Immune checkpoint inhibitors (ICIs) have emerged from numerous cancer treatments over the past decade or so, not only being approved for the treatment of more than 19 different cancers[1], but also becoming a first-line treatment option against many high morbidity and mortality cancers.
However, it should not be ignored that ICIs cause a wide range of autoimmune and autoinflammatory adverse events associated with immune activation, referred to as immune-related adverse events (irAE), which are clinically very similar to autoimmune diseases (ADs). Does having AD affect ICI treatment for cancer patients?
Recently, a team of Professor Yevgeniy R Semenov from Massachusetts General Hospital of Harvard Medical School published important research results at the Journal of the National Cancer Institute[2] to answer this clinical question.
Overall, by analyzing 17,497 patients diagnosed with AD prior to treatment with PD-1/PD-L1 inhibitors from TriNetX Diamond's large clinical database, and 17,497 matching controls without a history of AD, Semenov's team found that the risk of death was no higher than that of patients without AD controls.
However, specifically, the history of Hashimoto's thyroiditis was associated with a 25% reduction in mortality (HR=0.75, p=0.002), a history of vitiligo was associated with a 48% reduction in mortality (HR=0.52, p=0.003), and 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, Semenov's team believes that AD should not be considered a contraindication to ICI clinical trials and cancer treatment.
Screenshot of the first page of the paper
Because irAE reflects immune activation in treatment, previous studies have shown that the occurrence of irAE is associated with ICI response and improved overall patient survival [3-5]. Despite the similarities between AD and irAE, in order to avoid the exacerbation of AD and the increased risk of irAE, most current ICI clinical trials will still "turn away" 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), Semenov's team included four of the most common indications for ICI, namely C34 (bronchi and lungs), C15-26 (digestive organs), C43 (melanoma), and C64-68 (urinary tract). Baseline AD is defined as having confirmed the diagnosis of any AD prior to the first ICI treatment.
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), with median follow-up times of 1.76 years and 1.84 years in the study and control groups.
Semenov's team matched AD and non-AD patients with a 1:1 propensity score for age, sex, ethnicity, cancer, and staging (with or without distant metastasis).
The results of the analysis showed no significant difference in the risk of death between patients with a history of AD and non-AD control groups (HR=1.03; 95% CI, 1.00-1.07; p=0.05).
Patient baseline characteristics and mortality
In individual analyses of AD, a 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) were associated with a reduced risk of death. A history of celiac disease, lichen planus, and alopecia areata also correlated with a reduced risk of death in patients, but did not achieve statistical significance. However, a history of type 1 diabetes is associated with an increased risk of death (HR =1.11; 95% CI, 1.03–1.19; p=0.002).
In addition, the overall duration of treatment for AD patients and non-AD control groups was also very similar (7.2 vs 7.5 ICI cycles), indicating that the AD history did not significantly increase ICI discontinuation.
Risk ratio of AD to patient mortality
Next, Semenov's team divided the patients into a single-agent treatment group for PD-1/PD-L1 inhibitors and a combination of PD-1 inhibitors and CTLA-4 inhibitors (ipilimumab) for further analysis.
There was no significant risk of death between patients with a history of AD and non-AD controls in the PD-L1 inhibitor monotherapy group (HR=1.08; 95% CI, 0.98-1.18; p=0.13) and PD-1/CTLA-4 combined inhibitor group (HR=1.04; 95% CI, 0.92-1.18; p=0.54).
Patients with a history of AD had a slight increased risk of death (HR=1.14; 95% CI, 1.10-1.18; p 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 mellitus (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) 4 ADs.
Results of risk analysis of death after treatment classification
As the first large-scale study of the effect of AD on ICI treatment outcomes in cancer patients to date, semenov's team's research results have important clinical significance. Although the patient's AD may recur in ICI treatment, the AD history does not increase the patient's mortality and the possibility of early discontinuation of the ICI, so cancer patients with a history of AD can also receive ICI treatment.
Overall, this study suggests that the history of AD is not closely related to mortality from ICI treatment in cancer patients and, in some cases, is also associated with a more favorable prognosis.
The authors also note that the different effects of different ADs observed on patient mortality may be related to whether corticosteroids are clinically used in the treatment of such AD diseases. Steroids are known to weaken the immune response triggered 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, and are also disorders that are not commonly treated with corticosteroids. Conversely, rheumatoid arthritis, inflammatory bowel disease, and mucositis, which are more severe, often require treatment with systemic immunosuppressants such as corticosteroids, which may also be an important cause of increased mortality in patients in the results of the analysis.
Although further research and clinical data are needed to decipher the underlying problems with immunosuppressive therapy in patients with AD, this study has preliminarily demonstrated that the history of AD does not affect the benefit of cancer patients from ICI treatment, so AD is regarded as the criterion for clinical research and treatment contraindications of ICI that needs to be reconsidered.
bibliography
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
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
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