Tecentriq Hybreza Dailymed

1 Indications And Usage

TECENTRIQ HYBREZA is a combination of atezolizumab, a programmed death-ligand 1 (PD-L1) blocking antibody, and hyaluronidase, an endoglycosidase indicated:

Non-Small Cell Lung Cancer (NSCLC)

• as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-approved test. (1.2, 2.1)
• for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. (1.2, 2.1)
• in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. (1.2)
• in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. (1.2)
• 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 HYBREZA. (1.2)

Small Cell Lung Cancer (SCLC) (1.3)

• in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.3)

Hepatocellular Carcinoma (HCC) (1.4)

• in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic HCC who have not received prior systemic therapy. (1.4)

Melanoma (1.5)

• in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test. (1.5, 2.1)

Alveolar Soft Part Sarcoma (ASPS) (1.6)

• for the treatment of adult patients with unresectable or metastatic ASPS. (1.6)

1.1Non-Small Cell Lung Cancer

• TECENTRIQ HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA [see Clinical Studies (14.1)] non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA-approved test [see Dosage and Administration (2.1)].
• TECENTRIQ HYBREZA, as monotherapy, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [see Dosage and Administration (2.1)].
• TECENTRIQ HYBREZA, 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 HYBREZA, in combination with paclitaxel protein-bound and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
• TECENTRIQ HYBREZA, as monotherapy, 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 HYBREZA.

1.2Small Cell Lung Cancer

TECENTRIQ HYBREZA, 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).

1.3Hepatocellular Carcinoma

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

1.4Melanoma

TECENTRIQ HYBREZA, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test [see Dosage and Administration (2.1)].

1.5Alveolar Soft Part Sarcoma

TECENTRIQ HYBREZA, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic alveolar soft part sarcoma (ASPS).

2 Dosage And Administration

• TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products. (2.2)
• TECENTRIQ HYBREZA is not indicated for use in pediatric patients. (2.2)
• TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. (2.2)
• Do not administer TECENTRIQ HYBREZA intravenously. (2.2)
• Recommended dosage: TECENTRIQ HYBREZA 15 mL (1,875 mg atezolizumab and 30,000 units hyaluronidase) subcutaneously into the thigh over approximately 7 minutes every 3 weeks. (2.2)
• TECENTRIQ HYBREZA must be administered by a healthcare professional. (2.2)

NSCLC Dosage

• In the adjuvant setting, administer TECENTRIQ HYBREZA following resection and up to 4 cycles of platinum-based chemotherapy every 3 weeks for up to 1 year. (2.2)
• In the metastatic setting, administer TECENTRIQ HYBREZA every 3 weeks. (2.2)
• When administering with chemotherapy with or without bevacizumab, administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day. (2.2)

SCLC Dosage

Administer TECENTRIQ HYBREZA every 3 weeks. When administering with carboplatin and etoposide, administer TECENTRIQ HYBREZA prior to chemotherapy when given on the same day. (2.2)

HCC Dosage

• Administer TECENTRIQ HYBREZA every 3 weeks.
• Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks. (2.2)

Melanoma Dosage

• Following completion of a 28-day cycle of cobimetinib and vemurafenib, administer TECENTRIQ HYBREZA every 3 weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily. (2.2)

ASPS Dosage

• Administer TECENTRIQ HYBREZA every 3 weeks. (2.2)

2.1 Patient Selection for Treatment of Non-Small Cell Lung Cancer and Melanoma

Select adult patients with:

• Stage II to IIIA NSCLC for adjuvant treatment with TECENTRIQ HYBREZA as a monotherapy (following tumor resection and platinum-based chemotherapy) based on PD-L1 expression on tumor cells [see Clinical Studies (14.2)].
• Metastatic NSCLC for first-line treatment with TECENTRIQ HYBREZA as monotherapy based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells [see Clinical Studies (14.2)].
• Unresectable or metastatic melanoma for treatment with TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib after confirming the presence of a BRAF V600 mutation [see Clinical Studies (14.5)].

