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June

Enfortumab Vedotin management for advanced or metastatic urothelial carcinoma

Written by: Andrew Ruplin, PharmD, Seattle Cancer Care Alliance
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The purpose of this PQI is understand the management techniques and interventions when utilizing enfortumab vedotin.

Background

Enfortumab vedotin is a nectin-4 targeting antibody conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE).1 Enfortumab vedotin was granted accelerated approval by the FDA for the treatment of advanced or metastatic urothelial carcinoma in patients who have previously received a programmed death receptor (PD-1) or programmed death receptor (PD-L1) inhibitor, and a platinum-based chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.1 In the pivotal phase II trial, patients were heavily pretreated (50% received ≥3 prior treatments), and the objective response rate was 44%, including 12% complete responses.2 Adverse effects were common, and 54% of patients had a grade ≥ 3 treatment-related adverse event, but these adverse events were manageable and no single grade ≥ 3 adverse event occurred in more than 10% of patients.2 Treatment-related adverse effects led to dose reduction in 32% of patients and discontinuation in 12% of patients.2

PQI Process:

Upon order of enfortumab vedotin administration

  • Confirm appropriateness of enfortumab vedotin utilizing the EMR
  • Review the adverse events Table (#1) on Page 2 with the interventions suggested as needed.
  • Review Table (#2) on Page 3 for dose specific adjustments as required
  • Drug Interaction Considerations1
    • Enfortumab vedotin is metabolized via CYP 3A4, and concomitant use of an antibody-drug conjugate containing MMAE and strong CYP3A4 inhibitors should be considered. Dose adjustment is typically not required.

Table 1: Selected Adverse Events and interventions suggested

EventSeverity/IncidenceSuggested InterventionComments
Skin Reactions54% (any Grade)1Fragrance-free moisturizers/ointments

Topical steroids as indicated

Systemic steroids as indicated

Median time of onset for severe skin reactions was 0.8 months (range 0.2 – 5.3).1
Hyperglycemia11% (any Grade)1 regardless of known hyperglycemia at baseline.

 

68% of patients with baseline hyperglycemia did not experience worsening

Blood glucose test prior to infusion

 

(If unable: a basic metabolic panel is possible to use).

 

Does not need to be fasting.

BMI and elevated A1c correlated to a higher incidence of Grade 3/4 hyperglycemia.1

 

Patients with baseline A1c ≥ 8% were excluded from the trial.1,2

 

Patients with baseline A1c ≥ 6.5% should be referred to an appropriate provider for glucose management.1

Ocular ToxicityOcular disorders including blurred vision – 46%1

 

Dry eye symptoms – 36%1

 

Consider prophylactic artificial tears1

 

Consider topical ophthalmic steroids after ophthalmic exams1

Median time to onset for ocular disorders was 1.9 months (range 0.3 – 6.2).1
Neuropathy49% (any Grade).1

Peripheral sensory neuropathy was the most common reason for dose reduction.

Recommend dose reduction as initial strategy

 

Consider use of gabapentin/duloxetine

The median time to onset of Grade ≥ 2 was 3.8 months (range: 0.6 – 9.2).

 

At the last follow-up in the trial, 19% had complete resolution and 26% had partial improvement. 76% had resolution or ongoing Grade 1 neuropathy.

Diarrhea42% (any Grade)1Prepare anti-diarrheal medications for patient as needed

Table 2: Dose Adjustments for Adverse Events1

AdministrationIV infusion over 30 minutes on days 1, 8, 15 of a 28-day cycle until progression or toxicity
Starting dose1.25 mg/kg up to 125 mg*
First dose reduction1 mg/kg up to 100 mg*
Second dose reduction0.75 mg/kg up to 75 mg*
Third dose reduction0.5 mg/kg up to 50 mg*
Renal/hepatic dysfunction considerationsNo dose adjustment is required for renal dysfunction

No current studies in moderate to severe hepatic dysfunction – consider avoiding use in this scenario. Mild hepatic dysfunction does not require an upfront dose reduction.

Adverse EventGrade/SeverityDose Modification
HyperglycemiaBlood glucose

> 250 mg/dL

Withhold until ≤ 250 mg/dL, then resume at same dose level.
Peripheral neuropathy2Withhold until Grade ≤ 1, then resume at same dose level. If recurrence, withhold until Grade ≤ 1, then resume and reduce one dose level.
≥ 3Permanently discontinue
Skin reactions3Withhold until Grade ≤ 1, then resume at same dose level or consider reducing by one dose level
4 or recurrent 3Permanently discontinue
Other non-hematologic toxicities3Withhold until Grade ≤ 1, then resume at same dose level or consider reducing by one dose level
4Permanently discontinue
Hematologic toxicity3 or Grade 2 thrombocytopeniaWithhold until Grade ≤ 1, then resume at same dose level or consider reducing by one dose level
4Withhold until Grade ≤ 1, then resume and reduce one dose level or discontinue treatment

*Based on actual body weight. Dose is capped for patients ≥100 kg

Patient Centered Activities:

  • Advise patients that skin toxicities for enfortumab vedotin are likely to manifest as dry skin, pruritus, and/or maculopapular rash.1
    • Severe skin toxicities (10% incidence) included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia.1
  • Advise patients to self-monitor for peripheral sensory neuropathy and motor neuropathy. Sensory neuropathy (44%) was more common than motor (14%).2
  • Enfortumab vedotin has an NCCN emetic risk category of “Moderate” on the day of treatment and patients should receive anti-emetic medications prior to infusion according to institutional standards.3

References:

  1. Padcev (enfortumab vedotin- ejfv) [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc.; December 2019.
  2. 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.
  3. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2020. February 19, 2020.
Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
Joshua

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