Use of enfortumab vedotin (Padcev), which was approved less than 2 years ago for the treatment of metastatic urothelial cancer, has been associated with cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal.
The cases came to light during routine surveillance, say staff from the Division of Pharmacovigilance of the US Food and Drug Administration (FDA) in a research letter published online September 8 in JAMA Dermatology.
Eight cases of serious skin reactions characterized as SJS/TEN were identified from the FDA’s Adverse Event Reporting System (FAERS). In five of these cases, the diagnosis of SJS/TEN was confirmed by a dermatologist and/or biopsy findings.
The median time to onset of SJS/TEN was 11 days (range, 9 – 21 days) from the start of treatment.
In the eight cases, serious outcomes were reported. In four cases, deaths that were attributed to SJS/TEN occurred, note the researchers. “Other serious outcomes included admission to the burn unit in 4 cases,” they write.
Enfortumab vedotin is a first-in-class agent directed against cell adhesion molecule nectin-4, which is located on the surface of cells and is highly expressed in bladder cancer. The product is an antibody conjugate, in which the antibody directs the product to these cells and then releases the cytoxic monomethyl auristantin E. It is administered intravenously.
The product was granted accelerated approval by the FDA in December 2019. This approval was based on response data from the EV-201 study, a phase 2 clinical trial that involved 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.
The results were presented in June 2019 at the annual meeting of the American Society of Clinical Oncology. The overall response rate (ORR) was 44%; 12% of patients achieved a complete response, and 32% had a partial response. The median duration of response was 7.6 months.
At the meeting, Daniel P. Petrylak, MD, professor of medicine (medical oncology) and urology at Yale Cancer Center, New Haven, Connecticut, noted that there is a “high unmet need” among patients with advanced and metastatic urothelial cancer. There has been a flurry of new drug approvals for this disease. Five immune checkpoint inhibitor drugs have been approved in recent years. Most patients (75% to 80%) experience disease progression after receiving immunotherapy.
Enfortumab vedotin is the “first novel therapeutic to demonstrate substantial clinical activity” in patients whose disease has progressed after platinum chemotherapy and immunotherapies, commented Petrylak.
At the time, maculopapular rash of grade 3 or higher was reported in 4% of the cohort. That was the only serious dermatologic adverse event noted.
Clinically Significant Findings
The cases of severe skin reactions now being reported come from postmarketing surveillance, note the authors, led by Michelle Nadeau Nguyen, PharmD, BCOP, BCPS, and colleagues from the FDA’s Division of Pharmacovigilance, Office of Surveillance and Epidemiology. They reviewed data from FAERS, PubMed, and Embase from December 18, 2019, the date the product was approved, through October 7, 2020.
Other than the eight cases reported to FAERS, no additional cases were identified from PubMed or Embase.
The authors note that because cases of SJS/TEN are rare but serious, these well-documented postmarketing reports are clinically significant. “Moreover, we find the rapid accumulation of cases over an approximate 12-month marketing period a concerning observation,” they write.
The rate at which these reactions were reported is higher than would be expected, they comment.
The annual incidence of locally advanced urothelial cancer, the disease most likely to be treated with this drug, is around 12,494 to 40,000 cases per year in the United States. The expected incidence rate of SJS/TEN is about one to seven cases per 1,000,000 patients. The team calculated from the reports that among patients who received enfortumab vedotin, the rate was 20 cases per 1,000,000 patients.
This reporting rate is likely to be underestimated, inasmuch as underreporting is known to be a limitation of spontaneous reporting systems such as FAERS, the authors note.
The mechanism for toxic skin effects with enfortumab vedotin is as yet unknown, but it may be related to the inhibitory effects of the drug on nectin-4 expression, they suggest. Nectin-4 is expressed by epithelial tissues, including skin.
Nguyen and colleagues note that on approval, the US prescribing information for the drug noted that skin reactions were seen in 55% of patients in clinical trials.
The prescribing information was recently revised to include SJS/TEN and to recommend permanent discontinuance of the drug if cases of SJS/TEN are suspected.
“This revision is intended to increase clinicians’ awareness of the risk for SJS/TEN and mitigate serious outcomes by improving the likelihood of early identification and intervention,” they add.
The authors also encourage continued reporting of adverse events with enfortumab vedotin to the FDA via the MedWatch portal.
The authors have disclosed no relevant financial relationships.
JAMA Dermatol. Published online September 8, 2021. Abstract