Dr Postow on the Timing of Delayed or Re-Emergent irAEs in Melanoma

“Chronic [adverse] effects [AEs] are those that continue beyond 3 years after the last dose. It’s important [to understand] that these drugs, permanently in some situations…rewire the immune system. That can lead to long-term, chronic, inflammatory AEs that we’re just beginning to understand.”

Michael A. Postow, MD, chief of the Melanoma Service at Memorial Sloan Kettering Cancer Center, discussed the evolving understanding of immune checkpoint inhibitors (ICIs) in melanoma and the unique toxicity profiles associated with these agents.

Unlike traditional cancer therapies, where adverse effects (AEs) often emerge early during treatment and resolve after therapy cessation, immune checkpoint inhibition presents a distinct clinical challenge because of its capacity to alter immune system function in prolonged, and in some cases permanent, ways, Postow began.

Immune-related AEs (irAEs) can vary substantially in both presentation and timing. Although some patients experience minimal or no toxicity with ICIs, others may develop significant inflammatory complications that occur months or even years after treatment initiation, Postow said. Importantly, these toxicities are not always confined to the active treatment period. Delayed irAEs may emerge more than one year after therapy begins, while some chronic toxicities can persist beyond 3 years after the final dose of treatment.

Recognition and appropriate categorization of these long-term AEs is critical, Postow explained, noting that delayed toxicities are defined as AEs that occur long after treatment initiation, whereas chronic toxicities refer to persistent inflammatory or autoimmune complications that continue well after discontinuation of therapy. This distinction is increasingly relevant as more patients receive ICIs across tumor types and survive longer following treatment.

The prolonged immune modulation that may result from immunotherapy may contribute to sustained inflammatory conditions affecting multiple organ systems, including endocrine, dermatologic, gastrointestinal, pulmonary, and rheumatologic pathways, Postow added. Because the oncology community is still in the early stages of understanding these mechanisms, Postow emphasized the importance of maintaining a high index of suspicion when evaluating new or persistent symptoms in patients previously exposed to immunotherapy.

Through shared responsibility, oncologists, multidisciplinary care teams, and patients can help screen and monitor for late-emerging toxicities. Education surrounding the potential duration and unpredictability of irAEs is essential to ensure prompt diagnosis and intervention. Ultimately, continued research and clinical awareness aimed at optimizing recognition, management, and long-term supportive care strategies is needed for patients experiencing chronic or delayed immunotherapy-related toxicities, Postow concluded.