Information on FDA-approved tests for the determination of PD-L1 expression in metastatic NSCLC or for detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

2.2Important Dosage and Administration Information

• TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products.
  • To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared is subcutaneously administered TECENTRIQ HYBREZA and not intravenously administered atezolizumab.
  • Do not substitute TECENTRIQ HYBREZA for or with intravenous atezolizumab products because they have different recommended dosages.
  • Adult patients who are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose.
  • Adult patients who are treated with TECENTRIQ HYBREZA can switch to intravenous atezolizumab at their next scheduled dose.
• TECENTRIQ HYBREZA is not indicated for use in pediatric patients.
• TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. Administer over approximately 7 minutes. Inject in healthy skin and never into areas where the skin is red, bruised, tender, or hard.
• When possible, alternate injections between the left and right thigh. Ensure the injection site is at least 2.5 cm from the previous site.
• Do not administer TECENTRIQ HYBREZA intravenously.
• TECENTRIQ HYBREZA must be administered by a healthcare professional.
• Do not administer the remaining volume in the tubing to the patient.
• If using concomitant subcutaneous drugs, administer at sites other than the thighs.

2.3Recommended Dosage and Administration Instructions

The recommended dosage of TECENTRIQ HYBREZA is one 15 mL injection (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase, referred to as TECENTRIQ HYBREZA) administered subcutaneously in the thigh over approximately 7 minutes every 3 weeks.

Administration instructions for TECENTRIQ HYBREZA as monotherapy and in combination with other therapeutic agents are presented in Table 1. For the recommended dosage of each therapeutic agent administered in combination with TECENTRIQ HYBREZA refer to the product's respective Prescribing Information.

Table 1: TECENTRIQ HYBREZA Administration Instructions and Duration of Therapy

Indication	Administration Instructions for TECENTRIQ HYBREZA	Duration of Therapy
Adjuvant Treatment of Non-Small Cell Lung Cancer	Administer TECENTRIQ HYBREZA as monotherapy	Up to one year, unless there is disease recurrence or unacceptable toxicity
Metastatic Non-Small Cell Lung Cancer		Until disease progression or unacceptable toxicity
Non-Small Cell Lung Cancer	Administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day.	Until disease progression or unacceptable toxicity
Small Cell Lung Cancer	Administer TECENTRIQ HYBREZA prior to chemotherapy when given on the same day.
Hepatocellular Carcinoma	Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks.
Melanoma	Prior to initiating TECENTRIQ HYBREZA, patients should receive the following 28-day treatment cycle of cobimetinib and vemurafenib: Days 1 to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice daily Days 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily
Alveolar Soft Part Sarcoma	Administer TECENTRIQ HYBREZA as monotherapy	Until disease progression or unacceptable toxicity

2.4Dosage Modifications for Adverse Reactions

No dose reduction for TECENTRIQ HYBREZA is recommended. In general, withhold TECENTRIQ HYBREZA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue TECENTRIQ HYBREZA 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 the daily corticosteroid dosage to 10 mg or less of prednisone or equivalent corticosteroid dosage within 12 weeks of initiating corticosteroids.

Dosage modifications for TECENTRIQ HYBREZA for adverse reactions that require management different from these general guidelines are summarized in Table 2.

Table 2: Recommended Dosage Modifications for Adverse Reactions

Adverse Reaction	SeverityBased on Common Terminology Criteria for Adverse Events (CTCAE), version 5	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	WithholdResume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids
	Grades 3 or 4	Permanently discontinue
Colitis	Grades 2 or 3	Withhold
	Grade 4	Permanently discontinue
Hepatitis with no tumor involvement of the liver	AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN	Withhold
	AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Hepatitis with tumor involvement of the liverIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ HYBREZA based on recommendations for hepatitis with no liver involvement	Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN	Withhold
	AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Endocrinopathies	Grades 3 or 4	Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal Dysfunction	Grades 2 or 3 increased blood creatinine	Withhold
	Grade 4 increased blood creatinine	Permanently discontinue
Exfoliative Dermatologic Conditions	Suspected SJS, TEN, or DRESS	Withhold
	Confirmed SJS, TEN, or DRESS	Permanently discontinue
Myocarditis or pericarditis	Grades 2, 3, or 4	Permanently discontinue
Neurological Toxicities	Grade 2	Withhold
	Grades 3 or 4	Permanently discontinue
Other Adverse Reactions
Infusion-Related Reactions [see Warnings and Precautions (5.2)]	Grades 1 or 2	Pause or slow the rate of injection Premedication with antipyretic and antihistamines may be considered for subsequent doses.
	Grades 3 or 4	Permanently discontinue

2.5Preparation Instructions

TECENTRIQ HYBREZA does not contain any antimicrobial preservative. If the TECENTRIQ HYBREZA dose is not administered immediately, refer to "Storage Instructions" [see Dosage and Administration (2.6)].

