Tecentriq Drug Information

Generic name: ATEZOLIZUMAB

Programmed Death Receptor-1 Blocking Antibody [EPC]

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Uses of Tecentriq

Non-Small Cell Lung Cancer

TECENTRIQ, as a single-agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-authorized test. TECENTRIQ, as a single agent, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area ), as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations. TECENTRIQ, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.

TECENTRIQ, as a single-agent, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ.

Small Cell Lung Cancer TECENTRIQ, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). TECENTRIQ, in combination with lurbinectedin, is indicated for the maintenance treatment of adult patients with ES-SCLC whose disease has not progressed after first-line induction therapy with TECENTRIQ or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide.

Hepatocellular Carcinoma TECENTRIQ, in combination with bevacizumab, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.

Melanoma TECENTRIQ, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Alveolar Soft Part Sarcoma

TECENTRIQ, as a single agent, is indicated for the treatment of adult and pediatric patients 2 years of age and older with unresectable or metastatic alveolar soft part sarcoma (ASPS).

Muscle Invasive Bladder Cancer

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

Dosage & Administration of Tecentriq

Recommended Dosage

The recommended dosages of TECENTRIQ are presented in Table 1. Administer TECENTRIQ as an intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

Refer to the respective Prescribing Information for each therapeutic agent administered in combination with TECENTRIQ for the recommended dosage information, as appropriate. Table 2: Recommended Dosage of TECENTRIQ in Combination with Other Therapeutic Agents s No dose reduction for TECENTRIQ is recommended. In general, withhold TECENTRIQ for severe (Grade 3) immune-mediated adverse reactions.

Permanently discontinue TECENTRIQ for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for TECENTRIQ for adverse reactions that require management different from these general guidelines are summarized in Table 3. Table 3: Recommended

Preparation and Administration Preparation

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial.

Prepare the solution for infusion as follows: Select the appropriate vial(s) based on the prescribed dose. Withdraw the required volume of TECENTRIQ from the vial(s) using sterile needle and syringe. Dilute in an infusion bag containing 0.9% Sodium Chloride Injection, USP to a final concentration between 3.2 mg/mL and 16.8 mg/mL.

TECENTRIQ is compatible with an infusion bag made of polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO). Mix diluted solution by gentle inversion. Do not shake.

Discard used or empty vials of TECENTRIQ. Storage of Infusion Solution This product does not contain a preservative. Administer immediately once prepared.

If diluted TECENTRIQ infusion solution is not used immediately, store solution either: At room temperature for no more than 6 hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration of the infusion, or Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 7 days from time of preparation. Do not freeze.

Do not shake. Administration Administer the initial infusion over 60 minutes through an intravenous line with or without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron). Do not coadminister other drugs through the same intravenous line.

Do not administer as an intravenous push or bolus.

Table 1: Recommended Dosage of TECENTRIQ as a Single Agent
Indication	Recommended Dosage of TECENTRIQ	Duration of Therapy
Metastatic NSCLC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks	Until disease progression or unacceptable toxicity
Adjuvant Treatment of NSCLC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks	Up to one year, unless there is disease recurrence or unacceptable toxicity
ASPS (adult)	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks	Until disease progression or unacceptable toxicity
ASPS (pediatric, 2 years of age and older)	15 mg/kg (up to a maximum 1200 mg) every 3 weeks	Until disease progression or unacceptable toxicity
MIBC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks	Up to one year, unless there is disease recurrence or unacceptable toxicity

Table 2: Recommended Dosage of TECENTRIQ in Combination with Other Therapeutic Agents
Indication	Recommended Dosage of TECENTRIQ	Duration of Therapy
NSCLC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ prior to chemotherapy and bevacizumab when given on the same day.	Until disease progression or unacceptable toxicity
SCLC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ prior to chemotherapy when given on the same day.
HCC	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ prior to bevacizumab when given on the same day. Bevacizumab is administered at 15 mg/kg every 3 weeks.
Melanoma	840 mg every 2 weeks or 1200 mg every 3 weeks or 1680 mg every 4 weeks Administer TECENTRIQ with cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 720 mg orally twice daily. Prior to initiating TECENTRIQ, patients should receive a 28-day treatment cycle of cobimetinib 60 mg orally once daily (21 days on and 7 days off) and vemurafenib 960 mg orally twice daily from Days 1-21 and vemurafenib 720 mg orally twice daily from Days 22-28.

Table 3: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction	Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4	Dosage Modification
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic epidermal necrolysis
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ]
Pneumonitis	Grade 2	Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids
Pneumonitis	Grades 3 or 4	Permanently discontinue
Colitis	Grades 2 or 3	Withhold
Colitis	Grade 4	Permanently discontinue
Hepatitis with no tumor involvement of the liver	AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN	Withhold
Hepatitis with no tumor involvement of the liver	AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ based on recommendations for hepatitis with no liver involvement	Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN	Withhold
	AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Endocrinopathies	Grades 3 or 4	Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal Dysfunction	Grades 2 or 3 increased blood creatinine	Withhold
Nephritis with Renal Dysfunction	Grade 4 increased blood creatinine	Permanently discontinue
Exfoliative Dermatologic Conditions	Suspected SJS, TEN, or DRESS	Withhold
Exfoliative Dermatologic Conditions	Confirmed SJS, TEN, or DRESS	Permanently discontinue
Myocarditis or Pericarditis	Grades 2, 3, or 4	Permanently discontinue
Neurological Toxicities	Grade 2	Withhold
Neurological Toxicities	Grades 3 or 4	Permanently discontinue
Other Adverse Reactions
Infusion-Related Reactions [see Warnings and Precautions (5.2) ]	Grades 1 or 2	Interrupt or slow the rate of infusion
	Grades 3 or 4	Permanently discontinue

Side Effects of Tecentriq

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in WARNINGS AND PRECAUTIONS reflect exposure to TECENTRIQ as a single-agent in 2616 patients in two randomized, active-controlled studies (POPLAR, OAK) and three open-label, single arm studies (PCD 0 mg intravenously every 3 weeks in all studies except PCD4989g. Using the dataset described for patients who received TECENTRIQ as a single-agent, the most common adverse reactions in ≥ %).

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 IMpower patients with NSCLC and SCLC who received TECENTRIQ in combination with other antineoplastic drugs, the most common adverse reactions in ≥ administered in combination with cobimetinib and vemurafenib in 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.

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.

Adverse reactions leading to interruption of TECENTRIQ occurred in 29% of patients; the most common (>1%) were rash (3.0%), hyperthyroidism ( %). 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 6 0 Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with Early-Stage NSCLC Receiving Metastatic Chemotherapy-Naïve NSCLC IMpower110 The safety of TECENTRIQ was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations.

Patients received TECENTRIQ 1200 mg every 3 weeks (n=286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n=263) until disease progression or unacceptable toxicity. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 1% of the tumor area). The median duration of exposure to TECENTRIQ was 5.3 months (0 to 33 months).

Fatal adverse reactions occurred in 3.8% of patients receiving TECENTRIQ; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each). 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. 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. 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 % and sepsis, septic shock, staphylococcal sepsis, aspiration, respiratory distress, cardiorespiratory arrest, ventricular tachycardia, death (not otherwise specified), and hepatic cirrhosis (0.2% each). TECENTRIQ was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia ( %). 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 IMpower: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ Previously Treated Metastatic NSCLC OAK The safety of TECENTRIQ was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The study population characteristics were: median age of % 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.

