Correlations between adverse events and overall survival, clinical response, or biomarker categories. Overall survival was not different between patients stratified according to the occurrence of adverse events (AEs) in general (A) or immune-related AEs (irAEs). (B). Kaplan-Meier analysis is presented and censoring is indicated by vertical lines; p-values were calculated by log rank statistics (A&B). No correlations were observed between the occurrence of irAEs during ipilimumab treatment and the best tumor response (C, D) nor with the proposed combination groups of baseline biomarkers according to the combination model 1 (E) or combination model 2 (F). The best overall tumor response according to immune-related response criteria (irRC) was analyzed either as the rate of patients with an irRC response (sum of those with complete or partial responses) or irRC benefit (sum of those with complete responses, partial responses and stable disease). Differences were not statistically significant.
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.
