June 22, 2024

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Will AD affect ICI treatment for cancer patients?

Will AD affect ICI treatment for cancer patients?


Will AD affect ICI treatment for cancer patients?


Immune checkpoint inhibitors (ICIs) have emerged from numerous cancer treatments over the past decade, and have not only been approved for the treatment of more than 19 different cancers [1], but have also become the first choice in the fight against many cancers with high morbidity and mortality. first-line treatment options.


However, it cannot be ignored that ICIs cause a wide range of autoimmune and autoinflammatory adverse events related to immune activation, referred to as immune-related adverse events (irAEs), which are clinically very similar to autoimmune diseases (ADs). similar . Does having AD itself affect the ICI treatment of cancer patients?


Recently, the team of Professor Yevgeniy R Semenov from the Massachusetts General Hospital of Harvard Medical School published important research results in the Journal of the National Cancer Institute [2], which answered this clinical question.


Overall, by analyzing 17,497 patients with AD diagnosed before receiving PD-1/PD-L1 inhibitor therapy and 17,497 matched controls with no history of AD from the TriNetX Diamond large clinical database, Semenov’s team found that AD Patients with a medical history were not at higher risk of death than controls without AD .


However, specifically, a history of Hashimoto’s thyroiditis was associated with a 25% lower mortality rate (HR=0.75, p=0.002), a history of vitiligo was associated with a 48% lower mortality rate (HR=0.52, p=0.003), A history of type 1 diabetes was associated with an 11% increased risk of death (HR=1.11, p=0.002) .


Based on the above research data, the Semenov team believes that AD should not be considered a contraindication to ICI clinical trials and cancer treatment .


Will AD affect ICI treatment for cancer patients?


Since irAEs reflect immune activation during treatment, previous studies have shown that the occurrence of irAEs is associated with ICI treatment response and improved overall survival [3-5]. Despite the similarities between AD and irAEs, in order to avoid the aggravation of AD and the increased risk of irAEs, most ICI clinical trials will still “shut out” patients with a history of AD.


Based on the diagnostic classification of malignant tumors in the 10th edition of the International Classification of Diseases (ICD-10), the Semenov team included the four most common indication categories for ICIs, namely C34 (bronchial and lung), C15-26 (digestive organs), C43 (melanoma) and C64-68 (urinary tract). Baseline AD was defined as any AD diagnosed prior to the first ICI treatment .


Will AD affect ICI treatment for cancer patients?

AD disease list and ICD-10 code


This retrospective cohort analysis included a total of 34,994 patients treated with PD-1 inhibitors (cemiplimab, nivolumab, or pembrolizumab) or PD-L1 inhibitors (atezolizumab, avelumab, or durvalumab) . Follow-up times were 1.76 and 1.84 years, respectively.


The Semenov team matched AD and non-AD patients for age, sex, race, cancer, and stage (presence of distant metastases) using a 1:1 propensity score.


There was no significant difference in the risk of death between patients with a history of AD and non-AD controls (HR=1.03; 95% CI, 1.00-1.07; p=0.05).


Will AD affect ICI treatment for cancer patients?

Patient Baseline Characteristics and Mortality


In the individual analysis of AD, history of Hashimoto’s thyroiditis (HR=0.75; 95% CI, 0.62-0.90; p=0.002) and vitiligo (HR=0.52; 95% CI, 0.34-0.81; p=0.003) ) was associated with a reduced risk of death in patients. Celiac disease, lichen planus and a history of alopecia areata were also associated with a lower risk of death in patients, but they did not reach statistical significance. However, a history of type 1 diabetes was associated with an increased risk of death (HR=1.11; 95% CI, 1.03-1.19; p=0.002).


In addition, the total duration of treatment in AD patients and non-AD controls was also very similar (7.2 vs 7.5 ICI cycles), suggesting that a history of AD did not significantly increase ICI discontinuation.


Hazard ratios for the effect of AD on patient mortality


Next, the Semenov team divided the patients into PD-1/PD-L1 inhibitor monotherapy group and PD-1 inhibitor combined with CTLA-4 inhibitor (ipilimumab) for further analysis.