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.

These included pneumonia, respiratory failure, neutropenia, and death (1 patient each). The most frequent adverse reaction requiring permanent discontinuation in >2% of patients was infusion-related reactions (2.5%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with carboplatin and etoposide in IMpower: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ in combination with lurbinectedin was evaluated in IMforte.

Primary prophylaxis of G-CSF was administered to 84% of patients. Permanent discontinuation of TECENTRIQ due to an adverse reaction occurred in 2.5% of patients. The adverse reactions requiring permanent discontinuation in ≥ 1% of patients who received TECENTRIQ were immune-mediated nephritis, peripheral neuropathy, nephropathy, pneumonitis, anemia, neutropenia, and thrombocytopenia.

Dosage interruptions of TECENTRIQ due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia, fatigue, decreased neutrophil count, pneumonitis, and decreased platelet count. Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received TECENTRIQ with lurbinectedin in IMforte.

Table 16: Adverse Reactions (≥10%) in Patients with ES-SCLC Who Received 2 Clinically relevant adverse reactions in < 10% of patients who received TECENTRIQ in combination with lurbinectedin included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity and increased creatine phosphokinase. Table 17: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES-SCLC Who Received TECENTRIQ in Combination with Lurbinectedin in IMforte 0 Hepatocellular Carcinoma (HCC) IMbrave150 The safety of TECENTRIQ in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment. Patients received 1, given orally twice daily, until disease progression or unacceptable toxicity.

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.

Adverse reactions leading to discontinuation of TECENTRIQ occurred in 9% of patients in the TECENTRIQ and bevacizumab arm. Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 12% of patients in the TECENTRIQ and bevacizumab arm. Tables 18 and 19 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received: Laboratory Abnormalities Worsening from Baseline Occurring in ≥, administered with cobimetinib and vemurafenib was evaluated in IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma.

Patients received TECENTRIQ with cobimetinib and vemurafenib (N=230) or placebo with cobimetinib and vemurafenib (n=281). 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. 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. Table 20: Adverse Reactions Occurring in ≥10% of Patients on the TECENTRIQ plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 7 Clinically important adverse reactions in < 10% of patients who received TECENTRIQ plus cobimetinib and vemurafenib were: Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged Eye Disorders: Uveitis Gastrointestinal disorders: Pancreatitis Infections and infestations: Pneumonia, urinary tract infection Metabolism and nutrition disorders: Hyperglycemia Nervous system Disorders: Dizziness, dysgeusia, syncope: 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 IMspire Unresectable or Metastatic Alveolar Soft Part Sarcoma (ASPS) ML39345 Study The safety of TECENTRIQ was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345. The median duration of exposure to TECENTRIQ was 8.9 months (1 to 40 months).

The most frequent serious adverse reactions (>2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each). The most common adverse reactions (≥3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each). Tables 22 and 23 summarize adverse reactions and laboratory abnormalities in Study ML: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ Muscle Invasive Bladder Cancer (MIBC) IMvigor011 The safety of TECENTRIQ was evaluated in IMvigor011, a multi-center, randomized, double-blind, placebo-controlled trial in 248 patients with MIBC after cystectomy who had circulating tumor D cycles or 1 year (whichever occurred first) unless either unacceptable toxicity or disease recurrence occurred.

The median duration of exposure to TECENTRIQ was 6.5 months (0 to 11.8 months). Serious adverse reactions occurred in 27% of patients who received TECENTRIQ. Serious adverse reactions in ≥ 2% of patients included urinary tract infection (9%), and acute kidney injury (2.4%).

Fatal adverse reactions occurred in 3% of patients who received TECENTRIQ including septic shock, skin infection, death of unknown cause, interstitial lung disease, and congestive cardiac failure (1 patient each). Permanent discontinuation of TECENTRIQ due to adverse reactions occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of TECENTRIQ in ≥1% of patients included pneumonitis (1.8%).

Dosage interruptions of TECENTRIQ due to adverse reactions occurred in 24% of patients. Tables 24 and 25 summarize the adverse reactions and laboratory abnormalities in patients receiving: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 0

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TECENTRIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: pericarditis, pericardial effusion, cardiac tamponade Musculoskeletal and Connective Tissue: tenosynovitis

Table 4: Adverse Reactions Occurring in ≥10% of Patients with Early-Stage NSCLC Receiving TECENTRIQ in IMpower010
Adverse Reaction Graded per NCI CTCAE v4.0	TECENTRIQ N = 495		Best Supportive Care N = 495
Adverse Reaction Graded per NCI CTCAE v4.0	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Skin and Subcutaneous Tissue
Rash Includes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform	17	1.2	1.4	0
Pruritus	10	0	0.6	0
Endocrine Disorders
Hypothyroidism Includes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased	14	0	0.6	0
Respiratory, Thoracic and Mediastinal
Cough Productive cough, upper airway cough syndrome, cough	16	0	11	0
General
Pyrexia Includes pyrexia, body temperature increased, hyperthermia	14	0.8	2.2	0.2
Fatigue Includes fatigue, asthenia	14	0.6	5	0.2
Nervous System Disorders
Peripheral neuropathy Includes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy	12	0.4	7	0.2
Musculoskeletal and Connective Tissue
Musculoskeletal pain Includes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain	14	0.8	9	0.2
Arthralgia Includes arthralgia, arthritis	11	0.6	6	0

Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with Early-Stage NSCLC Receiving TECENTRIQ in IMpower010
Laboratory Abnormality Graded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0).	TECENTRIQ The denominators used to calculate the rate varied from 78-480 for BSC arm and 483 for TECENTRIQ are for all tests of interest based on the number of patients with a baseline value and at least one post-treatment value.		Best Supportive Care
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Chemistry
Increased aspartate aminotransferase	34	2.5	18	0
Increased alanine aminotransferase	30	3.3	19	0.4
Hyperkalemia	24	3.5	15	2.5
Increased blood creatinine	31	0.2	23	0.2

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

Table 7: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower110
Laboratory Abnormality	TECENTRIQ		Platinum-Based Chemotherapy
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: TECENTRIQ (range: 278-281); platinum-based chemotherapy (range: 256-260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range.
Hematology
Anemia	69	1.8	94	20
Lymphopenia	47	9	59	17
Chemistry
Hypoalbuminemia	48	0.4	39	2
Increased alkaline phosphatase	46	2.5	42	1.2
Hyponatremia	44	9	36	7
Increased ALT	38	3.2	32	0.8
Increased AST	36	3.2	32	0.8
Hyperkalemia	29	3.9	36	2.7
Hypocalcemia	24	1.4	24	2.7
Increased blood creatinine	24	0.7	33	1.5
Hypophosphatemia	23	3.6	21	2

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

Table 9: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in IMpower150
Laboratory Abnormality	TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin		Bevacizumab, Paclitaxel and Carboplatin
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with bevacizumab, paclitaxel, and carboplatin range: 337-380); bevacizumab, paclitaxel, and carboplatin (range: 337-382). Graded per NCI CTCAE v4.0
Hematology
Anemia	83	10	83	9
Neutropenia	52	31	45	26
Lymphopenia	48	17	38	13
Chemistry
Hyperglycemia	61	0	60	0
Increased BUN	52	NA NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities	44	NA
Hypomagnesemia	42	2	36	1
Hypoalbuminemia	40	3	31	2
Increased AST	40	4	28	0.8
Hyponatremia	38	10	36	9
Increased Alkaline Phosphatase	37	2	32	1
Increased ALT	37	6	28	0.5
Increased TSH	30	NA	20	NA
Hyperkalemia	28	3	25	2
Increased Creatinine	28	1	19	2
Hypocalcemia	26	3	21	3
Hypophosphatemia	25	4	18	4
Hypokalemia	23	7	14	4
Hyperphosphatemia	25	NA	19	NA

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

Table 11: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Receiving TECENTRIQ in IMpower130
Laboratory Abnormality	TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin N = 473		Paclitaxel Protein-Bound and Carboplatin N = 232
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ with paclitaxel protein-bound and carboplatin (range: 423 - 467); paclitaxel protein-bound and carboplatin (range: 218 - 229). Graded per NCI CTCAE v4.0.
Hematology
Anemia	92	33	87	25
Neutropenia	75	50	67	39
Thrombocytopenia	73	19	59	13
Lymphopenia	71	23	61	16
Chemistry
Hyperglycemia	75	8	66	8
Hypomagnesemia	50	3.4	42	3.2
Hyponatremia	37	9	28	7
Hypoalbuminemia	35	1.3	31	0
Increased ALT	31	2.8	24	3.9
Hypocalcemia	31	2.6	27	1.8
Hypophosphatemia	29	6	20	3.2
Increased AST	28	2.2	24	1.8
Increased TSH	26	NA NA = Not applicable. NCI CTCAE does not provide a Grades 3-4 definition for these laboratory abnormalities	5	NA
Hypokalemia	26	6	24	4.4
Increased Alkaline Phosphatase	25	2.6	22	1.3
Increased Blood Creatinine	23	2.8	16	0.4
Hyperphosphatemia	21	NA	13	NA

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

Table 13: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with NSCLC Receiving TECENTRIQ in OAK
Laboratory Abnormality	TECENTRIQ		Docetaxel
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0
Hematology
Anemia	67	3	82	7
Lymphocytopenia	49	14	60	21
Chemistry
Hypoalbuminemia	48	4	50	3
Hyponatremia	42	7	31	6
Increased Alkaline Phosphatase	39	2	25	1
Increased AST	31	3	16	0.5
Increased ALT	27	3	14	0.5
Hypophosphatemia	27	5	23	4
Hypomagnesemia	26	1	21	1
Increased Creatinine	23	2	16	1

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
Adverse Reaction	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General
Fatigue/asthenia	39	5	33	3
Gastrointestinal
Nausea	38	1	33	1
Constipation	26	1	30	1
Vomiting	20	2	17	3
Skin and Subcutaneous Tissue
Alopecia	37	0	35	0
Metabolism and Nutrition
Decreased appetite	27	1	18	0

Table 15: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with SCLC Receiving TECENTRIQ in IMpower133
Laboratory Abnormality	TECENTRIQ with Carboplatin and Etoposide		Placebo with Carboplatin and Etoposide
Laboratory Abnormality	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ (range: 181-193); Placebo (range: 181-196). Graded per NCI CTCAE v4.0
Hematology
Anemia	94	17	93	19
Neutropenia	73	45	76	48
Thrombocytopenia	58	20	53	17
Lymphopenia	46	14	38	11
Chemistry
Hyperglycemia	67	10	65	8
Increased Alkaline Phosphatase	38	1	35	2
Hyponatremia	34	15	33	11
Hypoalbuminemia	32	1	30	0
Decreased TSH TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories.	28	NA NA = Not applicable.	15	NA
Hypomagnesemia	31	5	35	6
Hypocalcemia	26	3	28	5
Increased ALT	26	3	31	1
Increased AST	22	1	21	2
Increased Blood Creatinine	22	4	15	1
Hyperphosphatemia	21	NA	23	NA
Increased TSH	21	NA	7	NA

Table 16: Adverse Reactions (≥10%) in Patients with ES-SCLC Who Received TECENTRIQ with Lurbinectedin in IMforte
Adverse Reaction	TECENTRIQ with Lurbinectedin N = 242		TECENTRIQ N = 240
Adverse Reaction	All Grades (%)	Grades 3 or 4 (%)	All Grades (%)	Grades 3 or 4 (%)
Graded per NCI CTCAE v5.0
Gastrointestinal
Nausea	36	3	4	1
Diarrhea Includes diarrhea and colitis.	15	0	8	0
Vomiting	14	1	3	0
Constipation	12	0	6	1
General disorders and administration site conditions
Fatigue Includes fatigue and asthenia.	32	5	13	2
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity.	19	2	16	1
Metabolism and Nutrition
Decreased appetite	17	0	7	0
Respiratory, thoracic and mediastinal disorders
Cough Includes cough, productive cough, and upper-airway cough syndrome.	12	0	8	0
Dyspnea Includes dyspnea and dyspnea exertional.	11	2	10	2

Table 17: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES-SCLC Who Received TECENTRIQ in Combination with Lurbinectedin in IMforte
Laboratory Abnormality	TECENTRIQ with Lurbinectedin N = 242		TECENTRIQ N = 240
Laboratory Abnormality	All Grades (%)	Grades 3 or 4 (%)	All Grades (%)	Grades 3 or 4 (%)
Graded per NCI CTCAE v5.0
Hematology
Lymphopenia	55	17	31	11
Thrombocytopenia	54	15	15	3
Anemia	51	13	12	3
Neutropenia	36	18	7	4
Chemistry
Increased alkaline phosphatase	29	1	14	0
Decreased sodium	27	4	30	5
Increased ALT	25	3	18	2
Increased AST	24	3	22	1
Decreased calcium	24	3	8	1
Increased creatinine	21	3	14	0

Table 18: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving TECENTRIQ in IMbrave150
Adverse Reaction	TECENTRIQ in combination with Bevacizumab (n = 329)		Sorafenib (n=156)
Adverse Reaction	All Grades Graded per NCI CTCAE v4.0 (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Vascular Disorders
Hypertension	30	15	24	12

General Disorders and Administration Site Conditions
Fatigue/asthenia Includes fatigue and asthenia	26	2	32	6
Pyrexia	18	0	10	0
Renal and Urinary Disorders
Proteinuria	20	3	7	0.6
Investigations
Weight Decreased	11	0	10	0
Skin and Subcutaneous Tissue Disorders
Pruritus	19	0	10	0
Rash	12	0	17	2.6
Gastrointestinal Disorders
Diarrhea	19	1.8	49	5
Constipation	13	0	14	0
Abdominal Pain	12	0	17	0
Nausea	12	0	16	0
Vomiting	10	0	8	0
Metabolism and Nutrition Disorders
Decreased Appetite	18	1.2	24	3.8
Respiratory, Thoracic and Mediastinal Disorders
Cough	12	0	10	0
Epistaxis	10	0	4.5	0
Injury, Poisoning and Procedural Complications
Infusion-Related Reaction	11	2.4	0	0

