Tecentriq Hybreza^™

atezolizumab and hyaluronidase-tqjs

Indications & Important Safety Information

TECENTRIQ HYBREZA Indications

Non-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-IIIA non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥1% of tumor cells, as determined by an FDA-approved test.

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.

TECENTRIQ HYBREZA, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous, non-small cell lung cancer (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 non-small cell lung cancer (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.

Extensive-Stage Small 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).

Unresectable or Metastatic Hepatocellular 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.

Unresectable or Metastatic Melanoma
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.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PD-L1=programmed death-ligand 1.

TECENTRIQ HYBREZA Important Safety Information

Contraindications
TECENTRIQ HYBREZA is contraindicated in patients with known hypersensitivity to hyaluronidase or to any of its excipients.

Warnings and Precautions
Severe and Fatal Immune-Mediated Adverse Reactions
TECENTRIQ HYBREZA 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. The following immune-mediated adverse reactions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions can occur in any organ system or tissue and at any time after starting TECENTRIQ HYBREZA. While immune-mediated adverse reactions usually manifest during treatment with TECENTRIQ HYBREZA, they can also manifest after discontinuation of treatment. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of TECENTRIQ HYBREZA.

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 HYBREZA depending on severity. In general, if TECENTRIQ HYBREZA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less, then 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.

Immune-Mediated Pneumonitis

• TECENTRIQ HYBREZA can cause immune-mediated pneumonitis, including fatal adverse reactions. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation
• Immune-mediated pneumonitis occurred in 2% (5/247) of patients receiving TECENTRIQ HYBREZA, including Grade 2 (0.8%) and Grade 1 (1.2%) adverse reactions. Pneumonitis led to withholding of TECENTRIQ HYBREZA in 1 patient
• Systemic corticosteroids were required in 40% (2/5) of patients with pneumonitis. Pneumonitis resolved in both patients. The single patient in whom TECENTRIQ HYBREZA was withheld for pneumonitis reinitiated TECENTRIQ HYBREZA after symptom improvement
• Immune-mediated pneumonitis occurred in 13% (29/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib, including Grade 3 (1.3%) and Grade 2 (7%) adverse reactions. Pneumonitis led to permanent discontinuation of intravenous atezolizumab in 2.6% and withholding of intravenous atezolizumab in 7.4% of patients. Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients. Of the 17 patients in whom intravenous atezolizumab was withheld for pneumonitis, 10 reinitiated intravenous atezolizumab after symptom improvement; of these, 50% had recurrence of pneumonitis

Immune-Mediated Colitis

• TECENTRIQ HYBREZA can cause immune-mediated colitis, including Grade 3 adverse reactions. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal 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

Immune-Mediated Hepatitis

• TECENTRIQ HYBREZA can cause immune-mediated hepatitis, including fatal adverse reactions
• Immune-mediated hepatitis occurred in 1.2% (3/247) of patients receiving TECENTRIQ HYBREZA, including Grade 1 (0.4%) and Grade 3 (0.8%) adverse reactions. Hepatitis led to withholding of TECENTRIQ HYBREZA in 0.4% of patients
• Systemic corticosteroids were required in 67% (2/3) of patients with hepatitis who received TECENTRIQ HYBREZA. Hepatitis resolved in 1 of the 3 patients
• Immune-mediated hepatitis occurred in 6.1% (14/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib, including Grade 4 (1.3%), Grade 3 (1.7%), and Grade 2 (1.3%) adverse reactions. Hepatitis led to permanent discontinuation of intravenous atezolizumab in 2.2% and withholding of intravenous atezolizumab in 1.7% of patients. Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the 4 patients in whom intravenous atezolizumab was withheld for hepatitis, 3 reinitiated intravenous atezolizumab after symptom improvement; of these, 33% had recurrence of hepatitis

Immune-Mediated Endocrinopathies
Adrenal Insufficiency

• TECENTRIQ HYBREZA can cause primary or secondary adrenal insufficiency, including Grade 3 adverse reactions. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated 
• Immune-mediated adrenal insufficiency occurred in 0.8% (2/247) of patients receiving TECENTRIQ HYBREZA, including Grade 2 (0.4%) adverse reactions. Adrenal insufficiency led to withholding of TECENTRIQ HYBREZA in both patients. Systemic corticosteroids were required in 50% (1/2) of patients with adrenal insufficiency who received TECENTRIQ HYBREZA; this patient remained on systemic corticosteroids

Hypophysitis

• TECENTRIQ HYBREZA can cause immune-mediated hypophysitis, including Grade 2 adverse reactions. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated
• Immune-mediated hypophysitis occurred in 0.4% (1/247) of patients receiving TECENTRIQ HYBREZA, including Grade 1 (0.4%) adverse reactions. Hypophysitis led to withholding of TECENTRIQ HYBREZA in this patient

