Información de la revista
Vol. 115. Núm. 1.
Páginas 97-101 (enero 2024)
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Vol. 115. Núm. 1.
Páginas 97-101 (enero 2024)
Case and Research Letter
Acceso a texto completo
Immune-Mediated Adverse Effects in the Immunotherapy Treatment of Patients With Metastatic Melanoma Versus Adjuvant Regimen: A Study in a Daily Practice Setting
Efectos adversos inmunomediados en el tratamiento con inmunoterapia de pacientes con melanoma metastásico vs régimen de adyuvancia: estudio de práctica real
Visitas
2688
L. Martos-Cabreraa, T. Gallegob, A. Fernandez-Galvána, P. Rodríguez-Jiméneza,
Autor para correspondencia
a Dermatology Department, Hospital Universitario de la Princesa, Madrid, Spain
b Pharmacology Department, Hospital Universitario de la Princesa, Madrid, Spain
Contenido relacionado
L. Martos-Cabrera, T. Gallego, A. Fernandez-Galván, P. Rodríguez-Jiménez
Este artículo ha recibido
Información del artículo
Texto completo
Bibliografía
Descargar PDF
Estadísticas
Tablas (2)
Table 1. Baseline characteristics of the patients. Comparison between groups of patients who are on adjuvant therapy or in metastasis disease regimens.
Table 2. Comparison between groups of patients who had/not had immune-related adverse events.
Mostrar másMostrar menos
Texto completo
To the Editor:

Immune checkpoint inhibitors (CI), used to boost the immune system, have substantially improved the prognosis of patients with advanced melanoma.1,2 However, they are associated with a unique spectrum of side effects: immune-related adverse events (IRAEs), which are important to be recognized and promptly treated.3 Despite clinical trials data regarding IRAEs, real-life comparison between IRAEs, when CI is used in metastatic disease (MD) or as adjuvant therapy (AT), is still missing. Therefore, we conducted a retrospective, observational, cohort study to assess the frequency, type, and severity of IRAEs in melanoma patients receiving AT compared with those receiving MD regimen (MDR). Additionally, we explored any clinical factor related to IRAEs appearance or treatment-effectiveness correlation. We included all melanoma patients treated with a standard regimen of CI in daily-practice conditions for at least 3 months.

Our cohort included 49 patients with either nivolumab (n=23), pembrolizumab (16), ipilimumab (n=8) or ipilimumab+nivolumab (n=2). Baseline characteristics are shown in Table 1. Out of all of them, 51.9% (n=27) where on AT and 42.3% (n=22) on MDR. We found that 46.9% of the patients experienced an IRAE. They were typically mild to moderate in intensity, being severe (grade 3 of the common terminology criteria for adverse events3) in 18.2% of patients, and mostly resolved with topical/oral corticosteroids (Table 1). When comparing AT versus MDR, IRAEs frequency, type or management was similar in both groups (Table 1). IRAEs severity differed statistically, grading less in the AT group. This data might be of importance when deciding treatment initiation in the different stage III setting that we face in clinical practice. IRAEs lead to treatment discontinuation in 4 patients (n=1, AT; n=3, MDR) and no CI-related deaths were reported. In terms of disease progression, patients with IRAEs were less likely to progress and they had longer disease-free survival. Finally, melanoma ulceration was also related to a higher number of IRAEs (Tables 1 and 2). Ulceration is a biologic entity and over the years, researchers have identified several characteristics linked to the ulcerated melanoma phenotype such as: increased tumor vascularity, a loss of cell-to-cell adhesion as well as increased density of various tumor infiltrating immune cells and neutrophils, dendritic cells, macrophages and an increased number of PD-L1 positive tumor cells. This might explain the stronger response to interpheron alpha treatment in this subset of melanoma and could account to the greater rate of IRAEs4–6 As previously published, this analysis revealed that most IRAEs’ first occurrence took place early during treatment (Table 2).4,5 Similarly, dermatological, endocrine, gastrointestinal, and hepatic effects were the more frequently reported (Table 1).3

Table 1.

Baseline characteristics of the patients. Comparison between groups of patients who are on adjuvant therapy or in metastasis disease regimens.

