Background Immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy can involve multiple organ systems, of which cutaneous irAEs (c-irAEs) are the most common.1–5 Understanding co-occurrence patterns and prognostic outcomes of irAEs is critical for immunotherapy management. However, previous studies have been limited by cohort size, thus limiting generalizability.6–8 In addition, the prior study approaches primarily utilized pairwise comparison analyses, which limited the examination of irAE relationships to two organ systems at a time. In this study, we leverage a population-level database and compare results to a multi-institutional cohort from a tertiary-level academic healthcare system to investigate the co-occurrence patterns irAEs and their impact on immunotherapy outcomes through non-negative matrix factorization (NMF),9 which allows for multi-organ analyses.
Methods After propensity-matching in a 1:2 ratio based on demographic and cancer-related variables and exclusion of ambiguous cases, the study analyses included 9,273 patients in the Mass General Brigham Healthcare System (MGB) cohort and 23,689 patients in the TriNetX network (figure 1). The identification of irAEs was based on ICD codes. Pairwise correlation analysis and NMF were conducted to investigate the co-occurrence patterns. Multivariate landmark analyses were conducted to evaluate the associated impact on overall survival, adjusting for demographics, cancer type, and ICI type.
Results Characteristics of the TriNetX and MGB are shown in (table 1). Pairwise co-occurrence analyses showed patients with c-irAEs were at increased risk of developing an irAE in nine of the eleven organ systems evaluated. The co-occurrence of c-irAEs and non-cutaneous irAEs (nc-irAEs) was associated with improved survival (HR:0.68, CI, 0.61–0.76; p<0.001) (table 2). NMF identified four unique patient clusters, of which three were consistent between the TriNetX and MGB cohorts: c-irAEs, endocrine irAEs, and multiple internal organ irAEs (comprising mostly neurologic, respiratory, gastrointestinal irAEs) (figure 2). The Cutaneous and endocrine clusters showed strongly favorable prognoses across all landmark times (table 3). The endocrine-dominant cluster displayed a better prognosis (MGB: HR=0.48, p<0.001; TriNetX: HR=0.58, p<0.001) compared to the Cutaneous-dominant cluster (MGB: HR=0.55, p<0.001; TriNetX: HR=0.65, p<0.001).
Conclusions Our study demonstrates that patients who develop c-irAEs are at significantly increased risk of developing toxicities in other organs. This emphasizes the importance of monitoring, diagnosing, and managing c-irAEs given their valuable prognostic benefit. In addition, we specifically found a significant survival benefit among patients who develop cutaneous and endocrine irAEs. This may suggest underlying mechanisms that differ from other ICI and organ system interactions, which will require future studies to elucidate.
Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(1):1–21. Doi:10.1038/s41572–020-0160–6
Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. Doi:10.1186/S40425–017-0300-Z
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology. 2018;36(17):1714–1768. Doi:10.1200/JCO.2017.77.6385
Le TK, Brown I, Goldberg R, et al. Cutaneous Toxicities Associated with Immune Checkpoint Inhibitors: An Observational, Pharmacovigilance Study. J Invest Dermatol. 2022;142(11):2896–2908.e4. doi:10.1016/J.JID.2022.04.020
Wongvibulsin S, Pahalyants V, Kalinich M, et al. Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune-checkpoint inhibitors: A United States population-level analysis. J Am Acad Dermatol. 2022;86(3):563–572. Doi:10.1016/J.JAAD.2021.03.094
Chieng JHL, Htet ZW, Zhao JJ, et al. Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment. Cancers (Basel). 2022;14(11):2687. Doi:10.3390/CANCERS14112687
Yamada K, Nakamura M, Yamamura T, et al. Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival. World J Gastroenterol. 2021;27(41):7190. Doi:10.3748/WJG.V27.I41.7190
Asdourian MS, Shah N, Jacoby T V, et al. Development of multiple cutaneous immune-related adverse events among cancer patients after immune checkpoint blockade. J Am Acad Dermatol. 2023;88(2):485–487. Doi:10.1016/j.jaad.2022.06.030
Pedregosa FABIANPEDREGOSA F, Michel V, Grisel OLIVIERGRISEL O, et al. Scikit-learn: Machine Learning in Python. Journal of Machine Learning Research. 2011;12(85):2825–2830. Accessed February 24, 2023. http://jmlr.org/papers/v12/pedregosa11a.html
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.