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. 2022 Feb 27;14(5):1237.
doi: 10.3390/cancers14051237.

Timeline of Adverse Events during Immune Checkpoint Inhibitors for Advanced Melanoma and Their Impacts on Survival

Lorena Villa-Crespo  1 , Sebastian Podlipnik  1 , Natalia Anglada  2 , Clara Izquierdo  2 , Priscila Giavedoni  1 , Pablo Iglesias  1 , Mireia Dominguez  1 , Francisco Aya  3 , Ana Arance  3 , Josep Malvehy  1   2   4 , Susana Puig  1   2   4 , Cristina Carrera  1   2   4
Affiliations

Timeline of Adverse Events during Immune Checkpoint Inhibitors for Advanced Melanoma and Their Impacts on Survival

Lorena Villa-Crespo et al. Cancers (Basel). .

Abstract

Immune-related adverse events (irAEs) are frequent and could be associated with improved response to immune checkpoint inhibitors (ICIs). A prospective cohort of advanced melanoma patients receiving ICI as first-line therapy was retrospectively reviewed (January 2011−February 2019). A total of 116 of 153 patients presented with at least one irAE (75.8%). The most frequent irAEs were dermatological (derm irAEs, 50%), asthenia (38%), and gastrointestinal (29%). Most irAEs appeared within the first 90 days, while 11.2% appeared after discontinuation of the therapy. Mild grade 1−2 derm irAEs tended to appear within the first 2 months of therapy with a median time of 65.5 days (IQR 26-139.25), while grade 3−4 derm irAEs appeared later (median 114 days; IQR 69-218) and could be detected at any time during therapy. Only derm irAE occurrence was related to improved survival (HR 6.46). Patients presenting derm irAEs showed better 5-year overall survival compared to those with no derm irAEs (53.1% versus 24.9%; p < 0.001). However, the difference was not significant when adjusting for the duration of therapy. In conclusion: the timeline of immune-related-AEs differs according to the organ involved. The (apparent) improved survival of patients who present derm AEs during immunotherapy could be partially explained by longer times under treatment.

Keywords: dermatological adverse events; dermatological drug reactions; immune checkpoint inhibitors; immune-related adverse events; immunotherapy; melanoma; outcome; survival.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Details of toxicities box plots showing the percentage of patients who presented specific toxicities. Panel (A) shows the frequency of immune-related adverse events (irAEs) stratified by target organs. Fever and asthenia were considered as target symptoms due to the frequency of these side effects. Panel (B) shows dermatological irAEs in detail. Abbreviations: EM, erythema multiforme; MCT, musculoskeletal and connective tissue; PPE, palmar-plantar erythrodysesthesia; NMSC, non-melanoma skin cancer; SSS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.
Figure 2
Figure 2
Density plot and boxplot toxicities. Box plots showing the percentages of patients who presented specific toxicities. Panel (A,B) show the frequency of immune-related adverse events (irAEs) stratified by target organs. Fever and asthenia were considered as target symptoms due to the frequency of these side effects. Panel (C,D) show the frequency of severe (grade 3–4) irAEs stratified by target organs. Abbreviations: EM, erythema multiforme; MCT, musculoskeletal and connective tissue; PPE, palmar-plantar erythrodysesthesia; NMSC, non-melanoma skin cancer; SSS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.
Figure 3
Figure 3
Kaplan–Meier plots for overall survival.
See this image and copyright information in PMC

References

    1. Freeman-Keller M., Kim Y., Cronin H., Richards A., Gibney G., Weber J.S. Nivolumab in resected and unresectable metastatic melanoma: Characteristics of immune-related adverse events and association with outcomes. Clin. Cancer Res. 2016;22:886–894. doi: 10.1158/1078-0432.CCR-15-1136. - DOI - PMC - PubMed
    1. Hao C., Tian J., Tian J., Liu H., Li F., Niu H., Zhu B. Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials. Medicine. 2017;96:e7325. doi: 10.1097/MD.0000000000007325. - DOI - PMC - PubMed
    1. Kruger S., Ilmer M., Kobold S., Cadilha B.L., Endres S., Ormanns S., Schuebbe G., Renz B.W., D’Haese J.G., Schloesser H., et al. Advances in cancer immunotherapy 2019—Latest trends. J. Exp. Clin. Cancer Res. 2019;38:1–11. doi: 10.1186/s13046-019-1266-0. - DOI - PMC - PubMed
    1. Schachter J., Ribas A., Long G.V., Arance A., Grob J.J., Mortier L., Daud A., Carlino M.S., McNeil C., Lotem M., et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006) Lancet. 2017;390:1853–1862. doi: 10.1016/S0140-6736(17)31601-X. - DOI - PubMed
    1. Duan J., Cui L., Zhao X., Bai H., Cai S., Wang G., Zhao Z., Zhao J., Chen S., Song J., et al. Use of Immunotherapy with Programmed Cell Death 1 vs Programmed Cell Death Ligand 1 Inhibitors in Patients with Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2020;6:375–384. doi: 10.1001/jamaoncol.2019.5367. - DOI - PMC - PubMed