Table 19: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with HCC Receiving TECENTRIQ in IMbrave150
Laboratory Abnormality	TECENTRIQ in combination with Bevacizumab (n = 329)		Sorafenib (n=156)
Laboratory Abnormality	All Grades Graded per NCI CTCAE v4.0 (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ plus bevacizumab (222-323) and sorafenib (90-153)
Chemistry
Increased AST	86	16	90	16
Increased Alkaline Phosphatase	70	4	76	4.6
Increased ALT	62	8	70	4.6
Decreased Albumin	60	1.5	54	0.7
Decreased Sodium	54	13	49	9
Increased Glucose	48	9	43	4.6
Decreased Calcium	30	0.3	35	1.3
Decreased Phosphorus	26	4.7	58	16
Increased Potassium	23	1.9	16	2
Hypomagnesemia	22	0	22	0
Hematology
Decreased Platelet	68	7	63	4.6
Decreased Lymphocytes	62	13	58	11
Decreased Hemoglobin	58	3.1	62	3.9
Increased Bilirubin	57	8	59	14
Decreased Leukocyte	32	3.4	29	1.3
Decreased Neutrophil	23	2.3	16	1.1

Table 20: Adverse Reactions Occurring in ≥10% of Patients on the TECENTRIQ plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 TECENTRIQ in IMspire150)
Adverse Reaction	TECENTRIQ in combination with Cobimetinib and Vemurafenib (n=230)		Placebo with Cobimetinib and Vemurafenib (n=281)
Adverse Reaction	All Grades (%)	Grade 3–4 (%)	All Grades (%)	Grade 3–4 (%)

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

Table 21: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving TECENTRIQ Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4) in IMspire150
Laboratory Abnormality	TECENTRIQ in combination with Cobimetinib and Vemurafenib (n=230)		Placebo with Cobimetinib and Vemurafenib (n=281)
Laboratory Abnormality	All Grades (%)	Grade 3–4 (%)	All Grades (%)	Grade 3–4 (%)
Graded per NCI CTCAE v4.0.
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230).
Hematology
Decreased Lymphocytes	80	24	72	17
Decreased Hemoglobin	77	2.6	72	2.2
Decreased Platelet	34	1.3	24	0.4
Decreased Neutrophils	26	2.2	19	1.5
Chemistry
Increased Creatine Kinase	88	22	81	18
Increased AST	80	13	68	6
Increased ALT	79	18	62	12
Increased Triacylglycerol Lipase	75	46	62	35
Increased Alkaline Phosphatase	73	6	63	2.9
Decreased Phosphorus	67	22	64	14
Increased Amylase	51	13	45	13
Increased Blood Urea Nitrogen	47	NA NA= Not applicable. NCI CTCAE v4.0 does not include these laboratories.	37	NA
Decreased Albumin	43	0.9	34	1.5
Increased Bilirubin	42	3.1	33	0.7
Decreased Calcium	41	1.3	28	0
Decreased Sodium	40	5	34	7
Decreased Thyroid-Stimulating Hormone	38	NA	23	NA
Increased Thyroid-Stimulating Hormone Increased Thyroid Stimulating Hormone has a difference <5% (All Grades) between arms and is included for clinical completeness.	37	NA	33	NA
Decreased Potassium	36	5	22	4.3
Increased Triiodothyronine	33	NA	18	NA
Increased Free Thyroxine	32	NA	21	NA
Decreased Total Triiodothyronine	32	NA	8	NA
Increased Potassium	29	1.3	19	1.4
Decreased Triiodothyronine	27	NA	21	NA
Increased Sodium	20	0	13	0.4

Table 22: Adverse Reactions Occurring in ≥15% of Patients with ASPS Receiving TECENTRIQ in ML39345
Adverse Reaction	TECENTRIQ N = 49
Adverse Reaction	All Grades (%)	Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General disorders and administration site conditions
Fatigue	55	2
Pyrexia	25	2
Influenza like illness	18	0
Gastrointestinal disorders
Nausea	43	0
Vomiting	37	0
Constipation	33	0
Diarrhea	27	2
Abdominal pain Includes abdominal pain and abdominal pain upper	25	0
Metabolism and nutrition disorders
Decreased appetite	22	2
Respiratory, Thoracic and Mediastinal
Cough Includes cough, upper-airway cough syndrome, and productive cough	45	0
Dyspnea	33	0
Rhinitis allergic	16	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain Includes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain	67	8
Skin and subcutaneous tissue disorders
Rash Includes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption	47	2
Nervous system disorders
Headache	43	4
Dizziness Includes vertigo and dizziness	29	4
Vascular disorders
Hypertension	43	6
Hemorrhage Includes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage	29	2
Psychiatric disorders
Insomnia	27	0
Anxiety	25	0
Cardiac Disorders
Arrhythmia Includes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia	22	2
Endocrine disorders
Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased	25	0
Investigations
Weight decreased	18	0
Weight increased	16	6

Table 23: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with ASPS Receiving TECENTRIQ in ML39345
Laboratory Abnormality Laboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges.	TECENTRIQ The denominators used to calculate the rate varied from 4-49 for all tests of interest based on the number of patients with a baseline value and at least one on-study laboratory measurement available.
	All Grades (%)	Grades 3–4 (%)
Hematology
Decreased Hemoglobin	63	0
Decreased Platelets	27	0
Increased Platelets	29	0
Chemistry
Increased Alkaline Phosphatase	29	0
Decreased Amylase	40	0
Increased Amylase	20	20
Decreased Bilirubin	49	0
Decreased Calcium	47	0
Increased Calcium	25	14
Decreased Glucose	33	0
Increased Glucose	78	0
Decreased Glucose (fasting)	25	0
Decreased Magnesium	21	0
Increased Magnesium	26	26
Increased AST	39	2
Increased ALT	33	2
Decreased Sodium	43	0
Increased Lipase	25	25

Table 24: Adverse Reactions Occurring in ≥10% of Patients with MIBC Who Received TECENTRIQ [at a Higher Incidence (Between Arm Difference of ≥2%) Compared to Placebo] in IMvigor011
Adverse Reaction Graded per NCI-CTCAE v5.0	TECENTRIQ N = 165		Placebo N=83
Adverse Reaction Graded per NCI-CTCAE v5.0	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Renal and Urinary Disorders
Urinary tract infection Includes multiple related terms	22	8.5	18	4.8
Skin and Subcutaneous Tissue
Pruritus	18	0	11	0
Rash	13	0.6	3.6	0
Endocrine Disorders
Hypothyroidism	13	0	4.8	0
Gastrointestinal
Constipation	11	0	7	0

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

Warnings & Cautions for Tecentriq

Severe and Fatal Immune-Mediated Adverse Reactions TECENTRIQ is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue.

Immune-mediated adverse reactions can occur at any time after starting a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection.

Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue TECENTRIQ depending on severity. In general, if TECENTRIQ requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less.

Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis TECENTRIQ can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. 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.

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.

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. 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. 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. 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. 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.

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.

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.

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. 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.

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. 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.

Antithyroid therapy was required in 38% (12/32) of patients with hyperthyroidism. Of the 14 patients in whom TECENTRIQ was withheld for hyperthyroidism, 9 patients reinitiated TECENTRIQ. 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 the 24 patients in whom TECENTRIQ was withheld for hyperthyroidism, 18 patients reinitiated TECENTRIQ; of these, 28% had recurrence of hyperthyroidism. 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.

Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism. Of the 39 patients in whom TECENTRIQ was withheld for hypothyroidism, 9 reinitiated TECENTRIQ after symptom improvement. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism.

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.

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. Nephritis led to permanent discontinuation of TECENTRIQ in this patient. This patient required systemic corticosteroids.

In this patient, nephritis did not resolve. 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. Dermatologic adverse reactions led to permanent discontinuation of TECENTRIQ in 0.1% and withholding of TECENTRIQ in 0.2% of patients.

Systemic corticosteroids were required in 20% (3/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 87% of the 15 patients. Of the 4 patients in whom TECENTRIQ was withheld for immune-mediated dermatologic adverse reactions, none re-initiated TECENTRIQ.

Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients who received TECENTRIQ or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment.

Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurence of either two or all three adverse reactions.

Infusion-Related Reactions TECENTRIQ can cause severe or life-threatening infusion-related reactions, including anaphylaxis. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue TECENTRIQ based on the severity.

For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. The frequency and severity of infusion-related reactions were similar whether TECENTRIQ was given as a single-agent in patients with various cancers, in combination with other antineoplastic drugs in NSCLC and SCLC, and across the recommended dose range (840 mg Q2W to 1680 mg Q4W).

Complications of Allogeneic

HSCT after PD-1/PD-L1 Inhibitors Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockage and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

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

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

Pregnancy Safety for Tecentriq

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

Advise females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Animal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development.

A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice.

Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Pediatric Use of Tecentriq

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

The course of unresectable or metastatic ASPS is sufficiently similar between pediatric patients 2 to 11 years old and that of adults and adolescent patients to allow extrapolation of efficacy and safety to pediatric patients 2 years and older. The safety and effectiveness of TECENTRIQ for ASPS have not been established in pediatric patients younger than 2 years of age. Solid Tumors and Lymphomas The safety and effectiveness of TECENTRIQ in pediatric patients have not been established in non-small cell lung cancer, small-cell lung cancer, hepatocellular carcinoma, melanoma, or muscle invasive bladder cancer.

The safety and effectiveness of TECENTRIQ were assessed, but not established in a single-arm, multi-center, multi-cohort trial (NCT02541604) in 60 pediatric patients aged 7 months to <17 years with relapsed or progressive solid tumors and lymphomas. No new safety signals were observed in pediatric patients in this study.

Clinical Studies of Tecentriq

Non-Small Cell Lung Cancer Adjuvant Treatment of Stage II-IIIA NSCLC with PD-L1 Expression ≥ 1% The efficacy of TECENTRIQ was evaluated in IMpower010 (NCT02486718), a multi-center, randomized, open-label trial for the adjuvant treatment of patients with NSCLC who had complete tumor resection and were eligible to receive cisplatin-based adjuvant chemotherapy. Eligible patients were required to have Stage IB (tumors ≥ 4 cm) – Stage IIIA NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system, 7th edition. Patients were excluded if they had a history of autoimmune disease; a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis; administration of a live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization.

A total of 1005 patients who had complete tumor resection and received cisplatin-based adjuvant chemotherapy were randomized (1:1) to receive TECENTRIQ 1200 mg intravenous infusion every 3 weeks for 16 cycles, unless disease recurrence or unacceptable toxicity occurred, or best supportive care (BSC). Randomization was stratified by sex, stage of disease, histology, and PD-L1 expression. Tumor assessments were conducted at baseline of the randomization phase and every 4 months for the first year following Cycle 1, Day 1 and then every 6 months until year five, then annually thereafter.

The majority of patients were White (73%) and Asian (24%). Most patients were current or previous smokers (78%) and baseline Eastern Cooperative Oncology Group (ECOG) performance status in patients was Overall, 12% of patients had Stage IB, 47% had Stage II and 41% had Stage IIIA disease. The primary efficacy outcome measure was disease-free survival (DFS) as assessed by the investigator.

The primary efficacy analysis population (n = 476) was patients with Stage II – IIIA NSCLC with PD-L1 expression on ≥ 1% of tumor cells (PD-L1 ≥ 1% TC). DFS was defined as the time from the date of randomization to the date of occurrence of any of the following: first documented recurrence of disease, new primary NSCLC, or death due to any cause, whichever occurred first. A key secondary efficacy outcome measure was overall survival (OS) in the intent-to-treat population.

At the time of the interim DFS analysis, the study demonstrated a statistically significant improvement in DFS in the PD-L1 ≥ 1% TC, Stage II – IIIA patient population. Efficacy results are presented in Table 26 and Figure 1. Table 26: Efficacy Results from IMpower010 in Patients with Stage II - IIIA NSCLC with PD-L1 expression ≥ 1% TC In a pre-specified secondary subgroup analysis of patients with PD-L1 TC ≥ 50% Stage II – IIIA NSCLC (n=229), the median DFS was not reached (95% CI: 42.3 months, NE) for patients in the TECENTRIQ arm and was 35.7 months (95% CI: 29.7, NE) for patients in the best supportive care arm, with a HR of Figure 1: Kaplan-Meier Plot of Disease-Free Survival in IMpower010 in Patients with Stage II – IIIA NSCLC with PD-L1 expression ≥ 1% TC At the time of the DFS interim analysis, 19% of patients in the PD-L1 ≥1% TC Stage II – IIIA patient population had died.

An exploratory analysis of OS in this population resulted in a stratified HR of Figure 1 Metastatic Chemotherapy-Naïve NSCLC with High PD-L1 Expression The efficacy of TECENTRIQ was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in patients with stage IV NSCLC whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 1% of the tumor area ), who had received no prior chemotherapy for metastatic disease. PD-L1 tumor status was determined based on immunohistochemistry (IHC) testing using the VENTANA PD-L1 (SP142) Assay. The evaluation of efficacy is based on the subgroup of patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), excluding those with EGFR or ALK genomic tumor aberrations.

The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization. Randomization was stratified by sex, ECOG performance status, histology (non-squamous vs. squamous) and PD-L1 expression (TC ≥ 1% and any IC vs. TC < 1% and IC ≥ 1%).

Administration of TECENTRIQ was permitted beyond RECIST-defined disease progression. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. The majority of patients were White (82%) and Asian (17%).

Baseline ECOG performance status was were current or previous smokers; and 76% of patients had non-squamous disease while 24% of patients had squamous disease. The trial demonstrated a statistically significant improvement in OS for patients with high PD-L1 expression (TC ≥50% or IC ≥10%) at the time of the OS interim analysis. Efficacy results for patients with NSCLC with high PD-L1 expression are presented in Table 27 and Figure 2.

The investigator-assessed confirmed ORR was in the TECENTRIQ arm and in the platinum-based chemotherapy arm. Figure 2 Metastatic Chemotherapy-Naive Non-Squamous NSCLC IMpower150 The efficacy of TECENTRIQ with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), a multicenter, international, randomized (1:1:1), open-label trial in patients with metastatic non-squamous NSCLC. Patients with stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease but could have received prior EGFR or ALK kinase inhibitor if appropriate, regardless of PD-L1 or T-effector gene (tGE) status and ECOG performance status 0 or 1 were eligible.

