ASCO Connection

July 2017

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Table 2. Adverse Reactions in *10% of Patients in UC Cohort Study 1 (cont'd) IMFINZI™ (durvalumab) injection, for intravenous use 3 IMFINZI N=182 Adverse Reaction All Grades (%) Grades 3 - 4 (%) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 5 24 4 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea/Exertional Dyspnea 13 2 Cough/Productive Cough 10 0 Skin and Subcutaneous Tissue Disorders Rash 6 11 1 1 Includes abdominal pain upper, abdominal pain lower and flank pain 2 Includes asthenia, lethargy, and malaise 3 Includes edema, localized edema, edema peripheral, lymphedema, peripheral swelling, scrotal edema, and scrotal swelling 4 Includes cystitis, candiduria and urosepsis 5 Includes back pain, musculoskeletal chest pain, musculoskeletal pain and discomfort, myalgia, and neck pain 6 Includes dermatitis, dermatitis acneiform, dermatitis psoriasiform, psoriasis, rash maculo-papular, rash pruritic, rash papular, rash pustular, skin toxicity, eczema, erythema, erythema multiforme, rash erythematous, acne, and lichen planus Table 3. Grade 3-4 Laboratory Abnormalities Worsened from Baseline Occurring in ≥1% Patients in UC Cohort Study 1 Laboratory Test Grade 3 - 4 % Hyponatremia 12 Lymphopenia 11 Anemia 8 Increased alkaline phosphatase 4 Hypermagnesemia 4 Hypercalcemia 3 Hyperglycemia 3 Increased AST 2 Increased ALT 1 Hyperbilirubinemia 1 Increased creatinine 1 Neutropenia 1 Hyperkalemia 1 Hypokalemia 1 Hypoalbuminemia 1 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to IMFINZI to the incidence of antibodies to other products may be misleading. Due to the limitations in assay performance, the incidence of antibody development in patients receiving IMFINZI has not been adequately determined. Of 1124 patients who were treated with IMFINZI 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADAs), 3.3% patients tested positive for treatment-emergent ADAs. The clinical significance of anti-durvalumab antibodies is unknown. USE IN SPECIFIC POPULATIONS Pregnancy Risk summary Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in the full Prescribing Information]. There are no data on the use of IMFINZI in pregnant women. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery resulted in increased premature delivery, fetal loss and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC). Administration of durvalumab resulted in pre- mature delivery, fetal loss (abortion and stillbirth) and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. Lactation Risk Summary There is no information regarding the presence of durvalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG1 is excreted in human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data). Because of the potential for adverse reactions in breastfed infants from durvalumab, advise a lactating woman not to breastfeed during treatment with IMFINZI and for at least 3 months after the last dose. Data In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC). Administration of durvalumab resulted in premature neonatal death. Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI, and for at least 3 months following the last dose of IMFINZI. Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients. Geriatric Use Of the 182 patients treated with IMFINZI, 112 patients were 65 years or older and 34 patients were 75 years or older. The overall response rate in patients 65 years or older was 15.2% (17/112) and was 11.8% (4/34) in patients 75 years or older. Grade 3 or 4 adverse reactions occurred in 38% (42/112) of patients 65 years or older and 35% (12/34) of patients 75 years or older. Study results in patients ≥ 65 years of age and particularly in those ≥ 75 years of age should be viewed with caution given the small number of patients. OVERDOSAGE There is no information on overdose with IMFINZI. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI, including: % Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1) in the full Prescribing Information]. % Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2) in the full Prescribing Information]. % Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [see Warnings and Precautions (5.3) in the full Prescribing Information]. % Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis or type 1 diabetes mellitus [see Warnings and Precautions (5.4) in the full Prescribing Information]. % Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash, nephritis, aseptic meningitis, thrombo- cytopenic purpura, myocarditis, hemolytic anemia, myositis, uveitis and keratitis [see Warnings and Precautions (5.5) in the full Prescribing Information]. % Infection: Advise patients to contact their healthcare provider immediately for infection [see Warnings and Precautions (5.6) in the full Prescribing Information]. % Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7) in the full Prescribing Information]. % Embryo-Fetal Toxicity: Advise females of reproductive potential that IMFINZI can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.3) in the full Prescribing Information]. • Lactation: Advise female patients not to breastfeed while taking IMFINZI and for at least 3 months after the last dose [see Warnings and Precautions (5.8) and Use in Specific Populations (8.2) in the full Prescribing Information]. Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: AstraZeneca UK Limited 1 Francis Crick Ave. Cambridge, England CB2 0AA US License No. 2043 IMFINZI is a trademark of AstraZeneca group of companies. ©AstraZeneca 2017 05/17 3301628 5/17

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