Includes dyspnea, dyspnea exertional and wheezing 5 Includes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular.

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 (%)
Hematology
Anemia	92	33	87	25
Neutropenia	75	50	67	39
Thrombocytopenia	73	19	59	13
Lymphopenia	71	23	61	16
Chemistry
Hyperglycemia	75	8	66	8
Hypomagnesemia	50	3.4	42	3.2
Hyponatremia	37	9	28	7
Hypoalbuminemia	35	1.3	31	0
Increased ALT	31	2.8	24	3.9
Hypocalcemia	31	2.6	27	1.8
Hypophosphatemia	29	6	20	3.2
Increased AST	28	2.2	24	1.8
Increased TSH	26	NA1	5	NA1
Hypokalemia	26	6	24	4.4
Increased Alkaline Phosphatase	25	2.6	22	1.3
Increased Blood Creatinine	23	2.8	16	0.4
Hyperphosphatemia	21	NA1	13	NA1
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. 1 NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities

Previously Treated Metastatic NSCLC

The safety of TECENTRIQ was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.1)]. A total of 609 patients received TECENTRIQ 1200 mg intravenously every 3 weeks until unacceptable toxicity, radiographic progression, or clinical progression or docetaxel (n=578) 75 mg/m2 intravenously every 3 weeks until unacceptable toxicity or disease progression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The median duration of exposure was 3.4 months (0 to 26 months) in TECENTRIQ-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.

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

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

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

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

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

Table 12: Adverse Reactions Occurring in ≥10% of Patients with NSCLC Receiving
TECENTRIQ in OAK

Adverse Reaction	TECENTRIQ N = 609		Docetaxel N = 578
	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
General
Fatigue/Asthenia 1	44	4	53	6
Pyrexia	18	<1	13	<1
Respiratory
Cough 2	26	<1	21	<1
Dyspnea	22	2.8	21	2.6
Metabolism and Nutrition
Decreased appetite	23	<1	24	1.6
Musculoskeletal
Myalgia/Pain 3	20	1.3	20	<1
Arthralgia	12	0.5	10	0.2
Gastrointestinal
Nausea	18	<1	23	<1
Constipation	18	<1	14	<1
Diarrhea	16	<1	24	2
Skin
Rash 4	12	<1	10	0
Graded per NCI CTCAE v4.0 1 Includes fatigue and asthenia 2 Includes cough and exertional cough 3 Includes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia 4 Includes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid

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 (%)
Hematology
Anemia	67	3	82	7
Lymphocytopenia	49	14	60	21
Chemistry
Hypoalbuminemia	48	4	50	3
Hyponatremia	42	7	31	6
Increased Alkaline Phosphatase	39	2	25	1
Increased AST	31	3	16	0.5
Increased ALT	27	3	14	0.5
Hypophosphatemia	27	5	23	4
Hypomagnesemia	26	1	21	1
Increased Creatinine	23	2	16	1
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546−585) and docetaxel (range: 532−560). Graded according to NCI CTCAE version 4.0

Small Cell Lung Cancer (SCLC)

The safety of TECENTRIQ with carboplatin and etoposide was evaluated in IMpower133, a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ESSCLC received TECENTRIQ 1200 mg and carboplatin AUC 5 mg/mL/min on Day 1 and etoposide 100 mg/m2 intravenously on Days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by TECENTRIQ 1200 mg every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. Among 198 patients receiving TECENTRIQ, 32% were exposed for 6 months or longer and 12% were exposed for 12 months or longer.

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

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

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

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

Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower133.

Table 14: Adverse Reactions Occurring in ≥20% of Patients with SCLC
Receiving TECENTRIQ in IMpower133

Adverse Reaction	TECENTRIQ with Carboplatin and Etoposide N = 198		Placebo with Carboplatin and Etoposide N = 196
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
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
Graded per NCI CTCAE v4.0

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 (%)
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 TSH2	28	NA1	15	NA1
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	NA5	23	NA1
Increased TSH2	21	NA1	7	NA1
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 1 NA = Not applicable. 2 TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories.

