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-ejfv.
Background
Enfortumab vedotin-ejfv is a nectin-4 targeting antibody conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE).1 Enfortumab vedotin-ejfv 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 or are ineligible for cisplatin-containing chemotherapy and have previously received one or more lines of therapy.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 The EV-301 trial demonstrated the benefit of enfortumab vedotin-ejfv compared to chemotherapy (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval, 0.56 to 0.89; P=0.001 with comparable incidence of treatment-emergent adverse events (93.9% in the enfortumab vedotin-ejfv group and 91.8% in the chemotherapy group).3
PQI Process: Upon order of enfortumab vedotin-ejfv administration
- Confirm appropriateness of enfortumab vedotin-ejfv utilizing the EMR
- Review adverse events and interventions suggested as needed (see Supplemental Information: Table 1)
- Review dose specific adjustments as required (see Supplemental Information: Table 2)
- Drug interaction considerations1
- Enfortumab vedotin-ejfv is metabolized via CYP3A4, and concomitant use of an antibody-drug conjugate containing MMAE and strong CYP3A4 inhibitors should be considered. Dose adjustment is typically not required
Patient Centered Activities:
- Advise patients that skin toxicities for enfortumab vedotin-ejfv are likely to manifest as dry skin, pruritus, and/or maculopapular rash1
- Severe skin toxicities (10% incidence) included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia1
- Advise patients to self-monitor for peripheral sensory neuropathy and motor neuropathy. Sensory neuropathy (44%) was more common than motor (14%)2
- Enfortumab vedotin-ejfv 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 standards4
Supplemental Information:
Table 1: Selected Adverse Events and Suggested Interventions
| Event | Severity/Incidence | Suggested Intervention | Comments |
| Skin Reactions | 54% (any grade)1 | Fragrance-free moisturizers/ointments Topical steroids and antihistamines as indicated Systemic steroids as indicated | Median time of onset for severe skin reactions was 0.8 months (range 0.2 – 5.3)1 Patients in EV-301 with grade 3 rash did not require treatment interruption if symptoms were manageable3 |
| Hyperglycemia | 11% (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 – a basic metabolic panel suffices
Does not need to be fasting | BMI and elevated A1c correlated to a higher incidence of grade 3/4 hyperglycemia1
Patients with baseline A1c ≥ 8% were excluded from EV-2012
Patients with baseline A1c ≥ 6.5% should be referred to an appropriate provider for glucose management1 |
| Ocular Toxicity | Ocular 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 |
| Neuropathy | 49% (any grade).1 Peripheral sensory neuropathy was the most common reason for dose reduction | Recommend dose reduction as initial strategy
Consider use of gabapentin or duloxetine | The median time to onset of grade ≥ 2 was 3.8 months (range: 0.6 – 9.2)
At the last follow-up in EV-201, 19% had complete resolution and 26% had partial improvement. 76% had resolution or ongoing grade 1 neuropathy2 |
| Diarrhea | 42% (any grade)1 | Recommend anti-diarrheal medications for patient as required | Grade 4 diarrhea that resolves to grade ≤2 within 72 hours with supportive management does not require treatment interruption3 |
Table 2: Dose Adjustments for Adverse Events1
| Administration | IV infusion over 30 minutes on days 1, 8, 15 of a 28-day cycle until progression/toxicity | |
| Starting dose | 1.25 mg/kg up to 125 mg* | |
| First dose reduction | 1 mg/kg up to 100 mg* | |
| Second dose reduction | 0.75 mg/kg up to 75 mg* | |
| Third dose reduction | 0.5 mg/kg up to 50 mg* | |
| Renal/hepatic dysfunction considerations | No dose adjustment is required for renal dysfunction No current studies in moderate to severe hepatic dysfunction – consider avoiding use Mild hepatic dysfunction does not require an upfront dose reduction | |
| Adverse Event | Grade/Severity | Dose Modification |
| Hyperglycemia | Blood glucose > 250 mg/dL | Withhold until ≤ 250 mg/dL, then resume at same dose level |
| Peripheral neuropathy | 2 | Withhold until grade ≤ 1, then resume at same dose level. If recurrence, withhold until Grade ≤ 1, then resume and reduce one dose level |
| ≥ 3 | Permanently discontinue | |
| Skin reactions | 3 | Withhold until grade ≤ 1, then resume at same dose level or consider reducing by one dose level |
| 4 or recurrent 3 | Permanently discontinue | |
| Other non-hematologic toxicities | 3 | Withhold until grade ≤ 1, then resume at same dose level or consider reducing by one dose level |
| 4 | Permanently discontinue | |
| Hematologic toxicity | 3 or Grade 2 thrombocytopenia | Withhold until grade ≤ 1, then resume at same dose level or consider reducing by one dose level |
| 4 | Withhold 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
References:
- Padcev® (enfortumab vedotin-ejfv) [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc.; March 2021.
- Rosenberg JE, O’donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin-ejfv in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019;37(29):2592-2600.
- Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin-ejfv in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021;384(12):1125-1135.
- National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2021. December 23, 2020.
