Immune Issues After Adjuvant Anti–PD-1 Therapy in Melanoma

Megan Brooks

August 10, 2023

New research confirms that chronic immune-related adverse events (AEs) from adjuvant anti-programmable cell death-1 (anti–PD-1) immunotherapy are common, can affect diverse organ systems, and will likely require extended monitoring and management.

Among more than 300 patients treated with adjuvant anti–PD-1 therapy for advanced/metastatic melanoma, nearly two thirds developed acute immune-related AEs during treatment and almost half developed chronic ones lasting at least 3 months following therapy. These chronic immune-related AEs persisted for nearly 3 years in close to two thirds of patients.

"Long-term toxicities are an issue that should be considered alongside the risk of cancer recurrence when considering patients for immune checkpoint inhibitors in the adjuvant setting," senior author Douglas Johnson, MD, Department of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee, told Medscape Medical News.

The study was published online August 3 in JAMA Network Open.

Anti-PD-1 immunotherapy improves relapse-free survival in high-risk resected melanoma but can also trigger acute immune-related AEs. While these can resolve with glucocorticoids, acute AEs become chronic in roughly 40% of patients. Understanding the long-term impact of immune-related AEs is essential, the investigators explained, given the growing use of anti–PD-1 across various tumor types.

In the current analysis, Johnson and colleagues retrospectively evaluated the incidence and spectrum of long-term outcomes of chronic immune-related AEs in 318 patients (median age, 61 years) who received adjuvant anti–PD-1 therapy for advanced/metastatic melanoma.

Among all patients, 226 (63.7%) developed acute immune-related AEs during treatment and 53 (17%) experienced delayed toxic effects from treatment. Most of these acute AEs were grade 2 or higher, with half (50.4%) requiring steroids. The most common acute immune-related AEs included dermatitis or pruritus, thyroiditis or hypothyroid, arthritis or arthralgias, and colitis or diarrhea.

Chronic immune-related AEs, persisting at least 3 months after the end of treatment, developed in 147 patients (46%), with half experiencing grade 2 or higher severity. Adrenal insufficiency, hypophysitis, thyroiditis/hypothyroid, neuropathy, and nephritis appeared most likely to evolve into a chronic AE, whereas colitis or diarrhea, dermatitis or pruritus, hepatitis and pneumonitis had lower rates of chronicity.

During long-term follow-up, which lasted a median of 2.9 years, chronic immune-related AEs resolved in 54 patients (37%), with median time to resolution of about 11 months from the end of anti–PD-1 therapy.

However, 93 patients (63%) had persistent toxic effects present at their last follow-up, and more than half (58%) had persistent endocrinopathies. Endocrine toxic effects, including adrenal insufficiency, hypophysitis, and thyroiditis or hypothyroid, were more likely to become chronic and persist than nonendocrine toxic effects; however, other more symptomatic immune-related AEs persisted at low rates individually, including cutaneous, rheumatologic, oral, and ocular events.

"The persistent nature of [immune-related] AEs, particularly endocrinopathies, suggests that permanent damage may occur in some patients," the investigators said.

In an exploratory analysis, Johnson and colleagues also found that patients with chronic immune-related AEs had longer median recurrence-free and overall survival compared with those without chronic immune-related AEs.

The high prevalence of chronic immune-related AEs highlights the need for oncologists to consider the risk–benefit ratio when starting adjuvant therapy as well as the need for prolonged monitoring and management of these issues.

"Insights into the long-term impact of adjuvant anti-PD-1 therapy are crucial to optimize patient outcomes," Johnson and colleagues say, adding that it will be important to identify patients predisposed to persistent toxic effects in future research.  

Support for the study was provided by the Susan and Luke Simons Directorship for Melanoma, the James C. Bradford Melanoma Fund, and the Van Stephenson Melanoma Fund. The authors report no relevant financial relationships.

JAMA Netw Open. Published online August 3, 2023. Full text

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