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.

Abstract

BACKGROUND\nProgrammed cell death receptor-1 (PD-1) inhibitors are front-line therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear.\n\n\nMETHODS\nIn this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed.\n\n\nRESULTS\nOf the entire cohort of 947 patients, 509(54%) developed irAEs. In the MGH cohort (irAE(+)n=90), early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose-GCC use ({greater than or equal to}60mg prednisone equivalent qd) was independently associated with poorer post-irAE PFS/OS (post-irAE PFS: HR5.37, 95%CI 2.10-13.70, P<.001; post-irAE OS: HR5.95, 95%CI 2.20-16.09, P<.001) compared to irAE without early-high-dose-GCC use. These findings were validated in the combined validation cohort (irAE(+)n=419, post-irAE PFS: HR1.69, 95%CI 1.04-2.76, P=.04; post-irAE OS: HR1.97, 95%CI 1.15-3.39, P=.01). Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results.\n\n\nCONCLUSIONS\nEarly high-dose-GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.