Corticosteroids, later onset of immune-related adverse events linked to greater odds of developing chronic autoinflammatory toxic effects in melanoma patients.
New research suggests using corticosteroids to manage the immune-related side effects of anti-programmed cell death protein 1 treatment in melanoma can cause chronic issues.
“Anti-PD1 ICIs have shown durable benefit among patients with advanced melanoma,” the researchers wrote in JAMA Network Open. “[But] ICIs can trigger T-cell activation and lead to immune-related adverse events (irAEs), which are autoinflammatory toxic effects that can impact many organ systems.”
“Because anti-PD-1 ICIs are increasingly used across many tumour types and can lead to long-term survivorship, it is critical to further assess their chronic effects. Currently, we lack reliable ways to identify patients at risk for developing chronic irAEs. To address this knowledge gap, we conducted a large, multicentre cohort study that built on a recent investigation of patients with and without irAEs from adjuvant anti-PD-1 therapy.”
Three hundred and three patients with resected stage III to IV melanoma who were treated with anti-PD-1 therapy between 2015 and 2024 at one of seven academic medical centres across Australia and the US were included in the current retrospective analysis (61% men, median age at anti-PD-1 therapy initiation 64 years). Patients who were not followed for at least 12 months after discontinuing anti-PD-1 therapy were excluded. The median follow-up period was 67.0 months overall, and 57.1 months after treatment discontinuation.
One hundred and forty-six patients (48% of the overall sample) developed chronic irAEs. There were 51 patients with chronic endocrine irAEs, 85 with chronic nonendocrine irAEs, and 10 with both chronic endocrine and nonendocrine irAEs. In the 146 patients who went on to develop chronic irAEs, the most common adverse events were hypothyroidism (31%), arthritis (17%), dermatitis (12%), xerostomia (8%), and adrenal insufficiency (6%). There were also 25 patients who experienced chronic toxic effects beyond the classical irAEs, namely fatigue, orthostasis, and headache.
Observing additional chronic toxic effects was consistent with previous evidence that ICIs are associated with non-classical, off-target, and long-term effects, the authors said.
“In a large retrospective multicentre study of 517 patients receiving anti–PD-1 treatment, fatigue was one of the most common ICI-induced toxic effects, with early fatigue seeming to be a negative prognostic indicator,” they wrote. “[And] although [it is] less common, dysautonomia has also been reported in case reports as a result of ICI therapy.”
Multivariable analyses designed to explore the interactions between the time between irAE onset and corticosteroid use, the time between irAE onset and whether the patient received anti-PD-1 treatment, and patient age and sex revealed a significant association between corticosteroid exposure and irAEs onset.
Specifically, in patients with an earlier onset of irAEs (<42 days), the odds of developing chronic irAEs were three times higher (adjusted odds ratio and 95% confidence interval 3.00, 1.45-6.22) in patients treated with corticosteroids compared to patients not treated with corticosteroids. However, this associated weakened as the onset of irAEs occurred later; the odds ratio dropped to 1.77 (1.02-3.08) if the onset of irAEs occurred at between 42 and 259 days after starting treatment, and 1.14 (0.60-2.16) if it took more than 259 days for irAE onset to occur.
“It is possible this represents the limitations of modest sample size but could also suggest a speculative model where: (1) early-onset irAEs that are severe enough to require corticosteroids may be high risk for chronicity, while (2) milder, later-onset toxic effects may not be treated with corticosteroids as frequently, thus never resolving and becoming chronic,” the researchers wrote.
“Similar findings were seen with anti–PD-1 treatment status: early discontinuation was associated with less risk of chronic toxic effects whereas the association was less pronounced later in the treatment course.”
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A subset of patients with ongoing symptomatic, chronic nonendocrine irAEs also had molecular data available. When their cytokine levels were compared to patients who did not have irAEs 12 months after starting anti-PD-1 treatment, there were eight that were expressed at greater levels in the treatment group: FEF-23, MMP-1, CSF-1, CCL19, Flt3L, VEGFA, CCL25, and MMP-10.
“Our identification of elevated cytokines in chronic irAEs could suggest precision-targeted therapies that could reduce the burden of toxic effects while preserving the effectiveness of ICIs,” the researchers wrote. “Systemic corticosteroids are the current mainstay for managing nearly all nonendocrine irAEs [as] corticosteroids provide broad immunosuppression but cause well-documented long-term adverse effects that affect nearly every organ system.”
“In contrast, targeted therapies against specific cytokines could offer a more focused mechanism of action. Preclinical murine models demonstrate that blocking IL-25 or IL-17RA alongside anti-PD-1 and anti-CTLA-4 therapy prevents irAEs such as pneumonitis and hepatitis while preserving antitumour effectiveness.”
The researchers noted that the retrospective approach to the current study meant their review of toxic effects may not be as stringent as adverse event reporting is in clinical trials, and that they were unable to establish causal relationships between risk factors and the development of chronic irAEs.
These limitations aside, the researchers felt that dedicating more attention to understanding irAEs was a necessary next step as more patients with high-risk resected melanoma survive for longer after receiving anti-PD-1 therapy.
“Our findings highlighted that living longer increasingly equates to living with – and needing management for – chronic ICI-induced toxic effects,” they concluded. “Given the long-term survival of patients who receive adjuvant anti-PD-1 therapy, further research should aim to identify patients at higher risk of irAEs and investigate novel treatment approaches.”
