Association of Cutaneous Immune-related Adverse Events with Overall Survival and Progression-free Survival in Oncology Patients Receiving Immune Checkpoint Inhibitors: A Prospective Study of 189 Patients in a Spanish Tertiary Care Hospital

Authors

  • Gloria Juan-Carpena Department of Dermatology, Morales Meseguer University Hospital, Murcia, Spain; Toxirel Investigation Group https://orcid.org/0000-0002-4541-5328
  • Natividad Martínez Banaclocha Toxirel Investigation Group, Alicante Spain; Department of Oncology, Dr. Balmis University General Hospital, Alicante, Spain; Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
  • Juan Carlos Palazón Cabanes Department of Dermatology, 12 de Octubre University Hospital, Madrid, Spain
  • Maria Niveiro-de Jaime Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain; Department of Pathology, Alicante University General Hospital, Alicante, Spain
  • Isabel Betlloch Mas Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain; Department of Dermatology, Dr. Balmis University General Hospital, Alicante, Spain; Miguel Hernández University of Elche, Alicante, Spain
  • Mar Blanes-Martínez Toxirel Investigation Group, Alicante Spain; Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain; Department of Dermatology, Dr. Balmis University General Hospital, Alicante, Spain

DOI:

https://doi.org/10.2340/actadv.v105.42023

Keywords:

overall survival (OS), progression-free survival, cutaneous immune-related adverse events, Immune Checkpoint Inhibitors, skin toxicity, immunotherapy

Abstract

Cutaneous immune-related adverse events (cirAEs) may be associated with tumoral response and survival in patients using immune checkpoint inhibitors, but this relationship remains unclear because previous reports on the topic have various limitations. The purpose of this study was to examine the association of cirAEs with overall survival and progression-free survival in patients starting immune checkpoint inhibitors. A prospective observational study was conducted in a Spanish tertiary care hospital, including participants between March 2020 and May 2022. The statistical analysis involved the Kaplan–Meier method, log-rank test, and multivariable Cox proportional hazards regression models. At total of 189 patients were included, of whom 82 (43.4%) presented cirAEs. Most participants (56.6%) were diagnosed with non-small cell lung cancer (NSCLC). Mortality and progression rates were lower in patients with vs without cirAEs (p <0.0001). Cox models showed that cirAEs were a protective factor for overall survival (adjusted HR 0.50; p < 0.0001) and progression-free survival (adjusted HR 0.54; p = 0.001) independently of cancer type, tumour stage or immune checkpoint inhibitor category. There were similar results for extracutaneous irAEs. A limitation was the single-centre design. CirAE occurrence is positively associated with longer survival and less cancer progression among immune checkpoint inhibitor recipients independently of other factors.

Downloads

Download data is not yet available.

References

Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378: 158–168.

https://doi.org/10.1056/NEJMra1703481 DOI: https://doi.org/10.1056/NEJMra1703481

Barrios DM, Do MH, Phillips GS, Postow MA, Akaike T, Nghiem P, et al. Immune checkpoint inhibitors to treat cutaneous malignancies. J Am Acad Dermatol 2020; 83: 1239–1253.

https://doi.org/10.1016/j.jaad.2020.03.131 DOI: https://doi.org/10.1016/j.jaad.2020.03.131

Pasquali S, Hadjinicolaou A V., Chiarion Sileni V, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2018; 2: CD011123.

https://doi.org/10.1002/14651858.CD011123.pub2 DOI: https://doi.org/10.1002/14651858.CD011123.pub2

Rose LM, DeBerg HA, Vishnu P, Frankel JK, Manjunath AB, Flores JPE, et al. Incidence of skin and respiratory immune-related adverse events correlates with specific tumor types in patients treated with checkpoint inhibitors. Front Oncol 2021; 10: 1–9.

https://doi.org/10.3389/fonc.2020.570752 DOI: https://doi.org/10.3389/fonc.2020.570752

Haslam A, Prasad V. Estimation of the percentage of us patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open 2019; 2: e192535.

https://doi.org/10.1001/jamanetworkopen.2019.2535 DOI: https://doi.org/10.1001/jamanetworkopen.2019.2535

Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA 2018; 320: 1702–1703.

https://doi.org/10.1001/jama.2018.13995 DOI: https://doi.org/10.1001/jama.2018.13995

Sonpavde GP, Grivas P, Lin Y, Hennessy D, Hunt JD. Immune-related adverse events with PD-1 versus PD-L1 inhibitors: a meta-analysis of 8730 patients from clinical trials. Futur Oncol 2021; 17: 2545–2558.

https://doi.org/10.2217/fon-2020-1222 DOI: https://doi.org/10.2217/fon-2020-1222

Chen C, Wu B, Zhang CY, Xu T. Immune-related adverse events associated with immune checkpoint inhibitors: An updated comprehensive disproportionality analysis of the FDA adverse event reporting system. Int Immunopharmacol 2021; 95: 107498

https://doi.org/10.1016/j.intimp.2021.107498 DOI: https://doi.org/10.1016/j.intimp.2021.107498

Shankar B, Zhang J, Naqash AR, Forde PM, Feliciano JL, Marrone KA, et al. Multisystem Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors for Treatment of Non-Small Cell Lung Cancer. JAMA Oncol 2020; 6: 1952–1956

https://doi.org/10.1093/annonc/mdx225

Min Lee CK, Li S, Tran DC, Zhu GA, Kim J, Kwong BY, et al. Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: A retrospective case-control study. J Am Acad Dermatol 2018; 79: 1047–1052

https://doi.org/10.1111/cup.12858

Nelson CA, Singer S, Chen T, Puleo AE, Lian CG, Wei EX, et al. Bullous pemphigoid after anti-PD-1 therapy: a retrospective case-control study evaluating impact on tumor response and survival outcomes. J Am Acad Dermatol 2020; 10: S0190-9622(20)30048-7

https://doi.org/10.1016/j.ad.2021.09.009

Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 2016; 152: 45–51

https://doi.org/10.1001/jamaoncol.2020.5012 DOI: https://doi.org/10.1001/jamaoncol.2020.5012

Guida M, Strippoli S, Maule M, Quaglino P, Ramondetta A, Chiaron Sileni V, et al. Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study. ESMO Open 2021; 6: 100064

https://doi.org/10.1016/j.jaad.2018.05.035 DOI: https://doi.org/10.1016/j.jaad.2018.05.035

Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long G V., Atkinson V, et al. Association between Immune-Related Adverse Events and Recurrence-Free Survival among patients with Stage III Melanoma randomized to receive Pembrolizumab or placebo: A secondary analysis of a randomized clinical trial. JAMA Oncol 2020; 6: 519–527

https://doi.org/10.1016/j.jaad.2019.12.068 DOI: https://doi.org/10.1016/j.jaad.2019.12.068

Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28: iv119–142 DOI: https://doi.org/10.1093/annonc/mdx225

https://doi.org/10.1001/jamadermatol.2015.2707 DOI: https://doi.org/10.1001/jamadermatol.2015.2707

Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol 2017; 44: 158–176 DOI: https://doi.org/10.1111/cup.12858

https://doi.org/10.1016/j.esmoop.2021.100064 DOI: https://doi.org/10.1016/j.esmoop.2021.100064

Juan-Carpena G, Palazón-Cabanes JC, Blanes-Martínez M. Characteristics, management, and prognostic implications of adverse effects of immune checkpoint inhibitors: a systematic review. Actas Dermosifilogr 2022; 113: 376–387 DOI: https://doi.org/10.1016/j.ad.2021.09.009

https://doi.org/10.1001/jamaoncol.2019.5570 DOI: https://doi.org/10.1001/jamaoncol.2019.5570

