Rx Road Map: Enfortumab Vedotin (Padcev)

Enfortumab Vedotin (Padcev)

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Who Is This Drug Approved For

Enfortumab vedotin (EV) is an antibody–drug conjugate (ADC) approved by the FDA for the treatment of adult patients with locally advanced (la) or metastatic urothelial cancer (mUC).

All Approved Indications and Timeline

• 12/2019: EV was approved as a single agent for adult patients with la/mUC who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant, adjuvant, or locally advanced or metastatic setting.
• 07/2021: EV received expanded approval in adult patients with la/mUC who were cisplatin ineligible and had received 1 or more lines of therapy.
• 04/2023: EV in combination with pembrolizumab (Keytruda) was approved for first-line therapy for la/mUC in patients who are cisplatin ineligible.
• 12/2023: EV in combination with pembrolizumab was approved for first-line therapy for all patients with la/mUC.

Relevant Clinical Trial and Efficacy Data That Supported FDA Approval

Single-agent trials

EV-201 (NCT03219333): Cohort 1 in patients with la/mUC who received a prior immune checkpoint inhibitor (ICI) and a platinum-containing agent. This was the first indication for EV as a third-line therapy with an objective response rate (ORR) of 44%, a complete response (CR) rate of 12%, and median duration of response (DOR) of 7.6 months. These data led to the EV-301 trial.

Cohort 2 in patients with la/mUC who had received prior ICI or other platinum-containing chemotherapy, but who were cisplatin ineligible. Second-line therapy showed an ORR of 51%, CR rate of 22%, and median DOR of 13.8 months.

EV-301 (NCT03474107): Phase 3 trial in patients with la/mUC with prior ICI and platinum-based chemotherapy in the third line. The median overall survival (OS) benefit was 12.9 months vs 9 months with chemotherapy. Median progression-free survival (PFS) was 5.6 months vs 3.7 months.

Combination trials

EV-103 (NCT03288545): Phase 2 trial in cisplatin-ineligible patients for first-line therapy with EV-positive pembrolizumab with an ORR of 68%. The CR rate was 12% and the median DOR was 22.1 months.

EV-302 (NCT04223856): Phase 3 combination trial in the first line for all patients (cisplatin eligible and cisplatin ineligible) showed median OS of 31.5 months vs 16.1 months in those receiving chemotherapy, Median PFS of 12.5 months vs 6.3 months, ORR of 67.7% vs % 44.4%, and CR rate of 29.1 vs 12.5%.

How It Works

EV is an ADC that targets Nectin-4, a tumor surface protein that is found in almost all urothelial cancer cells. The antibody targets and binds to this protein, enabling the cytotoxic payload to be delivered directly into the tumor cell.

Drug Class/Mechanism of Action

EV is an antibody targeting Nectin-4 that is linked to a microtubule inhibitor conjugate (monomethyl auristatin E).

How Is It Administered

EV is administered via intravenous (IV) infusion over 30 minutes on days 1 and 8 every 21 days when given with pembrolizumab. It is administered on days 1, 8, and 15 every 28 days when given as a single agent.

Recommended Duration of Therapy

EV is recommended to be given as a single agent until disease progression or unacceptable toxicity.

EV administered in combination with pembrolizumab is given for a median of 7 to 9 cycles as tolerated, mainly to avoid the risk of cumulative neurotoxicity. Pembrolizumab is then continued as monotherapy for up to 24 months or until disease progression or unacceptable toxicity during that period.

Dosing Information

EV as a single agent is administered IV at 1.25 mg/kg (up to a maximum of 125 mg for patients weighing ≥100 kg) on days 1 and 8 of a 21-day cycle.

EV in combination with pembrolizumab is administered IV at 1.25 mg/kg (up to a maximum of 125 mg for patients weighing ≥100 kg) on days 1 and 8 of a 21-day cycle.

Important Adverse Event Information

EV carries a boxed warning for severe and sometimes fatal skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Serious adverse events (AEs) associated with EV include pneumonitis/interstitial lung disease (ILD), hyperglycemia, peripheral neuropathy, ocular disorders, infusion site extravasation, and fetal toxicity.

