The specific combination of monoclonal antibody, linker, and cytotoxic drug affects the toxicity profile of the ADC. ADCs with cleavable or unstable linkers and higher drug-to-antibody ratios (ie, trastuzumab deruxtecan, sacituzumab govitecan, enfortumab vedotin) have higher rates of off-target toxicities caused by diffusion of cytotoxins locally into surrounding tissues or systemically to affect rapidly dividing cells, like keratinocytes, if the drug conjugate is highly permeable. Additionally, expression of target antigens on keratinocytes or adnexal structures (eg, sweat glands, hair follicles, such as nectin-4 protein) can result in on-target, off-tumor cutaneous toxicities.
Among adverse events reported in clinical trials of ADCs, cutaneous reactions made up 31.3% of all grades and 15.5% of grade 3 or higher adverse events. Cutaneous reactions most commonly begin after the first infusion, with a median time of onset of 11 days (ranging from 4 days to 2 months), and may worsen with subsequent infusions. Certain ADCs, such as enfortumab vedotin, brentuximab vedotin, loncastuximab tesirine, tisotumab vedotin, ado-trastuzumab deruxtecan, polatuzumab vedotin, and sacituzumab govitecan, are more frequently associated with cutaneous toxicities.
Cutaneous eruptions attributed to ADCs encompass a wide range of morphologies and reactions patterns. The most common presentation is all-grade nonspecific morbilliform (exanthematous, maculopapular) rash, reported in 11%-58% of patients on ADC monotherapy. Grade 3 or 4 adverse cutaneous reactions occur in 1%-14% of patients on ADCs. Severe cutaneous adverse reactions, typically grade 3 or 4, are more frequently observed when ADCs are used in combination with a second monoclonal antibody, such as pembrolizumab, or with enfortumab vedotin. Other common dermatologic adverse reactions include alopecia in 13%-47% of patients, pruritus in 6%-33% of patients, and stomatitis / mucositis in 2%-20% of patients.
Enfortumab vedotin has been associated with a range of cutaneous effects including toxic erythema of chemotherapy (TEC) and its subtypes (palmoplantar erythrodysesthesia and a presentation resembling symmetrical drug-related intertriginous and flexural exanthema [SDRIFE]). Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS / TEN) and a bullous eruption have also been reported, which may represent severe bullous variants of TEC.
Less commonly observed cutaneous reactions include telangiectasias reported in patients on ado-trastuzumab emtansine or loncastuximab tesirine-lpyl, and palmar-plantar erythrodysesthesia, most associated with ado-trastuzumab emtansine use. Miliaria-like eruptions, photosensitivity, and drug-induced hypersensitivity syndrome (DIHS) have also rarely been reported in association with ADCs. The Clinical Terminology Criteria for Adverse Events (CTCAE) is a grading system for adverse event reporting associated with cancer therapy. This grading system, and modified versions thereof, can be employed to grade the severity of cutaneous adverse reactions to ADCs as follows:
- Grade 1: Asymptomatic or presence of mild symptoms along with clinical or diagnostic observations. No intervention needed at this time.
- Grade 2: Presence of moderate symptoms necessitating minimal, local, or noninvasive interventions, including limiting age-appropriate instrumental activities of daily living (ADLs).
- Grade 3: Presence of disabling, severe, or medically significant but not immediately life-threatening symptoms. Hospitalization or prolongation of hospitalization may be indicated as well as limitation of self-care ADLs.
- Grade 4: Presence of life-threatening symptoms and consequences necessitating urgent intervention.
- Grade 5: Adverse event(s) resulting in death.