Hepatocellular Carcinoma (HCC)

The safety of TECENTRIQ in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.3)]. Patients received 1,200 mg of TECENTRIQ intravenously followed by 15 mg/kg bevacizumab (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 7.4 months (range: 0-16 months) and to bevacizumab was 6.9 months (range: 0-16 months).

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

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

Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the

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

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

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

Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ and bevacizumab in IMbrave150.

Table 16: 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 Grades2 (%)	Grades 3–42 (%)	All Grades2 (%)	Grades 3–42 (%)
Vascular Disorders
Hypertension	30	15	24	12
General Disorders and Administration Site Conditions
Fatigue/asthenia]	26	7	32	6
Pyrexia	18	0	10	0
Renal and Urinary Disorders
Proteinuria	20	3	7	0.6
Investigations
Weight Decreased	11	0	10	0
Skin and Subcutaneous Tissue Disorders
Pruritus	19	0	10	0
Rash	12	0	17	2.6
Gastrointestinal Disorders
Diarrhea	19	1.8	49	5
Constipation	13	0	14	0
Abdominal Pain	12	0	17	0
Nausea	12	0	16	0
Vomiting	10	0	8	0
Metabolism and Nutrition Disorders
Decreased Appetite	18	1.2	24	3.8
Respiratory, Thoracic and Mediastinal Disorders
Cough	12	0	10	0
Epistaxis	10	0	4.5	0
Injury, Poisoning and Procedural Complications
Infusion-Related Reaction	11	2.4	0	0
1Includes fatigue and asthenia 2Graded per NCI CTCAE v4.0

Table 17: 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 Grades1 (%)	Grades 3–41 (%)	All Grades1 (%)	Grades 3–41 (%)
Chemistry
Increased AST	86	16	90	16
Increased Alkaline Phosphatase	70	4	76	4.6
Increased ALT	62	8	70	4.6
Decreased Albumin	60	1.5	54	0.7
Decreased Sodium	54	13	49	9
Increased Glucose	48	9	43	4.6
Decreased Calcium	30	0.3	35	1.3
Decreased Phosphorus	26	4.7	58	16
Increased Potassium	23	1.9	16	2
Hypomagnesemia	22	0	22	0
Hematology
Decreased Platelet	68	7	63	4.6
Decreased Lymphocytes	62	13	58	11
Decreased Hemoglobin	58	3.1	62	3.9
Increased Bilirubin	57	8	59	14
Decreased Leukocyte	32	3.4	29	1.3
Decreased Neutrophil	23	2.3	16	1.1
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) 1Graded per NCI CTCAE v4.0

Melanoma

The safety of TECENTRIQ, administered with cobimetinib and vemurafenib was evaluated in IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma [see Clinical Studies (14.4)]. Patients received TECENTRIQ with cobimetinib and vemurafenib (N=230) or placebo with cobimetinib and vemurafenib (n=281).

Among the 230 patients who received TECENTRIQ administered with cobimetinib and vemurafenib, the median duration of exposure to TECENTRIQ was 9.2 months (range: 0-30 months) to cobimetinib was 10.0 months (range: 1-31 months) and to vemurafenib was 9.8 months (range: 1-31 months).

Fatal adverse reactions occurred in 3% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. Adverse reactions leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest.

Serious adverse reactions occurred in 45% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) serious adverse reactions were hepatotoxicity (7%), pyrexia (6%), pneumonia (4.3%), malignant neoplasms (2.2%), and acute kidney injury (2.2%).

Adverse reactions leading to discontinuation of TECENTRIQ occurred in 21% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) adverse reactions leading to TECENTRIQ discontinuation were increased ALT (2.2%) and pneumonitis (2.6%).

Adverse reactions leading to interruption of TECENTRIQ occurred in 68% of patients in the TECENTRIQ plus cobimetinib and vemurafenib arm. The most frequent (≥ 2%) adverse reactions leading to TECENTRIQ interruption were pyrexia (14%), increased ALT (13%), hyperthyroidism (10%), increased AST (10%), increased lipase (9%), increased amylase (7%), pneumonitis (5%), increased CPK (4.3%), diarrhea (3.5%), pneumonia (3.5%), asthenia (3%), rash (3%), influenza (3%), arthralgia (2.6%), fatigue (2.2%), dyspnea (2.2%), cough (2.2%), peripheral edema (2.2%), uveitis (2.2%), bronchitis (2.2%), hypothyroidism (2.2%), and respiratory tract infection (2.2%).

