Delayed Immune-Related Adverse Events With Anti–PD-1–Based Immunotherapy in Melanoma


 

TAKE-HOME MESSAGE

  • The authors of this multicenter retrospective study describe 140 delayed immune-related adverse events (irAE) among 118 patients with melanoma treated with anti–PD-1–based immune checkpoint inhibitor therapy for >1 year. The median onset of delayed irAEs was 16 months after starting treatment. Although 74% of delayed irAEs occurred during treatment, 12% occurred <3 months after the last dose, and 14% occurred >3 months after the last dose. More than 50% of patients with a delayed irAE had also had an early irAE (ie, occurring during the first year of therapy). In most of these patients, the early irAEs affected a different organ than the delayed irAE. Colitis, rash, and pneumonitis were the most common delayed irAEs; 39% of delayed irAEs were grade ≥3.

  • The continued risk for serious, life-threatening irAEs after 1 year of anti–PD-1 therapy should be considered when deciding the duration of therapy in patients with melanoma.
–  Paul J. Hampel, MD

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.

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