Randomization was stratified by sex, presence of liver metastases, and PD-L1 expression status on tumor cells (TC) and tumor-infiltrating immune cells (IC) as follows: TC3 and any IC vs. TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1.

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

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

Approximately 14% of patients had liver metastases at baseline, and most patients were current or previous smokers (80%). Baseline ECOG performance status was PD-L1 was TC3 and any IC in 12%, TC0/1/2 and IC2/3 in 13%, and TC0/1/2 and IC0/1 in 75%. The demographics for the 696 patients in the ITT-WT subpopulation were similar to the ITT population except for the absence of patients with EGFR- or ALK- positive NSCLC.

The trial demonstrated a statistically significant improvement in PFS between Arms B and C in both the tGE-WT and ITT-WT subpopulations, but did not demonstrate a significant difference for either subpopulation between Arms A and C based on the final PFS analyses. In the interim analysis of OS, a statistically significant improvement was observed for Arm B compared to Arm C, but not for Arm A compared to Arm C. Efficacy results for the ITT-WT subpopulation are presented in Table 28 and Figure 3.

Table 28: Efficacy Results in ITT-WT Population in IMpower150 in ITT-WT Population in IMpower150 Exploratory analyses showed that the subset of patients in the four drug regimen arm who were ADA positive by week 4 (30%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (70%). In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly ADA negative patients in the TECENTRIQ, bevacizumab, paclitaxel, and carboplatin arm were compared with a matched population in the bevacizumab, paclitaxel, and carboplatin arm.

Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, tobacco history, metastatic site, TC level, and IC level. The hazard ratio comparing the ADA-positive subgroup with its matched control was The hazard ratio comparing the ADA-negative subgroup with its matched control was Figure 3 IMpower130 The efficacy of TECENTRIQ with paclitaxel protein-bound and carboplatin was evaluated in IMpower130 (NCT02367781), a multicenter, randomized (2:1), open-label trial in patients with stage IV non-squamous NSCLC. Randomization was stratified by sex, presence of liver metastases, and PD-L1 tumor expression according to the VENTANA PD-L1 (SP142) assay as follows: TC3 and any IC vs.

Tumor assessments were conducted every 6 weeks for the first 48 weeks, then every 9 weeks thereafter. Major efficacy outcome measures were PFS by RECIST v1.1 and OS in the subpopulation of patients evaluated for and documented to have no EGFR or ALK genomic tumor aberrations (ITT-WT). A total of 724 patients were enrolled; of these, 681 (94%) were in the ITT-WT population.

PD-L1 tumor expression was TC0/1/2 and IC0/1 in 73%; TC3 and any IC in 14%; and TC0/1/2 and IC2/3 in 13%. Efficacy results for the ITT-WT population are presented in Table 29 and Figure 4. Table 29: Efficacy Results from IMpower130 in IMpower130 Figure 4 Previously Treated Metastatic NSCLC OAK The efficacy of TECENTRIQ was evaluated in a multicenter, international, randomized (1:1), open-label study (OAK; NCT02008227) conducted in patients with locally advanced or metastatic NSCLC whose disease progressed during or following a platinum-containing regimen.

Patients with a history of autoimmune disease, symptomatic or corticosteroid-dependent brain metastases, or requiring systemic immunosuppression within 2 weeks prior to enrollment were ineligible. Randomization was stratified by PD-L1 expression tumor-infiltrating immune cells (IC), the number of prior chemotherapy regimens (1 vs. 2), and histology (squamous vs. non-squamous). Tumor assessments were conducted every 6 weeks for the first 36 weeks and every 9 weeks thereafter.

Major efficacy outcome measure was overall survival (OS) in the first 850 randomized patients and OS in the subgroup of patients with PD-L1-expressing tumors (defined as ≥ 1% PD-L1 expression on tumor cells or immune cells ). Additional efficacy outcome measures were OS in all randomized patients (n = 1225), OS in subgroups based on PD-L1 expression, overall response rate (ORR), and progression free survival as assessed by the investigator per RECIST v.1.1. Efficacy results are presented in Table 30 and Figure 5.

In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was in the high PD-L1 expression subgroup and in patients who did not have high PD-L1 expression. ADA positive patients by week 4 appeared to have similar OS compared to docetaxel-treated patients. The hazard ratio comparing the ADA positive subgroup with its matched control was The hazard ratio comparing the ADA negative subgroup with its matched control was IMpower133 enrolled patients with ES-SCLC who had received no prior chemotherapy for extensive stage disease and ECOG performance status 0 or 1.

Randomization was stratified by sex, ECOG performance status, and presence of brain metastases. Patients treated beyond disease progression had tumor assessment conducted every 6 weeks until treatment discontinuation. Major efficacy outcome measures were OS and PFS as assessed by investigator per RECIST v1.1 in the intent-to-treat population.

Additional efficacy outcome measures included ORR and DoR as assessed by investigator per RECIST v1.1. A total of 403 patients were randomized, including 201 to the TECENTRIQ arm and 202 to the chemotherapy alone arm. Baseline ECOG performance status was of patients had a history of brain metastases, and 97% were current or previous smokers.

Efficacy results are presented in Table 31 and Figure 6. Table 31: Efficacy Results from IMpower133 in IMpower133 Figure 6 IMforte The efficacy of TECENTRIQ in combination with lurbinectedin as maintenance treatment was evaluated in IMforte (NCT05091567), a randomized, multicenter, open-label study in patients with ES-SCLC. Patients were eligible if their disease had not progressed after completion of four cycles of TECENTRIQ, carboplatin and etoposide (induction treatment) and they had an ECOG performance status of 0 or 1.

The trial excluded patients with CNS metastases, history of autoimmune disease, or administration of systemic immunosuppressive medications within 1 week prior to enrollment. Unless contraindicated, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was mandated for patients assigned to the TECENTRIQ with lurbinectedin arm. The trial randomized 483 patients who had not experienced disease progression following the completion of four cycles of TECENTRIQ with carboplatin and etoposide to one of the following two treatment arms: TECENTRIQ 1200 mg IV in combination with lurbinectedin 3.2 mg/m 2 IV once every 3 weeks until disease progression or unacceptable toxicity, or TECENTRIQ 1200 mg IV once every 3 weeks until disease progression or unacceptable toxicity Randomization was stratified by ECOG performance status prior to randomization (0 vs. 1), lactate dehydrogenase (LDH) (≤ ULN vs. > ULN) prior to randomization, presence of liver metastases prior to initial study enrollment (yes vs. no), and prior receipt of prophylactic cranial irradiation (yes vs. no).

The major efficacy outcome measures were OS and PFS by Independent Review Facility (IRF) per RECIST v1.1. A total of 483 patients were randomized, including 242 to the TECENTRIQ with lurbinectedin arm and 241 to the TECENTRIQ arm. Baseline ECOG performance status was Efficacy results are presented in Table 32 and Figures 7 and 8.

Table 32: Efficacy Results from IMforte Figure 7: Kaplan-Meier Plot of IRF-assessed Progression-Free Survival in IMforte Figure 8: Kaplan-Meier Plot of Overall Survival in IMforte Figure 7 Figure 8

Hepatocellular Carcinoma

The efficacy of TECENTRIQ in combination with bevacizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (<400 vs. ≥400 ng/mL), and by ECOG performance status (0 vs. 1). Patients could discontinue either TECENTRIQ or bevacizumab (e.g., due to adverse events) and continue on single-agent therapy until disease progression or unacceptable toxicity associated with the single-agent.

