Dr. Jean Bolognia presented information about antibody-drug conjugates (ADCs), including enfortumab vedotin, trastuzumab emtansine, trastuzumab deruxtecan, and loncastuximab tesirine. ADCs are monoclonal antibodies (mAbs) combined with a chemotherapeutic agent via a linker. They are associated with cutaneous side effects that dermatologists need to know about.
Jean Bolognia, MD, professor of dermatology at the Yale University School of Medicine
First, Bolognia explained the nomenclature of ADCs. The first part of the ADC name describes the mAb; the second part describes the chemotherapeutic agent and its linker. The second part of the ADC name also indicates its mechanism of action: vedotin and emtansine disrupt microtubules; deruxtecan is a topoisomerase 1 inhibitor; tesirine binds to DNA and leads to crosslinks.
Bolognia discussed enfortumab vedotin and associated cutaneous side effects, including toxic erythema of chemotherapy (TEC). Enfortumab vedotin combines the anti-nectin-4 mAb enfortumab with monomethyl auristatin E (MMAE) via a cleavable linker. It is FDA approved for locally advanced or metastatic urothelial cancer.
Nectin-4 mediates cell-cell adhesion and is expressed in the transitional epithelium of the bladder as well as epidermal keratinocytes. It is also found in several types of carcinoma, including urothelial, breast, ovarian, gastric, head and neck, esophageal, and lung. The most common adverse reactions leading to treatment discontinuation are peripheral neuropathy and rash. Cutaneous side effects include itching, pruritic maculopapular eruptions, skin fragility, miliaria-like eruptions, TEC, and Stevens-Johnson syndrome/toxic epidermal necrolysis.
Enfortumab vedotin is the most common ADC associated with TEC. TEC is an umbrella term used to describe skin diseases that occur 2–4 weeks after receiving chemotherapy. It appears as bilateral and symmetric erythematous to dusky violaceous patches or thin plaques that subsequently can undergo sloughing of the epidermis leading to eroded areas. For patients receiving enfortumab vedotin, TEC most commonly involves the intertriginous zones. TEC will recur if the same or higher dose of the treatment is given.
Bolognia then described trastuzumab emtansine and trastuzumab deruxtecan, both based on the humanized anti-human epidermal growth factor receptor (HER2) mAb trastuzumab. Trastuzumab emtansine combines trastuzumab with the chemotherapeutic agent DM1 via a stable linker. It is FDA approved for metastatic HER2-positive breast cancer. Cutaneous side effects of trastuzumab emtansine include large telangiectasias (often the spider type), mucosal bleeding, mucositis, and TEC. Telangiectasias can be treated with propranolol. Trastuzumab deruxtecan combines trastuzumab with the topoisomerase inhibitor 1 payload DXd via a cleavable linker. It is FDA approved for unresectable or metastatic HER2-positive breast cancer.
Finally, Bolognia discussed loncastuximab tesirine, which combines the humanized mAb specific for human CD19 of the IgG1 kappa isotype with the cytotoxic agent pyrrolobenzodiazepine (PBD) dimer via a cleavable linker. It is FDA approved for relapsed/refractory diffuse large B-cell lymphoma. It has been associated with photosensitivity, cutaneous collagenous vasculopathy, and generalized essential telangiectasia.
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