ASCO Connection

July 2017

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IMFINZI™ (durvalumab) injection, for intravenous use 2 or diarrhea occurred in 18 (1.3%) patients including Grade 4 in one (<0.1%) and Grade 3 in four (0.3%) patients. The median time to onset was 73 days (range: 13-345 days). Of these patients, one (<0.1%) had Grade 4 and four (0.3%) had Grade 3 immune-mediated colitis or diarrhea. Ten (0.7%) of the 18 patients received high-dose corticosteroid treatment. Two (0.1%) patients received non-steroidal immunosuppressants. IMFINZI was interrupted in five (0.4%) patients and discontinued in six (0.4%) patients. Resolution occurred in 11 (0.8%) patients. Immune-Mediated Endocrinopathies Immune-related thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/ hypopituitarism have occurred in patients receiving IMFINZI. Monitor patients for clinical signs and symptoms of endocrinopathies. Thyroid Disorders Monitor thyroid function prior to and periodically during treatment with IMFINZI. Asymptomatic patients with abnormal thyroid function tests can receive IMFINZI. Manage patients with abnormal thyroid function tests with hormone replacement (if indicated) and treatment modifications [see Dosage and Administration (2.2) in the full Prescribing Information]. In the Study 1, hypothyroidism or thyroiditis leading to hypothyroidism occurred in ten (5.5%) patients. All patients had Grade 1-2 hypothyroidism. The median time to first onset was 42 days (range: 15-239). Thyroid stimulating hormone (TSH) was elevated and above the patient's baseline in 25 (15.3%) of 163 patients with a follow-up measurement. In Study 1, hyperthyroidism or thyroiditis leading to hyperthyroidism occurred in nine (4.9%) patients. All patients had Grade 1-2 hyperthyroidism. The median time to first onset was 43 days (range: 14-71). Thyroid stimulating hormone (TSH) was decreased and below the patient's baseline in 26 (16%) of 163 patients with a follow-up measurement. In the combined safety database, hypothyroidism occurred in 136 (9.6%) patients, while hyper- thyroidism occurred in 81 (5.7%) patients. Thyroiditis occurred in ten patients, including Grade 3 in one patient who had a myocardial infarction. In nine patients with thyroiditis, transient hyperthyroidism preceded hypothyroidism. Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in five of these patients. Adrenal Insufficiency Monitor patients for clinical signs and symptoms of adrenal insufficiency. Administer cortico- steroids and hormone replacement as clinically indicated [see Dosage and Administration (2.2) in the full Prescribing Information]. In Study 1, adrenal insufficiency occurred in one (0.5%) patient (Grade 1). In the combined safety database, adrenal insufficiency occurred in 13 (0.9%) patients, including Grade 3 in two (0.1%) patients. Seven (0.5%) of these patients were treated with systemic corticosteroids. Type 1 Diabetes Mellitus Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate insulin for type 1 diabetes mellitus and manage patients with treatment modifications [see Dosage and Administration (2.2) in the full Prescribing Information]. New onset type 1 diabetes mellitus without an alternative etiology occurred in one patient (<0.1%) in the combined safety database. Hypophysitis Monitor for signs and symptoms of hypophysitis or hypopituitarism. Administer corticosteroids and hormone replacement as clinically indicated [see Dosage and Administration (2.2) in the full Prescribing Information]. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in one patient (<0.1%) in the combined safety database. Other Immune-Mediated Adverse Reactions IMFINZI has caused immune-mediated rash. Other immune-related adverse reactions, including aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, nephritis, and ocular inflammatory toxicity including uveitis and keratitis, have occurred in ≤1.0% of patients treated with IMFINZI. Immune-mediated Rash Monitor for signs and symptoms of rash [see Dosage and Administration (2.2) in the full Prescribing Information]. In Study 1, 20 (11.0%) of patients developed rash including Grade 3 rash in one (0.5%) patient. In the combined safety database, 220 (15.6%) patients developed rash and four (0.3%) patients developed vitiligo. Systemic corticosteroids were administered in 17 (1.2%) patients. The rash resolved in 133 (9.4%) patients. Immune Thrombocytopenic Purpura Monitor patients for signs and symptoms of immune thrombocytopenic purpura [see Dosage and Administration (2.2) in the full Prescribing Information]. In the combined safety database, immune thrombocytopenic purpura led to death in one (<0.1%) patient. The patient received high-dose corticosteroids, human immunoglobulin, and rituximab. Nephritis Monitor patients for abnormal renal function tests prior to and each cycle during treatment with IMFINZI and manage with treatment modifications and corticosteroids [see Dosage