Thyroid Disorders

• TECENTRIQ HYBREZA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated
• Immune-mediated thyroiditis occurred in 0.8% (2/247) of patients receiving TECENTRIQ HYBREZA, including Grade 2 (0.4%) adverse reactions. Thyroiditis resolved in 50% of patients
• Immune-mediated hyperthyroidism occurred in 2% (5/247) of patients receiving TECENTRIQ HYBREZA, including Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to withholding of TECENTRIQ HYBREZA in 0.8% of patients. Antithyroid therapy was required in 40% (2/5) of patients with hyperthyroidism who received TECENTRIQ HYBREZA. Of these 2 patients, 1 remained on antithyroid treatment. Of the 2 patients in whom TECENTRIQ HYBREZA was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ HYBREZA; this patient did not have recurrence of hyperthyroidism
• Hyperthyroidism occurred in 19% (43/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib, including Grade 3 (0.9%) and Grade 2 (7.8%) adverse reactions. Hyperthyroidism led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 10% of patients. Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom intravenous atezolizumab was withheld for hyperthyroidism, 18 patients reinitiated intravenous atezolizumab; of these, 28% had recurrence of hyperthyroidism
• TECENTRIQ HYBREZA can cause immune-mediated hypothyroidism, including Grade 4 adverse reactions. Immune-mediated hypothyroidism occurred in 10% (25/247) of patients receiving TECENTRIQ HYBREZA. Hormone replacement was required in 68% (17/25) of patients with hypothyroidism who received TECENTRIQ HYBREZA. Two patients with hypothyroidism remained on thyroid hormone replacement
• Hypothyroidism occurred in 11% (277/2421) of patients with NSCLC or SCLC receiving intravenous atezolizumab in combination with platinum-based chemotherapy, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (5.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of intravenous atezolizumab in 0.1% and withholding of intravenous atezolizumab in 1.6% of patients. Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 39 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 9 reinitiated intravenous atezolizumab after symptom improvement
• Hypothyroidism occurred in 26% (60/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib, including Grade 2 (9.1%) adverse reactions. Hypothyroidism led to withholding of intravenous atezolizumab in 2.6% of patients. Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 6 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 4 reinitiated intravenous atezolizumab after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid replacement

Type 1 Diabetes Mellitus, Which Can Present With Diabetic Ketoacidosis

• TECENTRIQ HYBREZA can cause type 1 diabetes mellitus, including Grade 3 adverse reactions and diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated

Immune-Mediated Nephritis With Renal Dysfunction

• TECENTRIQ HYBREZA can cause immune-mediated nephritis, including Grade 3 adverse reactions
• Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib, including Grade 2 (1.3%) adverse reactions. Nephritis led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 0.9% of patients. Systemic corticosteroids were required in 67% (2/3) of patients with nephritis. Nephritis resolved in all 3 of these patients. Of the 2 patients in whom intravenous atezolizumab was withheld for nephritis, both reinitiated intravenous atezolizumab after symptom improvement and neither had recurrence of nephritis

Immune-Mediated Dermatologic Adverse Reactions

• TECENTRIQ HYBREZA can cause immune-mediated rash or dermatitis, including Grade 3 and fatal adverse reactions. 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
• One fatal case of an immune-mediated dermatologic adverse reaction, due to TEN, occurred (0.4%, 1/247) in patients receiving TECENTRIQ HYBREZA

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 intravenous atezolizumab or were reported with the use of other PD-1/PD-L1 blocking antibodies
  • Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
  • Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy
  • Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss
  • Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis
  • Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic
  • Endocrine: Hypoparathyroidism
  • Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection
     

Infusion-Related Reactions

• TECENTRIQ HYBREZA can cause severe or life-threatening infusion-related reactions, including Grade 3 adverse reactions. Monitor for signs and symptoms of infusion-related reactions. Pause, slow the rate of, or permanently discontinue TECENTRIQ HYBREZA based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses

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 HYBREZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA 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 HYBREZA. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with TECENTRIQ HYBREZA and for at least 5 months after the last dose
   

Use in Specific Populations
Nursing Mothers

• There is no information regarding the presence of atezolizumab or hyaluronidase in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown
• Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ HYBREZA, advise female patients not to breastfeed while taking TECENTRIQ HYBREZA and for at least 5 months after the last dose

Fertility

• Based on animal studies, TECENTRIQ HYBREZA may impair fertility in females of reproductive potential while receiving treatment
   

Most Common Adverse Reactions
The most common adverse reactions (rate ≥10%) in patients who received TECENTRIQ HYBREZA were fatigue (19%), musculoskeletal pain (15%), cough (13%), dyspnea (12%), and decreased appetite (11%).

The most common adverse reactions (rate ≥20%) in patients who received intravenous atezolizumab alone were fatigue/asthenia (48%), decreased appetite (25%), nausea (24%), cough (22%), and dyspnea (22%).

The most common adverse reactions (rate ≥20%) in patients who received intravenous atezolizumab in combination with other antineoplastic drugs for NSCLC and SCLC were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%), and decreased appetite (27%).

The most common adverse reactions (rate ≥20%) in patients who received intravenous atezolizumab in combination with bevacizumab for HCC were hypertension (30%), fatigue/asthenia (26%), and proteinuria (20%).

The most common adverse reactions (rate ≥20%) in patients who received intravenous atezolizumab in combination with cobimetinib and vemurafenib for melanoma were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see full TECENTRIQ HYBREZA Prescribing Information for additional Important Safety Information.