Immune-related adverse events of immune checkpoint inhibitors and the impact of sex—what we know and what we need to learn

Özdemir, Berna C.; Coukos, George; Wagner, A.D.

doi:10.1093/annonc/mdx818

Cited by 14 publications

(11 citation statements)

References 6 publications

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“…The greater incidence of autoimmune disease among women might be not enough to explain it; furthermore, this difference comes out from the multivariate analysis, which was performed together with pre-existing AIDs. Sex could surely affect immune responses [31], but to date, "gender medicine" has not yet investigated the sexual dimorphism in ICIs response, and only speculative reflections have been made on the topic [32]. As previously stated [27][28][29], the greater incidence of irAEs among females could be related to the longer OS, which at the same time is aligned with sex-related difference in survival among patients with cancer overall [33], and does not contradict the recent evidences of a greater benefit from immunotherapy with ICIs in male patients [34,35].…”

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study

et al. 2019

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Background Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors. Materials and Methods Consecutive patients with advanced cancer, treated with anti‐programmed death‐1 (PD‐1) agents, were evaluated according to the presence of pre‐existing AIDs. The incidence of immune‐related adverse events (irAEs) and clinical outcomes were compared among subgroups. Results A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non‐small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%); kidney cancer, 94 (12.5%); and others, 6 (0.8%). Male/female ratio was 499/252. Eighty‐five patients (11.3%) had pre‐existing AIDs, further differentiated in clinically active (17.6%) and inactive (82.4%). Among patients with pre‐existing AIDs, incidence of irAEs of any grade was significantly higher when compared with patients without AIDs (65.9% vs. 39.9%). At multivariate analysis, both inactive (p = .0005) and active pre‐existing AIDs (p = .0162), female sex (p = .0004), and Eastern Cooperative Oncology Group Performance Status <2 (p = .0030) were significantly related to a higher incidence of irAEs of any grade. No significant differences were observed regarding grade 3/4 irAEs and objective response rate among subgroups. Pre‐existing AIDs were not significantly related with progression‐free survival and overall survival. Conclusion This study quantifies the increased risk of developing irAEs in patients with pre‐existing AIDs who had to be treated with anti‐PD‐1 immunotherapy. Nevertheless, the incidence of grade 3/4 irAEs is not significantly higher when compared with control population. The finding of a greater incidence of irAEs among female patients ranks among the “hot topics” in gender‐related differences in immuno‐oncology. Implications for Practice Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors but are frequent in clinical practice. This study quantifies the increased risk of developing immune‐related adverse events (irAEs) in patients with pre‐existing AIDs who had to be treated with anti‐programmed death‐1 immunotherapy. Nevertheless, their toxicities are mild and the incidence of grade 3/4 irAEs is not significantly higher compared with those of controls. These results will help clinicians in everyday practice, improving their ability to offer a proper counselling to patients, in order to offer an immunotherapy treatment even to patients with pre‐existing autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study

et al. 2019

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“…The purpose of our study was to verify our hypothesis that the efficacy of PD‐1 inhibitors and CTLA‐4 inhibitor varies in males and females. Several preclinical and clinical trials of ICI depicted this phenomenon, nevertheless, the lack of sufficient statistical power may cause controversy and inaccuracies. This meta‐analysis indicated that males benefits more from CTLA‐4 inhibitor (ipilimumab) and PD‐1 inhibitors (nivolumab and pembrolizumab) than females (Table ).…”

Section: Discussionmentioning

confidence: 99%

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Jia

et al. 2018

Intl Journal of Cancer

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Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression-free survival (PFS) were used. Six thousand and ninety-six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA-4 inhibitor was more influenced by sex variable compared with PD-1 inhibitors. A significant sex-related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.

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“…Immune-related adverse events can include dermatologic, endocrine, neurologic, gastrointestinal, respiratory, and musculoskeletal pathologies that can often be limited by steroidal treatments [52]. While ample consideration has been given to the differential constellation of immune-related adverse events that occur based on the type and dose of checkpoint inhibitors, to date, no studies have considered whether these adverse events may occur differently in males than females [9,53]. Because autoimmune responses occur more frequently in females than males, we hypothesize that the frequency and magnitude of immune-related adverse events, including those that mirror autoimmune-like responses, may be more likely in females than males.…”

Section: Checkpoint Inhibitors For Cancermentioning

confidence: 99%

“…Because autoimmune responses occur more frequently in females than males, we hypothesize that the frequency and magnitude of immune-related adverse events, including those that mirror autoimmune-like responses, may be more likely in females than males. Greater consideration should be given to whether the efficacy and toxicity of checkpoint inhibitors differ between the sexes [9,53]. Because immunotherapies for cancer treatment are a relatively recent therapy option, this could explain the apparent discrepancy between greater death from cancer and greater efficacy of checkpoint inhibitors among males than females.…”

Section: Checkpoint Inhibitors For Cancermentioning

confidence: 99%

The impact of sex and gender on immunotherapy outcomes

2020

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Immunotherapies are often used for the treatment, remission, and possible cure of autoimmune diseases, infectious diseases, and cancers. Empirical evidence illustrates that females and males differ in outcomes following the use of biologics for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA), infectious diseases, e.g., influenza, and solid tumor cancers. Females tend to experience more adverse reactions than males following the use of a class of biologics referred to as immunotherapies. For immunotherapies aimed at stimulating an immune response, e.g., influenza vaccines, females develop greater responses and may experience greater efficacy than males. In contrast, for immunotherapies that repress an immune response, e.g., tumor necrosis factor (TNF) inhibitors for RA or checkpoint inhibitors for melanoma, the efficacy is reportedly greater for males than females. Despite these differences, discrepancies in reporting differences between females and males exist, with females have been historically excluded from biomedical and clinical studies. There is a critical need for research that addresses the biological (i.e., sex) as well as sociocultural (i.e., gender) causes of male-female disparities in immunotherapy responses, toxicities, and outcomes. One-size-fits-all approaches to immunotherapies will not work, and sex/gender may contribute to variable treatment success, including adherence, in clinical settings.

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Immune-related adverse events of immune checkpoint inhibitors and the impact of sex—what we know and what we need to learn

Cited by 14 publications

References 6 publications

Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study

Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

The impact of sex and gender on immunotherapy outcomes

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