Delayed immune-related adverse events with anti-PD1-based immunotherapy in melanoma

BACKGROUND: IrAEs typically occur within 4 months of starting anti-PD1-based therapy (anti-PD1 +/- anti-CTLA4), but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAE in patients receiving anti-PD1-based immunotherapy.METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.RESULTS: 118 patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4); with an estimated incidence of 5.3% (95% CI 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53). 87 patients (74%) were on anti-PD1 at irAE onset, 15 patients (12%) were <3 months from last dose, 16 patients (14%) were >3 months from last dose of anti-PD1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥G3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD1, and a multiple organ-irAE with onset 11 months after ceasing anti-PD1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%).CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAE, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD1. The risk of delayed irAE should be considered when deciding duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.