15 Ml Atezolizumab-tqjs 125 Mg/ml / Hyaluronidase-tqjs 2000 Unt/ml Injection [tecentriq Hybreza]

Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:

Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade 3 (1.3%) and Grade 2 (7%) adverse reactions. Pneumonitis led to permanent discontinuation of intravenous atezolizumab in 2.6% of patients and withholding of intravenous atezolizumab in 7.4% of patients.

Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients. Of the 17 patients in whom intravenous atezolizumab was withheld for pneumonitis, 10 reinitiated intravenous atezolizumab after symptom improvement; of these, 50% had recurrence of pneumonitis.

Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:

Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade 4 (1.3%), Grade 3 (1.7%) and Grade 2 (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of intravenous atezolizumab in 2.2% and withholding of intravenous atezolizumab in 1.7% of patients.

Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the 4 patients in whom intravenous atezolizumab was withheld for hepatitis, 3 reinitiated intravenous atezolizumab after symptom improvement; of these, 33% had recurrence of hepatitis.

Adrenal Insufficiency:

TECENTRIQ HYBREZA can cause primary or secondary adrenal insufficiency, including Grade 3 adverse reactions. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].

Immune-mediated adrenal insufficiency occurred in 0.8% (2/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade 2 (0.4%) adverse reactions. Adrenal insufficiency led to the withholding of TECENTRIQ HYBREZA in both patients. Systemic corticosteroids were required in 50% (1/2) of patients with adrenal insufficiency who received TECENTRIQ HYBREZA as monotherapy; this single patient remained on systemic corticosteroids.

Hypophysitis:

TECENTRIQ HYBREZA can cause immune-mediated hypophysitis, including Grade 2 adverse reactions. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].

Immune-mediated hypophysitis occurred in 0.4% (1/247) of patients with locally advanced or metastatic NSCLC in the IMscin001 trial [see Adverse Reactions (6.1)] receiving TECENTRIQ HYBREZA as monotherapy, including Grade 1 (0.4%) adverse reactions. Hypophysitis led to the withholding of TECENTRIQ HYBREZA in this patient.

Thyroid Disorders:

TECENTRIQ HYBREZA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].

Thyroiditis:

Immune-mediated thyroiditis occurred in 0.8% (2/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade 2 (0.4%) adverse reactions. Thyroiditis resolved in 50% of patients.

Hyperthyroidism:

Immune-mediated hyperthyroidism occurred in 2% (5/247) of patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)], including Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to withholding of TECENTRIQ HYBREZA in 0.8% of patients.

Anti-thyroid therapy was required in 40% (2/5) of patients with hyperthyroidism who received TECENTRIQ HYBREZA as monotherapy. Of these 2 patients, one remained on anti-thyroid treatment. Of the 2 patients in whom TECENTRIQ HYBREZA was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ HYBREZA; this patient did not have recurrence of hyperthyroidism.

Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:

Hyperthyroidism occurred in 19% (43/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade 3 (0.9%) and Grade 2 (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 10% of patients. Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom intravenous atezolizumab was withheld for hyperthyroidism, 18 patients reinitiated intravenous atezolizumab; of these, 28% had recurrence of hyperthyroidism.

Hypothyroidism:

TECENTRIQ HYBREZA can cause immune-mediated hypothyroidism, including Grade 4 adverse reactions. Immune-mediated hypothyroidism occurred in 10% (25/247) of patients with locally advanced or metastatic NSCLC who received TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial [see Adverse Reactions (6.1)].

Hormone replacement was required in 68% (17/25) of patients with hypothyroidism who received TECENTRIQ HYBREZA as monotherapy. Two patients with hypothyroidism remained on thyroid hormone replacement.

Intravenous Atezolizumab in Combination with Platinum-based Chemotherapy:

Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC (N = 2223) or SCLC (N = 198) enrolled in five randomized, active-controlled trials, including IMpower150, IMpower130 and IMpower133 receiving intravenous atezolizumab in combination with platinum-based chemotherapy, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (5.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of intravenous atezolizumab in 0.1% and withholding of intravenous atezolizumab in 1.6% of patients.

Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 39 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 9 reinitiated intravenous atezolizumab after symptom improvement.

Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:

Hypothyroidism occurred in 26% (60/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade 2 (9.1%) adverse reactions. Hypothyroidism led to withholding of intravenous atezolizumab in 2.6% of patients. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 6 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 4 reinitiated intravenous atezolizumab after symptom improvement. The majority of patients with hypothyroidism required long term thyroid replacement.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis:

TECENTRIQ HYBREZA can cause type 1 diabetes mellitus, including Grade 3 adverse reactions and diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity [see Dosage and Administration (2.3)].

Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib:

Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial [see Adverse Reactions (6.1)], including Grade 2 (1.3%) adverse reactions. Nephritis led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 0.9% of patients.

Systemic corticosteroids were required in 67% (2/3) of patients with nephritis. Nephritis resolved in all 3 of these patients. Of the 2 patients in whom intravenous atezolizumab was withheld for nephritis, both reinitiated intravenous atezolizumab after symptom improvement and neither had recurrence of nephritis.

Adverse Reactions in Adult Patients with NSCLC Treated with Intravenous Atezolizumab

The safety of TECENTRIQ HYBREZA for its approved NSCLC indications [see Indications and Usage (1.1)] has been established in adequate and well-controlled studies of intravenous atezolizumab for the:

adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells (IMpower010 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), with no EGFR or ALK genomic tumor aberrations (IMpower110 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study).

Below is a description of adverse reactions of intravenous atezolizumab in these adequate and well-controlled NSCLC studies.

Non-Small Cell Lung Cancer (NSCLC)

IMpower010

The safety of intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab; these included multiple organ dysfunction syndrome, pneumothorax, interstitial lung disease, arrhythmia, acute cardiac failure, myocarditis, cerebrovascular accident, death of unknown cause, and acute myeloid leukemia (1 patient each).

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

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

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

Tables 5 and 6 summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower010.

Adverse ReactionGraded per NCI CTCAE v4.0	Intravenous Atezolizumab N = 495		Best Supportive Care N = 495
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Skin and Subcutaneous Tissue
RashIncludes 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
HypothyroidismIncludes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased	14	0	0.6	0
Respiratory, Thoracic and Mediastinal
CoughProductive cough, upper airway cough syndrome, cough	16	0	11	0
General
PyrexiaIncludes pyrexia, body temperature increased, hyperthermia	14	0.8	2.2	0.2
FatigueIncludes fatigue, asthenia	14	0.6	5	0.2
Nervous System Disorders
Peripheral neuropathyIncludes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy	12	0.4	7	0.2
Musculoskeletal and Connective Tissue
Musculoskeletal painIncludes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain	14	0.8	9	0.2
ArthralgiaIncludes arthralgia, arthritis	11	0.6	6	0

Laboratory AbnormalityGraded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0).	Intravenous AtezolizumabThe denominators used to calculate the rate varied from 78–480 for BSC arm and 483 for intravenous atezolizumab are for all tests of interest based on the number of patients with a baseline value and at least one post-treatment value.		Best Supportive Care
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Chemistry
Increased aspartate aminotransferase	34	2.5	18	0
Increased alanine aminotransferase	30	3.3	19	0.4
Hyperkalemia	24	3.5	15	2.5
Increased blood creatinine	31	0.2	23	0.2

IMpower110

The safety of intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab was 5.3 months (0 to 33 months).

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

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

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

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

Tables 7 and 8 summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower110.

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

Laboratory Abnormality	Intravenous Atezolizumab		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: intravenous atezolizumab (range: 278–281); platinum-based chemotherapy (range: 256–260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range.
Hematology
Anemia	69	1.8	94	20
Lymphopenia	47	9	59	17
Chemistry
Hypoalbuminemia	48	0.4	39	2
Increased alkaline phosphatase	46	2.5	42	1.2
Hyponatremia	44	9	36	7
Increased ALT	38	3.2	32	0.8
Increased AST	36	3.2	32	0.8
Hyperkalemia	29	3.9	36	2.7
Hypocalcemia	24	1.4	24	2.7
Increased blood creatinine	24	0.7	33	1.5
Hypophosphatemia	23	3.6	21	2

IMpower150

The safety of intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab was 8.3 months in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin.

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

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

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

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

Tables 9 and 10 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin in IMpower150.

Adverse Reaction	Intravenous Atezolizumab 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
NeuropathyIncludes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy	56	3	47	3
Headache	16	0.8	13	0
General
Fatigue/Asthenia	50	6	46	6
Pyrexia	19	0.3	9	0.5
Skin and Subcutaneous Tissue
Alopecia	48	0	46	0
RashIncludes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform	23	2	10	0.3
Musculoskeletal and Connective Tissue
Myalgia/PainIncludes 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
DiarrheaIncludes diarrhea, gastroenteritis, colitis, enterocolitis	33	6	25	0.5
Constipation	30	0.3	23	0.3
Vomiting	19	2	18	1
Metabolism and Nutrition
Decreased appetite	29	4	21	0.8
Vascular
Hypertension	25	9	22	8
Respiratory
Cough	20	0.8	19	0.3
Epistaxis	17	1	22	0.3
Renal
ProteinuriaBased on adverse reaction terms since laboratory data for proteinuria was not systematically collected	16	3	15	3

Laboratory Abnormality	Intravenous Atezolizumab 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: Intravenous Atezolizumab 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	NANA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities	44	NA
Hypomagnesemia	42	2	36	1
Hypoalbuminemia	40	3	31	2
Increased AST	40	4	28	0.8
Hyponatremia	38	10	36	9
Increased Alkaline Phosphatase	37	2	32	1
Increased ALT	37	6	28	0.5
Increased TSH	30	NA	20	NA
Hyperkalemia	28	3	25	2
Increased Creatinine	28	1	19	2
Hypocalcemia	26	3	21	3
Hypophosphatemia	25	4	18	4
Hypokalemia	23	7	14	4
Hyperphosphatemia	25	NA	19	NA

IMpower130

The safety of intravenous atezolizumab 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 intravenous atezolizumab 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m² intravenously on Days 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by intravenous atezolizumab 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among patients receiving intravenous atezolizumab, 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 intravenous atezolizumab; these included pneumonia (1.1%), pulmonary embolism (0.8%), myocardial infarction (0.6%), cardiac arrest (0.4%), pneumonitis (0.4%) and sepsis, septic shock, staphylococcal sepsis, aspiration, respiratory distress, cardiorespiratory arrest, ventricular tachycardia, death (not otherwise specified), and hepatic cirrhosis (0.2% each).

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

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

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

Tables 11 and 12 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with paclitaxel protein-bound and carboplatin in IMpower130.

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

Laboratory Abnormality	Intravenous Atezolizumab 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: intravenous atezolizumab with paclitaxel protein-bound and carboplatin (range: 423–467); paclitaxel protein-bound and carboplatin (range: 218–229). Graded per NCI CTCAE v4.0.
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	NANA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities	5	NA
Hypokalemia	26	6	24	4.4
Increased Alkaline Phosphatase	25	2.6	22	1.3
Increased Blood Creatinine	23	2.8	16	0.4
Hyperphosphatemia	21	NA	13	NA

OAK

The safety of intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab-treated patients and 2.1 months (0 to 23 months) in docetaxel-treated patients.

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

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

Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in OAK.

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

Laboratory Abnormality	Intravenous Atezolizumab		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: intravenous atezolizumab (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0
Hematology
Anemia	67	3	82	7
Lymphocytopenia	49	14	60	21
Chemistry
Hypoalbuminemia	48	4	50	3
Hyponatremia	42	7	31	6
Increased Alkaline Phosphatase	39	2	25	1
Increased AST	31	3	16	0.5
Increased ALT	27	3	14	0.5
Hypophosphatemia	27	5	23	4
Hypomagnesemia	26	1	21	1
Increased Creatinine	23	2	16	1

IMpower133

The safety of intravenous atezolizumab with carboplatin and etoposide was evaluated in IMpower133, a randomized, multicenter, double-blind, placebo-controlled trial in which 198 patients with ES-SCLC received intravenous atezolizumab 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 intravenous atezolizumab 1200 mg every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.2)]. Among 198 patients receiving intravenous atezolizumab, 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 intravenous atezolizumab. These included pneumonia, respiratory failure, neutropenia, and death (1 patient each).

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

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

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

Tables 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with carboplatin and etoposide in IMpower133.

Adverse Reaction	Intravenous Atezolizumab 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

Laboratory Abnormality	Intravenous Atezolizumab 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: Intravenous Atezolizumab (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 TSHTSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories.	28	NANA = 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 intravenous atezolizumab in combination with lurbinectedin was evaluated in IMforte [see Clinical Studies (14.2)]. Patients received intravenous atezolizumab 1200 mg IV and lurbinectedin 3.2 mg/m² 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 intravenous atezolizumab with lurbinectedin, the median duration of exposure to intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab due to an adverse reaction occurred in 2.5% of patients. The adverse reactions requiring permanent discontinuation in ≥ 1% of patients who received intravenous atezolizumab were immune-mediated nephritis, peripheral neuropathy, nephropathy, pneumonitis, anemia, neutropenia, and thrombocytopenia.

Dosage interruptions of intravenous atezolizumab 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 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with lurbinectedin in IMforte.

Adverse Reaction	Intravenous Atezolizumab with Lurbinectedin N = 242		Intravenous Atezolizumab 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
DiarrheaIncludes diarrhea and colitis.	15	0	8	0
Vomiting	14	1	3	0
Constipation	12	0	6	1
General disorders and administration site conditions
FatigueIncludes fatigue and asthenia.	32	5	13	2
Musculoskeletal and connective tissue disorders
Musculoskeletal PainIncludes 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
CoughIncludes cough, productive cough, and upper-airway cough syndrome.	12	0	8	0
DyspneaIncludes dyspnea and dyspnea exertional.	11	2	10	2

Clinically relevant adverse reactions in < 10% of patients who received intravenous atezolizumab in combination with lurbinectedin included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity and increased creatine phosphokinase.

Laboratory Abnormality	Intravenous Atezolizumab with Lurbinectedin N = 242		Intravenous Atezolizumab N = 240
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
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

IMbrave150

The safety of intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab was 7.4 months (range: 0–16 months) and to bevacizumab was 6.9 months (range: 0–16 months).

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

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

Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 9% of patients in the intravenous atezolizumab and bevacizumab arm. The most common adverse reactions leading to intravenous atezolizumab discontinuation were hemorrhages (1.2%), including gastrointestinal, subarachnoid, and pulmonary hemorrhages; increased transaminases or bilirubin (1.2%); infusion-related reaction/cytokine release syndrome (0.9%); and autoimmune hepatitis (0.6%).

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

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

Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab and bevacizumab in IMbrave150.

Adverse Reaction	Intravenous Atezolizumab in combination with Bevacizumab (n = 329)		Sorafenib (n = 156)
	All GradesGraded per NCI CTCAE v4.0 (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Vascular Disorders
Hypertension	30	15	24	12
General Disorders and Administration Site Conditions
Fatigue/AstheniaIncludes fatigue and asthenia	26	2	32	6
Pyrexia	18	0	10	0
Renal and Urinary Disorders
Proteinuria	20	3	7	0.6
Investigations
Weight Decreased	11	0	10	0
Skin and Subcutaneous Tissue Disorders
Pruritus	19	0	10	0
Rash	12	0	17	2.6
Gastrointestinal Disorders
Diarrhea	19	1.8	49	5
Constipation	13	0	14	0
Abdominal Pain	12	0	17	0
Nausea	12	0	16	0
Vomiting	10	0	8	0
Metabolism and Nutrition Disorders
Decreased Appetite	18	1.2	24	3.8
Respiratory, Thoracic and Mediastinal Disorders
Cough	12	0	10	0
Epistaxis	10	0	4.5	0
Injury, Poisoning and Procedural Complications
Infusion-Related Reaction	11	2.4	0	0

Laboratory Abnormality	Intravenous Atezolizumab in combination with Bevacizumab (n = 329)		Sorafenib (n = 156)
	All GradesGraded per NCI CTCAE v4.0 (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus bevacizumab (222-323) and sorafenib (90-153)
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

IMspire150

The safety of intravenous atezolizumab, 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 intravenous atezolizumab with cobimetinib and vemurafenib (n = 230) or placebo with cobimetinib and vemurafenib (n = 281).

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

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

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

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

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

Tables 21 and 22 summarize the incidence of adverse reactions and laboratory abnormalities in IMspire150.

Adverse Reaction	Intravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230)		Placebo with Cobimetinib and Vemurafenib (n=281)
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Skin and Subcutaneous Tissue Disorders
RashIncludes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalized and rash morbilliform	75	27	72	23
Pruritus	26	< 1	17	< 1
Photosensitivity reaction	21	< 1	25	3.2
General Disorders and Administration Site Conditions
FatigueIncludes fatigue, asthenia and malaise	51	3	45	1.8
PyrexiaIncludes pyrexia and hyperpyrexia	49	1.7	35	2.1
EdemaIncludes edema peripheral, lymphoedema, edema, face edema, eyelid edema, periorbital edema, lip edema and generalized edema	26	< 1	21	0
Gastrointestinal Disorders
HepatotoxicityIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal	50	21	36	13
Nausea	30	< 1	32	2.5
StomatitisIncludes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis	23	1.3	15	< 1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painIncludes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain	62	4.3	48	3.2
Endocrine Disorders
HypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased	22	0	10	0
Hyperthyroidism	18	< 1	8	0
Injury, Poisoning and Procedural Complications
Infusion-related reactionIncludes infusion related reaction and hypersensitivity	10	2.6	8	< 1
Respiratory, Thoracic and Mediastinal Disorders
PneumonitisIncludes pneumonitis and interstitial lung disease	12	1.3	6	< 1
Vascular Disorders
HypertensionIncludes hypertension, blood pressure increased, hypertensive crisis	17	10	18	7

Clinically important adverse reactions in < 10% of patients who received intravenous atezolizumab 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

Laboratory Abnormality	Intravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230)		Placebo with Cobimetinib and Vemurafenib (n=281)
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Graded per NCI CTCAE v4.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230).
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	NANA = Not applicable. NCI CTCAE v4.0 does not include these laboratories	37	NA
Decreased Albumin	43	0.9	34	1.5
Increased Bilirubin	42	3.1	33	0.7
Decreased Calcium	41	1.3	28	0
Decreased Sodium	40	5	34	7
Decreased Thyroid-Stimulating Hormone	38	NA	23	NA
Increased Thyroid-Stimulating HormoneIncreased Thyroid Stimulating Hormone has a difference < 5% (All Grades) between arms and is included for clinical completeness	37	NA	33	NA
Decreased Potassium	36	5	22	4.3
Increased Triiodothyronine	33	NA	18	NA
Increased Free Thyroxine	32	NA	21	NA
Decreased Total Triiodothyronine	32	NA	8	NA
Increased Potassium	29	1.3	19	1.4
Decreased Triiodothyronine	27	NA	21	NA
Increased Sodium	20	0	13	0.4

ML39345 Study

The safety of intravenous atezolizumab was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345 [see Clinical Studies (14.5)]. Adult patients received intravenous atezolizumab 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 intravenous atezolizumab was 8.9 months (1 to 40 months).

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

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

Tables 23 and 24 summarize adverse reactions and laboratory abnormalities in Study ML39345.

Adverse Reaction	Intravenous Atezolizumab 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 painIncludes abdominal pain and abdominal pain upper	25	0
Metabolism and nutrition disorders
Decreased appetite	22	2
Respiratory, Thoracic and Mediastinal
CoughIncludes cough, upper-airway cough syndrome, and productive cough	45	0
Dyspnea	33	0
Rhinitis allergic	16	0
Musculoskeletal and connective tissue disorders
Musculoskeletal painIncludes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain	67	8
Skin and subcutaneous tissue disorders
RashIncludes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption	47	2
Nervous system disorders
Headache	43	4
DizzinessIncludes vertigo and dizziness	29	4
Vascular disorders
Hypertension	43	6
HemorrhageIncludes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage	29	2
Psychiatric disorders
Insomnia	27	0
Anxiety	25	0
Cardiac Disorders
ArrhythmiaIncludes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia	22	2
Endocrine disorders
HypothyroidismIncludes hypothyroidism and blood thyroid stimulating hormone increased	25	0
Investigations
Weight decreased	18	0
Weight increased	16	6

Laboratory AbnormalityLaboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges	Intravenous AtezolizumabThe denominators used to calculate the rate varied from 4–49 for all tests of interest based on the number of patients with 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

Animal Data:

TECENTRIQ HYBREZA for subcutaneous injection contains atezolizumab and hyaluronidase [see Description (11)].

