Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study

Italian Melanoma Intergroup (IMI)

Research output: Contribution to journalArticle

Abstract

CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.

Original languageEnglish
Pages (from-to)97-107
Number of pages11
JournalCancer Immunology and Immunotherapy
Volume68
Issue number1
DOIs
Publication statusE-pub ahead of print - Oct 11 2018

Fingerprint

Melanoma
Biomarkers
ipilimumab
Survival Analysis
Serum
Gastrointestinal Tract
Logistic Models
Enzyme-Linked Immunosorbent Assay
Survival
Mortality

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological/therapeutic use
  • Biomarkers, Tumor/blood
  • CTLA-4 Antigen/blood
  • Female
  • Humans
  • Ipilimumab/therapeutic use
  • Italy
  • Kaplan-Meier Estimate
  • Male
  • Melanoma/drug therapy
  • Middle Aged
  • Neoplasm Metastasis
  • Predictive Value of Tests
  • Solubility
  • Young Adult

Cite this

Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab : an Italian melanoma intergroup study. / Italian Melanoma Intergroup (IMI).

In: Cancer Immunology and Immunotherapy, Vol. 68, No. 1, 11.10.2018, p. 97-107.

Research output: Contribution to journalArticle

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abstract = "CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80{\%} (OR = 0.23; 95{\%}CL = 0.03-1.88) and 89{\%} (OR = 0.11; 95{\%}CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95{\%}CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95{\%}CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.",
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T1 - Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab

T2 - an Italian melanoma intergroup study

AU - Italian Melanoma Intergroup (IMI)

AU - Pistillo, Maria Pia

AU - Fontana, Vincenzo

AU - Morabito, Anna

AU - Dozin, Beatrice

AU - Laurent, Stefania

AU - Carosio, Roberta

AU - Banelli, Barbara

AU - Ferrero, Francesca

AU - Spano, Laura

AU - Tanda, Enrica

AU - Ferrucci, Pier Francesco

AU - Martinoli, Chiara

AU - Cocorocchio, Emilia

AU - Guida, Michele

AU - Tommasi, Stefania

AU - De Galitiis, Federica

AU - Pagani, Elena

AU - Antonini Cappellini, Gian Carlo

AU - Marchetti, Paolo

AU - Quaglino, Pietro

AU - Fava, Paolo

AU - Osella-Abate, Simona

AU - Ascierto, Paolo Antonio

AU - Capone, Mariaelena

AU - Simeone, Ester

AU - Romani, Massimo

AU - Spagnolo, Francesco

AU - Queirolo, Paola

PY - 2018/10/11

Y1 - 2018/10/11

N2 - CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.

AB - CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents, Immunological/therapeutic use

KW - Biomarkers, Tumor/blood

KW - CTLA-4 Antigen/blood

KW - Female

KW - Humans

KW - Ipilimumab/therapeutic use

KW - Italy

KW - Kaplan-Meier Estimate

KW - Male

KW - Melanoma/drug therapy

KW - Middle Aged

KW - Neoplasm Metastasis

KW - Predictive Value of Tests

KW - Solubility

KW - Young Adult

U2 - 10.1007/s00262-018-2258-1

DO - 10.1007/s00262-018-2258-1

M3 - Article

C2 - 30311027

VL - 68

SP - 97

EP - 107

JO - Cancer Immunology and Immunotherapy

JF - Cancer Immunology and Immunotherapy

SN - 0340-7004

IS - 1

ER -