Tables 18 and 19 summarize the incidence of adverse reactions and laboratory abnormalities in Study IMspire150.

Table 18: Adverse Reactions Occurring in ≥10% of Patients on the
TECENTRIQ plus Cobimetinib and Vemurafenib Arm or the Placebo plus
Cobimetiniband Vemurafenib Arm and at a Higher Incidence (Between Arm
Difference of ≥ 5% AllGrades 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 1	75	27	72	23
Pruritus	26	<1	17	<1
Photosensitivity reaction	21	<1	25	3.2
General Disorders and Administration Site Conditions
Fatigue 2	51	3	45	1.8
Pyrexia 3	49	1.7	35	2.1
Edema 4	26	<1	21	0
Gastrointestinal Disorders
Hepatotoxicity 5	50	21	36	13
Nausea	30	<1	32	2.5
Stomatitis 6	23	1.3	15	<1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain 7	62	4.3	48	3.2
Endocrine Disorders
Hypothyroidism 8	22	0	10	0
Hyperthyroidism	18	<1	8	0
Injury, Poisoning and Procedural Complications
Infusion-related reaction 9	10	2.6	8	<1
Respiratory, Thoracic and Mediastinal Disorders
Pneumonitis 10	12	1.3	6	<1
Vascular Disorders
Hypertension 11	17	10	18	7
1 Includes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysaesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalised and rash morbilliform 2 Includes fatigue, asthenia and malaise 3 Includes pyrexia and hyperpyrexia 4 Includes edema peripheral, lymphoedema, oedema, face oedema, eyelid oedema, periorbital oedema, lip oedema and generalised oedema 5 Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasaemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinaemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal 6 Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis 7 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 8 Includes hypothyroidism and blood thyroid stimulating hormone increased 9 Includes infusion related reaction and hypersensitivity 10 Includes pneumonitis and interstitial lung disease 11 Includes hypertension, blood pressure increased, hypertensive crisis

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 19: 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 (%)
Hematology
Decreased Lymphocytes	80	24	72	17
Decreased Hemoglobin	77	2.6	72	2.2
Decreased Platelet	34	1.3	24	0.4
Decreased Neutrophils	26	2.2	19	1.5
Chemistry
Increased Creatine Kinase	88	22	81	18
Increased AST	80	13	68	6
Increased ALT	79	18	62	12
Increased Triacylglycerol Lipase	75	46	62	35
Increased Alkaline Phosphatase	73	6	63	2.9
Decreased Phosphorus	67	22	64	14
Increased Amylase	51	13	45	13
Increased Blood Urea Nitrogen	47	NA1	37	NA1
Decreased Albumin	43	0.9	34	1.5
Increased Bilirubin	42	3.1	33	0.7
Decreased Calcium	41	1.3	28	0
Decreased Sodium	40	5	34	7
Decreased Thyroid- Stimulating Hormone	38	NA1	23	NA1
Increased Thyroid- Stimulating Hormone 2	37	NA1	33	NA1
Decreased Potassium	36	5	22	4.3
Increased Triiodothyronine	33	NA1	18	NA1
Increased Free Thyroxine	32	NA1	21	NA1
Decreased Total Triiodothyronine	32	NA1	8	NA1
Increased Potassium	29	1.3	19	1.4
Decreased Triiodothyronine	27	NA1	21	NA1
Increased Sodium	20	0	13	0.4
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). 1 NA= Not applicable. NCI CTCAE v4.0 does not include these laboratories. 2 Increased Thyroid Stimulating Hormone has a difference <5% (All Grades) between arms and is included for clinical completeness.

