Corticosteroids for Immune-Related Adverse Events and Checkpoint Inhibitor Efficacy

1. When comparing corticosteroid peak dose for immunosuppression for anti–PD-1 plus anti–CTLA-4–related adverse events, the HR for OS was 1.66 for 2.0mg/kg vs 0.5 mg/kg.

2. When comparing cumulative corticosteroid dose the HR for OS was 0.96 per 1,000-mg increase.

Evidence Rating Level: 2 (Good)

Study Rundown: Immune checkpoint inhibitors (ICIs) can often cause immune-related adverse events (irAEs), which if severe, require high-dose corticosteroids. While irAEs are linked to longer survival, recent studies suggest that aggressive immunosuppressive treatment might negate this benefit. This study investigated whether corticosteroid use and second-line immunosuppressants impact survival in patients treated with combined anti–PD-1 and anti–CTLA-4 therapies across multiple tumor types using clinical trial data. Primary outcomes included overall survival (OS) and progression-free survival (PFS). It was found that overall, 43% of patients received systemic immunosuppression for irAEs but the frequency ranged between studies, from 25% (patients with esophageal SCC) to 67% (patients with melanoma). The most frequent irAEs were GI (11%), hepatobiliary (8%), endocrine (8%), cutaneous (6%), and pulmonary (6%). The median corticosteroid peak dose was 1.0 mg/kg prednisolone (IQR, 0.54-1.51), and ranged 0.75 mg/kg in esophageal SCC to 1.22 mg/kg in melanoma. The median cumulative corticosteroid dose was 1,850 mg (IQR, 680-3,712) and ranged from 977 mg in esophageal SCC to 2,670 mg in melanoma. Median OS was 27 months (95%CI, 25-29) in all patients who received anti–PD-1 plus anti–CTLA-4 therapy and 47 months (95%CI, 32-82) in patients who received immunosuppression for irAEs. These results were similar when correcting for trAE grade or type. When investigating cumulative corticosteroid dose the HR for PFS was 0.98 (95%CI, 0.93-1.03; 95%PI, 0.92-1.04) per 1,000-mg increase, and similarly, the HR for OS was 0.96 (95%CI, 0.91-1.01; 95%PI, 0.90-1.01) per 1,000-mg increase. There was no significant association between second-line immunosuppressant use and PFS or OS. The strengths of this study included the sample size, and the limitations included variability in treatment protocols across the included studies, as well as accounting for additional residual confounding factors. Overall, this study found that there might be an associated impaired survival with higher corticosteroid peak dose for immunosuppression for anti–PD-1 plus anti–CTLA-4–related adverse events, whereas cumulative dose was not associated with impaired survival.

Click to read the study in JCO

Relevant Reading: Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti–PD-1 Monotherapy

In-Depth [prospective cohort]: This post hoc analysis investigated patients (n=1,959) who received systemic immunosuppression for immune-related adverse events (irAEs) the treatment arm of six pivotal phase II/III clinical trials (CheckMate-067, -142, -214, -648, -743, and -9LA) that examined combined anti–PD-1 plus anti–CTLA-4 inhibition for the treatment of irresectable or metastatic solid tumors. Median follow-up post anti–PD-1 plus anti–CTLA-4 initiation was 24 months (95%CI, 24-25). It was found that overall, 43% of patients received systemic immunosuppression for irAEs but the frequency ranged between studies, from 25% (patients with esophageal SCC) to 67% (patients with melanoma). Most frequent irAEs were GI (11%), hepatobiliary (8%), endocrine (8%), cutaneous (6%), and pulmonary (6%). The median corticosteroid peak dose was 1.0 mg/kg prednisolone (IQR, 0.54-1.51), and ranged 0.75 mg/kg in esophageal SCC to 1.22 mg/kg in melanoma. Median cumulative corticosteroid dose was 1,850 mg (IQR, 680-3,712) and ranged from 977 mg in esophageal SCC to 2,670 mg in melanoma. Median OS was 27 months (95%CI, 25-29) in all patients who received anti–PD-1 plus anti–CTLA-4 therapy and 47 months (95%CI, 32-82) in patients who received immunosuppression for irAEs. When isolating those who received immunosuppression for irAEs, the HR for PFS for corticosteroid peak dose was 1.15 (95%CI, 1.02-1.29; 95%PI, 1.07-1.24) for 1.0 versus 0.5 mg/kg, 1.43 (95%CI, 1.05-1.96; 95%PI, 1.17-1.75) for 2.0 versus 0.5 mg/kg, and 1.25 (95%CI, 1.03-1.52; 95%PI, 1.10-1.41) for 2.0 versus 1.0 mg/kg. The HR for OS similar with 1.21 (95%CI, 1.06-1.39; 95%PI, 1.08-1.37) for 1.0 v 0.5 mg/kg, 1.66 (95%CI, 1.17-2.37; 95%PI, 1.23-2.24) for 2.0 v 0.5 mg, and 1.37 (95%CI, 1.10-1.70; 95%PI, 1.14-1.64) for 2.0 v 1.0 mg/kg. These results were similar when correcting for trAE grade or type. When investigating cumulative corticosteroid dose the HR for PFS was 0.98 (95%CI, 0.93-1.03; 95%PI, 0.92-1.04) per 1,000-mg increase, and similarly, the HR for OS was 0.96 (95%CI, 0.91-1.01; 95%PI, 0.90-1.01) per 1,000-mg increase. There was no significant association between second-line immunosuppressant use and PFS or OS. Overall, this study found that there might be an associated impaired survival with higher corticosteroid peak dose for immunosuppression for anti–PD-1 plus anti–CTLA-4–related adverse events, whereas cumulative dose was not associated with impaired survival.

Image: PD

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