ASCO Connection

July 2017

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6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Immune-Related Pneumonitis [see Warnings and Precautions (5.1)] • Immune-Related Hepatitis [see Warnings and Precautions (5.2)] • Immune-Related Colitis [see Warnings and Precautions (5.3)] • Immune-Related Endocrinopathies [see Warnings and Precautions (5.4)] • Other Immune-Related Adverse Reactions [see Warnings and Precautions (5.5)] • Infection [see Warnings and Precautions (5.6)] • Infusion-Related Reactions [see Warnings and Precautions (5.7)] 6.1 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. Urothelial Carcinoma Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma The safety of TECENTRIQ was evaluated in Study 4, a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients received 1200 mg of TECENTRIQ intravenously every 3 weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15.0 weeks (range 0, 87 weeks). The most common adverse reactions (≥ 20%) were fatigue (52%), decreased appetite ( 24%), diarrhea (24%), and nausea (22%). The most common Grade 3–4 adverse reactions (≥ 2%) were fatigue, urinary tract infection, anemia, diarrhea, blood creatinine increase, intestinal obstruction, ALT increase, hyponatremia, decreased appetite, sepsis, back/neck pain, renal failure, and hypotension. Five patients (4.2%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. One additional patient (0.8%) was experiencing herpetic meningoencephalitis and disease progression at the time of death. TECENTRIQ was discontinued for adverse reactions in 4.2% (5/119) of patients. The adverse reactions leading to discontinuation were diarrhea/colitis (1.7%), fatigue (0.8%), hypersensitivity (0.8%), and dyspnea (0.8%). Adverse reactions leading to interruption of TECENTRIQ occurred in 35% of patients, the most common (≥ 1%) were intestinal obstruction, fatigue, diarrhea, urinary tract infection, infusion related reaction, cough, abdominal pain, peripheral edema, pyrexia, respiratory tract infection, upper respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, pruritus, and venous thromboembolism. Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (≥ 2%) were diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure. Immune-related adverse reactions requiring systemic corticosteroids or hormone replacement therapy occurred in 19.3% (23/119) patients, including 12.6% (15/119) patients who required systemic corticosteroid therapy and 6.7% (8/119) patients who required only hormone replacement therapy. Six patients (5.0%) received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)]. Table 1 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 2 summarizes Grade 3–4 selected laboratory abnormalities that occurred in ≥ 1% of patients treated with TECENTRIQ in Study 4. Table 1: All Grade Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in Study 4 TECENTRIQ N = 119 Adverse Reaction All Grades (%) Grades 3–4 (%) General Disorders Fatigue a 52 8 Peripheral edema b 17 2 Pyrexia 14 0.8 Gastrointestinal Disorders Diarrhea c 24 5 Nausea 22 2 Vomiting 16 0.8 Constipation 15 2 Abdominal pain d 15 0.8 Metabolism and Nutrition Disorders Decreased appetite e 24 3 Musculoskeletal and Connective Tissue Disorders Back/Neck pain 18 3 Arthralgia 13 0 Skin and Subcutaneous Tissue Disorders Pruritus 18 0.8 Rash f 17 0.8 Infections Urinary tract infection g 17 5 Respiratory, Thoracic, and Mediastinal Disorders Cough h 14 0 Dyspnea i 12 0 a Includes fatigue, asthenia, lethargy, and malaise b Includes edema peripheral, scrotal edema, lymphedema, and edema c Includes diarrhea, colitis, frequent bowel movements, autoimmune colitis d Includes abdominal pain, upper abdominal pain, lower abdominal pain, and flank pain e Includes decreased appetite and early satiety f Includes rash, dermatitis, dermatitis acneiform, rash maculo-papular, rash erythematous, rash pruritic, rash macular, and rash papular g Includes urinary tract infection, urinary tract infection bacterial, cystitis, and urosepsis h Includes cough and productive cough i Includes dyspnea and exertional dyspnea Table 2: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 4 in ≥ 1% of Patients Laboratory Test Grades 3–4 (%) Hyponatremia 15 Hyperglycemia 10 Lymphopenia 9 Anemia 7 Table 2: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 4 in ≥ 1% of Patients (continued) Laboratory Test Grades 3–4 (%) Increased Alkaline phosphatase 7 Increased Creatinine 5 Hypophosphatemia 4 Increased ALT 4 Increased AST 4 Hyperkalemia 3 Hypermagnesemia 3 Hyperbilirubinemia 3 Previously Treated Patients with Locally Advanced or Metastatic Urothelial Carcinoma The safety of TECENTRIQ was evaluated in Study 1, a multicenter, open-label, single-arm trial that included 310 patients in a single arm trial with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received 1200 mg of TECENTRIQ intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (range: 0.1, 46 weeks). The most common adverse reactions (≥ 20%) were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most common Grade 3–4 adverse reactions (≥ 2%) were urinary tract infection, anemia, fatigue, dehydration, intestinal obstruction, urinary obstruction, hematuria, dyspnea, acute kidney injury, abdominal pain, venous thromboembolism, sepsis, and pneumonia. Three patients (1.0%) who were treated with TECENTRIQ experienced one of the following events which led to death: sepsis, pneumonitis, or intestinal obstruction. TECENTRIQ was discontinued for adverse reactions in 3.2% (10/310) of the 310 patients. Sepsis led to discontinuation in 0.6% (2/310) of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state. Immune-related adverse reactions requiring systemic corticosteroids or hormone replacement therapy occurred in 11.0% (34/310) patients, including 8.4% (26/310) patients who required systemic corticosteroid therapy and 2.6% (8/310) patients who required only hormone replacement therapy. Eighteen patients (5.8%) received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)]. Table 3 summarizes the adverse reactions that occurred in ≥ 10% of patients while Table 4 summarizes Grade 3–4 selected laboratory abnormalities that occurred in ≥ 1% of patients treated with TECENTRIQ in Study 1. Table 3: All Grade Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in Study 1 TECENTRIQ N=310 Adverse Reaction All Grades (%) Grades 3–4 (%) Gastrointestinal Disorders Nausea 25 2 Constipation 21 0.3 Diarrhea 18 1 Abdominal pain 17 4 Vomiting 17 1 General Disorders Fatigue 52 6 Pyrexia 21 1 Peripheral edema 18 1 Infections Urinary tract infection 22 9 Metabolism and Nutrition Disorders Decreased appetite 26 1 Musculoskeletal and Connective Tissue Disorders Back/Neck pain 15 2 Arthralgia 14 1 Renal and urinary disorders Hematuria 14 3 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 16 4 Cough 14 0.3 Skin and Subcutaneous Tissue Disorders Rash 15 0.3 Pruritus 13 0.3 Table 4: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 1 in ≥ 1% of Patients Laboratory Test Grades 3–4 (%) Lymphopenia 10 Hyponatremia 10 Anemia 8 Hyperglycemia 5 Increased Alkaline phosphatase 4 Increased Creatinine 3 Increased ALT 2 Increased AST 2 Hypoalbuminemia 1

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