Chronic immune-related adverse events with anti–PD-1 therapy are more common than previously recognised and may persist unresolved, new research shows.

While most irAEs with anti–PD-1 therapy occur in visceral organs in the first 12 weeks of treatment, almost half of patients may also develop chronic low-level irAEs in non-visceral organs, according to a study that included several Australian centres with patients receiving adjuvant therapy for melanoma.

A multicentre cohort study of 387 patients with stage III to IV melanomas treated with adjuvant pembrolizumab or nivolumab found that 43% of patients developed a chronic irAE, beyond 12 weeks of treatment. And although most (96.4%) were mild, a high proportion  (85.6%) persisted until last available follow-up.

Chronic irAEs most commonly affected nonvisceral systems such as endocrine (hypothyroidism, adrenal insufficiency), joints (arthritis), salivary glands (xerostomia), eye, and peripheral nerves (neurotoxicities).

The study found that acute irAEs were common (69%) and mostly affected visceral organs such as liver, colon, lungs, kidneys. While almost 20% were grade 3-5 adverse events, they mostly resolved with glucocorticoid treatment and there were low rates of becoming chronic effects.

With the chronic irAEs, only 14.4% of these resolved during the median 529-day follow-up; and about half of irAEs were symptomatic. Systemic therapy such as glucocorticoids were required in one third (32.9%) of patients, including 12 patients taking replacement-dose steroids for pituitary/adrenal insufficiency.

Overall, 20% of patients experienced symptomatic chronic irAEs (nonendocrinopathies), including some that required persistent immunosuppression

“One perhaps overly simplistic explanation for this differential chronicity may be the small volume of affected nonvisceral organs (eg, hormone-producing endocrine cells, salivary ducts, synovium, eyes, distal peripheral nerves) compared with the larger volume of the colon, lungs, liver, etc,” the study investigators wrote in JAMA Oncology.

Differential regenerative capacity could also play a role, they added.

The authors said the findings had clinical significance given the widening indications for use of  antiPD-1 therapy and the  increasing number of long-term cancer survivors treated with these agents.

“The adjuvant patient population presents unique considerations; they may have been cured by surgery alone and have longer or normal life expectancies. Thus persistent, life-altering, or life-threatening irAEs should be characterised in detail and integrated into patient counselling and treatment decision-making,” they wrote.