Variable  Category  ATMDRTotal 
    N  N  N  P score 
SexF  12  44.4%  40.9%  21  42.9%  0.804
M  15  55.6%  13  59.1%  28  57.1% 
CI drugIpilimumab (I)  22.2%  9.1%  16.3%  0.205
Nivolumab (N)  11  40.7%  12  54.5%  23  46.9% 
N+0.0%  9.1%  4.1% 
Pembrolizumab  10  37.0%  27.3%  16  32.7% 
AJCC stageIIIB  10  37.0%  0.0%  10  20.4%  0.001**
IIIC  17  63.0%  0.0%  17  34.7% 
IV  0.0%  22  100.0%  22  44.9% 
Primary melanomaUnknown primary  14.8%  36.4%  12  24.5%  0.300
SSM  12  44.4%  27.3%  18  36.7% 
ALM  3.7%  4.5%  4.1% 
NM  10  37.0%  27.3%  16  32.7% 
AM  0.0%  4.5%  2.0% 
UlcerationNo  10  43.5%  14.3%  12  3.4%  Fisher0.084
Yes  13  56.5%  12  85.7%  25  67.6% 
MitosisNo  21.7%  35.7%  10  27.0%  Fisher0.454
Yes  18  78.3%  64.3%  27  73.0% 
Previous ADNo  27  100.0%  21  95.5%  48  98.0%  Fisher0.449
Yes  0.0%  4.5%  2.0% 
Previous ITNo  23  85.2%  19  86.4%  42  85.7%  Fisher0.999
Yes  14.8%  13.6%  14.3% 
Previous IT, typeInterferon  75.0%  66.7%  71.4%  0.350
Ipilimumab  25.0%  0.0%  14.3% 
Nivolumab  0.0%  33.3%  14.3% 
AE, non-IRAEsNo  13  48.1%  12  54.5%  25  51.0%  0.656
Yes  14  51.9%  10  45.5%  24  49.0% 
Non-IRAEs, typeAmhenorrea  6.7%  0.0%  4.3%  0.333
Dizziness  13.3%  0.0%  8.7% 
Fatigue  10  66.7%  100.0%  18  78.3% 
Xerostomia  13.3%  0.0%  8.7% 
IRAEsNo  15  55.6%  11  50.0%  26  53.1%  0.698
Yes  12  44.4%  11  50.0%  23  46.9% 
IRAEs, typeNo  15  51.7%  12  52.2%  27  51.9%  0.495
Arthritis  3.4%  4.3%  3.8% 
Dermatological  27.6%  17.4%  12  23.1% 
Enterocolitis  0.0%  8.7%  3.8% 
Hypotiroidism  10.3%  4.3%  7.7% 
Sarcoidosis  6.9%  4.3%  5.8% 
Uveitis  0.0%  4.3%  1.9% 
Adrenal insufficiency  0.0%  4.3%  1.9% 
IRAEs severity (G1–G4)G1  10  71.4%  27.3%  13  52.0%  0.013
G2  28.6%  27.3%  28.0% 
G3  0.0%  45.5%  20.0% 
IRAEs treatmentOral CS  27.3%  36.4%  31.8%  0.845
Hormone replacement  27.3%  18.2%  22.7% 
Other IS  9.1%  18.2%  13.6% 
Topical CS  36.4%  27.3%  31.8% 
IRAEs treatment discontinuationNo  11  91.7%  72.7%  19  82.6%  Fisher0.317
Yes  8.3%  27.3%  17.4% 
Disease progressionNo  16  59.3%  13.6%  19  38.8%  0.001**
Yes  11  40.7%  19  86.4%  30  61.2% 
Situation on follow-upExitus  22.2%  18  81.8%  24  49.0%  0.001**
Free of disease  12  44.4%  9.1%  14  28.6% 
Stable  25.9%  9.1%  18.4% 
Stable with iBraf/iMek  7.4%  0.0%  41.0% 

Unless otherwise stated, X2 tests (Chi or Chi square of independence) are performed for qualitative variables and Student's t tests for quantitative ones.

IRAEs, immune-related adverse events; n, number of patients; F, female; M, male; AD, autoimmune disease; CI, check-point inhibitors; IT, immunotherapy; AE, adverse events; AT, adjuvant therapy; MDR, metastasis disease regimens; G, grade; CS, corticosteroids; IS, immunosuppression; SSM, superficial spreading melanoma; ALM, acral lentiginous melanoma; NM, nodular melanoma; AM, amelanotic melanoma.

**

(p<0.001) statistically significant differences are found.