and Administration (2.2) in the full Prescribing Information]. In Study 1, one patient received systemic corticosteroids for immune-mediated nephritis. In the combined safety database, immune- mediated nephritis occurred in three (0.2%) patients including Grade 3 in two (0.1%) patients. All three patients received high-dose corticosteroids treatment. IMFINZI was discontinued in all three patients. Resolution occurred in all three patients. Infection Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis, occurred in patients receiving IMFINZI. Monitor patients for signs and symptoms of infection and treat with anti-infectives for suspected or confirmed infections. Withhold IMFINZI for ≥Grade 3 infection [see Dosage and Administration (2.2) and Adverse Reactions (6.1) in the full Prescribing Information]. In Study 1, infections occurred in 54 (29.7%) patients. Grade 3 or 4 infection occurred in eleven (6.0%) patients, while five (2.7%) patients were experiencing infection at the time of death. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in eight (4.4%) patients. In the combined safety database, infections occurred in 531 (37.6%) patients. Infusion-Related Reactions Severe infusion-related reactions have been reported in patients receiving IMFINZI. Monitor for signs and symptoms of an infusion-related reaction. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue IMFINZI in patients with Grade 3 or 4 infusion reactions [see Dosage and Administration (2.2) in the full Prescribing Information]. Infusion related reactions occurred in three (1.6%) patients in Study 1 and 26 (1.8%) patients in the combined safety database. There were five (0.4%) Grade 3 and no Grade 4 or 5 reactions. Four (0.3%) patients developed urticaria within 48 hours of dosing. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. % Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1) in the full Prescribing Information]. % Immune-Mediated Hepatitis [see Warnings and Precautions (5.2) in the full Prescribing Information]. % Immune-Mediated Colitis [see Warnings and Precautions (5.3) in the full Prescribing Information]. % Immune-Mediated Endocrinopathies [see Warnings and Precautions (5.4) in the full Prescribing Information]. % Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.5) in the full Prescribing Information]. % Infection [see Warnings and Precautions (5.6) in the full Prescribing Information]. % Infusion-Related Reactions [see Warnings and Precautions (5.7) in the full Prescribing Information]. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in Table 2 reflect exposure to IMFINZI in 182 patients with locally advanced or metastatic urothelial carcinoma in Study 1 whose disease has progressed during or after one standard platinum-based regimen. Patients received 10 mg/kg IMFINZI via intravenous infusion every 2 weeks [see Clinical Studies (14.1) in the full Prescribing Information]. The median duration of exposure was 10.2 weeks (range: 0.14, 52.4). Thirty-one percent (31%) of patients had a drug delay or interruption for an adverse reaction. The most common (>2%) were liver injury (4.9%), urinary tract infection (3.3%), acute kidney injury (3.3%), and musculoskeletal pain (2.7%). The most common adverse reactions (≥15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%) and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions (≥3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration. Eight patients (4.4%) who were treated with IMFINZI experienced Grade 5 adverse events of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. IMFINZI was discontinued for adverse reactions in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (>2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, pyrexia/tumor associated fever (2.7% each). Immune-mediated adverse reactions requiring systemic corticosteroids or hormone replacement therapy occurred in 8.2% (15/182) patients, including 5.5% (10/182) patients who required systemic corticosteroid therapy and 2.7% (5/182) patients who required only hormone replacement therapy. Seven patients (3.8%) received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5) in the full Prescribing Information]. Table 2 summarizes the adverse reactions that occurred in ≥10% of patients, while Table 3 summarizes the Grade 3 - 4 selected laboratory abnormalities that occurred in ≥1% of patients treated with IMFINZI in Study 1. Table 2. Adverse Reactions in ≥10% of Patients in UC Cohort Study 1 IMFINZI N=182 Adverse Reaction All Grades (%) Grades 3 - 4 (%) All Adverse Reactions 96 43 Gastrointestinal Disorders Constipation 21 1 Nausea 16 2 Abdominal pain 1 14 3 Diarrhea/Colitis 13 1 General Disorders and Administration Fatigue 2 39 6 Peripheral edema 3 15 2 Pyrexia/Tumor associated fever 14 1 Infections Urinary tract infection 4 15 4 Metabolism and Nutrition Disorders Decreased appetite/Hypophagia 19 1

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