The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to enfortumab vedotin-ejfv (Padcev™; Astellas Pharma and Seattle Genetics) in combination with Merck’s (known as MSD outside the United States and Canada) anti-PD-1 therapy pembrolizumab (Keytruda®) for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.
It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020.  Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.  Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide. 
The recommended first-line treatment for patients with advanced urothelial cancer is cisplatin-based chemotherapy. For patients who are unable to receive cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens. 
Enfortumab vedotin-ejfv, a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer, was conditionally approved by the FDA in December 2019 based on the Accelerated Approval Program. 
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 
The drug is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting.
Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). 
The Breakthrough Therapy process is designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. The designation is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints. In the case of enfortumab vedotin, the designation was based on the initial results from Phase Ib/II EV-103 Clinical Trial.
“The FDA’s Breakthrough Therapy designation reflects the encouraging preliminary evidence for the combination of enfortumab vedotin and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options,” said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.
“We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.”
“This is an important step in our investigation of enfortumab vedotin in combination with pembrolizumab as first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy,” said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics.
“Based on encouraging early clinical activity, we recently initiated a phase III trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.”
The Breakthrough Therapy designation was granted based on results from the dose-escalation cohort and expansion cohort A of the Phase Ib/II trial, EV-103 (NCT03288545), evaluating patients with locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy-treated in the first-line setting with enfortumab vedotin-ejfv in combination with pembrolizumab.
The initial results from the trial were presented at the European Society of Medical Oncology (ESMO) 2019 Congress, and updated findings at the 2020 Genitourinary Cancers Symposium.
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase Ib/II trial of enfortumab vedotin-ejfv alone or in combination, evaluating the safety, tolerability, and efficacy in muscle-invasive, locally advanced and first- and second-line metastatic urothelial cancer.
Serious adverse reactions occurred in 46% of patients treated with enfortumab vedotin-ejfv. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).
Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).
The most common adverse reactions (≥20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue (6%).
Hyperglycemia occurred in patients treated with enfortumab vedotin-ejfv, including death and diabetic ketoacidosis (DKA), in patients with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C ≥8% were excluded.
Physicians are recommended to closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia and, if blood glucose is elevated (>250 mg/dL), withhold the drug.
Peripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Two percent (2%) of patients experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with enfortumab vedotin-ejf with or without preexisting peripheral neuropathy.
The median time to onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement.
- Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of enfortumab vedotin-ejf when peripheral neuropathy occurs.
- Permanently discontinue enfortumab vedotin-ejf in patients that develop Grade ≥3 peripheral neuropathy.
Ocular disorders occurred in 46% of the 310 patients treated with enfortumab vedotin-ejf. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with enfortumab vedotin-ejf.
The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2).
Physicians should monitor patients for ocular disorders and consider:
- Artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve.
- Treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam
- Dose interruption or dose reduction of enfortumab vedotin-ejf for symptomatic ocular disorders.
Skin reactions occurred in 54% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Twenty-six percent (26%) of patients had a maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3).
Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement.
Physicians should monitor patients for skin reactions, and consider:
- Appropriate treatment, such as topical corticosteroids and antihistamines for skin reactions, as clinically indicated. For severe (Grade 3) skin reactions, withhold enfortumab vedotin-ejf until improvement or resolution and administer appropriate medical treatment.
- Permanently discontinue enfortumab vedotin-ejf in patients that develop Grade 4 or recurrent Grade 3 skin reactions.
Infusion site extravasation
Skin and soft tissue reactions secondary to extravasation have been observed after the administration of enfortumab vedotin-ejf. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed.
Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation.
Physicians should ensure adequate venous access prior to starting enfortumab vedotin-ejf and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Enfortumab vedotin-ejf can cause fetal harm when administered to a pregnant woman.
Physicians should advise patients of the potential risk to the fetus and advise female patients of reproductive potential to use effective contraception during enfortumab vedotin-ejf treatment and for 2 months after the last dose. At the same time, they should advise male patients with female partners of reproductive potential to use effective contraception during treatment with enfortumab vedotin-ejf and for 4 months after the last dose.
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
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 Enfortumab vedotin-ejfv (Padcev™; Astellas Pharma [package insert]. Northbrook, IL)
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