Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab

Alexander Martens, Kilian Wistuba-Hamprecht, Marnix Geukes Foppen, Jianda Yuan, Michael A. Postow, Phillip Wong, Emanuela Romano, Amir Khammari, Brigitte Dreno, Mariaelena Capone, Paolo A. Ascierto, Anna Maria Di Giacomo, Michele Maio, Bastian Schilling, Antje Sucker, Dirk Schadendorf, Jessica C. Hassel, Thomas K. Eigentler, Peter Martus, Jedd D. WolchokChristian Blank, Graham Pawelec, Claus Garbe, Benjamin Weide

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan-Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin-CD14+HLA-DR-/low -MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+ CD25+ FoxP3+ -Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated with OS (P <0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted.

Original languageEnglish
Pages (from-to)2908-2918
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number12
DOIs
Publication statusPublished - Jun 15 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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