Life-threatening skin reaction with Enfortumab Vedotin: Six cases

Abstract

The prognosis of advanced or metastatic urothelial carcinoma is poor with a median overall survival of < 2 years. First-line treatment relies upon platinum-based chemotherapy followed by maintenance avelumab. Subsequent treatments include PD-1/PD-L1 inhibitors in immunotherapy-naïve patients, FGFR inhibitors in patients with FGFR mutations/translocations and Enfortumab Vedotin (EV). EV is a humanized monoclonal antibody–drug conjugate that delivers a microtubule-disrupting agent, monomethyl auristatin E (MMAE) to cells that express nectin-4, resulting in apoptotic death of tumoral cells [ [1] Rosenberg J. Sridhar S.S. Zhang J. Smith D. Ruether D. Flaig T.W. et al. EV-101: aphase I study of single-agent enfortumabvedotin in patients with nectin-4–positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol. 1 avr 2020; 38: 1041-1049 Crossref PubMed Scopus (78) Google Scholar ]. In 2019, the US Food and Drug Administration and more recently the European Medical Agency approved EV for patients with failure of two previous lines of treatment. Cutaneous adverse drug reactions (CADR) to EV were reported in approximatively one third of treated patients [ [1] Rosenberg J. Sridhar S.S. Zhang J. Smith D. Ruether D. Flaig T.W. et al. EV-101: aphase I study of single-agent enfortumabvedotin in patients with nectin-4–positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol. 1 avr 2020; 38: 1041-1049 Crossref PubMed Scopus (78) Google Scholar ], most often after the first cycle. These were mainly non severe reactions described as “rash” (67%), “flexural exanthema,” and “toxic epidermal necrolysis (TEN).” Grade 3–4 eruptions concerned 13% of patients [ [2] Padcev (enfortumabvedotin) : prescribing information. 2020 Google Scholar ]. In the phase III trial, only 7% skin toxicity was reported with no fatal issue [ [3] Powles T. Rosenberg J.E. Sonpavde G.P. Loriot Y. Durán I. Lee J.-L. et al. Enfortumabvedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 25 mars 2021; 384: 1125-1135 Crossref PubMed Scopus (139) Google Scholar ]. However, these CADR remain poorly described in terms of clinical and histopathological features, severity, management, and prognosis [ [4] Nguyen M.N. Reyes M. Jones S.C. Postmarketingcases of enfortumabvedotin–associated skin reactions reported as stevens-johnson syndrome or toxic epidermal necrolysis. JAMA Dermatol. 1 oct 2021; 157: 1237 Crossref Scopus (3) Google Scholar , [5] Dobry A.S. Virgen C.A. Hosking A.-M. Mar N. Doan L. Lee B. et al. Cutaneous reactions with enfortumabvedotin: a case series and review of the literature. JAAD Case Rep. août 2021; 14: 7-9 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar ].