Corticosteroids for Immune-Related Adverse Events and Checkpoint Inhibitor Efficacy: Analysis of Six Clinical Trials

Author(s): Rik J. Verheijden, MSc^1,2; Jolien S. de Groot, MD, PhD³; Babs O. Fabriek, PhD³; Miki N. Hew, MD, PhD³; Anne M. May, PhD²; Karijn P.M. Suijkerbuijk, MD, PhD¹

Source: https://doi.org/10.1200/JCO.24.00191

Dr. Anjan Patel's Thoughts

Pooled data of nearly 2000 patients across six trials in melanoma using IO therapy. It seems clear that high dose corticosteroid use was associated with worse outcomes, especially with high peak doses. What may be worth considering is if non-steroid based immunosuppression can be used as an adjunct to blunt this concerning effect.

PURPOSE

Retrospective studies suggest that immunosuppressive treatment of immune-related adverse events (irAEs) impairs survival in patients with melanoma who received immune checkpoint inhibitors. Here, we study this association across tumor types using data from six international phase II/III registrational trials.

METHODS

A post hoc analysis was performed on individual patient data from the anti–programmed cell death-1 (anti–PD-1) + anti–cytotoxic T lymphocyte–associated protein-4 (anti–CTLA-4) treatment arms of six clinical trials (CheckMate-067, -142, -214, -648, -743, and -9LA). Among patients who received systemic immunosuppression for treatment-related adverse events (trAEs), associations of peak and cumulative corticosteroid dose, and use of second-line immunosuppression with overall survival (OS) and progression-free survival (PFS) were assessed using multilevel Cox regression with adjustment for age and sex.

RESULTS

Of the 1,959 patients who received anti–PD-1 + anti–CTLA-4 therapy, 834 patients who were treated with immunosuppression for trAEs were included. Eight hundred and thirty-two patients (100%) received corticosteroids and 81 patients (10%) received second-line immunosuppressants. High corticosteroid peak dose was associated with worse PFS: adjusted hazard ratio (HRadj), 1.15 (95% CI, 1.02 to 1.29) for 1 versus 0.5 mg/kg prednisolone and HRadj, 1.43 (95% CI, 1.05 to 1.96) for 2 versus 0.5 mg/kg. Similar effects were observed for OS: HRadj, 1.21 (95% CI, 1.06 to 1.39) and HRadj, 1.66 (95% CI, 1.17 to 2.37) for 1 and 2 versus 0.5 mg/kg, respectively. Cumulative corticosteroid dose was not associated with survival. HRadj of use of second-line immunosuppression was 1.23 (95% CI, 0.90 to 1.68) for PFS and 1.25 (95% CI, 0.88 to 1.77) for OS.

CONCLUSION

Higher corticosteroid peak dose for trAEs is associated with worse survival across tumor types, while cumulative dose is not. Too few patients received second-line immunosuppressants to confirm or reject an association with survival. These data argue for a reconsideration of irAE management approaches, starting with lower corticosteroid dose whenever feasible.

Author Affiliations

¹Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; ²Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands; ³Medicines Evaluation Board, Utrecht, the Netherlands

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