Tebentafusp is a first-in-class ImmTAC (immune-mobilizing T-cell receptor against cancer) approved for HLA-A02:01-positive adults with metastatic uveal melanoma. It is administered intravenously. The drug consists of a bispecific fusion protein that combines an engineered T-cell receptor recognizing the melanoma-associated antigen gp100 with an anti-CD3 antibody fragment that activates T cells. By linking melanoma cells to polyclonal T cells, tebentafusp redirects and stimulates cytotoxic T-cell activity against the tumor. This same mechanism also targets normal melanocytes, leading to immune-mediated melanocyte damage and inflammatory cytokine release, which account for the high frequency of cutaneous adverse effects seen with treatment.

Cutaneous adverse events are among the most frequent toxicities of tebentafusp, occurring in approximately 80%-90% of patients. In a phase 3 trial, treated patients experienced rash (83%), pruritus (69%), erythema (29%), and edema (20%). These reactions typically began within hours of the first infusion and were most prominent during the first 3 to 4 weeks of therapy, with incidence and severity decreasing with subsequent doses. Histologic analyses confirm that rash represents an on-target, off-tumor immune response, driven by CD8⁺ T-cell infiltration and destruction of gp100-expressing melanocytes, rather than a hypersensitivity reaction. In a prospective cohort of 33 patients, skin toxicity occurred in 78.8% and included symmetrical erythematous patches (83.8%), hemorrhagic macules (11.8%), urticarial lesions (7.4%), and bullous lesions (1.5%).

Most cutaneous events are grade 1-2, although up to 18% may reach grade 3-4 severity. Events are typically self-limited, improve after the first few cycles, and rarely require treatment discontinuation.

Pigmentary changes are delayed effects of tebentafusp therapy, typically arising after several weeks to months. In a large phase 3 trial, depigmentation or hypopigmentation was reported in about 27% of patients, whereas hyperpigmentation occurred in 11%. In contrast, a smaller prospective cohort of 33 patients reported vitiligo-like depigmentation in 8.5% and leukotrichia in 11.4%.

Depigmentation, reflecting direct melanocyte loss, occurs in approximately 27% of patients, whereas hyperpigmentation resulting from postinflammatory changes, is seen in about 11%.

To date, no cases of toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, or other life-threatening cutaneous emergencies have been attributed to tebentafusp.