Case Report: Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Case Series on the Clinical and Histopathologic Spectrum of Adverse Cutaneous Reactions From Fatal Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis to Dermal Hypersensitivity Reaction

Abstract

Enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate approved in metastatic urothelial carcinoma following progression on a platinum-containing chemotherapy and immune checkpoint blockade. On-target dermatologic toxicity may occur from Nectin-4 expression in the skin. We highlight a case of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis following enfortumab infusions that was ultimately fatal. The second case describes an erythema multiforme-like rash with interface dermatitis related to enfortumab. Dermatologic findings, immunohistochemistry studies, and immune profiling are detailed. These cases demonstrate the potentially catastrophic outcomes in some patients treated with enfortumab. Patients must be monitored for cutaneous toxicities with early involvement of dermatology and dermatopathology.

Keywords: SJS/TEN; adverse (side) effects; bladder cancer; enfortumab vedotin; erythema multiform; urothelial cancer.

Figure 1

Clinical timelines for Patient 1 and Patient 2.

Figure 2

Clinicopathologic illustration of Patient 1. (A, B) Dusky erythematous patches and detachment of skin of the axillary vaults. (C) Patient 1 skin biopsy with epidermal detachment and blister cavity with scattered necrotic epidermal keratinocytes. An associated dermal superficial dermis shows interstitial and perivascular lymphohistiocytic infiltrate and few eosinophils and neutrophils (hematoxylin and eosin, original magnification, 40x). (D, E) Immunohistochemical studies show that the inflammatory infiltrates are composed of CD4+ T-cells with a subset of CD8+ T-cells (Immunohistochemistry, anti-CD4 and anti-CD8 x400). (F, G) Multiplex immunofluorescence (mIF) studies with immune-oncology toxicity panel of anti-CD3, anti-CD8, anti-FoxP3, anti-TBet, anti-Gata3, and anti-RORγT antibodies for patient 1. Stevens-Johnson syndrome/toxic epidermal necrolysis lesion shows inflammatory infiltrate in superficial dermis composed of CD3+ T-cells (orange) admixed with CD8+ T-cells (red). The infiltrate consists of increased numbers of Gata3+ cells (pink) and Th2 immunophenotype. Rare subsets of cells are positive for FoxP3 (cyan) and RORγT (green) corresponding to Tregs and Th17 immunophenotype, respectively.

Figure 3

The density of skin infiltrating lymphocytes in the epidermis and skin biopsy by multiplex immunofluorescence (mIF) in patient 1 with Stevens-Johnson syndrome/toxic epidermal necrolysis SJS/TEN and patient 2 interface dermatitis toxicity (lesion 1) and bullous toxicity (lesion 2). (A) Skin infiltrating lymphocytes were absent in the epidermis in patient 1 with SJS/TEN. In patient 2, the interface dermatitis toxicity (lesion 1) and the bullous toxicity (lesion 2) exhibited CD3+ T-cells with variable density of CD8+ T-cells and Tregs and Th2 positive cells. (B) Examination of the total density of skin infiltrating lymphocytes by mIF analysis revealed that all three (SJS/TEN, interface dermatitis toxicity, and bullous toxicity) lesions analyzed consisted of CD3+ T-cells with a subset of CD8+ T-cells. All three lesions exhibited similar density of FoxP3+ cells and a minor population of TBet+ cells. The lesions from patient 2 exhibited higher density of RORγT+ cells compared to SJS/TEN lesion from patient 1.

Figure 4

Clinicopathologic illustration of Patient 2. (A) Crusted thin red papules on the chest. (B) Patient 2 skin biopsy with interface dermatitis toxicity (lesion 1) with scattered dyskeratotic cells and the superficial perivascular dermal inflammatory infiltrate with eosinophils (hematoxylin and eosin, original magnification, 40x). (C, D) Immunohistochemical studies show that the inflammatory infiltrates are composed of CD4+ T-cells with a subset of CD8+ T-cells (Immunohistochemistry, anti-CD4 and anti-CD8, x400). (E, F) Multiplex immunofluorescence (mIF) studies with immune-oncology toxicity panel of anti-CD3, anti-CD8, anti-FoxP3, anti-TBet, anti-Gata3, and anti-RORγT antibodies. Patient 2, interface dermatitis toxicity (lesion 1) shows dermal inflammatory infiltrate that exhibits Th2 immunophenotype with Gata3+ cells (pink). There is a subset of Tregs, Foxp3+ cells (cyan), and Th17, RORγT positive cells (green) in the inflammatory infiltrate. (G) Erythematous patches on the abdomen. (H) Patient 2 skin biopsy with bullous toxicity (lesion 2) with scattered dyskeratotic cells (white arrows) and the superficial perivascular dermal inflammatory infiltrate with eosinophils and few neutrophils [hematoxylin and eosin (H&E), original magnification]. (I, J) Immunohistochemical studies show that the inflammatory infiltrates are composed of CD4+ T-cells with a subset of CD8+ T-cells (immunohistochemistry, anti-CD4 and anti-CD8, x400). (K, L) Multiplex immunofluorescence (mIF) studies with immune-oncology toxicity panel for patient 2; bullous toxicity (lesion 2) shows similar Th2 immunophenotype with Gata3+ cells (pink) and subsets of Tregs, Foxp3+ cells (cyan), and Th17, RORγT positive cells (green) [Vectra 3.0 spectral multiplex immunofluorescence (mIF) imaging system (PerkinElmer) and InForm 2.4.8 image analysis software Colors: Blue, DAPI; Red, CD3; Orange, CD8; Cyan, FOXP3; Yellow, TBet; Pink, GATA3; Green, RORγT].