Atezolizumab: Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. 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 atezolizumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Hyaluronidase: In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is > 2,400 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 400 times higher than the human dose.

In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1,200 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

Pediatric patients

Atezolizumab exposure following subcutaneous administration of atezolizumab 1875 mg and 30,000 units hyaluronidase every 3 weeks in pediatric patients aged 12 years and older who weigh 40 kg or greater is predicted to be within range of those observed in adult patients at the same dosage.

Adjuvant Treatment of Early-stage NSCLC

Metastatic Chemotherapy-Naïve NSCLC

First-Line Metastatic Non-squamous NSCLC

Previously Treated Metastatic NSCLC

IMpower133

The efficacy of intravenous atezolizumab 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:

intravenous atezolizumab 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 intravenous atezolizumab 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/m² 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 intravenous atezolizumab 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 intravenous atezolizumab arm and 202 to the chemotherapy alone arm. The median age was 64 years (range: 26 to 90) and 65% were male. The majority of patients were White (80%); 17% were Asian, 4% were Hispanic and 1% were Black. Baseline ECOG performance status was 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 32 and Figure 6.

	Intravenous Atezolizumab 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)	(10.8, 15.9)	(9.3, 11.3)
Hazard ratioStratified by sex and ECOG performance status (95% CI)	0.70 (0.54, 0.91)
p-valueBased on the stratified log-rank test , Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary	0.0069
Progression-Free SurvivalAs 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)	(4.4, 5.6)	(4.2, 4.5)
Hazard ratio (95% CI)	0.77 (0.62, 0.96)
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)	(53, 67)	(57, 71)
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)	(4.1, 4.5)	(3.1, 4.2)

Figure 6: Kaplan-Meier Plot of Overall Survival in IMpower133

IMforte

The efficacy of intravenous atezolizumab 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 intravenous atezolizumab, 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 intravenous atezolizumab with lurbinectedin arm.

The trial randomized 483 patients who had not experienced disease progression following the completion of four cycles of intravenous atezolizumab with carboplatin and etoposide to one of the following two treatment arms:

Intravenous atezolizumab 1200 mg IV in combination with lurbinectedin 3.2 mg/m² IV once every 3 weeks until disease progression or unacceptable toxicity, or Intravenous atezolizumab 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 per RECIST v1.1.

A total of 483 patients were randomized, including 242 to the intravenous atezolizumab with lurbinectedin arm and 241 to the intravenous atezolizumab 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 33 and Figures 7 and 8.

	Intravenous Atezolizumab with Lurbinectedin N=242	Intravenous Atezolizumab 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)	(11.9, 16.4)	(9.5, 12.2)
Hazard ratioStratified by ECOG performance status, LDH level, presence of liver metastases and prior receipt of prophylactic cranial irradiation (95% CI)	0.73 (0.57, 0.95)
p-valueBased 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)	(4.2, 5.8)	(1.6, 2.7)
Hazard ratio (95% CI)	0.54 (0.43, 0.67)
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

IMbrave150

The efficacy of intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab or bevacizumab (e.g., due to adverse events) and continue on monotherapy until disease progression or unacceptable toxicity associated with the monotherapy.

The study enrolled patients who were ECOG performance score 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 34 and Figure 9.