Unresectable or Metastatic Alveolar Soft Part Sarcoma (ASPS)

The safety of TECENTRIQ was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5)]. Adult patients received TECENTRIQ 1200 mg every 3 weeks and pediatric patients received 15 mg/kg up to a maximum 1200 mg every 3 weeks until disease progression or unacceptable toxicity. The median duration of exposure to TECENTRIQ was 8.9 months (1 to 40 months).

Serious adverse reactions occurred in 41% of patients receiving TECENTRIQ. The most frequent serious adverse reactions (>2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each).

Dosage interruptions of TECENTRIQ due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (≥3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each).

Tables 20 and 21 summarize adverse reactions and laboratory abnormalities in Study ML39345.

Table 20: Adverse Reactions Occurring in ≥15% of Patients with ASPS
Receiving TECENTRIQ in ML39345

Adverse Reaction	TECENTRIQ N = 49
	All Grades (%)	Grades 3–4 (%)
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 pain1	25	0
Metabolism and nutrition disorders
Decreased appetite	22	2
Respiratory, Thoracic and Mediastinal
Cough2	45	0
Dyspnea	33	0
Rhinitis allergic	16	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain3	67	8
Skin and subcutaneous tissue disorders
Rash4	47	2
Nervous system disorders
Headache	43	4
Dizziness5	29	4
Vascular disorders
Hypertension	43	6
Hemorrhage6	29	2
Psychiatric disorders
Insomnia	27	0
Anxiety	25	0
Cardiac Disorders
Arrhythmia7	22	2
Endocrine disorders
Hypothyroidism8	25	0
Investigations
Weight decreased	18	0
Weight increased	16	6
Graded per NCI CTCAE v4.0 1Includes abdominal pain and abdominal pain upper 2Includes cough, upper-airway cough syndrome, and productive cough 3Includes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain 4Includes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption 5Includes vertigo and dizziness 6Includes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage 7Includes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia 8Includes hypothyroidism and blood thyroid stimulating hormone increased

Table 21: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of
Patients with ASPS Receiving TECENTRIQ in ML39345

Laboratory Abnormality 1	TECENTRIQ2
	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
1 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. 2 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.

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

Drug Interactions for Tecentriq

No information provided

DRUG ABUSE AND DEPENDENCE

No information provided

Warnings for Tecentriq

Included as part of the PRECAUTIONS section.

Precautions 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 PD1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue TECENTRIQ depending on severity [see Dosage and Administration (2.3)]. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

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 [see Dosage and Administration (2.3)].

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.

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

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 [see Dosage and Administration (2.3)]. For Grade 1 or 2 infusion-related reactions, consider using premedications with subsequent doses.

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

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 [see Use in Specific Populations (8.1, 8.3)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

Animal Toxicology and/or Pharmacology

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

Patient Information for Tecentriq

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

Immune-Mediated Adverse Reactions

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

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

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].

Complications of Allogeneic HSCT after PD-1/PD-L1 inhibitors

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 [see Warnings and Precautions (5.3)].

Embryo-Fetal Toxicity

Advise females of reproductive potential that TECENTRIQ can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].

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

Lactation

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

Overdose Information for Tecentriq

No Information provided

Contraindications for Tecentriq

None.

Clinical Pharmacology for Tecentriq

Mechanism of Action

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

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

In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T cell infiltration and activation compared to targeted therapy alone.

Pharmacodynamics

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

Pharmacokinetics

Atezolizumab exposure increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg (0.07 to 1.33 times of the approved recommended doses), including a dose of 1200 mg administered every 3 weeks. Steady state was achieved after 6 to 9 weeks following multiple doses. The systemic accumulation ratio for every 2 weeks administration and every 3 weeks administration is 3.3- and 1.9- fold, respectively.

Distribution

The volume of distribution at steady state is 6.9 L.

Elimination

The clearance (CV%) is 0.2 L/day (29%) and the terminal half-life is 27 days. Atezolizumab clearance was found to decrease over time, with a mean maximal reduction (CV%) from baseline value of 17% (41%); however, the decrease in clearance was not considered clinically relevant.

