Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab

Silvana Morello,Diana Giannarelli,Domenico Mallardo,Gabriele Madonna,Paolo Antonio Ascierto,Antonio M Grimaldi,Claudia Sorrentino,Mariaelena Capone,Aldo Pinto

doi:10.1186/s12967-017-1348-8

Abstract

BackgroundNivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients.MethodsIn this single-center retrospective analysis, we investigated the CD73 enzyme activity in patients with metastatic melanoma stage IV and its correlation with the response to nivolumab. The soluble CD73 (sCD73) enzyme activity was measured in the serum of 37 melanoma patients before receiving nivolumab and the Harrel’s C index was used to find the best cut-off for this biomarker. The multivariate Cox proportional hazard model was used to evaluate the prognostic value of CD73 enzyme activity for survival and progression-free survival.ResultsOur results show that high levels of sCD73 enzyme activity were significantly associated with poor overall survival and progression-free survival in patients with metastatic melanoma. The median progression–free survival was 2.6 months [95% confidence interval (CI) 1.9–3.3] in patients with high sCD73 enzyme activity (> 27.8 pmol/min/mg protein), and 14.2 months (95% CI 4.6–23.8) in patients with lower CD73 enzyme activity, when patients were follow-up for a median of 24 months range. The median overall survival was not reached in patients with low sCD73 activity (< 27.8 pmol/min/mg protein) compared with 6.1 months (95% CI 0–14.8) in patients with higher sCD73 activity. In multivariate analyses, the sCD73 enzyme activity emerged as the strongest prognostic factor for overall survival and progression-free survival. Elevated basal levels of sCD73 enzyme activity, before starting nivolumab treatment, were associated with lower response rates to therapy.ConclusionsWe observed a significant association between the activity of sCD73 in the blood and clinical outcomes in patients with metastatic melanoma stage IV, receiving nivolumab. Although our results need to be confirmed and validated, we suggest that sCD73 might be used as serologic prognostic biomarker. Potentially evaluating sCD73 enzyme activity in the peripheral blood before treatment could help to estimate the response to nivolumab.

Highlights

Nivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients
Similar results were observed in patients with metastatic melanoma treated with pembrolizumab, a highly selective inhibitor of PD1, approved for metastatic melanoma patients who progressed after ipilimumab or BRAF inhibitors treatment if appropriated [22, 23]
To the best of our knowledge, this is the first observation that the activity of soluble CD73 (sCD73) determined in the peripheral blood of melanoma patients may have a value as prognostic factor, and these results need to be confirmed and validated in larger randomized studies, they would suggest that prospectively CD73 could be used as serologic biomarker, in addition to known clinical prognostic parameters on multivariate analysis in patients with advanced melanoma

Summary

Introduction

Nivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients. Severe immune-related adverse events are common in patients receiving ipilimumab, and occasionally toxicity may cause severe morbidity or even mortality [7,8,9,10]. Nivolumab is an antibody anti-PD1 approved for the treatment of advanced melanoma patients for monotherapy and combination therapy [13,14,15,16,17,18,19]. Grade 3 or 4 adverse events to nivolumab occur in 14.4% of patients, significantly lower than those observed in patients receiving ipilimumab (45.9%); while 17.5% of patients experience any grade treatment-related effects [21]. Similar results were observed in patients with metastatic melanoma treated with pembrolizumab, a highly selective inhibitor of PD1, approved for metastatic melanoma patients who progressed after ipilimumab or BRAF inhibitors treatment if appropriated [22, 23]

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Discussion

Conclusion