Imfinzi

Overdose

There is no information on overdose with IMFINZI.

Contraindications

None.

Undesirable effects

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-Mediated Pneumonitis.
• Immune-Mediated Hepatitis.
• Immune-Mediated Colitis.
• Immune-Mediated Endocrinopathies.
• Other Immune-Mediated Adverse Reactions.
• Infection.
• Infusion-Related Reactions.

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. 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.

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

Table 3: Grade 3-4 Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 1% Patients in UC Cohort Study 1

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.

Therapeutic indications

IMFINZI is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

• have disease progression during or following platinum-containing chemotherapy.
• have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Pharmacodynamic properties

The exposure-response relationships for efficacy and safety are unknown.

Durvalumab is unlikely to prolong the QT/QTc interval.

Pharmacokinetic properties

The pharmacokinetics of durvalumab was studied in 1324 patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three or four weeks.

PK exposure increased more than dose-proportionally at doses less than 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses greater than or equal to 3 mg/kg. Steady state was achieved at approximately 16 weeks.

The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution was 5.6 (17%) L.

Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 22.9% (46.3%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.24 mL/h (37.3%); the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life was approximately 17 (23.2%) days.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. 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 in 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.

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 premature 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.

Qualitative and quantitative composition

Injection: 120 mg/2.4mL (50 mg/mL) and 500 mg/10mL (50 mg/mL) clear to opalescent, colorless to slightly yellow solution in a single-dose vial.

IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial either as:

500 mg/10 mL (NDC 0310-4611-50)
120 mg/2.4 mL (NDC 0310-4500-12)

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

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. For more information, call 1-800-236-9933 or go to www.IMFINZI.com. Revised: Apr 2017

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Immune-mediated pneumonitis or interstitial lung disease occurred in patients receiving IMFINZI. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and manage with treatment modifications and corticosteroids.

In Study 1 (n=182), one patient (0.5%) died from immune-mediated pneumonitis. In the combined safety database (n=1414), of patients treated with IMFINZI 10 mg/kg every 2 weeks, immune-mediated pneumonitis occurred in 32 (2.3%) patients including fatal pneumonitis in one (0.1%) patient and Grade 3-4 in six (0.4%) patients. The median time to onset was 55.5 days (range: 24-423 days). Seventeen  (1.2%) patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was interrupted in 12 patients and discontinued in five (0.4%) patients. Resolution occurred in 18 (1.3%) patients.

Immune-mediated hepatitis occurred in patients receiving IMFINZI. Monitor patients for abnormal liver tests each cycle during treatment with IMFINZI. Manage immune-mediated hepatitis with treatment modifications and corticosteroids.

In Study 1, one (0.5%) patient died from immune-mediated hepatitis. An additional two (1.1%) patients experienced immune-mediated hepatitis, including Grade 3 in one (0.5%) patient. In the combined safety database, immune-mediated hepatitis occurred in 16 (1.1%) patients including fatal hepatitis in one ( < 0.1%) patient and Grade 3 in nine (0.6%) patients. The median time to onset was 51.5 days (range: 15-312 days). Twelve (0.8%) of the 16 patients received high-dose corticosteroid treatment. One patient also received mycophenolate treatment. IMFINZI was interrupted in five (0.3%) patients and discontinued in three (0.2%) patients. Resolution occurred in nine (0.6%) patients. In the combined safety database, Grade 3 or 4 elevations in ALT occurred in 40/1342 (3.0%) of patients, AST in 58/1336 (4.3%), and total bilirubin in 37/1341 (2.8%) of patients.

Immune-mediated colitis or diarrhea occurred in patients receiving IMFINZI. Monitor patients for signs and symptoms of colitis or diarrhea and manage with treatment modifications, anti-diarrheal agents, and corticosteroids.

In Study 1, colitis or diarrhea occurred in 23 (12.6%) patients including Grade 3 or 4 diarrhea in two (1.1%) patients. No patients in Study 1 received systemic corticosteroids or immunosuppressants for diarrhea or colitis. In the combined safety database, immune-mediated colitis 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-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.

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.

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 hyperthyroidism 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.

Monitor patients for clinical signs and symptoms of adrenal insufficiency. Administer corticosteroids and hormone replacement as clinically indicated.

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.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate insulin for type 1 diabetes mellitus and manage patients with treatment modifications. New onset type 1 diabetes mellitus without an alternative etiology occurred in one patient ( < 0.1%) in the combined safety database.

Monitor for signs and symptoms of hypophysitis or hypopituitarism. Administer corticosteroids and hormone replacement as clinically indicated. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in one patient ( < 0.1%) in the combined safety database.

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.

Monitor for signs and symptoms of rash. 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.

Monitor patients for signs and symptoms of immune thrombocytopenic purpura. 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.

Monitor patients for abnormal renal function tests prior to and each cycle during treatment with IMFINZI and manage with treatment modifications and corticosteroids. 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.

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.

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.

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.

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.

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.

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.
• 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.
• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.
• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis or type 1 diabetes mellitus.
• Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash, nephritis, aseptic meningitis, thrombocytopenic purpura, myocarditis, hemolytic anemia, myositis, uveitis and keratitis.
• Infection: Advise patients to contact their healthcare provider immediately for infection.
• Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.
• 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. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI.
• Lactation: Advise female patients not to breastfeed while taking IMFINZI and for at least 3 months after the last dose.

The carcinogenic and genotoxic potential of durvalumab have not been evaluated.

Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.

Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. 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 in 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.

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 premature 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.

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.

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

Based on its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman. 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.

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

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.

Dosage (Posology) and method of administration

The recommended dose of IMFINZI is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

No dose reductions are recommended. Withhold and/or discontinue IMFINZI to manage adverse reactions as described in Table 1.

Table 1: Recommended Treatment Modifications for IMFINZI

• Visually inspect drug product for particulate matter and discoloration. IMFINZI is clear to opalescent, colorless to slightly yellow solution, free from visible particles. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
• Do not shake the vial.
• Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL.
• Discard partially used or empty vials of IMFINZI.

IMFINZI does not contain a preservative. Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from vial puncture to the start of the administration should not exceed:

• 24 hours in a refrigerator at 2°C to 8°C (36°F to 46°F)
• 4 hours at room temperature up to 25°C (77°F)

Do not freeze.

Do not shake.

• Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
• Do not co-administer other drugs through the same infusion line.

Interaction with other medicinal products and other forms of interaction

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-Mediated Pneumonitis.
• Immune-Mediated Hepatitis.
• Immune-Mediated Colitis.
• Immune-Mediated Endocrinopathies.
• Other Immune-Mediated Adverse Reactions.
• Infection.
• Infusion-Related Reactions.

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. 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.

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

Table 3: Grade 3-4 Laboratory Abnormalities Worsened from Baseline Occurring in ≥ 1% Patients in UC Cohort Study 1

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.

No information provided.