This presentation provides pharmacists and other HCPs with the tools to effectively prescribe and monitor the use of a newly FDA-approved bladder cancer medication, Enfortumab Vedotin. Additionally, we examine a patient case that further elucidates Enfortumab's place in therapy.

1. Enfortumab
Drug
Monograph &
Patient Case
Jay Butani – Pharm D. Candidate 20’

2. Patient Case
• AB is a 53 yo male
• HPI: Stage T3, N0, M1 (bone, lung, pleura,
brain) metastatic high-grade urothelial
carcinoma of bladder admitted for pain
crises
• SH: Non-smoker, heavy EtOH up until 2014
• FH: Father had gout. Mental Illness,
Diabetes, Hyperlipidemia (neg h/x)
• PMH: Agoraphobia, Bipolar 2 disorder,
major depressive episode
• Allergies: Tamsulosin (itching), IBU
• Ht: 170.2 cm (67”) Wt: 66.5 kg (146 lbs),
BSA: 1.77 m^2, BMI 22.76 kg/m^2
• CrCl: 73.7 mL/min

3. Imaging:
• CT Urogram from ER visit on 2/23/18 showed presence left lateral posterior
bladder wall mass concerning for neoplasm
• MRI on 04/25/18 revealed significant increase in tumor size
• CT on 10/20/18 showed a rounded area of consolidation in right lower lobe
w/ swirled appearance of the adjacent vasculature and adjacent pleural
disease may be due to developing rounded atelectasis
• 5/22/19 MRI findings: Two metastases in supratentorial brain and left
cerebellar metastases observed
• On 12/25/19, extensive pleural/chest wall-based masses w/ bony
destructive changes of the right-sided rib cage discovered. Additional CT
showed metastasis to ribs
• CT imaging 01/02/20 shows destruction of ribs due to his lung cancer with
right lung metasisis and no obvious pneumonia w/ very small effusion, no
PE

4. Oncological Treatment Overview
• AB underwent 1st TURBT on 2/28/18, L side of bladder & left hemi trigone was debulked w/o
complete tumor resection, residual tumor found to go beyond muscle layer
• Pathology from procedure to resect tumor & insert stent showed high grade invasive transitional
cell carcinoma w/ squamous differentiation
• Underwent definitive RT and was started on Cisplatin & Paclitaxel in 06/18 for Four 7D cycles
• AB seen again in ER for SOB/CP on 3/21/19  pleural effusion found & on thoracentesis
contained malignant cells of urothelial origin
• Began 2nd line t/x w/ Keytruda monotherapy 200 mg in March 2018 (21D 3C) but repeat scans on
5/10/19 showed significant progression w/ new developing lung nodules & worsening pleural
disease
• MVAC initiated on 5/13/2019 (MTX, Vinblastine, Adriamycin, & Cisplatin) for Eight 28D cycles
• Furthermore AB was continued on Gemcitabine/Cisplatin therapy received but AB developed
cytopenias and renal dysf/x that precluded further platinum-based chemo  started on HD
C1D1 Keytruda 200 mg (12/4/2019)
• Keytruda held (2nd C to be started on 12/26), Enfortumab approved for metastatic urothelial
cancer Dec 18, 2019

