Multi-Organ Immune-related Adverse Events from Immune Checkpoint Inhibitors

1. Co-occurrences could be clustered together into 7 clusters based on the predominant organ system affected; endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological.

2. Some clusters had overall survival benefits (endocrine, cutaneous), whereas others had worsened outcomes (respiratory, neurological).

Evidence Rating Level: 2 (Good)

Study Rundown: Immune checkpoint inhibitors can cause immune-related adverse events (irAEs) in up to 70% of patients and can affect multiple organ systems. Some previous studies suggested the co-occurrence patterns of irAEs may impact treatment outcome measures, however a further understanding is needed. This retrospective used large multi-institutional datasets (MGBD and TriNetX) to further investigate these concepts. The overall rate of irAEs was found to be 37.7% in the MGBD cohort and 30.5% in the TriNetX cohort with endocrine (36-37%) and cutaneous (24-25%) organ systems the most common affected. The modal irAE severity was grade 2. It was found that co-occurrences could be clustered together into 7 clusters based on the predominant organ system affected; endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological. With regards to outcome measures, the primary analysis focused on a 6-month overall survival. By comparison with patients without irAEs, it was found that the endocrine and cutaneous clusters had favorable outcomes (HR < 1, significant), the respiratory and neurological clusters had unfavorable outcomes (HR > 1, significant), and other clusters (gastrointestinal, musculoskeletal, hepatic) had neutral outcomes (HR ~ 1, non-significant). After factoring in the use of systemic immunosuppressive therapy in irAEs, the overall survival association of the favourable group remained significant (HR 0.56 – 0.67) in both cohorts, and the survival association of the unfavorable group became slightly less pronounced but remained significant (HR 1.16 – 1.38). The strengths of this study included its large cohort size and the limitations included reliance on ICD codes and potential misclassification (false positive/negatives). Overall, this study identified seven patient clusters with distinct irAE co-occurrence patterns and their subsequent survival outcomes.

Click to read the study in Lancet

Relevant Reading: Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival

In-Depth [retrospective cohort]: This study identified two cohorts of patients who received immune checkpoint inhibitors, MGBD (three hospitals in Boston, May 2015 – June 2022, n = 13086), and TriNetX (health-care organization across the USA, April 2010 – Oct 2021, n = 26172) who were propensity score matched (1:2), and their subsequent computational (ICD) irAEs/outcomes were extracted. Manual chart review was only done among a small sample of randomly selected patients and the level of concordance for negative irAEs was 89% and for positive irAEs was 78%. The overall rate of irAEs was found to be 37.7% in the MGBD cohort and 30.5% in the TriNetX cohort with endocrine (36-37%) and cutaneous (24-25%) organ systems the most commonly affected. The modal irAE severity was grade 2. It was found that co-occurrences could be clustered together into 7 clusters based on the predominant organ system affected; endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological. With regard to outcome measures, the primary analysis focused on a 6-month overall survival. By comparison with patients without irAEs, it was found that the endocrine (HR 0.53 [95%CI, 0.40-0.70, p<00001]) and cutaneous clusters (HR 0.61 [0.46-0.81, p=0.0007]) had favourable outcomes, the respiratory (HR 1.60 [1.25-2.03, p=0.0001]) and neurological clusters (HR 1.30 [1.06-1.59, p=0.013]) had unfavourable outcomes, and other clusters (gastrointestinal, musculoskeletal, hepatic) had neutral outcomes (HR ~ 1). After factoring in the use of systemic immunosuppressive therapy in irAEs, the overall survival association of the favourable group remained significant (HR 0.56 – 0.67) in both cohorts, and the survival association of the unfavourable group became slightly less pronounced but remained significant (HR 1.16 – 1.38). Overall, this study identified seven patient clusters with distinct irAE co-occurrence patterns and their subsequent survival outcomes.

Image: PD

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