	Intravenous Atezolizumab in combination with Bevacizumab (N= 336)	Sorafenib (N=165)
+ Denotes a censored value CI = confidence interval; HCC mRECIST = Modified RECIST Assessment for Hepatocellular Carcinoma; NE = not estimable; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors v1.1
Overall Survival
Number of deaths (%)	96 (29)	65 (39)
Median OS in months	NE	13.2
(95% CI)	(NE, NE)	(10.4, NE)
Hazard ratioStratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (< 400 vs. ≥ 400 ng/mL) (95% CI)	0.58 (0.42, 0.79)
p-valueBased on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method	0.0006
Progression-Free SurvivalPer independent radiology review
Number of events (%)	197 (59)	109 (66)
Median PFS in months (95% CI)	6.8 (5.8, 8.3)	4.3 (4.0, 5.6)
Hazard ratio (95% CI)	0.59 (0.47, 0.76)
p-value	< 0.0001
Overall Response Rate , Confirmed responses (ORR), RECIST 1.1
Number of responders (%)	93 (28)	19 (12)
(95% CI)	(23, 33)	(7,17)
p-valueBased on two-sided Cochran-Mantel-Haesnszel test	< 0.0001
Complete responses, n (%)	22 (7)	0
Partial responses, n (%)	71 (21)	19 (12)
Duration of Response , (DOR) RECIST 1.1
	(n=93)	(n=19)
Median DOR in months	NE	6.3
(95% CI)	(NE, NE)	(4.7, NE)
Range (months)	(1.3+, 13.4+)	(1.4+, 9.1+)
Overall Response Rate , (ORR), HCC mRECIST
Number of responders (%)	112 (33)	21 (13)
(95% CI)	(28, 39)	(8, 19)
p-value	< 0.0001
Complete responses, n (%)	37 (11)	3 (1.8)
Partial responses, n (%)	75 (22)	18 (11)
Duration of Response , (DOR) HCC mRECIST
	(n=112)	(n=21)
Median DOR in months	NE	6.3
(95% CI)	(NE, NE)	(4.9, NE)
Range (months)	(1.3+, 13.4+)	(1.4+, 9.1+)

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 [see Clinical Pharmacology (12.6)]. 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 intravenous atezolizumab and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (< 400 ng/mL vs ≥ 400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology (HBV vs. HCV vs. non-viral) and Child-Pugh Score (A5 vs. A6). The OS hazard ratio comparing the ADA-positive subgroup of the intravenous atezolizumab and bevacizumab arm to sorafenib was 0.93 (95% CI: 0.57, 1.53). The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was 0.39 (95% CI: 0.26, 0.60).

IMspire150

The efficacy of intravenous atezolizumab 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) [less than or equal to upper limit of normal (ULN) vs. greater than ULN].

Eligible patients were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma as detected by 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.

Intravenous atezolizumab 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 intravenous atezolizumab 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 35 and Figure 10. Patients had a median survival follow up time of 18.9 months.

	Intravenous Atezolizumab + Cobimetinib + Vemurafenib N = 256	Placebo + Cobimetinib + Vemurafenib N = 258
Progression-Free SurvivalAs determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI = confidence interval
Number of events (%)	148 (58)	179 (69)
Median, months	15.1	10.6
(95% CI)	(11.4, 18.4)	(9.3, 12.7)
Hazard ratioStratified by baseline LDH (95% CI)	0.78 (0.63, 0.97)
p-valueBased on the stratified log-rank test	0.0249
Overall Response Rate , Confirmed responses
Number of responders (%)	170 (66)	168 (65)
(95% CI)	(60, 72)	(59, 71)
Complete responses, n (%)	41 (16)	46 (18)
Partial response, n (%)	129 (50)	122 (47)
Duration of Response ,	n = 170	n = 168
Median, months	20.4	12.5
(95% CI)	(15.1, NE)	(10.7, 16.6)

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 intravenous atezolizumab plus cobimetinib and vemurafenib arm, and 25.1 months with 112 (43%) deaths in the placebo plus cobimetinib and vemurafenib arm. The hazard ratio for OS was 0.85 (95% CI: 0.64, 1.11) and the p-value was 0.2310.

IMvigor011

The efficacy of intravenous atezolizumab 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: Intravenous atezolizumab 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 intravenous atezolizumab arm compared with placebo. Efficacy results are presented in Table 37 and Figures 11 and 12.

	Intravenous Atezolizumab N=167	Placebo N=83
CI=confidence interval; NE=not estimable
Investigator-assessed DFS
Number of events (%)	112 (67%)	66 (80%)
MedianBased on Kaplan-Meier estimates, months	9.9	4.8
(95% CI)	(7.2, 12.7)	(4.1, 8.3)
Hazard ratioBased 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 (0.47, 0.87)
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 (0.39, 0.90)
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 intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab 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 intravenous atezolizumab arm and 18.4 months, not reached in the placebo arm).