5. Chemotherapy Regimen
NCCN Standard of Care
• Cisplatin Induction w/ Paclitaxel
• Advanced or Metastatic
• Paclitaxel: IV: 150 mg/m2 every 2 weeks (in
combination with gemcitabine)
• Cisplatin: IV: 75 mg/m2 day 2
• Pembrolizumab Monotherapy
• Locally advanced or Metastatic
• IV: 200 mg once every 3 weeks until disease
progression, unacceptable toxicity, or (in
patients without disease progression) for up
to 24 months
• Dose-dense MVAC
• Methotrexate: IV: 30 mg/m2 day 1, [total
dose/cycle = 30 mg/m2]
• Vinblastine: IV: 3 mg/m2 day 2, [total dose/cycle
= 3 mg/m2]
• Doxorubicin: IV: 30 mg/m2 day 2, [total
dose/cycle = 30 mg/m2]
• Cisplatin: IV: 70 mg/m2 day 2, [total dose/cycle
= 70 mg/m2]
• Gemcitabine/Cisplatin
• Advanced or metastatic
• Cisplatin 70 mg/m2 on day 2 every 28 days
(in combination with gemcitabine) for up to
6 cycles
• Gemccitabine IV: 1,000 mg/m2 over 30 to
60 minutes days 1, 8, and 15; repeat cycle
every 28 days
SBCH Regimen
Date (mo/yr)
& Cycle Start
Regimen Dose/Administration
6/18 C1 Cisplatin +
Paclitaxel (7D
4C)
Cisplatin (PLATINOL) 119 mg in NS 500 mL, chemo infusion
Paclitaxel (TAXOL) : 260 mg in NS 500mL, chemo infusion
Initial w/ RT followed by maximal resection of the bladder mass
Pleural effusion found and on Thoracentesis had malignant cells of urothethial
orgini
3/19 C1 Pembrolizumab
Monotherapy
(21D 3C)
Pembrolizumab (KEYTRUDA) 200 mg in NS 100 mL, chemo infusion
• 200 mg (3 mg/kg × 65 kg), IV
• Administer over 30 mins, ONCE
New lung nodules found bilaterally as well as worsening pleural disease
5/19 C1 MVAC (28D 8C) • Methotrexate Sodium 53 mg in NS 100mL chemo infusion
• Doxorubicin (ADRIAMYCIN) chemo injection 52.5 mg
• Vinblastine (VELBAN) injection SOLN 5.2 mg
• Cisplatin (PLATINOL) 122.5 mg in NS 1,000 mL chemo infusion
CT of chest, abd, and pelvis showed decrease size and number of lung nodules
10/19 C1 Cisplatin +
Gemcitabine
(28D 3C)
Cisplatin (PLATINOL) 119 mg in NS 500 mL, chemo infusion
• Stopped after 1st dose on 10/31/19
Gemcitabine (GEMZAR) 1,360 mg in NS 250 mL chemo infusion
Pt was having increasing renal dysfunction and cytopenia
12/19 C1 Pembrolizumab
Monotherapy
(21D 1C)
Pembrolizumab (KEYTRUDA) 200 mg in NS 100 mL, chemo infusion
• 200 mg (3 mg/kg × 65 kg), IV
• Administer over 30 mins, ONCE

6. Enfortumab Vedotin
• Brand Name: Padcev®
• Pharm category: Anti Nectin-4
Antibody Drug Conjugate
• Use: Urothelial cancer, locally
advanced or metastatic: Treatment
in adults who have previously
received a PDL-1 AND a platinum-
containing chemotherapy in the
neoadjuvant/adjuvant, locally
advanced or metastatic setting

7. Mechanism of Action
• Enfortumab vedotin is an antibody
drug conjugate (ADC) directed at
Nectin-4
• Nectin-4 is highly expressed in
urothelial carcinoma as well as
breast, gastric, & lung cancers. It
contains an IgG1 anti-Nectin-4
antibody conjugated to a
microtubule-disrupting agent,
monomethyl auristatin E (MMAE).
• MMAE is attached to the antibody
via a protease cleavable linker. The
ADC binds to Nectin-4 expressing
cells to form a complex which is
internalized within the cell.
• Released MMAE binds to the
tubules and disrupts the cellular
microtubule network, inducing cell
cycle arrest and apoptosis of
Nectin-4 expressing cells

8. Place in
Therapy
• NCCN. The NCCN Clinical Practical Guidelines in Oncology Bladder Cancer (Version 3.2019).
2019; http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed 10 January
2019.

9. EV-201 Phase II
Study
Rosenberg JE, Sridhar SS, Zhang J, et al.
Updated results from the enfortumab
vedotin phase 1 (EV-101) study in
patients with metastatic urothelial
cancer (mUC). American Society of
Clinical Oncology; 2018.
• Median Time to
Response: 1.84 months
(1.2-9.2 mo range)
• Median Duration of
Response: 7.6 months
(0.95-11.301 mo range)

10. Rosenberg JE, Sridhar SS, Zhang J, et al. Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic
urothelial cancer (mUC). American Society of Clinical Oncology; 2018.

11. Dosing (Adult): Urothelial
cancer*: 1.25 mg/kg (max: 125
mg) on D1, 8, & 15, q28 days
until disease progression or
unacceptable toxicity
• Renal impairment: No
dose adj required
• Hepatic impairment:
• Mild (Child-Pugh class
A): No dosage
adjustment necessary
• Moderate to severe
impairment (Child-
Pugh classes B & C):
Avoid enfortumab
vedotin use
Recommended Enfortumab Vedotin Dosage Reduction
Levels
Initial (usual) dose
1.25 mg/kg up to a
maximum of 125 mg
First dose reduction level
1 mg/kg up to a
maximum of 100 mg
Second dose reduction level
0.75 mg/kg up to a
maximum of 75 mg
Third dosage reduction level
0.5 mg/kg up to a
maximum of 50 mg

12. Enfortumab Vedotin Dosage Adjustment for Toxicities
Toxicity Severity Enfortumab Vedotin Dose Modification
Hematologic Toxicities
Grade 3, or grade 2
thrombocytopenia
Hold Enfortumab until ≤ grade 1, then resume treatment
at the same dose level or consider dose reduction by 1
dose level.
Grade 4
Hold Enfortumab until ≤ grade 1, then reduce dose by 1
dose level or DC treatment.
Hyperglycemia Blood glucose >250 mg/dL
Hold Enfortumab until ↑ blood glucose has improved to
≤250 mg/dL, then resume t/x at the same dose level.
Peripheral Neuropathy
Grade 2
Hold Enfortumab until ≤ grade 1, then resume t/x at the
same dose level (if first occurrence). For a recurrence,
withhold until ≤ grade 1, then resume t/x with the dose
reduced by one dose level.
Grade 3 or higher Permanently DC Enfortumab
Dermatologic Toxicity
Grade 3 (severe)
Hold Enfortumab until ≤ grade 1, then resume t/x at the
same dose level or consider dose reduction by 1 dose
level.
Grade 4 or recurrent grade 3 Permanently DC Enfortumab
Other nonhematologic toxicity
Grade 3
Hold Enfortumab until ≤ grade 1, then resume t/x at the
same dose level or consider dose reduction by 1 dose
level.
Grade 4 Permanently DC Enfortumab

13. Administration
• IV Administration: Infuse over 30 min. Do not admin as an IV push or bolus.
• Do not mix with or administer with other medications.
• May be an irritant. Ensure adequate venous access prior to infusion.
Monitor infusion site during admin for possible extravasation. If
extravasation occurs  stop infusion and monitor for adverse reactions.
Hazardous Drugs Handling Considerations
• This medication is not on the NIOSH (2016) list; however, it may meet the
criteria for a hazardous drug. Enfortumab vedotin is a cytotoxic drug (per
product labeling) and may cause teratogenicity and reproductive toxicity

14. Storage/Stability
• Store intact vials at 2ºC to 8ºC (36ºF to 46ºF); do not freeze.
• Store in the original carton; do not expose vials to direct sunlight.
• Do not shake.
• If not used immediately, reconstituted vials may be stored for up to 4 hours at
2°C to 8°C (36°F to 46°F); do not freeze.
• Discard unused vials with reconstituted solution beyond the recommended
storage time.
• Do not expose reconstituted vials or solutions diluted for infusion to direct
sunlight.
• Solutions diluted for infusion should be used immediately, however, they may
be stored at 2°C to 8°C (36°F to 46°F) for no longer than 8 hours; do not freeze.
Contraindications:
• There are no contraindications listed in the manufacturer's labeling.

15. Adverse Reactions
>10% - Central nervous system: Fatigue (56%), peripheral neuropathy (49% to 56%)
- Dermatologic: Skin rash (52% to 54%; including symmetrical drug-related intertriginous and flexural
exanthema), alopecia (50%), pruritus (26% to 30%), maculopapular rash (26%), xeroderma (26%)
- Endocrine & metabolic: ↓ serum phosphate (34%), ↓ serum potassium (19%)
- Gastrointestinal: ↓ appetite (52%), nausea (45%), diarrhea (42%), dysgeusia (42%), vomiting (18%), ↑ serum
lipase (14%)
- Hematologic & oncologic: ↓ hemoglobin (34%; grade 3/4: 10%), lymphocytopenia (32%; grade 3/4: 10%), ↓
neutrophils (14%; grade 3/4: 5%), leukopenia (14%; grade 3/4: 4%)
- Ophthalmic: Ocular toxicity (46%), dry eye syndrome (36% to 40%), blurred vision (14%)
- Renal: ↑ serum creatinine (20%)
1%-10% - Dermatologic: Cellulitis (5%)
- Endocrine & metabolic: ↓ serum sodium (8%), hyperglycemia (grade 3/4: 8%), ↑ uric acid (7%)
- Gastrointestinal: Severe diarrhea (4%)
- Genitourinary: Urinary tract infection (6%)
- Hematologic & oncologic: Febrile neutropenia (4%)
Freq. not
Defined:
- CNS: Abnormal gait, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy
- Dermatologic: Acneiform eruption, bullous dermatitis, contact dermatitis, erythema multiforme, erythematous
rash, exfoliation of skin, exfoliative dermatitis, palmar-plantar erythrodysesthesia, pustular rash, skin
photosensitivity, stasis dermatitis, urticaria, vesicular eruption
- Endocrine & metabolic: DKA

