Background High-dose systemic immunosuppression (ISP) is associated with poorer survival outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs).1–3 However, the effect of ISP timing on survival is not well-studied. The aim of this retrospective study is to examine the association between immunosuppression timing and overall survival among ICI recipients using a large multi-institutional cohort.
Methods We identified 2,077 ICI recipients who did not receive chemotherapy within 18 months before or after ICI initiation at the Mass General Brigham Healthcare System and the Dana-Farber Cancer Institute from 2011–2021 (figure 1). ISP use was defined as either 1) at least 10 mg/day prednisone equivalent of glucocorticoids for at least a week, 2) 1 dose of biologic immunosuppression, or 3) at least 1 week of non-steroidal systemic immunosuppression within the time window. Using this definition, 912 patients received ISP within 18 months before or after ICI initiation. Case and control cohorts are defined in (table 1). Multivariate Cox proportional hazard models were computed at different times relative to ICI initiation, adjusting for demographics, Charlson comorbidity index at ICI initiation, ICI type, and cancer type. The control group for all analyses was patients who did not receive ISPs (n=1,165).
Results The median follow-up was 23.0 (IQR: 6–42) months from ICI start. High-dose systemic glucocorticoids were the most common form of ISP (97.7%), followed by biologics (11.7%), and non-steroidal systemic immunosuppressants (10.9%). After covariate adjustment, we found that ISP use within 18 months before or after ICI initiation was associated with significantly increased mortality (HR: 1.44; 95% CI: 1.27–1.64; p<0.001)(table 2). When performing sliding window time analyses, we found that the increased risk of mortality escalated with ISP administration closer to ICI initiation and was the highest when patients received ISP within 1 month before or after ICI initiation (HR: 2.49; 95% CI: 2.05–3.01; p<0.001)(figure 2). The negative effect of ISP exposure tapered off 8–12 months after ICI initiation (HR: 1.29; 95% CI: 0.89, 1.29; q-value: 0.56)(figure 3).
Conclusions Overall, high-dose systemic immunosuppression (primarily glucocorticoid immunosuppression as observed in this cohort) is associated with increased mortality among ICI recipients and correlates with increasingly poorer survival the closer it is administered to ICI initiation. However, the deleterious effects of ISP seem to taper off if administered more than 8 months after ICI initiation. Clinicians should include the timing of ISP administration in the risk and benefit analysis of ISP therapy when counseling cancer patients receiving ICI.
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Petrelli F, Signorelli D, Ghidini M, et al. Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Cancers (Basel). 2020;12(3):546. doi:10.3390/cancers120305462.
Tison A, Quéré G, Misery L, et al. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study. Arthritis Rheumatol. 2019;71(12):2100–2111. doi:10.1002/art.41068
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