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Supplementary Figure 5 from Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab

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posted on 2023-03-31, 18:52 authored by 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. Wolchok, Christian Blank, Graham Pawelec, Claus Garbe, Benjamin Weide

Overall survival and distribution after first dose of ipilimumab according to subsequent treatments. Of 209 patients, 71 received at least one additional systemic line of treatment after ipilimumab. 137 individuals did not receive further therapy and data were not available for one patient. 47 (combination model 1) or 67 (combination model 2) of 71 patients had complete data for classification according to biomarker combination models. The representation of PD-1/PD-L1-treated patients in the biomarker groups was shifted towards favorable biomarker combination groups for both combination models compared to those without subsequent PD-1/PD-L1 treatment. Therefore, a confounding effect of subsequent treatment with PD-1/PD-L1 antibodies on the biomarker results of this study cannot be ruled out (A). To investigate the potential confounding impact on OS and biomarker findings, subsequent treatments were categorized into three different groups: BRAF/MEK inhibitors (n=24), PD-1/PD-L1 antibodies (n=28), and chemotherapy/other treatments (n=33) and analyzed by the Kaplan-Meier method (B). Patients treated with PD-1/PD-L1 antibodies had a significant better survival compared to all 71 patients (p=0.006), while no significant difference was observed for the other two groups. Kaplan Meier analysis of overall survival of patients classified according to combination model 1 (C) or combination model 2 (D) is presented after exclusion of individuals who received subsequent treatment with anti-PD-1 or PD-L1 antibodies, as a confounding effect could not be ruled out. However, the prognostic impact of the proposed biomarker combinations at baseline of ipilimumab treatment remained strong (p<0.018 for all pairwise comparisons of categories of the respective model). Censoring is indicated by vertical lines. Programmed cell death protein-1 (PD-1), programmed cell death protein ligand-1 (PD-L1), Risk score (RS).

Funding

Bristol-Myers-Squibb (Munich, Germany) and EU Seventh Framework Program "PRIAT" (Profiling Responders In Antibody Therapies)

History

ARTICLE 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. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.