Survival Among Veterans Receiving Steroids for Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy

Abstract

ImportanceSystemic steroids are commonly used to manage immune-related adverse events (irAEs), but it remains unclear whether they may undermine immune checkpoint inhibitor (ICI) therapy outcomes. Few studies have assessed the impact of steroid timing and its association with continuation or cessation of ICI therapy.ObjectiveTo characterize how systemic steroids and steroid timing for irAEs are associated with survival in patients receiving ICI therapy.Design, Setting, and ParticipantsThis multicenter retrospective cohort study encompassed veterans receiving ICI for cancer between January 1, 2010, and December 31, 2021. Data analysis was conducted September 8, 2023.ExposuresIdentifiable primary diagnosis of cancer. Patients were categorized into 3 cohorts: those receiving no steroids, systemic steroids for irAEs, and steroids for non–irAE-associated reasons. All eligible patients received 1 or more doses of an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab). Eligible patients in the steroid group received at least 1 dose (intravenous, intramuscular, or oral) of dexamethasone, hydrocortisone, methylprednisolone, prednisone, or prednisolone. Steroid use at baseline for palliation or infusion prophylaxis or delivered as a single dose was deemed to be non–irAE associated. All other patterns of steroid use were assumed to be for irAEs.Main Outcomes and MeasuresThe primary outcome was overall survival, with a 5-year follow-up after ICI initiation. Kaplan-Meier survival analyses were performed with pairwise log-rank tests to determine significance. Risk was modeled with Cox proportional hazard regression.ResultsThe cohort consisted of 20 163 veterans receiving ICI therapy including 12 221 patients (mean [SD] age, 69.5 [8.0] years; 11 830 male patients [96.8%]; 9394 White patients [76.9%]) who received systemic steroids during ICI treatment and 7942 patients (mean [SD] age, 70.3 [8.5] years; 7747 male patients [97.5%]; 6085 White patients [76.6%]) who did not. Patients with an irAE diagnosis had significantly improved overall survival (OS) compared with those without (median [IQR] OS, 17.4 [6.6 to 48.5] months vs 10.5 [3.5 to 36.8] months; adjusted hazard ratio, 0.84; 95% CI, 0.81-0.84; P < .001). For patients with irAEs, systemic steroids for irAEs were associated with significantly improved survival compared with those who received steroids for non–irAE-related reasons or no steroid treatment (median [IQR] OS, 21.3 [9.3 to 58.2] months vs 13.6 [5.5 to 33.7] months vs 15.8 [4.9 to not reached] months; P <.001). However, among those who received steroids for irAEs, early steroid use (<2 months after ICI initiation) was associated with reduced relative survival benefit vs later steroid use, regardless of ICI continuation or cessation following steroid initiation (median [IQR] OS after ICI cessation 4.4 [1.9 to 19.5] months vs 16.0 [8.0 to 42.2] months; median [IQR] OS after ICI continuation, 16.0 [7.1 to not reached] months vs 29.2 [16.5 to 53.5] months; P <.001).Conclusions and RelevanceThis study suggests that steroids for irAE management may not abrogate irAE-associated survival benefits. However, early steroid administration within 2 months of ICI initiation is associated with shorter survival despite continuation of ICI therapy.

Endocrine Immune-Related Adverse Events Are Independent Predictors of Survival in Patients with Lung Cancer

“…However, unlike other irAEs, they tend to be irreversible, leading to a need for lifelong hormone supplementation [14,18,20]. The impact of corticosteroid therapy for irAEs on ICI efficacy is unclear; the organ system affected, the primary tumor type, as well as the timing and dose of systemic steroid therapy may be significant [21][22][23][24]. It has been suggested that the use of systemic corticosteroids is a poor prognostic factor independent of the use of ICIs; however, this has not been consistently shown in patients with LC [25,26].…”

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

“…However, steroid timing for immune-related adverse events may be associated with survival in patients receiving immune checkpoint inhibitor therapy. In large multicenter retrospective cohort study (n=20163), systemic steroids for immune-related adverse events were associated with significantly improved survival compared with those who received steroids for other reasons or no steroid treatment (mOS, 21.3 versus 13.6 versus 15.8 months; P<0.001) (129). However, among those who received steroids for immune-related adverse events, early steroid use (<2 months after immune checkpoint inhibitor…”

“…However, steroid timing for immune-related adverse events may be associated with survival in patients receiving immune checkpoint inhibitor therapy. In large multicenter retrospective cohort study (n=20163), systemic steroids for immune-related adverse events were associated with significantly improved survival compared with those who received steroids for other reasons or no steroid treatment (mOS, 21.3 versus 13.6 versus 15.8 months; P<0.001) ( 129 ). However, among those who received steroids for immune-related adverse events, early steroid use (<2 months after immune checkpoint inhibitor initiation) was associated with reduced relative survival benefit in comparison to later steroid use, regardless of immune checkpoint inhibitor continuation or cessation following steroid initiation (mOS after immune checkpoint inhibitor cessation, 4.4 versus 16.0 months; mOS after immune checkpoint inhibitor continuation, 16.0 versus 29.2 months; P<0.001) ( 129 ).…”

“…(mOS after immune checkpoint inhibitor cessation, 4.4 versus 16.0 months; mOS after immune checkpoint inhibitor continuation, 16.0 versus 29.2 months; P<0.001)(129).…”