Abstract 1672: Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers
Authors: Vishal Navani, Moira C. Graves, Giovana Celli Marchett, Hiren Mandaliya, Nikola A. Bowden, Andre Van Der Westhuizen
Journal: Cancer Research (2021)

Abstract Background: There are few clinically validated predictive biomarkers for benefit to immune checkpoint blockade (ICB) in metastatic melanoma. Real world evidence has shown patients with higher exposure to ICB have improved best overall response (BOR) and longer survival [1]. Increased expression of T cell exhaustion markers and specific chemokine signatures have been associated with poor response to ICB in metastatic melanoma [2]. We sought to determine the relationship between pharmacokinetic (PK) and clinical outcomes of patients with metastatic melanoma treated with pembrolizumab. Translational correlative objectives included identifying expression of circulating T cell exhaustion markers and specific chemokine signatures in patients with progressive disease. Methods: Metastatic melanoma patients received weight based pembrolizumab and had serial peripheral blood draws. BRAF mutation positive patients were pre-treated with targeted therapy, otherwise pembrolizumab was first line. Plasma trough levels were assessed using the Abcam® pembrolizumab ELISA kit. BOR groups: complete response (CR), partial response (PR) and progressive disease (PD), were classified as per irRECIST. The T-cell exhaustion and chemokine markers were determined using Flow Cytometry on the BD Science Fortessa® X20. The cohort was stratified into high versus low pembrolizumab trough concentrations, split by the median. Kaplan-Meier survival analysis for progression free (PFS) and overall survival (OS) was performed based on these groups. Non-parametric correlation analysis was used to test for correlations between clinical characteristics, pembrolizumab trough concentrations and translational markers. Results: Twenty-eight patients were enrolled. Median follow up was 32.5 months. The pembrolizumab plasma trough levels were not significantly different between BOR categorical groups. Trough levels are a valid surrogate for drug exposure[3]. There were no significant correlations between pembrolizumab trough levels and expression of T-cell exhaustion and chemokine markers over time.The high pembrolizumab exposure group experienced significantly longer OS (median not reached versus 48 months, p=0.014), than the low exposure group. A similar positive exposure PFS relationship was found (median not reached versus 48 months, p=0.045). There was significantly higher frequency of co-expression of CXCR6 and TIM3 on CD4+ T cells for PD (mean 21.5% CI 14.9% - 26.06%) compared to CR (mean 12.2% CI 9.40% - 14.99%) (p=0.003) and PR (mean 9.9% CI 7.76% - 12.05%) (p=0.0001). There was also significantly higher frequency of co-expression of CXCR6 and TIM3 on CD8+ T cells for PD (mean 32.59% CI 25.76% - 39.43%) compared to PR (mean 21.9% CI 18.22% - 25.56%) (p=0.032).Conclusions: We describe a positive exposure PFS and exposure OS relationship for pembrolizumab in metastatic melanoma. The data indicate the co-expression of CXCR6 and T-cell exhaustion markers on circulating CD4+ and CD8+ T cells are potential biomarkers of disease progression on single-agent pembrolizumab.AcknowledgementsThis study was funded by a Hunter Medical Research Institute Project Grant (HMRI983).Hunter Cancer Biobank Serial Blood Collection Project Citation Format: Vishal Navani, Moira C. Graves, Giovana Celli Marchett, Hiren Mandaliya, Nikola A. Bowden, Andre Van Der Westhuizen. Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1672.