Skin-Related Adverse Events May Indicate Immunotherapies Are Working in Patients With Cancer

New data suggest that patients undergoing immunotherapy achieved better survival outcomes after reporting cutaneous immune-related adverse events.

Cutaneous immune-related adverse events (cirAEs) may indicate a better prognosis for patients receiving immune checkpoint inhibitors (ICIs) to treat their cancer in the advanced setting, suggest findings from a study published in JAMA Dermatology.1 Researchers anticipate that these findings may significantly affect how clinicians counsel patients in the event that skin-related cirAEs emerge during immunotherapy treatment.

Researchers assessed a retrospective cohort of 7008 patients with cancer who reported cirAEs following treatment with either an anti–PD-1/PD-L1 agent and compared these findings to 7008 matched patients in a control group. The 6-month analysis revealed that patients who developed pruritus, drug eruption, xerosis, nonspecific rashes, and any other cirAE were at a significantly decreased risk of mortality.

Although immune checkpoint inhibitors (ICIs) have demonstrated impressive efficacy, cirAEs are known to occur among 20% to 40% of all patients who receive this treatment. Thus far, there has been little research exploring the relationship between cutaneous eruptions and patient survival. The objective behind this research was to determine the association between cirAE development and mortality outcomes.

“These data provide oncologists and dermatologists with important prognostic information when counseling immunotherapy recipients on the clinical implications of the skin toxicities,” senior author Yevgeniy R. Semenov, MD, an investigator in the Department of Dermatology at Massachusetts General Hospital, stated in a press release. “Also, skin toxicities tend to occur early in the course of immunotherapy and present an opportunity to evaluate efficacy soon after initiating treatment. As such, our findings may help identify patients who are more likely to benefit from their current immunotherapy regimen versus those who may need to be considered for a stronger or alternative treatment regimen.”

“Immune checkpoint inhibitors have revolutionized cancer therapy during the last decade. As of 2019, up to 230,000 patients were eligible for treatment with ICI therapy annually in the US alone,” commented study authors. Despite the efficacy of ICIs, immune-related adverse events [irAEs] occur in more than a third of all treated patients and are associated with lasting morbidity, mortality, and impaired quality of life. Cutaneous irAEs are the most frequently reported toxic effects, occurring in 20% to 40% of all treated patients.”

Researchers used data from the TriNetX Diamond Network, which provided the health records and claims data from more than 200 million US and European patients, to design a population-level cohort analysis. Eligible participants included patients with malignant neoplasms of digestive organs, bronchus or lung, melanoma, or urinary tract and who had a record of treatment with cemiplimab (Libtayo), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), or durvalumab (Imfinzi) therapy. Patients who received anti–CTLA-4 therapy with ipilimumab were excluded in order to reduce confounding data from combination therapy.

Within the study, cirAEs were defined as cutaneous eruptions within 6 months of ICI therapy initiation. Data was adjusted for age, sex, race, and disease subtype via 1:1 propensity score matching.

Among the 7008 patients in the experimental cohort, 3036 were women (43.3%) and the average age was 68.2 years. In comparison, 3044 women in the control matched cohort were women (43.4%) and the average age was 68.3 years.

A Benjamini-Hochberg correction revealed significant protection from mortality following the emergence of pruritus (HR, 0.695; 95% CI, 0.602-0.803; P < .001), drug eruption (HR, 0.755; 95% CI, 0.635-0.897; P = .001), xerosis (HR, 0.626; 95% CI, 0.469-0.834; P = .001), nonspecific rashes (HR, 0.704; 95% CI, 0.634-0.781; P < .001), and appearance of any cirAE (HR, 0.778; 95% CI, 0.726-0.834; P < .001).

Moreover, psoriasis (HR, 0.703; 95% CI, 0.497-0.994; P = .045) and lichen planus/lichenoid dermatitis (HR, 0.511; 95% CI, 0.279-0.939; P = .03) demonstrated significant protective capabilities. Other cirAEs including eczematous dermatitis (HR, 0.612; 95% CI, 0.314-1.195), vitiligo (HR, 0.534; 95% CI, 0.254-1.123), bullous pemphigoid (HR, 0.524; 95% CI, 0.140-1.956), and Grover disease (HR, 0.468; 95% CI, 0.115-1.898) were also linked to better survival outcomes in these populations.

Study authors acknowledged that the sample size included an insufficient number of rarer diagnoses and that this may have contributed to a lack of statistical significance among some dermatoses. In addition, population-level databases like TriNetX may have inconsistencies in recorded data because of their inherent heterogeneity.

Nevertheless, the results from this study suggest that future research into underlying immunopathogenesis may be warranted, and that continued efforts within this space may provide further insights into immunotherapy response. In addition, further research is needed to determine whether ICI therapy interruption or discontinuation might impact the link between these AEs and overall survival.

“This is the first population-level study and largest analysis to date of the association of cirAEs with clinical outcomes among patients with advanced cancer,” the study authors concluded.“The results suggest that cirAE development after ICI initiation is strongly associated with response to ICI therapy and patient survival. Except for mucositis and hyperhidrosis, there was a clinically protective effect of cirAEs across all individual morphologies investigated in this study.”


Tang K, Seo J, Tiu BC, et al. Association of cutaneous immune-related adverse events with increased survival in patients treated with anti–programmed cell death 1 and anti–programmed cell death ligand 1 therapy. JAMA Dermatol. Published online January 12, 2022. doi:10.1001/jamadermatol.2021.5476