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

Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter. The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The 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 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.

Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST. Efficacy results are presented in Table 33 and Figure 9. Table 33: Efficacy Results from IMbrave150 in IMbrave150 Exploratory analyses showed that the subset of patients (20%) who were ADA-positive by week 6 appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week 6.

ADA-positive patients by week 6 appeared to have similar overall survival compared to sorafenib-treated patients. In an exploratory analysis, inverse probability weighting was conducted to compare ADA-positive patients and ADA-negative patients in the TECENTRIQ and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (<400 ng/mL vs ≥400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology HBV vs.

HCV vs. non-viral and Child-Pugh Score (A5 vs. A6). The OS hazard ratio comparing the ADA-positive subgroup of the TECENTRIQ and bevacizumab arm to sorafenib was The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was Randomization was stratified by geographic location North America vs.

Europe vs. Australia, New Zealand, and others and baseline lactate dehydrogenase (LDH). Eligible patients were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma as detected by a locally available test and centrally confirmed with the FoundationOne™ assay.

Treatment continued until disease progression or unacceptable toxicity. There was no crossover at the time of disease progression. 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. Based on central testing, 74% were identified as having a V600E mutation, 11% as having V600K mutation, and 1% as having V600D or V600R mutations. Efficacy results are summarized in Table 34 and Figure 10.

Patients had a median survival follow up time of 18.9 months. Table 34: Efficacy Results from IMspire150 in IMspire150 At a pre-specified analysis at the time of the primary analysis of PFS, the OS data were not mature. The hazard ratio for OS was and the p-value was 0.2310.

Figure 10

Alveolar Soft Part Sarcoma

The efficacy of TECENTRIQ was evaluated in study ML39345 (NCT03141684), an open-label, single-arm study, in 49 adult and pediatric patients aged 2 years and older with unresectable or metastatic ASPS. Eligible patients were required to have histologically or cytologically confirmed ASPS that was not curable by surgery, and an ECOG performance status of ≤ 2. Patients were excluded if they had known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, known clinically significant liver disease, or history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.

The major efficacy outcomes were Overall Response Rate (ORR) and Duration of Response (DOR) by Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A total of 49 patients were enrolled. All patients had prior surgery for ASPS and 55% received at least one prior line of treatment for ASPS; 55% received radiotherapy and 53% received chemotherapy.

Of the patients who reported staging at initial diagnosis, all were Stage IV. Efficacy results of this study are summarized in Table 35. Table 35: Efficacy Results from Study ML39345

Muscle Invasive Bladder Cancer IMvigor011

The efficacy of TECENTRIQ was evaluated in IMvigor011 (NCT04660344), a multi-center, randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD). The trial enrolled patients with histologically confirmed MIBC who underwent radical cystectomy with lymph node dissection. Eligible patients had pathologic tumor staging of pT2-4a and/or positive lymph nodes following cystectomy, with no evidence of residual disease or metastasis on imaging, confirmed within 28 days before randomization.

Patients were eligible regardless of whether they had received prior neoadjuvant chemotherapy (NAC) or not. Patients were excluded if they had received any anti-cancer therapy within 3 weeks prior to trial enrollment or had a history of autoimmune disease. Serial ctDNA MRD testing was performed every 6 weeks for 9 months starting at least 6 weeks after cystectomy with a final test at one year.

Patients who did not develop ctDNA MRD within the testing period were monitored without study treatment, while those who had ctDNA MRD were screened for the treatment phase by confirming that they remained free of radiographic disease. The ctDNA MRD status was determined using either a Signatera™ clinical trial assay (whole exome-based tumor NGS sequencing and 16-plex NGS-based plasma sequencing) or a clinical trial assay performed locally in China. Randomization was stratified by nodal status (positive vs. negative), tumor stage (≤(y)pT2 vs. (y)pT3/pT4), PD-L1 immunohistochemistry (IHC) IC <5% vs.

IC ≥5%, and time from cystectomy to first ctDNA MRD positive sample (≤20 weeks vs. >20 weeks). 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. A total of 48% of patients in the TECENTRIQ arm received prior platinum containing neoadjuvant chemotherapy.

Overall Survival (OS) was an additional efficacy measure. The study demonstrated statistically significant improvements in DFS and OS for patients randomized to the TECENTRIQ arm compared with placebo. Efficacy results are presented in Table 36 and Figures 11 and 12.

The unstratified HR for OS was median OS was not reached in either arm (95% CI: 21.1 months, not reached in the TECENTRIQ arm and 18.4 months, not reached in the placebo arm). Figure 11 Figure 12

Table 26: Efficacy Results from IMpower010 in Patients with Stage II - IIIA NSCLC with PD-L1 expression ≥ 1% TC
	Arm A: TECENTRIQ N = 248	Arm B: Best Supportive Care N = 228
CI = Confidence interval, NE = Not estimable, NR = Not reached
Disease-Free Survival
Number of events (%)	88 (35)	105 (46)
Median, months	NR	35.3
(95% CI)	(36.1, NE)	(29.0, NE)
Hazard ratio Stratified by stage, sex, and histology (95% CI)	0.66 (0.50, 0.88)
p-value	0.004

Table 28: Efficacy Results in ITT-WT Population in IMpower150
	Arm C: Bevacizumab, Paclitaxel and Carboplatin	Arm B: TECENTRIQ with Bevacizumab, Paclitaxel, and Carboplatin	Arm A: TECENTRIQ with Paclitaxel, and Carboplatin
	N = 337	N = 359	N = 349
CI=confidence interval
Overall Survival Based on OS interim analysis
Deaths (%)	197 (59%)	179 (50%)	179 (51%)
Median, months	14.7	19.2	19.4
(95% CI)	(13.3, 16.9)	(17.0, 23.8)	(15.7, 21.3)
Hazard ratio Stratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC (95% CI)	---	0.78 (0.64, 0.96)	0.84 (0.72, 1.08)
p-value Based on the stratified log-rank test compared to Arm C	---	0.016 Compared to the allocated α=0.0174 (two sided) for this interim analysis	0.204 Compared to the allocated α=0.0128 (two sided) for this interim analysis
Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Number of events (%)	247 (73%)	247 (69%)	245 (70%)
Median, months	7.0	8.5	6.7
(95% CI)	(6.3, 7.9)	(7.3, 9.7)	(5.6, 6.9)
Hazard ratio (95% CI)	---	0.71 (0.59, 0.85)	0.94 (0.79, 1.13)
p-value	---	0.0002 Compared to the allocated α=0.006 (two sided) for the final PFS analysis	0.5219
Objective Response Rate
Number of responders (%)	142 (42%)	196 (55%)	150 (43%)
(95% CI)	(37, 48)	(49, 60)	(38, 48)
Complete Response	3 (1%)	14 (4%)	9 (3%)
Partial Response	139 (41%)	182 (51%)	141 (40%)
Duration of Response	n = 142	n = 196	n = 150
Median, months	6.5	10.8	9.5
(95% CI)	(5.6, 7.6)	(8.4, 13.9)	(7.0, 13.0)