Nakano E, Takahashi A, Namikawa K, Muto Y, Jinnai S, Kage Y, et al. Correlation between cutaneous adverse events and prognosis in patients with melanoma treated with nivolumab: A single institutional retrospective study. J Dermatol 2020; 47: 622–628

https://doi.org/10.1111/1346-8138.15309 DOI: https://doi.org/10.1111/1346-8138.15309

Tang K, Seo J, Tiu BC, Le TK, Pahalyants V, Raval NS, et al. Association of cutaneous immune-related adverse events with increased survival in patients treated with anti-programmed cell death 1 and anti-programmed cell death ligand 1 therapy. JAMA Dermatol 2022; 158: 189–193

https://doi.org/10.1001/jamadermatol.2021.5476 DOI: https://doi.org/10.1001/jamadermatol.2021.5476

Bottlaender L, Amini-Adle M, Maucort-Boulch D, Robinson P, Thomas L, Dalle S. Cutaneous adverse events: a predictor of tumour response under anti-PD-1 therapy for metastatic melanoma, a cohort analysis of 189 patients. J Eur Acad Dermatol Venereol 2020; 34: 2096–2105

https://doi.org/10.1111/jdv.16311 DOI: https://doi.org/10.1111/jdv.16311

Zhang S, Tang K, Wan G, Nguyen N, Lu C, Ugwu-Dike P, et al. Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study. J Am Acad Dermatol 2023; 88: 1024–1032

https://doi.org/10.1016/j.jaad.2022.12.048 DOI: https://doi.org/10.1016/j.jaad.2022.12.048

Chan L, Hwang SJE, Byth K, Kyaw M, Carlino MS, Chou S, et al. Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events. J Am Acad Dermatol. 2020; 82: 311–316

https://doi.org/10.1016/j.jaad.2019.06.035 DOI: https://doi.org/10.1016/j.jaad.2019.06.035

Nikolaou V, Sibaud V, Fattore D, Sollena P, Ortiz-Brugués A, Giacchero D, et al. Immune checkpoint-mediated psoriasis: A multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group. J Am Acad Dermatol 2021; 84: 1310–1320

https://doi.org/10.1016/j.jaad.2020.08.137 DOI: https://doi.org/10.1016/j.jaad.2020.08.137

Nardin C, Jeand’heur A, Bouiller K, Valnet-Rabier MB, Dresco F, Castagna J, et al. Vitiligo under anti–programmed cell death-1 therapy is associated with increased survival in melanoma patients. J Am Acad Dermatol 2020; 82: 770–772

https://doi.org/10.1016/j.jaad.2019.11.017 DOI: https://doi.org/10.1016/j.jaad.2019.11.017

Matsuya T, Nakamura Y, Matsushita S, Tanaka R, Teramoto Y, Asami Y, et al. Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study. J Dermatol 2020; 47: 629–635

https://doi.org/10.1111/1346-8138.15345 DOI: https://doi.org/10.1111/1346-8138.15345

Zhang B, Nie W, Han B. Immune-related adverse events and efficacy – The more it hurts, the better it works? JAMA Oncol 2020 DOI: https://doi.org/10.1001/jamaoncol.2021.0729

https://doi.org/10.1200/JCO.19.02446 DOI: https://doi.org/10.1200/JCO.19.02446

Gulati N, Donnelly D, Qian Y, Moran U, Johannet P, Zhong J, et al. Revisiting the association between skin toxicity and better response in advanced cancer patients treated with immune checkpoint inhibitors. J Transl Med 2020; 18: 1–6

https://doi.org/10.1186/s12967-020-02612-5 DOI: https://doi.org/10.1186/s12967-020-02612-5

Suijkerbuijk KPM, Kapiteijn E, Verheijden RJ. Management of Immune-Related Adverse Events affecting Outcome in patients treated with Checkpoint Inhibitors. JAMA Oncol 2017; 72: 156–165

https://doi.org/10.1016/j.ejca.2016.11.021 DOI: https://doi.org/10.1016/j.ejca.2016.11.021

