Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma

Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus...

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Published in:	European journal of cancer (1990) Vol. 207; p. 114172
Main Authors:	Verheijden, Rik J., Burgers, Femke H., Janssen, Josephine C., Putker, Anouk E., Veenstra, Sophie P.G.R., Hospers, Geke A.P., Aarts, Maureen J.B., Hehenkamp, Karel W., Doornebosch, Veerle L.E., Verhaert, Marthe, van den Berkmortel, Franchette W.P.J., Chatzidionysiou, Katerina, Llobell, Arturo, Barros, Milton, Maria, Alexandre T.J., Takeji, Akari, García Morillo, José-Salvador, Lidar, Merav, van Eijs, Mick J.M., Blank, Christian U., Aspeslagh, Sandrine, Piersma, Djura, Kapiteijn, Ellen, Labots, Mariette, Boers-Sonderen, Marye J., van der Veldt, Astrid A.M., Haanen, John B.A.G., May, Anne M., Suijkerbuijk, Karijn P.M.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-08-2024
Subjects:	Adrenal Cortex Hormones - adverse effects Adrenal Cortex Hormones - therapeutic use Adult Aged Aged, 80 and over Checkpoint inhibitor Corticosteroids Female Humans Immune Checkpoint Inhibitors - adverse effects Immune-related adverse events Immunosuppression Immunosuppressive Agents - adverse effects Immunosuppressive Agents - therapeutic use Male Melanoma Melanoma - drug therapy Melanoma - immunology Melanoma - mortality Middle Aged Retrospective Studies Skin Neoplasms - drug therapy Skin Neoplasms - immunology Skin Neoplasms - mortality Toxicity Checkpoint inhibitor Immunosuppression Corticosteroids Immune-related adverse events Toxicity Melanoma
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Summary:	Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4–8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4–14) and 55 (95 %CI 41–not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01–1.29; HRadj 1.29; 95 %CI 1.12–1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02–1.72) and OS (HRadj 1.34; 95 %CI 0.99–1.82) compared with corticosteroids alone. High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment. irAE guidelines advise starting with 1-2 mg/kg prednisone for most ≥grade 3 irAEs.Previous papers suggest that immunosuppression for irAEs impairs survival.Whether this is due to steroid dose or second-line immunosuppression is unknown.We show that both steroid peak dose and second-line immunosuppression are associated with survival.This suggest that it may be better to start with lower steroid doses whenever possible.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0959-8049 1879-0852 1879-0852
DOI:	10.1016/j.ejca.2024.114172