Specific Populations

The following factors had no clinically significant effect on the systemic exposure of atezolizumab: age (2 to 89 years), body weight, sex, albumin levels, tumor burden, region or race, mild or moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2], mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5 × ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3x ULN and any AST), level of PD-L1 expression, or performance status.

Pediatric Patients

Atezolizumab serum concentrations with weight-based dosing at 15 mg/kg up to a maximum of 1200 mg every 3 weeks, in pediatric patients (2 years to <17 years) with relapsed or progressive solid tumors and lymphomas, are comparable to those of adult patients receiving 1200 mg every 3 weeks; while the exposure tended to be lower in pediatric patients less than 12 years old, this is not considered to be clinically relevant.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other products.

During the first year of treatment with TECENTRIQ across 8 clinical studies, 13% to 36% of patients developed anti-atezolizumab antibodies. Median atezolizumab clearance in patients who tested positive for ADA was 19% (minimum 18%, maximum 49%) higher as compared to atezolizumab clearance in patients who tested negative for ADA; this change in clearance is not expected to be clinically significant.

In OAK and IMbrave150, exploratory analyses showed that the subset of patients who were ADA-positive appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for ADA [see Clinical Studies (14.1, 14.3)]. In study IMpower150, the impact of ADA on efficacy did not appear to be clinically significant [see Clinical Studies (14.1)]. In the remaining studies, there is insufficient information to characterize the effect of ADA on efficacy.

The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.

Across clinical studies, 4.3% to 27.5% of neutralizing antibody (NAb)-evaluable patients had a positive NAb status at any timepoint post-treatment. The effect of NAb on atezolizumab exposure and safety did not appear to be clinically significant. The effect of NAb on key efficacy endpoints is uncertain due to small sample sizes.

What is the most important information I should know about TECENTRIQ?

TECENTRIQ is a medicine that may treat certain cancers by working with your immune system. TECENTRIQ can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during your treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:

Lung problems.

cough

shortness of breath

chest pain

Intestinal problems.

• diarrhea (loose stools) or more frequent bowel movements than usual
• stools that are black, tarry, sticky, or have blood or mucus
• severe stomach-area (abdomen) pain or tenderness

Liver problems.

yellowing of your skin or the whites of your eyes severe nausea or vomiting pain on the right side of your stomach area (abdomen)

dark urine (tea colored) bleeding or bruising more easily than normal

Hormone gland problems.

headaches that will not go away or unusual headaches eye sensitivity to light eye problems rapid heart beat increased sweating extreme tiredness weight gain or weight loss feeling more hungry or thirsty than usual

urinating more often than usual hair loss feeling cold constipation your voice gets deeper dizziness or fainting changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness Kidney problems.

decrease in your amount of urine blood in your urine

swelling of your ankles loss of appetite

Skin problems.

rash itching skin blistering or peeling

painful sores or ulcers in mouth or nose, throat, or genital area fever or flu-like symptoms swollen lymph nodes

Problems can also happen in other organs.

These are not all of the signs and symptoms of immune system problems that can happen with TECENTRIQ. Call or see your healthcare provider right away for any new or worse signs or symptoms, including:

• chest pain, irregular heartbeat, shortness of breath, or swelling of ankles
• confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
• double vision, blurry vision, sensitivity to light, eye pain, changes in eye sight
• persistent or severe muscle pain or weakness, muscle cramps
• low red blood cells, bruising

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

chills or shaking itching or rash flushing shortness of breath or wheezing

dizziness feeling like passing out fever back or neck pain

Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with TECENTRIQ. Your healthcare provider will monitor you for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during your treatment with TECENTRIQ. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with TECENTRIQ if you have severe side effects.

What is TECENTRIQ?