• Remove the vial from the refrigerator and allow the solution to acclimate to room temperature. Visually inspect for particulate matter and discoloration prior to administration. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
• Do not shake, freeze, or dilute.
• The unpunctured vial may be stored at room temperature in ambient light for a maximum of 4 hours prior to the preparation for administration.
• Use an 18-gauge transfer needle and syringe to withdraw the entire contents of the TECENTRIQ HYBREZA solution from the vial. Discard the vial and any residual drug remaining.
• TECENTRIQ HYBREZA is compatible with stainless steel transfer and injection needles, and polypropylene, polycarbonate, polyvinyl chloride, and polyurethane syringe material and subcutaneous administration sets.
• Remove the transfer needle from the syringe and replace it with a subcutaneous administration set (e.g. winged/butterfly) containing 23-gauge, 24-gauge, or 25-gauge hypodermic needle and with a priming volume that does not exceed 0.5 mL for administration.
• Prime the subcutaneous administration line with TECENTRIQ HYBREZA to eliminate the air in the line and stop when the fluid reaches the needle.
• Ensure the syringe contains exactly 15 mL of TECENTRIQ HYBREZA after priming the administration line by expelling any excess volume from the syringe.
• Administer immediately to avoid needle clogging.
• Discard any unused portion remaining.

2.6Storage Instructions

• Do not store the prepared syringe that has been attached to the already-primed subcutaneous administration set.
• If the prepared syringe containing TECENTRIQ HYBREZA is not for immediate use, do not attach a subcutaneous administration set. The capped syringe may be stored at room temperature [at up to 25°C (77°F)] in ambient room lighting for up to 8 hours and in the refrigerator [2°C to 8°C (36°F to 46°F)] for up to 72 hours. Do not shake or freeze.
• If the prepared syringe is stored at 2°C to 8°C (36°F to 46°F), allow the syringe to acclimate to room temperature prior to administration.

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

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

• Most common adverse reactions (AR) (≥ 10%) with TECENTRIQ HYBREZA as monotherapy in patients with NSCLC were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. (6.1)
• Safety of TECENTRIQ HYBREZA for the approved NSCLC, EC-SCLC, HCC, melanoma and ASPS indications is based on safety of intravenous atezolizumab in these populations. Most common AR with intravenous atezolizumab are presented below by indication and regimen (6.1):

• Most common AR (≥ 20%) as monotherapy were:
  • First-line NSCLC: fatigue/asthenia.
  • Metastatic NSCLC: fatigue/asthenia, cough, decreased appetite, dyspnea, and myalgia/pain.
  • ASPS: musculoskeletal pain, fatigue, rash, cough, headache, nausea, hypertension, vomiting, constipation, dyspnea, dizziness, hemorrhage, diarrhea, insomnia, abdominal pain hypothyroidism, pyrexia, anxiety, arrhythmia and decreased appetite.
• Most common AR (≥ 20%) in combination with other antineoplastic drugs were:
  • NSCLC (with bevacizumab, paclitaxel, and carboplatin): neuropathy fatigue/asthenia, alopecia, myalgia, nausea, diarrhea, constipation, decreased appetite, arthralgia, hypertension, rash, cough.
  • Non-squamous NSCLC (with paclitaxel protein-bound and carboplatin): fatigue/asthenia, nausea, diarrhea, myalgia/pain, constipation, neuropathy, alopecia, dyspnea, decreased appetite, cough, vomiting and rash.
  • SCLC (with carboplatin and etoposide): fatigue/asthenia, nausea, alopecia, decreased appetite, constipation and vomiting.
  • HCC (with bevacizumab): hypertension, fatigue and proteinuria.
  • Melanoma (with cobimetinib and vemurafenib): rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction.

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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.

Adverse Reactions of TECENTRIQ HYBREZA in Adult Patients with NSCLC

The safety of TECENTRIQ HYBREZA was evaluated in IMscin001, open-label, multi-center, international, randomized trial for patients with locally advanced or metastatic NSCLC who have not been exposed to cancer immunotherapy and who have had disease progression on prior platinum-based therapy [see Clinical Studies (14.1)]. Patients with previously treated metastatic non-small cell lung cancer (NSCLC) either received TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously into the thigh over approximately 7 minutes every 3 weeks or intravenous atezolizumab every 3 weeks until disease progression or unacceptable toxicity. Among 247 patients who received TECENTRIQ HYBREZA, 32% were exposed for 6 months or longer and 8% were exposed for greater than one year.

