Durvalumab Immunotherapy (IMFINZI) For Metastatic Urothelial Carcinoma

Durvalumab (IMFINZI) is FDA approved immunotherapy that blocks PD-L1

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture.

Indication of Durvalumab (IMFINZI) 

IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody 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.

Warning & Precautions

Immune-Mediated Pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis. 

Immune-Mediated Hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation.

Immune-Mediated Colitis: Withhold for moderate and permanently discontinue for severe or life-threatening colitis. 

Immune-Mediated Endocrinopathies: Adrenal Insufficiency, Hypophysitis, or Type 1 Diabetes Mellitus: Withhold for moderate, severe or life-threatening.

Immune-Mediated Nephritis: Monitor for changes in renal function. Withhold for moderate and permanently discontinue for severe or life-threatening nephritis. 

Infection: Withhold for severe or life-threatening infection. 

Infusion-Related Reactions: Interrupt infusion or slow the rate of infusion for mild or moderate and permanently discontinue for severe or life-threatening infusion-related reactions. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. 

Adverse Reaction related to Durvalumab (Imfinzi): 

The most common adverse events (reported in ≥15% of patients) were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection. 

Formulation of IMFINZI (durvalumab) 

IMFINZI (durvalumab) Injection for intravenous use is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles. Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP. Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP.

Mechanism of Action of  Durvalumab: 

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 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. 

Pharmacokinetics: 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. 

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

Elimination: 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.  

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