Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy

PURPOSE: Immunotherapy experienced impressive progresses in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes and vitiligo are reported. Although frequent, they are have not been further characterized yet. In this analysis we aimed to systematically assess and characterize the adverse cutaneous reactions observed in melanoma patients treated with anti-PD-1 antibodies. EXPERIMENTAL DESIGN: Melanoma patients were treated with anti-PD-1 antibodies within clinical trials and early access program. Adverse cutaneous eruptions emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison to maculopapular drug rash, cutaneous graft versus host disease and the severe drug eruption toxic epidermal necrolysis. RESULTS: Between Feb 2013 and Sept 2015, 68 stage IV melanoma patients were treated at the University Hospital Zurich; 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes without signs of epidermal involvement to severe maculopapular rashes including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as toxic epidermal necrolysis-like reactions. CONCLUSIONS: As predicted by the PD-1 knock out mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases to a toxic epidermal necrolysis-like pattern suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions