medwireNews: Higher peak doses of corticosteroids for treatment-related adverse events (trAEs) are associated with worse outcomes across tumor types among patients receiving dual checkpoint blockade therapy, research suggests.
By contrast, there was no such correlation for cumulative dose, report Karijn Suijkerbuijk (University Medical Center Utrecht, the Netherlands) and colleagues in the Journal of Clinical Oncology.
They note that “[c]urrent guidelines recommend a stepdown approach for corticosteroids, advising 1-2 mg/kg prednisone for many grade 3 or higher irAEs [immune-related AEs],” but “[t]hese data argue for a reconsideration of irAE management approaches.”
The team continues: “Although prompt immunosuppression is needed to prevent chronicity and fatality in some cases, clinicians should consider starting with lower corticosteroid doses whenever possible.”
For the study, the investigators analyzed individual data of 1959 patients who received anti-PD-1 plus anti-CTLA-4 therapy in one of six phase 2 or 3 CheckMate clinical trials. Of these, 313 patients had advanced melanoma, 119 had microsatellite instability-high or mismatch repair-deficient colorectal cancer, 547 had advanced renal cell carcinoma, 322 had advanced esophageal squamous cell carcinoma, 300 had malignant pleural mesothelioma, and 358 had metastatic non-small-cell lung cancer.
In all, 834 (43%) received systemic immunosuppression for trAEs, most commonly for gastrointestinal (11%), hepatobiliary (8%), endocrine (8%), cutaneous (6%), and pulmonary (6%) AEs. Corticosteroids alone were used in 90% of the patients, with 9% given corticosteroids alongside second-line immunosuppressants, and just two patients received only non-corticosteroid drugs.
A pooled analysis of data from the trials showed that higher corticosteroid peak dose was significantly associated with worse progression-free survival (PFS), such that the hazard ratio (HR) for progression or death after adjustment for age and sex was 1.15 when comparing a dose of 1.0 mg/kg with 0.5 mg/kg, 1.43 for 2.0 versus 0.5 mg/kg, and 1.25 for 2.0 versus 1.0 mg/kg.
The findings were similar for overall survival (OS), with corresponding adjusted HRs of 1.21, 1.66 and 1.37.
Suijkerbuijk et al highlight that “the results were comparable” after accounting “for trAE grade or type, and when restricting to patients with grade 1-2 trAEs, patients with grade 3-4 trAEs, or patients from non-melanoma studies.”
There was no significant association, however, between cumulative corticosteroid dose and PFS or OS, with adjusted HRs of 0.98 and 0.96 per 1000 mg increase, respectively.
And although second-line immunosuppressant use appeared to be associated with reduced PFS and OS, with adjusted HRs of 1.33 and 1.72, respectively, the associations were not significant, “which may be due to the small number of patients,” note the researchers.
Commenting on the findings, associate editor of the journal Robert Maki (Memorial Sloan Kettering Cancer Center, New York, USA) says that “[w]hile a lower dose but longer course may be a preferred way to manage irAE based on these data, the severity of the irAE may not provide the option to use lower dose glucocorticoids.”
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