This document discusses urothelial carcinoma (UC), a type of bladder cancer. It provides statistics on UC in the US and India. Risk factors like smoking and occupational exposures are discussed. The drug Durvalumab is approved for treating advanced or metastatic UC. It works by blocking the PD-L1 protein, which inhibits the immune system's ability to fight cancer. Details are given on Durvalumab's mechanism of action, pharmacokinetics, dosage administration, storage, and common adverse reactions.

1. By: Dr.Shreya Lal
Junior Resident (Academic)
Guide : Dr. B.P.Loc
Associate professor,
Department of pharmacology

2. Introduction
 Urothelial carcinoma (UCC), is a type of cancer that
typically occurs in the urinary system, urothelium to be
more specific. Studies of urothelial bladder cancer have
identified multiple risk factors, the most important of
which are cigarette smoking and various occupational
exposures.
 Bladder cancer is the ninth most common cancer in the
world, with 430,000 new cases diagnosed in 2012. In the
United States in 2016, it is estimated that there will be
76,960 new diagnoses of bladder cancer, with
approximately 16,390 deaths.

3. Urothelial carcinoma – US statistics at a
glance

4. IND vs USA
•The Indian figures
differ from the
Western literature in
two aspects.
•First, the difference
in the incidence of
smoking among
Indian males and
females is much
more prominent
(74% vs. 22%
respectively) than in
the West.
•Second, the
incidence of bladder
cancer per se is much
more predominant
in Indian males. This
difference is lesser in
the Western series.

5.  Biswas et al published a retrospective epidemiological study of
88 patients diagnosed with carcinoma bladder at the
Departments of Urosurgery and Pathology from CNMC and H,
Kolkata, from December 2007 to November 2009.
# The median age of bladder cancer was 65–70 years.
# There was a male preponderance (86.4% male vs. 13.6%
female).
# Tobacco smoking (75% of the cases) revealed a strong
relationship with bladder cancer and that was quantity- and
duration-dependent.
# The authors observed maximum number (50%) of bladder
cancers among laborer and industry workers including
employees of leather and textile factories, hair-dye handlers
(barber), and shoe-makers.

6. DURVALUMAB
(Imfinzi)
Durvalumab is a human immunoglobulin G1 kappa
monoclonal antibody, approved by US-FDA in May 2017 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.

7. The role of programmed cell death ligand-1 (PD-L1)
• Expression of programmed cell death ligand-1 (PD-L1) can
be induced by inflammatory signals (eg, IFN-gamma) and
can be expressed on both tumor cells and tumor-associated
immune cells in tumor microenvironment.
• PD-L1 blocks T-cell function and activation through
interaction with PD-1 and CD80. By binding to its
receptors, PD-L1 reduces cytotoxic T-cell activity,
proliferation, and cytokine production.

8. PD-L1 may be expressed on both antigen-
presenting immune cells and tumor cells within
the tumor microenvironment :
 Antigen Presenting Cell – T Cell: Inhibiting the PD-L1 to
CD80 (B7.1) and PD-L1 to PD-1 interactions may help
restore T-cell activity.
 T-Cell – Tumor Cell: Inhibiting the PD-L1 to CD80 (B7.1)
and PD-L1 to PD-1 interactions may help restore antitumor
immune response.

10. Mechanism of action
 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.

12. Pharmacokinetics
 The pharmacokinetics of durvalumab was studied in 1324
patients with doses ranging from 0.1 mg/kg to 20 mg/kg
administered once every two, three or four weeks.
 Steady state was achieved at approximately 16 weeks.
 The steady state volume of distribution was 5.6 L .
 The terminal half-life is approximately 17 days.
 The effect of severe renal impairment or moderate hepatic
impairment or severe hepatic impairment on the
pharmacokinetics of durvalumab is unknown.

13. Pharmacodynamics
The exposure–response relationships for efficacy and safety
is unknown.
Dosage and administration
• The recommended dose of durvalumab is 10 mg/kg
administered as an intravenous infusion over 60 minutes
every 2 weeks until disease progression or unacceptable
toxicity.

14.  No dose reductions are recommended. The drug is
withhold and/or discontinued to manage adverse
reactions.
Preparation :
 Visually inspect the drug to detect any changes in its
appearance from normal state.
 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 or 5% dextrose.
 Mix the diluted solution by gentle inversion.
 The final concentration should be between 1 mg/mL and
15 mg/mL.

15. Storage of infusion solution
• Imfinzi does not contain preservative. So once prepared,
infusion solution should be administered immediately.
• Even if it 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.
> 4 hours at room temperature up to 25’C.
Administration
• The infusion solution is administered intravenously over 60
minutes through an intravenous line containing a sterile,
low protein binding 0.2 or 0.22 micron in-line filter.

16. Dosage forms and strength
Two strengths are available in
the form of injection :
(a) 120mg/2.4mL
(b) 500mg/10mL
The drug is clear to
opalescent, colorless to
slightly yellow solution in
a single dose vial.

17. Contraindications
None.
Adverse Reactions
The most common adverse reactions (≥15%) were
• fatigue (39%)
• musculoskeletal pain (24%)
• constipation (21%)
• decreased appetite (19%)
• nausea (16%)
• peripheral edema (15%)
• urinary tract infection (15%).

18. 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.

20. Over dosage
There is no information on over dosage of durvalumab.
Description
• Durvalumab is a human immunoglobulin G1 kappa (IgG1k)
monoclonal antibody that blocks the interaction of
programmed cell death ligand 1 (PD-L1) with the PD-1 and
CD80 molecules.
• Durvalumab is produced by recombinant DNA technology
in Chinese hamster ovary (CHO) cell suspension culture.