16. Pregnancy & Lactation
Pregnancy Considerations
- Based on the MOA & data from animal
reproduction studies, in utero exposure to
enfortumab vedotin may cause fetal harm.
- Evaluate pregnancy status prior to use in
females of reproductive potential. Males w/
female partners of reproductive potential
should use effective contraception during
therapy and for 4 mo. after the last dose of
enfortumab vedotin.
Breast-Feeding Considerations
- It is not known if enfortumab vedotin is
present in breast milk.
- Due to the potential for serious adverse
reactions in the breastfed infant,
breastfeeding is not recommended by the
manufacturer during therapy and for at least
3 wks after the last enfortumab vedotin
dose.

17. Drug Interactions
• Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the
therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
• CYP3A4 Inducers (Strong): May ↓ the serum conc. of Enfortumab.
Specifically, concentrations of the active MMAE component may ↓ Risk C:
Monitor therapy
• CYP3A4 Inhibitors (Strong): May ↑ the serum conc of Enfortumab.
Specifically, concentrations of the active MMAE component may ↑ Risk C:
Monitor therapy
Monitoring Parameters
• Monitor CBC w/ differential, blood glucose, and LFTs. Evaluate pregnancy
status prior to use in females of reproductive potential.
• Monitor for symptoms of new or worsening peripheral neuropathy, ocular
disorders, and/or dermatologic toxicity.
• Monitor infusion site during infusion for possible extravasation

18. Pharmacodynamics/Kinetics
• Distribution: Vdss: Antibody drug conjugate (ADC): 11 L.
• Protein binding: Monomethyl auristatin E (MMAE): 68% to 82%.
• Metabolism: Enfortumab vedotin is expected to undergo catabolism to small
peptides, amino acids, unconjugated MMAE, & unconjugated MMAE-related
catabolites. MMAE is released via proteolytic cleavage and is primarily
metabolized by CYP3A4.
• Half-life elimination: ADC: 3.4 days; MMAE: 2.4 days.
• Time to peak: ADC: at the end of the infusion; MMAE: At ~2 days after a dose.
• Clearance: 0.1 L/hour; MMAE (free): 2.7 L/hour.

19. AB Case Follow-up
• C1 Day 1 80 mg (1.25 mg/kg * 65 kg) admin’d 01/07 @ 200
mL/hr over 30 min
• C1 Day 8 80 mg admin’d 01/14 @ 200 mL/hr over 30 min
• Monitor CBC w/ differential, BG, LFTs, s/x of new peripheral
neuropathy, ocular disorders, and/or dermatologic toxicity.
• Monitor infusion site during infusion for possible
extravasation
• After second cycle (8 wks) assess for efficacy of enfortumab
vedotin was using appropriate imaging (computed
tomography or magnetic resonance imaging) q8 weeks

20. References
• <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia
and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia
Convention; 2020:74-92.
• Padcev (enfortumab vedotin) [prescribing information]. Northbrook, IL: Astellas
Pharma US, Inc; December 2019.
• Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in
urothelial carcinoma after platinum and anti-programmed death 1/programmed death
ligand 1 therapy. J Clin Oncol. 2019;37(29):2592-2600. doi:
10.1200/JCO.19.01140.[PubMed 31356140]
• US Department of Health and Human Services; Centers for Disease Control and
Prevention; National Institute for Occupational Safety and Health. NIOSH list of
antineoplastic and other hazardous drugs in healthcare settings 2016.
http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-
161.pdf. Updated September 2016. Accessed December 19, 2019.
• Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody–drug conjugate
targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer
models. Cancer research 2016;76:3003-13.

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