The median age was 64 years (range: 27 to 85); 69% male; 67% White, 22% Asian, 0.8% Black or African American; 74% were non-Hispanic or Latino; 26% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 74% had an ECOG PS of 1; and 70% of patients were current or previous smokers.

Serious adverse reactions occurred in 19% of patients who received TECENTRIQ HYBREZA. Serious adverse reactions (> 1%) included pneumonia, myocardial infarction, and pleural effusion. Fatal adverse reactions occurred in 6% of patients who received TECENTRIQ HYBREZA, including pneumonia (2.4%), myocardial infarction (1.2%), head injury (0.4%), ischemic stroke (0.4%), pleural effusion (0.4%), pulmonary embolism (0.4%), respiratory tract infection (0.4%), sepsis (0.4%), and toxic epidermal necrolysis (0.4%).

Permanent discontinuation of TECENTRIQ HYBREZA due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of TECENTRIQ HYBREZA in > 1% of patients included pneumonia (2%).

Dosage interruptions of TECENTRIQ HYBREZA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in > 1% of patients were COVID-19 (4.9%), increased aspartate aminotransferase (2.8%), increased alanine aminotransferase (2.4%), pneumonia (2.4%), anemia (1.6%), dyspnea (1.6%), fatigue (1.2%), and viral respiratory tract infection (1.2%). The most common adverse reactions of any grade (occurring in ≥ 10% of patients) were fatigue (19%), musculoskeletal pain (15%), cough (13%), dyspnea (12%), and decreased appetite (11%).

Tables 3 and 4 summarize adverse reactions and selected laboratory abnormalities, respectively in TECENTRIQ HYBREZA-treated patients in IMscin001.

Table 3: Adverse Reactions (≥ 10%) in Adult Patients with Locally Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001

Adverse ReactionGraded per NCI CTCAE v5.0	TECENTRIQ HYBREZA n = 247		Intravenous Atezolizumab n = 124
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
General Disorder and Administration Site Conditions
FatigueComposite term includes fatigue, asthenia	19	0.8	18	0
Musculoskeletal and Connective Tissue disorders
Musculoskeletal PainComposite term includes back pain, myalgia, bone pain, musculoskeletal chest pain, neck pain, spinal pain, non-cardiac chest pain	15	0.4	13	3.2
Respiratory, Thoracic and Mediastinal
CoughComposite term includes cough, productive cough	13	0	7	0
DyspneaComposite term includes dyspnea, dyspnea at rest, dyspnea exertional	12	1.2	15	1.6
Metabolism and Nutrition Disorders
Decreased appetite	11	0	11	0

Clinically relevant adverse reactions in < 10% of patients who received TECENTRIQ HYBREZA were local injection site reactions (4.5%) and pyrexia (1.2%).

Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients with Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001

Laboratory AbnormalityGraded per NCI CTCAE v5.0	TECENTRIQ HYBREZA (n = 247)		Intravenous Atezolizumab (n = 124)
	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 HYBREZA (48-233) and intravenous atezolizumab (19-117)
Hematology
Decreased Hemoglobin	67	6	63	5
Decreased lymphocytes	37	9	45	15
Chemistry
Decreased Sodium	46	3.9	47	5
Decreased Albumin	34	2.2	27	0
Increased Alkaline Phosphatase	33	1.3	27	0
Increased AST	28	2.6	32	2.6
Increased ALT	28	2.6	23	1.7
Decreased calcium	22	2.6	23	0.9
Increased calcium	20	2.6	24	1.7
Increased potassium	21	1.7	22	1.7
Increased INR	20	2	23	0
Increased Creatinine	19	1.7	26	0.9

Adverse Reactions in Adult Patients with NSCLC Treated with Intravenous Atezolizumab

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

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

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

Non-Small Cell Lung Cancer (NSCLC)

Adjuvant Treatment of Early-stage NSCLC

IMpower010

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

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

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

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

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

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

Table 5: Adverse Reactions Occurring in ≥ 10% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010