Table 29: Efficacy Results from IMpower130
	TECENTRIQ with Paclitaxel Protein-Bound and Carboplatin	Paclitaxel Protein-Bound and Carboplatin
CI=confidence interval
Overall Survival Based on OS interim analysis	n=453	n=228
Deaths (%)	228 (50%)	131 (57%)
Median, months	18.6	13.9
(95% CI)	(15.7, 21.1)	(12.0, 18.7)
Hazard ratio Stratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC) (95% CI)	0.80 (0.64, 0.99)
p-value Based on the stratified log-rank test	0.0384 Compared to the allocated α=0.0428 (two sided) for this interim analysis
Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)	n=453	n=228
Number of events (%)	330 (73%)	177 (78%)
Median, months	7.2	6.5
(95% CI)	(6.7, 8.3)	(5.6, 7.4)
Hazard ratio (95% CI)	0.75 (0.63, 0.91)
p-value	0.0024 Compared to the allocated α=0.006 (two sided) for the final PFS analysis
Overall Response Rate, Confirmed response	n=453	n=228
Number of responders (%)	207 (46%)	74 (32%)
(95% CI)	(41, 50)	(26, 39)
Complete Response	22 (5%)	2 (1%)
Partial Response	185 (41%)	72 (32%)
Duration of Response,	n=207	n=74
Median, months	10.8	7.8
(95% CI)	(9.0, 14.4)	(6.8, 10.9)

Table 30: Efficacy Results in OAK
	TECENTRIQ	Docetaxel
CI=confidence interval; NE=not estimable
Overall Survival in first 850 patients
Number of patients	N=425	N=425
Deaths (%)	271 (64%)	298 (70%)
Median, months	13.8	9.6
(95% CI)	(11.8, 15.7)	(8.6, 11.2)
Hazard ratio Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology (95% CI)	0.74 (0.63, 0.87)
p-value Based on the stratified log-rank test	0.0004 Compared to the pre-specified allocated α of 0.03 for this analysis
Progression-Free Survival
Number of Patients	N=425	N=425
Events (%)	380 (89%)	375 (88%)
Progression (%)	332 (78%)	290 (68%)
Deaths (%)	48 (11%)	85 (20%)
Median, months	2.8	4.0
(95% CI)	(2.6, 3.0)	(3.3, 4.2)
Hazard ratio (95% CI)	0.95 (0.82, 1.10)
Overall Response Rate Per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Number of Patients	N=425	N=425
ORR, n (%)	58 (14%)	57 (13%)
(95% CI)	(11%, 17%)	(10%, 17%)
Complete Response	6 (1%)	1 (0.2%)
Partial Response	52 (12%)	56 (13%)
Duration of Response	N=58	N=57
Median, months	16.3	6.2
(95% CI)	(10.0, NE)	(4.9, 7.6)
Overall Survival in all 1225 patients
Number of patients	N=613	N=612
Deaths (%)	384 (63%)	409 (67%)
Median, months	13.3	9.8
(95% CI)	(11.3, 14.9)	(8.9, 11.3)
Hazard ratio (95% CI)	0.79 (0.69, 0.91)
p-value	0.0013 Compared to the allocated α of 0.0177 for this interim analysis based on 86% information using O'Brien-Fleming boundary

Table 31: Efficacy Results from IMpower133
	TECENTRIQ with Carboplatin and Etoposide	Placebo with Carboplatin and Etoposide
CI=confidence interval
Overall Survival	N=201	N=202
Deaths (%)	104 (52%)	134 (66%)
Median, months	12.3	10.3
(95% CI)	(10.8, 15.9)	(9.3, 11.3)
Hazard ratio Stratified by sex and ECOG performance status (95% CI)	0.70 (0.54, 0.91)
p-value Based on the stratified log-rank test, Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary	0.0069
Progression-Free Survival As determined by investigator assessment, per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)	N=201	N=202
Number of events (%)	171 (85%)	189 (94%)
Median, months	5.2	4.3
(95% CI)	(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)

Table 32: Efficacy Results from IMforte
	TECENTRIQ with Lurbinectedin N=242	TECENTRIQ N=241
CI=confidence interval
Overall Survival Measured from the time of randomization
Deaths (%)	113 (47%)	136 (56%)
Median, months	13.2	10.6
(95% CI)	(11.9, 16.4)	(9.5, 12.2)
Hazard ratio Stratified 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-value Based on the stratified log-rank test, Compared to the allocated alpha of 0.0313 (two-sided) for this interim OS analysis.	0.0174
Progression-Free Survival, As determined by an IRF, per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Number of events (%)	174 (72%)	202 (84%)
Median, months	5.4	2.1
(95% CI)	(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

Table 33: Efficacy Results from IMbrave150
	TECENTRIQ in combination with Bevacizumab (N= 336)	Sorafenib (N=165)
CI=confidence interval; HCC mRECIST=Modified RECIST Assessment for Hepatocellular Carcinoma; NE=not estimable; RECIST 1.1=Response Evaluation Criteria in Solid Tumors v1.1
Overall Survival
Number of deaths (%)	96 (29)	65 (39)
Median OS in months (95% CI)	NE (NE, NE)	13.2 (10.4, NE)
Hazard ratio Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. ≥400 ng/mL) (95% CI)	0.58 (0.42, 0.79)
p-value Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method	0.0006
Progression-Free Survival Per independent radiology review
Number of events (%)	197 (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-value Based 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 (95% CI)	NE (NE, NE)	6.3 (4.7, NE)
Range (months)	(1.3 Denotes a censored value, 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 (95% CI)	NE (NE, NE)	6.3 (4.9, NE)
Range (months)	(1.3, 13.4 )	(1.4, 9.1 )

Table 34: Efficacy Results from IMspire150
	TECENTRIQ + Cobimetinib + Vemurafenib N=256	Placebo + Cobimetinib + Vemurafenib N=258
Progression-Free Survival As determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI=confidence interval
Number of events (%)	148 (58)	179 (69)
Median, months	15.1	10.6
(95% CI)	(11.4, 18.4)	(9.3, 12.7)
Hazard ratio Stratified by baseline LDH (95% CI)	0.78 (0.63, 0.97)
p-value Based 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)

Table 35: Efficacy Results from Study ML39345
Endpoint	All Patients (N=49)
CI: confidence interval; N: number of patients; +: Censored
Overall response rate (95% CI) 95% CI based on Clopper–Pearson exact method.	24% (13, 39)
Complete Responses, n	0
Partial Responses, n (%)	12 (24)
Duration of response
Median, month	NE
(95% CI)	(17.0, NE)
Range	1+, 41+
Durability of Response
≥6 months, n (%)	8 (67%)
≥12 months, n (%)	5 (42%)

Table 36: Efficacy Results from IMvigor011
	TECENTRIQ N=167	Placebo N=83
CI=confidence interval; NE=not estimable
Investigator - assessed DFS
Number of events (%)	112 (67%)	66 (80%)
Median Based on Kaplan-Meier estimates, months	9.9	4.8
(95% CI)	(7.2, 12.7)	(4.1, 8.3)
Hazard ratio Based on stratified Cox proportional hazards model, Stratified by programmed death-ligand 1 (PD-L1) status, nodal status, tumor stage after cystectomy (95% CI)	0.64 (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

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

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