Table 2.

Comparison between groups of patients who had/not had immune-related adverse events.

Variable  Category  IRAEs NOIRAEs YESTotal (n) 
    N  N  N  p 
SexF  10  38.5%  11  47.8%  21  42.9%  0.509
M  16  61.5%  12  52.2%  28  57.1% 
CI drugIpilimumab (I)  23.1%  8.7%  16.3%  0.270
Nivolumab (N)  34.6%  14  60.9%  23  46.9% 
N+3.8%  4.3%  4.1% 
Pembrolizumab  10  38.5%  26.1%  16  32.7% 
AJCC stageIIIB  19.2%  21.7%  10  20.4%  0.841
IIIC  10  38.5%  30.4%  17  34.7% 
IV  11  42.3%  11  47.8%  22  44.9% 
First melanomaUnknown primary  30.8%  17.4%  12  24.5%  0.120
SSM  26.9%  11  47.8%  18  36.7% 
ALM  0.0%  8.7%  4.1% 
NM  11  42.3%  21.7%  16  32.7% 
AM  0.0%  4.3%  2.0% 
UlcerationNo  16.7%  47.4%  12  32.4%  0.046
Yes  15  83.3%  10  52.6%  25  67.6% 
MitosisNo  16.7%  36.8%  10  27.0%  Fisher0.167
Yes  15  83.3%  12  63.2%  27  73.0% 
Previous ADNo  26  100.0%  22  95.7%  48  98.0%  Fisher0.469
Yes  0.0%  4.3%  2.0% 
Previous ITNo  23  88.5%  19  82.6%  42  85.7%  Fisher0.692
Yes  11.5%  17.4%  14.3% 
Previous IT, typeInterferon  33.3%  100.0%  71.4%  0.155
Ipilimumab  33.3%  0.0%  14.3% 
Nivolumab  33.3%  0.0%  14.3% 
AE, not IRAEsNo  17  65.4%  34.8%  25  51.0%  0.032
Yes  34.6%  15  65.2%  24  49.0% 
GroupAT  15  57.7%  12  52.2%  27  55.1%  0.698
MDR  11  42.3%  11  47.8%  22  44.9% 
IRAEs severity (G1–G4)G1  0.0%  12  57.1%  12  54.5%  0.095
G2  0.0%  28.6%  27.3% 
G3  100.0%  14.3.%  18.2% 
IRAEs treatmentOral CS  0.0%  38.9%  36.8%  0.515
Hormone replacement  0.0%  16.7%  15.8% 
Other IS  0.0%  16.7%  15.8% 
Topical CS  100.0%  27.8%  31.6% 
IRAEs treatment discontinuationNo  100.0%  15  78.9%  16  80.0%  Fisher1.000
Yes  0.0%  21.1%  20.0% 
Disease progressionNo  19.2%  14  60.9%  19  38.8%  0.003**
Yes  21  80.8%  39.1%  30  61.2% 
Situation on follow upExitus  15  57.7%  39.1%  24  49.0%  0.030**
Free of disease  11.5%  11  47.8%  14  28.6% 
Stable  23.1%  13.0%  18.4% 
Stable with iBraf/iMek  7.7%  0.0%  4.1% 
Quantitative variables  N  Mean (SD)  N  Mean (SD)  N  Mean (SD)   
Age (y)  26  60.7 (15.2)  23  61.7 (10.2)  49  61.1 (13.0)  0.778 
Breslow  18  6.5 (6.7)  19  3.1 (2.0)  37  4.7 (5.1)  0.051 
Time to onset of immune-mediated effect (w)  12  21  12.1 (5.3)  22  12.0 (5.2)  0.972 
Time to resolution of the immune-mediated effect (w)  NA  3.0 (1.7)  3.0 (1.7)  NA 
Melanoma progression after CI initiation (w)  25  27.6 (29.6)  17  30.4 (24.0)  42  28.7 (27.2)  0.752 
CI treatment duration (w)  26  21.6 (25.2)  23  19.0 (14.4)  49  20.4 (20.7)  0.653 
Follow-up time after last dose of CI (w)  26  17.7 (32.4)  23  10.3 (12.5)  49  61.1 (13)  0.289 

Unless otherwise stated, X2 tests (Chi or Chi square of independence) are performed for qualitative variables and Student's t tests for quantitative ones.

