Durvalumab

Durvalumab
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Overview

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is FDA approved for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Common adverse reactions include fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection, or cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition 1

• Dosing Information

• (Dosage)

Condition 2

• Dosing Information

• (Dosage)

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Condition 2

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Non–Guideline-Supported Use

Condition 1

• Dosing Information

• (Dosage)

Condition 2

• Dosing Information

• (Dosage)

Condition 3

• Dosing Information

• (Dosage)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

• Dosing Information

• (Dosage)

Condition 2

• Dosing Information

• (Dosage)

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Condition 2

• Developed by: (Organisation)

• Class of Recommendation: (Class) (Link)

• Strength of Evidence: (Category A/B/C) (Link)

• Dosing Information/Recommendation

• (Dosage)

Non–Guideline-Supported Use

Condition 1

• Dosing Information

• (Dosage)

Condition 2

• Dosing Information

• (Dosage)

Condition 3

• Dosing Information

• (Dosage)

Contraindications

CONTRAINDICATIONS

Warnings

Conidition 1

(Description)

Conidition 2

(Description)

Conidition 3

(Description)

Adverse Reactions

Clinical Trials Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

Condition 2

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

Postmarketing Experience

(Description)

Drug Interactions

• Drug 1
• Drug 2
• Drug 3
• Drug 4
• Drug 5

Drug 1

(Description)

Drug 2

(Description)

Drug 3

(Description)

Drug 4

(Description)

Drug 5

(Description)

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): (Description)
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Durvalumab in women who are pregnant.

Labor and Delivery

(Description)

Nursing Mothers

(Description)g

Pediatric Use

(Description)

Geriatic Use

(Description)

Gender

(Description)

Race

(Description)

Renal Impairment

(Description)

Hepatic Impairment

(Description)

Females of Reproductive Potential and Males

(Description)

Immunocompromised Patients

(Description)

Others

(Description)

Administration and Monitoring

Administration

(Oral/Intravenous/etc)

Monitoring

Condition 1

(Description regarding monitoring, from Warnings section)

Condition 2

(Description regarding monitoring, from Warnings section)

Condition 3

(Description regarding monitoring, from Warnings section)

IV Compatibility

There is limited information regarding the compatibility of Durvalumab and IV administrations.

Overdosage

Acute Overdose

Signs and Symptoms

(Description)

Management

(Description)

Chronic Overdose

Signs and Symptoms

(Description)

Management

(Description)

Pharmacology

Durvalumab
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Chemical data
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Mechanism of Action

• Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.
• Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC).
• PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

Structure

(Description with picture)

Pharmacodynamics

(Description)

Pharmacokinetics

• The pharmacokinetics of durvalumab was studied in 1902 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 < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ to 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks.

Distribution

• The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution was 5.6 (18%) L.

Elimination

• Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.2 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 18 (24%) days.

Specific Populations

• Age (19–96 years), body weight (34-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST), or ECOG/WHO performance status had no clinically significant effect on the pharmacokinetics of durvalumab.
• The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin > 1.5 to 3x ULN and any AST) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• 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.

Animal Toxicology and/or Pharmacology

• In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

Clinical Studies

Urothelial Carcinoma

• The efficacy of durvalumab was evaluated in the urothelial carcinoma cohort of Study 1108 (NCT01693562), a multicenter, multi-cohort, open-label clinical trial. In Study 1108, 182 patients with locally advanced or metastatic urothelial carcinoma were enrolled. Patients had progressed while on or after a platinum-based therapy, including those who progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant setting. These patients had initiated durvalumab at least 13 weeks prior to the data cut-off date. The trial excluded patients with a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg per day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection. All patients received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or disease progression. Tumor assessments were performed at Weeks 6, 12 and 16, then every 8 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR), and duration of response (DoR).
• The median age was 67 years (range: 34 to 88), 72% were male, 64% were White. Sixty-six percent (66%) of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Lymph node only metastasis were present in 13% of patients. Sixty-six percent (66%) of patients had ECOG score of 1 and 41% of patients had a baseline creatinine clearance < 60 mL/min. The Bellmunt risk score (which includes ECOG score, baseline hemoglobin, and liver metastases) was 0 in 23%, 1 in 38%, 2 in 29%, and 3 in 9% of patients. Twenty percent (20%) of patients had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy. Seventy percent (70%) of patients received prior cisplatin, 30% prior carboplatin and 35% received ≥ 2 prior lines of systemic therapy.
• Tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and immune cells (IC) at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Of the 182 patients, 52% were classified as PD-L1 high (if ICs involve > 1% of the tumor area, TC ≥ 25% or IC ≥ 25%; if ICs involve ≤ 1% of the tumor area, TC ≥ 25% or IC = 100%), 40% as PD-L1 low/negative (did not meet criterion for PD-L1 high), and samples for 8% were not evaluable.
• Table 6 summarizes the results in the urothelial carcinoma cohort of Study 1108. The median follow-up time was 5.6 months. In 37 patients who had received only neoadjuvant or adjuvant therapy prior to study entry, 24% responded.
• Among the total 31 responding patients, 45% had ongoing responses of 6 months or longer and 16% had ongoing responses of 12 months or longer.

This image is provided by the National Library of Medicine.

Non-Small Cell Lung Cancer (NSCLC)

• The efficacy of durvalumab was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs. ≥ 65 years) and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive durvalumab 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST 1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST 1.1 and overall survival (OS). Additional efficacy outcome measures included ORR assessed by BICR.
• A total of 713 patients were randomized: 476 patients to the durvalumab arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy and 2% switched between cisplatin and carboplatin).
• The pre-specified interim PFS analysis based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to durvalumab compared to placebo. Results are presented in Table 7 and Figure 1. OS data were not mature at the time of the interim PFS analysis.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

How Supplied

• 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)

Storage

• 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.

Images

Drug Images

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Package and Label Display Panel

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

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Patient Counseling Information

• Advise the patient to read the FDA-approved patient labeling.
• Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of durvalumab, 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, type 1 diabetes mellitus, or hypophysitis.
• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
• Dermatological Reactions: Advise patients to contact their healthcare provider immediately signs or symptoms of severe dermatological reactions.
• Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of 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 durvalumab 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 durvalumab.
• Lactation: Advise female patients not to breastfeed while taking durvalumab and for at least 3 months after the last dose.

This image is provided by the National Library of Medicine.

Precautions with Alcohol

Alcohol-Durvalumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Imfinzi

Look-Alike Drug Names

There is limited information regarding Durvalumab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.