Thompson LL, Nadelmann ER, Blum AE, Yoon J, Polyakov NJ, Kagan RD, et al. Patterns and prognostic significance of cutaneous immune-related adverse events in non–small cell lung cancer. Eur J Cancer 2021; 147: 13–16

https://doi.org/10.1016/j.ejca.2021.01.022 DOI: https://doi.org/10.1016/j.ejca.2021.01.022

Quach HT, Dewan AK, Davis EJ, Ancell KK, Fan R, Ye F, et al. Association of anti-programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma. JAMA Oncol 2019; 5: 906–908

https://doi.org/10.1001/jamaoncol.2019.0046 DOI: https://doi.org/10.1001/jamaoncol.2019.0046

Siegel J, Totonchy M, Damsky W, Berk-Krauss J, Castiglione F, Sznol M, et al. Bullous disorders associated with anti–PD-1 and anti–PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol 2018; 79: 1081–1088

https://doi.org/10.1016/j.jaad.2018.07.008 DOI: https://doi.org/10.1016/j.jaad.2018.07.008

Nordlund M D JJ, Forget BM, Albert D, Lemer A. Vitfiigo in patients A good prognostic with metastatic melanoma: sign. J Am Acad Dermatol 1983; 9: 689–696. DOI: https://doi.org/10.1016/S0190-9622(83)70182-9

Duhra P, Ilchyshyn A. Prolonged survival in metastatic malignant melanoma associated with vitiligo. Clin Exp Dermatol 1991; 16: 303–305

https://doi.org/10.1111/j.1365-2230.1991.tb00383.x DOI: https://doi.org/10.1111/j.1365-2230.1991.tb00383.x

Arpaia N, Cassano N, Vena GA. Regressing cutaneous malignant melanoma and vitiligo-like depigmentation. Int J Dermatol 2006; 45: 952–956

https://doi.org/10.1111/j.1365-4632.2004.02468.x DOI: https://doi.org/10.1111/j.1365-4632.2004.02468.x

Matsuoka H, Hayashi T, Takigami K, Imaizumi K, Shiroki R, Ohmiya N, et al. Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody. BMC Cancer 2020; 20: 1–8

https://doi.org/10.1186/s12885-020-07142-3 DOI: https://doi.org/10.1186/s12885-020-07142-3

National Comprehensive Cancer Network. NCCN Guidelines. Available at https://www.nccn.org/guidelines/category_1

Hasan Ali O, Bomze D, Ring SS, Berner F, Fässler M, Diem S, et al. BP180-specific IgG is associated with skin adverse events, therapy response, and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors. J Am Acad Dermatol 2020; 82: 854–861

https://doi.org/10.1016/j.jaad.2019.08.045 DOI: https://doi.org/10.1016/j.jaad.2019.08.045

Hirotsu KE, Scott MKD, Marquez C, Tran AT, Rieger KE, Novoa RA, et al. Histologic subtype of cutaneous immune-related adverse events predicts overall survival in patients receiving immune checkpoint inhibitors. J Am Acad Dermatol 2022; 87: 651–653

https://doi.org/10.1016/j.jaad.2021.11.050 DOI: https://doi.org/10.1016/j.jaad.2021.11.050

Published

2025-01-03

How to Cite

Juan-Carpena, G., Martínez Banaclocha, N., Palazón Cabanes , J. C., Niveiro-de Jaime, M., Betlloch Mas, I., & Blanes-Martínez, M. (2025). Association of Cutaneous Immune-related Adverse Events with Overall Survival and Progression-free Survival in Oncology Patients Receiving Immune Checkpoint Inhibitors: A Prospective Study of 189 Patients in a Spanish Tertiary Care Hospital. Acta Dermato-Venereologica, 105, adv42023. https://doi.org/10.2340/actadv.v105.42023