In the PD-L1 inhibitor monotherapy group (HR=1.08; 95% CI, 0.98-1.18; p=0.13) and the PD-1/CTLA-4 combination inhibitor therapy group (HR=1.04; 95% CI, 0.92 -1.18; p=0.54), there was no .


In the setting of PD-1 inhibitor monotherapy, patients with a history of AD had a slightly increased risk of death (HR=1.14; 95% CI, 1.10-1.18; p<0.001), mainly due to rheumatoid arthritis ( HR=1.09; 95% CI, 1.00-1.19; p=0.05), inflammatory bowel disease (HR=1.05; 95% CI, 1.01-1.10; p=0.03), type 1 diabetes (HR=1.12; 95% CI) , 1.04-1.21; p=0.002), and mucositis (HR=1.11; 95% CI, 1.02-1.20; p=0.02) caused by the four ADs.


Will AD affect ICI treatment for cancer patients?

Mortality risk analysis results after treatment classification


As the first large-scale study to date of the impact of AD on the outcome of ICI treatment in cancer patients , the research results of Semenov’s team have important clinical implications. Although a patient’s AD may recur during ICI treatment, a history of AD does not increase patient mortality and the possibility of premature discontinuation of ICI , so cancer patients with a history of AD can also receive ICI therapy.


Overall, this study shows that history of AD is not strongly associated with ICI-treated mortality in cancer patients, and in some cases is also associated with a more favorable prognosis .


The authors also pointed out that the different effects of different ADs on mortality observed this time may be related to whether corticosteroids are clinically used in the treatment of such AD diseases . Because steroids are known to attenuate the immune response elicited by ICIs [6,7].


Hashimoto’s thyroiditis, vitiligo, celiac disease, lichen planus, and alopecia areata are associated with a reduced risk of death in patients with AD, and are also diseases that are not commonly treated with corticosteroids. In contrast, more severe ADs such as rheumatoid arthritis, inflammatory bowel disease, and mucositis, which often require treatment with systemic immunosuppressive agents such as corticosteroids, may also be an important contributor to the increased mortality in the analysis.


Although further research and clinical data are needed to decipher the potential problems of immunosuppressive therapy in AD patients, this study has preliminarily demonstrated that AD history does not affect the benefit of cancer patients from ICI therapy. Therefore, AD is considered as an ICI clinical study and a The criteria for treatment contraindications are subject to reconsideration.








1. Twomey JD, Zhang B. Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics. AAPS J. 2021;23(2):39. Published 2021 Mar 7. doi:10.1208/s12248-021-00574-0

2. Tang K, Tiu BC, Wan G, et al. Pre-Existing Autoimmune Disease and Mortality in Patients Treated With Anti-PD-1 and Anti-PD-L1 Therapy [published online ahead of print, 2022 Feb 21]. J Natl Cancer Inst. 2022;djac046. doi:10.1093/jnci/djac046

3. Zhou X, Yao Z, Yang H, Liang N, Zhang X, Zhang F. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med. 2020;18(1):87. Published 2020 Apr 20. doi:10.1186/s12916-020-01549-2

4. Park R, Lopes L, Saeed A. Anti-PD-1/L1-associated immune-related adverse events as harbinger of favorable clinical outcome: systematic review and meta-analysis. Clin Transl Oncol. 2021;23(1):100-109. doi:10.1007/s12094-020-02397-5

5. 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. 2022;158(2):189-193. doi:10.1001/jamadermatol.2021.5476

6. Riudavets M, Mosquera J, Garcia-Campelo R, et al. Immune-Related Adverse Events and Corticosteroid Use for Cancer-Related Symptoms Are Associated With Efficacy in Patients With Non-small Cell Lung Cancer Receiving Anti-PD-(L)1 Blockade Agents. Front Oncol. 2020;10:1677. Published 2020 Sep 7. doi:10.3389/fonc.2020.01677

7. Bai X, Hu J, Betof Warner A, et al. Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clin Cancer Res. 2021;27(21):5993-6000. doi:10.1158/1078-0432.CCR-21-1283

Will AD affect ICI treatment for cancer patients?

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