Common AEs include fatigue, weight loss, skin changes (rash, dry skin, pruritus), peripheral neuropathy, gastrointestinal disturbances (nausea, diarrhea, constipation, dysgeusia, abdominal pain), hyperglycemia, liver function tests and renal function abnormalities, electrolyte imbalances, anemia, neutropenia, thrombocytopenia, and hypoalbuminemia.

When EV is given in combination with pembrolizumab, additional AEs include UTIs and hyperkalemia.

How to Manage Associated AEs

Close monitoring and accurate Common Terminology Criteria for Adverse Events grading of symptoms is critical in the appropriate management of AEs.

Skin Reactions: For grade 1 skin reactions, consider topical corticosteroids and antihistamines. Withhold EV for grade 2 and recurrent/persistent reactions until improved. Refer the patient to the dermatology department for suspected SJS, TEN, or grade 3 skin reactions. Permanently discontinue EV for SJS, TEN, grade 4, or recurrent grade 3 reactions.

Hyperglycemia and Diabetic Ketoacidosis: Check baseline body mass index and hemoglobin A1C levels and evaluate need for insulin therapy. Monitor glucose levels closely before each dose. Withhold dose of EV if blood glucose level is greater than 250 mg/dl.

Pneumonitis: Monitor for hypoxia, dyspnea, cough, or ILD on radiological exams. Refer patient to the pulmonology department as appropriate. Dose reduce for persistent/recurrent grade 2 pneumonitis and discontinue EV for grade 3 and 4 pneumonitis.

Peripheral Neuropathy: Monitor patients at baseline and during therapy for new or worsening symptoms. Consider dose reduction or interruption for mild to moderate symptoms. Discontinue drug for grade 3 or greater.

Ocular Disorders: Symptoms include but are not limited to dry eyes, blurred vision, keratitis, hyperlacrimation, and conjunctivitis. Consider prophylactic artificial tears. Refer patient for ophthalmology evaluation for new, persistent, or worsening symptoms.

Gastrointestinal Disturbances: Evaluate for nausea, diarrhea, constipation, taste alteration, anorexia, and weight loss. Seek nutrition counseling and pharmacologic management of diarrhea and nausea when indicated. Monitor for associated complications such as renal dysfunction and electrolyte abnormalities.

Hematologic Toxicities: Perform complete blood count prior to administering each dose. Transfuse as needed for hemoglobin level less than 8 gm. Dose reduce or withhold drug for grade 3 cytopenias and discontinue for grade 4 complications.

Essential Information for Patients About to Start Treatment

Discuss skin toxicities in detail and emphasize prompt reporting of symptoms. Women who can become pregnant and men with female partners who can become pregnant MUST use contraception for the duration of and for at least 4 months after the last dose of EV. Patients need to inform the health care team of the following:

• All medication use including prescription and over-the-counter products, vitamins, and herbal supplements
• Need for extra caution with glucose monitoring if they have diabetes or prediabetes
• History of lung or liver problems
• Symptoms of peripheral neuropathy before stating therapy with EV

Administration Information Specific to Infusion Nurses or Clinical Nurse Specialists

Pembrolizumab is administered after EV when given on the same day. Establish good IV access for infusion and monitor for extravasation during therapy.

Nursing Considerations, Concomitant Drug/Food Considerations, Symptoms to Monitor, and More

• Remind patients to use mild detergents, skin care, and sun protection factor products
• Discuss symptoms of peripheral neuropathy and assess impact on activities of daily living
• Counsel on oral hydration and specific instructions for management of diarrhea vs constipation. Also track weight changes, taste alteration, and nausea during therapy
• Refer patients to a nutritionist for weight loss and nutritional counseling
• Monitor lab results and perform a comprehensive assessment at each visit
• Reinforce how to mitigate treatment-related fatigue
• Remind patients to perform proper hand hygiene

How to Safely Handle This Drug

Infusion nurses should wear proper personal protective equipment and follow safe administration and disposal protocols set by their respective institutions.

References

1. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
2. Vlachostergios PJ, Jakubowski CD, Niaz MJ, et al. Antibody-drug conjugates in bladder cancer. Bladder Cancer. 2018;4(3):247-259. doi:10.3233/BLC-180169
3. Padcev. Prescribing information. Astellas Pharma US, Inc; 2019. Accessed April 10, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/
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