Effect of Systemic Glucocorticoid Immunosuppression Timing, Dose, and Duration on Overall Survival Among Immune Checkpoint Inhibitor Recipients

BackgroundSystemic immunosuppression (sISP), particularly with glucocorticoids, is commonly used among patients receiving immune checkpoint inhibitor (ICI) therapy. Although recent studies have demonstrated that sISP is associated with poor outcomes in ICI recipients, there is limited information on how the timing, dose, and duration of sISP affect overall survival (OS). This multi-cohort retrospective study aims to address these gaps. MethodsThis study included 13,086 ICI recipients from Massachusetts General Hospital, Brigham and Womens Hospital, and Dana-Farber Cancer Institute (MGBD) between May 31, 2015, and October 11, 2021. For independent validation, 26,172 ICI recipients were identified from the TriNetX database between April 30, 2010, and October 11, 2021, using 2:1 propensity score matching. Multivariable survival analyses were conducted with Accelerated Failure Time (AFT) models, reporting Time Ratios (TRs) and 95% Confidence Intervals (CIs), where TR<1 indicates shorter OS. FindingsIn the MGBD cohort, sISP within one year of ICI initiation was associated with worse OS compared to patients without sISP via landmark analysis. This association was accentuated among patients receiving sISP closer to ICI initiation, with those receiving sISP within one month of ICI initiation having the worst outcomes (TR: 0.49; 95% CI: 0.44-0.54; p<0.0001). Increased dose and duration of sISP were associated with a greater survival time loss, such that doses beyond 60 mg/day had a 40% survival time loss and durations longer than 7 days were associated with a 35% survival time loss. These findings were independently validated in the TriNetX cohort. InterpretationThree key factors are associated with significantly worse OS: sISP near ICI initiation, higher sISP dose, and longer sISP duration, regardless of indication. These findings provide clinicians with valuable information to guide sISP management among ICI recipients. FundingNIH, USA Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe reviewed PubMed and existing literature for studies on systemic immunosuppression (sISP), particularly glucocorticoids, and outcomes among immune checkpoint inhibitor (ICI) recipients. Previous research, including clinical trial studies, indicated that sISP, especially at higher doses or for managing immune-related adverse events (irAEs), was associated with poorer survival. However, studies were limited by small sample sizes, focused on single cancer types, or did not comprehensively assess the nuanced impacts of sISP timing relative to ICI initiation, dose, and duration across diverse cancer types and ICI indications. Thus, a clear understanding of these specific parameters in large, real-world cohorts was lacking. Added value of this studyThis multi-cohort study analyzed approximately 40,000 ICI recipients, leveraging data from a large academic medical center system (MGBD) and validating findings in a national, population-level database (TriNetX) with access to granular patient-level data. We comprehensively investigated how the timing, dose, and duration of systemic glucocorticoid immunosuppression influence overall survival across a pan-cancer population. Our large scale and detailed approach provide robust, generalizable insights into these critical factors, addressing limitations of prior, smaller, or more narrowly focused investigations. Implications of all the available evidenceOur findings offer clinicians critical, actionable insights for managing systemic glucocorticoid immunosuppression in patients receiving ICI therapy. Knowing that sISP administered near ICI initiation, at higher doses, or for longer durations is associated with significantly worse overall survival can guide clinical decision-making. This allows for more informed risk-benefit discussions, strategies to minimize steroid exposure when feasible (e.g., lowest effective dose, shortest duration), and consideration of steroid-sparing alternatives, ultimately aiming to optimize survival outcomes for cancer patients on ICI therapy.