Chronic irAEs Common After Anti-PD-1 Therapy in Patients With High-Risk Resected Melanoma

Among patients who receive adjuvant anti-programmed cell death-1 (anti-PD-1) therapy following resection of high-risk melanoma, chronic immune-related adverse events (irAEs) are common and frequently continue long-term, according to results of a retrospective multicenter study published in JAMA Network Open.

Researchers conducted a retrospective multicenter cohort study to evaluate the incidence, characteristics, and long-term outcomes of chronic immune-related adverse events resulting from adjuvant anti-PD-1 therapy. They sourced data from electronic medical records at 6 academic medical centers in the United States and Australia. Eligible patients had received at least 1 dose of adjuvant anti-PD-1, with follow-up data available for 18 months or longer. Acute irAEs were defined as those occurring during treatment, chronic irAEs were those occurring at least 3 months after treatment cessation, and delayed irAEs were defined as occurring within 6 months after treatment cessation.

The study included 318 patients (59.7% male), with a median age of 61 (interquartile range [IQR], 52.3-72.0) years. Cutaneous melanoma was the primary diagnosis in 84.9% of participants, 53.8% (n=171) had BRAF/NRAS wild-type variants, 35.5% (n=113) had resected stage IIIB melanoma, and 39% (n=124) had resected stage IIIC melanoma. Adjuvant anti-PD-1 therapy consisted of nivolumab (255 [80.2%] patients) and pembrolizumab (63 [19.8%] patients), administered for a median duration of 315 (IQR, 170-351) days. A total of 170 (53.5%) patients completed 12 months of therapy. A total of 89.3% of patients survived through a median follow-up of 1057 (IQR, 915-1321) days.

Overall, 71.1% of patients had an acute irAE, and 17.0% had delayed toxic effects. Among the acute irAEs, 63.7% were grade 2 or higher and 50.4% of patients required steroids. The most frequently occurring acute irAEs included dermatitis or pruritus (28.6% of patients).

Chronic toxic effects occurred in 147 patients (46.2%; 95% CI, 0.41%-0.52%), of whom 74 (50.3%; 23.3% of the full cohort) had a grade 2 or greater AE; 6 (4.1%) of those patients (1.9% of the full cohort) had a grade 3 to 5 AE. Corticosteroids were needed in 38.1% of patients with chronic toxic effects, and 100 patients (68.0%) had symptomatic chronic toxic effects. Among 75 patients with acute endocrine irAEs, in 64 (85.3%) the irAEs became chronic.

Among the 147 patients who experienced chronic toxic effects of anti-PD-1 therapy, at the last follow-up 36.7% had resolution of their chronic irAEs while 63.3% (95% CI, 0.55-0.71) had ongoing chronic toxic effects (representing 29.2% of the initial cohort; 95% CI, 0.25-0.34). Median time to resolution of chronic irAEs was 19.7 (IQR, 14.4-31.5) months from initiation of anti-PD-1 treatment and 11.2 (IQR, 8.1-20.7) months from treatment cessation.

Among the 93 patients with persistent toxic effects during the last follow-up, 41 (44.1% or 12.9% of the original cohort) remained symptomatic. In addition, 54 of 64 (84.4%) patients with chronic endocrine irAEs had persistent irAEs at the final follow-up. The median time to chronic nonendocrine irAE resolution was 19.5 (IQR, 14.1-29.9) months from initiation of anti-PD-1 therapy and 9.0 (IQR, 7.0-20.1) months from treatment cessation.

In a comparison of 77 (45.0%) patients without chronic irAEs, 48 (32.7%) patients with chronic irAEs experienced disease recurrence, 18 (12.2%) had regional recurrence, and 30 (20.4%) had metastatic recurrence. Among 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) patients had no effects on their chronic irAEs, 12 (32.4%) patients experienced a flare, and 20 (54.1%) had distinct irAEs.

Limitations include the use of clinical data and notes to review toxic effects and adverse events. In addition, the documentation may not have included every toxicity that each patient experienced. Also, recurrence-free survival analysis between patients with vs without chronic irAEs was likely to have been affected by time-dependent bias.

“These findings suggest that chronic irAEs are common and often persistent, emphasizing the importance of careful risk-benefit analysis and prolonged monitoring and management when considering adjuvant anti-PD-1 therapy,” the researchers concluded.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.