On December 18, 2019, the antibody-drug conjugate enfortumab vedotin-ejfv (PadcevTM) was granted accelerated approval for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.1,2 Enfortumab vedotin-ejfv is the first Nectin-4–directed antibody-drug conjugate to receive U.S. Food and Drug Administration (FDA) approval.
Supporting Efficacy Data
Accelerated approval was based on response rate and durability of response observed in the multicenter phase II EV-201 trial (ClinicalTrials.gov identifier NCT03219333).2,3 In the trial, 125 patients with locally advanced or metastatic urothelial cancer with prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy received enfortumab vedotin-ejfv at 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Patients were excluded if they had active central nervous system metastases, ongoing sensory or motor neuropathy ≥ grade 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥ 8% or ≥ 7% with associated diabetes symptoms.
Enfortumab vedotin-ejfv has warnings/precautions for hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion-site extravasation, and embryofetal toxicity.
The median age of patients was 69 years (range, 40–84 years); 70% were male; 85% were white; all had an Eastern Cooperative Oncology Group performance status of 0 (32%) or 1; 90% had visceral metastases, including 40% with liver metastases; and 67% had pure transitional cell carcinoma histology and 33% had transitional cell carcinoma with other histologic variants. Nectin-4 expression was detected in all 120 patients tested with a trial assay. The median number of prior systemic therapies was three (range, 1–6). Overall, 46% received a prior PD-1 inhibitor, 42% had a prior PD-L1 inhibitor, and 13% received both; 66% received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and 8% received both.
The objective response rate on blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1, was 44% (95% confidence interval [CI] = 35%–53%), with a complete response rate of 12%. The estimated median response duration was 7.6 months (95% CI = 6.3 months to not estimable).
How It Works
Enfortumab vedotin-ejfv is an antibody-drug conjugate comprising a human IgG1antibody directed against Nectin-4, an adhesion protein located on the surface of cells, and the small-molecule monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The antibody and small molecule are attached via a protease-cleavable linker. Preclinical data suggest that the activity of enfortumab vedotin-ejfv is due to the binding of the antibody-drug conjugate to Nectin-4–expressing cells, followed by internalization of the antibody drug conjugate–Nectin-4 complex, and release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, inducing cell-cycle arrest and apoptotic cell death.
How It Is Used
The recommended dose of enfortumab vedotin-ejfv is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) via a 30-minute intravenous infusion on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity.
Dose modification for adverse events includes stepwise dose reduction to 1.0 mg/kg up to 100 mg, 0.75 mg/kg up to 75 mg, and 0.5 mg/kg up to 50 mg. Product labeling provides instructions on dose modification, including dose reduction, withholding, and discontinuation for hyperglycemia, peripheral neuropathy, skin reactions, other grade 3 or 4 nonhematologic toxicities, and hematologic toxicities.
Use of enfortumab vedotin-ejfv should be avoided in patients with moderate or severe hepatic impairment. Concomitant use of strong inhibitors of CYP3A4 with enfortumab vedotin-ejfv may increase exposure to MMAE.
Among the 125 patients receiving enfortumab vedotin-ejfv in the EV-201 trial, the median duration of treatment exposure was 4.6 months. The most common adverse events of any grade (≥ 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%). Grade ≥ 3 adverse events occurred in 73% of patients, with the most common (≥ 5%) being rash (13%), diarrhea (6%), and fatigue (6%). The most common grade 3 or 4 laboratory abnormalities were decreased hemoglobin (10%), decreased lymphocytes (10%), decreased phosphate (10%), increased lipase (9%), increased glucose (8%), and decreased sodium (8%).
Serious adverse events occurred in 46% of patients, with the most common being urinary tract infection, cellulitis, febrile neutropenia, diarrhea, sepsis, acute kidney injury, dyspnea, and rash. Adverse events led to dose interruption in 64%, most commonly due to peripheral neuropathy, rash, and fatigue, and to dose reduction in 34%, most commonly due to peripheral neuropathy, rash, and fatigue. Adverse events led to treatment discontinuation in 16% of patients, most commonly due to peripheral neuropathy. Fatal adverse events occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis.
Enfortumab vedotin-ejfv has warnings/precautions for hyperglycemia, including potentially fatal diabetic ketoacidosis in patients with or without preexisting diabetes mellitus; peripheral neuropathy; ocular disorders including vision changes; skin reactions; infusion-site extravasation; and embryofetal toxicity. Blood glucose levels should be closely monitored in patients with or at risk for diabetes mellitus or hyperglycemia. Treatment should be withheld if blood glucose is > 250 mg/dL. Patients should be monitored for signs or symptoms of ocular disorders; prophylactic artificial tears for dry eyes and treatment with ophthalmic topical steroids should be considered after an ophthalmic exam. Patients should be monitored for new or worsening neuropathy. Adequate venous access should be ensured prior to administration of enfortumab vedotin-ejfv; the infusion site should be monitored during administration, with infusion stopped for suspected extravasation. Patients should be advised not to breastfeed while receiving enfortumab vedotin-ejfv. ■
1. U.S. Food and Drug Administration: FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-metastatic-urothelial-cancer. Accessed January 9, 2020.
2. Padcev (enfortumab vedotin-ejfv) for intravenous use, Seattle Genetics, December 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761137s000lbl.pdf. Accessed January 9, 2020.
3. 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 37:2592-2600, 2019.