Adverse ReactionGraded per NCI CTCAE v4.0	Intravenous Atezolizumab N = 495		Best Supportive CareN = 495
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Skin and Subcutaneous Tissue
RashIncludes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform	17	1.2	1.4	0
Pruritus	10	0	0.6	0
Endocrine Disorders
HypothyroidismIncludes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased	14	0	0.6	0
Respiratory, Thoracic and Mediastinal
CoughProductive cough, upper airway cough syndrome, cough	16	0	11	0
General
PyrexiaIncludes pyrexia, body temperature increased, hyperthermia	14	0.8	2.2	0.2
FatigueIncludes fatigue, asthenia	14	0.6	5	0.2
Nervous System Disorders
Peripheral neuropathyIncludes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy	12	0.4	7	0.2
Musculoskeletal and Connective Tissue
Musculoskeletal painIncludes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain	14	0.8	9	0.2
ArthralgiaIncludes arthralgia, arthritis	11	0.6	6	0

Table 6: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with Early-Stage NSCLC Receiving Intravenous Atezolizumab in IMpower010

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

Metastatic Chemotherapy-Naïve NSCLC

IMpower110

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

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

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

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

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

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

Table 7: Adverse Reactions Occurring in ≥ 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower110

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

Table 8: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab in IMpower110

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

First-Line Metastatic Non-squamous NSCLC

IMpower150

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

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

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

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

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

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

Table 9: Adverse Reactions Occurring in ≥ 15% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150

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

Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower150

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

IMpower130

The safety of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130, a multicenter, international, randomized, open-label trial in which 473 chemotherapy-naïve patients with metastatic non-squamous NSCLC received intravenous atezolizumab 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m² intravenously on Days 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by intravenous atezolizumab 1200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)]. Among patients receiving intravenous atezolizumab, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.

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

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

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

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

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

Table 11: Adverse Reactions Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in IMpower130

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

Table 12: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab in IMpower130

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

Previously Treated Metastatic NSCLC

OAK

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

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

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

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

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

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

Table 13: Adverse Reactions Occurring in ≥ 10% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAK

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

Table 14: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with NSCLC Receiving Intravenous Atezolizumab in OAK

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

Small Cell Lung Cancer (SCLC)

IMpower133

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

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

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

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

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

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

Table 15: Adverse Reactions Occurring in ≥ 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133

Adverse Reaction	Intravenous Atezolizumab with Carboplatin and EtoposideN = 198		Placebo with Carboplatin and EtoposideN = 196
	All Grades (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
Graded per NCI CTCAE v4.0
General
Fatigue/Asthenia	39	5	33	3
Gastrointestinal
Nausea	38	1	33	1
Constipation	26	1	30	1
Vomiting	20	2	17	3
Skin and Subcutaneous Tissue
Alopecia	37	0	35	0
Metabolism and Nutrition
Decreased appetite	27	1	18	0

Table 16: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with SCLC Receiving Intravenous Atezolizumab in IMpower133

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

Hepatocellular Carcinoma

IMbrave150

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

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

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

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

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

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

Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab and bevacizumab in IMbrave150.

Table 17: Adverse Reactions Occurring in ≥ 10% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150

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

Table 18: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with HCC Receiving Intravenous Atezolizumab in IMbrave150

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

Metastatic Melanoma

IMspire150

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

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

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

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

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

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

Tables 19 and 20 summarize the incidence of adverse reactions and laboratory abnormalities in IMspire150.

Table 19: Adverse Reactions Occurring in ≥ 10% of Patients on the Intravenous Atezolizumab 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 Intravenous Atezolizumb in IMspire150)

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

Clinically important adverse reactions in < 10% of patients who received intravenous atezolizumab plus cobimetinib and vemurafenib were:

Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged

Eye Disorders: Uveitis

Gastrointestinal disorders: Pancreatitis

Infections and infestations: Pneumonia, urinary tract infection

Metabolism and nutrition disorders: Hyperglycemia

Nervous system Disorders: Dizziness, dysgeusia, syncope

Respiratory, thoracic and mediastinal disorders: Dyspnea, oropharyngeal pain

Skin and Subcutaneous Tissue Disorders: Vitiligo

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

Alveolar Soft Part Sarcoma

ML39345 Study

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

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

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

Tables 21 and 22 summarize adverse reactions and laboratory abnormalities in Study ML39345.

Table 21: Adverse Reactions Occurring in ≥ 15% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345

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

Table 22: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with ASPS Receiving Intravenous Atezolizumab in ML39345

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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous atezolizumab. 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