IRAEs, immune-related adverse events; n, number of patients; F, female; M, male; AD, autoimmune disease; CI, check-point inhibitors; IT, immunotherapy; AE, adverse events; AT, adjuvant therapy; MDR, metastasis disease regimens; G, grade; CS, corticosteroids; IS, immunosuppression; SSM, superficial spreading melanoma; ALM, acral lentiginous melanoma; NM, nodular melanoma; AM, amelanotic melanoma; SD, standard deviation; y, years; w, weeks; NA, not applicable.

**

(p<0.001) statistically significant differences are found.

With several therapeutic options now available in the melanoma treatment setting, an understanding of the benefit–risk ratio in clinical practice is needed to perform treatment decisions. Our safety analysis with nivolumab, pembrolizumab, or/and ipilimumab was consistent with the established safety profiles published before for both, AT and MDR.2,4,7–10 However, fewer discontinuation rates in the pool data analysis were observed in our cohort (8.30%) compared with AT-ipilimumab (35–53%), which is no longer considered a prime candidate for AT),2 or with AT-pembrolizumab (13–14.8%),10 similar when comparing with AT-nivolumab (7.7%).7,8 Moreover, our results confirmed that select IRAEs in AT/MDT settings are manageable using established safety guidelines.3 As seen with AT-pembrolizumab,4 not yet with other drugs in AT,5 IRAEs were associated with a better prognosis.

Limitations include the study's retrospective nature and the small sample size, forcing us to analyze the pooled data. However, to our knowledge, this report is the largest analysis to date comparing the safety profile of CI in both, AT and MDR, in daily practice.

Overall, these findings add to the understanding of the benefit–risk profile of immunotherapy in patients with resected high-risk or advanced melanoma and may ultimately help in guiding clinicians.

Conflict of interests

The authors declare they have no conflict of interest.

References
[1]
A.M. Eggermont, V. Chiarion-Sileni, J.J. Grob, R. Dummer, J.D. Wolchok, H. Schmidt, et al.
Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial [published correction appears in Lancet Oncol. 2016 Jun;17 (6):e223].
Lancet Oncol, 16 (2015), pp. 522-530
[2]
J.S. Weber, F.S. Hodi, J.D. Wolchok, S.L. Topalian, D. Schadendorf, J. Larkin, et al.
Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma.
J Clin Oncol, 35 (2017), pp. 785-792
[3]
I. Puzanov, A. Diab, K. Abdallah, C.O. Bingham 3rd, C. Brogdon, R. Dadu, et al.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer, 5 (2017), pp. 95
[4]
A.M.M. Eggermont, M. Kicinski, C.U. Blank, M. Mandala, G.V. Long, V. Atkinson, 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.
[5]
M. Mandala, J. Larkin, P.A. Ascierto, M. Del Vecchio, H. Gogas, C.L. Cowey, et al.
Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival [published correction appears in J Immunother Cancer. 2021 Nov;9(11)].
J Immunother Cancer, 9 (2021), pp. e003188
[6]
A.M.M. Eggermont, P. Rutkowski, C. Dutriaux, R. Hofman-Wellenhof, P. Dziewulski, M. Marples, et al.
Adjuvant therapy with pegylated interferon-alfa2b vs observation in stage II B/C patients with ulcerated primary: results of the European Organisation for Research and Treatment of Cancer 18081 randomised trial.
Eur J Cancer, 133 (2020), pp. 94-103
[7]
J. Weber, M. Mandala, M. Del Vecchio, H.J. Gogas, A.M. Arance, C.L. Cowey, et al.
Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
N Engl J Med, 377 (2017), pp. 1824-1835
[8]
F.S. Hodi, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, P. Rutkowski, C.L. Cowey, et al.
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
Lancet Oncol, 19 (2018), pp. 1480-1492
[9]
C.A. Nebhan, D.B. Johnson.
Pembrolizumab in the adjuvant treatment of melanoma: efficacy and safety.
Expert Rev Anticancer Ther, 21 (2021), pp. 583-590
[10]
O. Hamid, C. Robert, A. Daud, F.S. Hodi, W.J. Hwu, R. Kefford, et al.
Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.
Ann Oncol, 30 (2019), pp. 582-588
Copyright © 2023. AEDV
Idiomas
Actas Dermo-Sifiliográficas
Opciones de artículo
Herramientas
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?