TECENTRIQ is a prescription medicine used to treat adults with:

• a type of lung cancer called non-small cell lung cancer (NSCLC).
  • TECENTRIQ may be used alone as a treatment for your lung cancer:
    • to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and
    • you have stage 2 to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and
    • your cancer tests positive for “PD-L1”.
  • TECENTRIQ may be used alone as your first treatment when your lung cancer:
    • has spread or grown, and
    • your cancer tests positive for “high PD-L1”, and
    • your tumor does not have an abnormal “EGFR” or “ALK” gene.
  • TECENTRIQ may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:
    • has spread or grown, and
    • is a type called “non-squamous NSCLC”, and
    • your tumor does not have an abnormal “EGFR” or “ALK” gene
  • TECENTRIQ may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:
    • has spread or grown, and
    • is a type called “non-squamous NSCLC”, and
    • your tumor does not have an abnormal “EGFR” or “ALK” gene.
  • TECENTRIQ may also be used alone when your lung cancer:
    • has spread or grown, and
    • you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
    • if your tumor has an abnormal “EGFR” or “ALK” gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.

• adults with a type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer
  • is a type called “extensive-stage SCLC,” which means that it has spread or grown.

• adults with a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:
  • has spread or cannot be removed by surgery, and
  • you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.

• adults with a type of skin cancer called melanoma. TECENTRIQ may be used with the medicines cobimetinib and vemurafenib when your melanoma:
  • has spread to other parts of the body or cannot be removed by surgery, and
  • has a certain type of abnormal “BRAF” gene. Your healthcare provider will perform a test to make sure this TECENTRIQ combination is right for you.

• adults and children 2 years of age and older with a type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ may be used when your sarcoma:
  • has spread to other parts of the body or cannot be removed by surgery.

It is not known if TECENTRIQ is safe and effective when used:

• in children younger than 2 years of age for the treatment of ASPS.
• • in children for the treatment of NSCLC, SCLC, HCC, or melanoma.

Before receiving TECENTRIQ, tell your healthcare provider about all of your medical conditions, including if you:

• have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
• have received an organ transplant
• have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
• have received radiation treatment to your chest area
• have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
• are pregnant or plan to become pregnant. TECENTRIQ can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ.

  Females who are able to become pregnant:

  • Your healthcare provider should do a pregnancy test before you start treatment with TECENTRIQ.
  • You should use an effective method of birth control during your treatment and for at least 5 months after the last dose of TECENTRIQ.
• are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ passes into your breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of TECENTRIQ.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive TECENTRIQ?

• Your healthcare provider will give you TECENTRIQ into your vein through an intravenous (IV) line over 30 to 60 minutes.
• TECENTRIQ is usually given every 2, 3, or 4 weeks.
• Your healthcare provider will decide how many treatments you need.
• Your healthcare provider will test your blood to check you for certain side effects.
• For treatment of a type of skin cancer called melanoma, your healthcare provider will also prescribe you cobimetinib and vemurafenib. Take cobimetinib and vemurafenib exactly as your healthcare provider tells you.
• If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.

What are the possible side effects of TECENTRIQ?

TECENTRIQ can cause serious side effects, including:

• See “What is the most important information I should know about TECENTRIQ?

The most common side effects of TECENTRIQ when used alone include:

feeling tired or weak decreased appetite

nausea cough

shortness of breath

The most common side effects of TECENTRIQ when used in lung cancer with other anti-cancer medicines include:

feeling tired or weak nausea

hair loss constipation

diarrhea decreased appetite

The most common side effects of TECENTRIQ when used in hepatocellular carcinoma with bevacizumab include:

high blood pressure

feeling tired or weak

too much protein in the urine

The most common side effects of TECENTRIQ when used in melanoma with cobimetinib and vemurafenib include:

skin rash joint, muscle, or bone pain feeling tired or weak liver injury

fever nausea itching swelling of legs or arms

mouth swelling (sometimes with sores) low thyroid hormone levels sunburn or sun sensitivity

TECENTRIQ may cause fertility problems in females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of TECENTRIQ.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of TECENTRIQ.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about TECENTRIQ that is written for health professionals.

What are the ingredients in TECENTRIQ?

Active ingredient: atezolizumab

Inactive ingredients: glacial acetic acid, L-histidine, polysorbate 20 and sucrose

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

U.S. License No.: 1048 TECENTRIQ is a registered trademark of Genentech, Inc.

For more information, call 1-844-832-3687 or go to www.TECENTRIQ.com.