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In Skin Cancer, Immunotherapy May Lead to Chronic Effects


Research showed that many patients with skin cancer who had been treated using immunotherapy, such as immune checkpoint inhibition, experienced chronic side effects.

Chronic immune-related side effects were common in patients with skin cancer who were treated with postsurgical Opdivo (nivolumab) or Keytruda (pembrolizumab), although for some individuals, these toxicities were resolved by the 18-month mark, according to a recent study1 published in JAMA Network Open.


“Insights into the long-term impact of adjuvant anti–PD-1 therapy are crucial to optimize patient outcomes as these agents are used across different tumor types,” the authors wrote in their published study. “The high prevalence of chronic (immune-related side effects) suggests the importance of considering the risk-benefit ratio when initiating adjuvant therapy and the need for prolonged monitoring and proactive management of (immune-related side effects).”

Immunotherapy agents, such as Opdivo and Keytruda, have become increasingly popular in the skin cancer space in recent years. These drugs block certain proteins on the cancer cell surface that help the tumors hide from the immune system. By doing so, immunotherapy agents help the patient’s immune system find and fight cancer.

The researchers involved in this study analyzed data from 318 patients who were treated with Opdivo or Keytruda after undergoing surgery for advanced or metastatic melanoma. Findings showed that 147 patients (46.2%) experienced at least one chronic (lasting three months or longer) immune-related side effect. This included 74 grade 2 or higher side effects and six were grade 3 through 5 (moderate, severe or fatal). All these side effects were symptomatic.

“(Immunothearpy drugs) targeting … PD-1/PD-L1 prolong recurrence-free survival when used as adjuvant therapy. … Anti–PD-1 also causes widespread T-cell activation and results in autoimmune side effects involving multiple organs, termed immune-related adverse events,” the authors wrote. “While most severe (immune-related adverse events) are acute and resolve with glucocorticoids, we recently reported that up to 43% of (immune-related adverse events) persist for at least 12 weeks following therapy cessation in patients with melanoma treated with adjuvant anti–PD-1.”

At a longer follow-up, (average of 34.7 months) 54 patients (36.7%) experiences resolution of their chronic side effects, with an average of 11.2 months between ending their immunotherapy treatment and having their toxicity resolve.

For those who were still experiencing side effects at the long-term follow-up, 59.1% had grade 2 or higher side effect, while 44.1% were symptomatic and 25.8% were using therapeutic steroid treatment.

Common immunotherapy side effects that sometimes became chronic included: adrenal insufficiency, arthritis or joint pain, skin inflammation, thyroid issues and colitis/diarrhea.

Among the 48 patients who experienced chronic side effects, 32.7% experienced disease recurrence, including 18 cases (12.2%) of regional recurrence and 30 (20.4%) of metastatic recurrence, meaning that the cancer spread to another part of the body. Additionally, some patient (32.4%) experienced a flare of the toxicity when they were retreated with immunotherapy.

“The resolution of some chronic (immune-related side effects), as well as the flares occurring with retreatment (32.4%) suggest some patients have ongoing inflammation. The persistent nature of (immune-related side effects), particularly endocrinopathies, suggests that permanent damage may occur in some patients. For this population, rechallenge with a lower risk of irAEs may be possible (although some still flare),” the researchers wrote. “Further research should aim to identify patients that are predisposed to persistent toxic effects.”


  1. Goodman RS, Lawless A, Woodford R, et al. Extended follow-up of chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma. JAMA Netw Open. 2023;6(8):e2327145. doi:10.1001/jamanetworkopen.2023.27145

[This article was originally published by our sister publication, Cure.]

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