- Title
- Overall survival in metastatic melanoma correlates with pembrolizumab exposure and T cell exhaustion markers
- Creator
- Navani, Vishal; Graves, Moira C.; Marchett, Giovana Celli; Mandaliya, Hiren; Bowden, Nikola A.; van der Westhuizen, Andre
- Relation
- Pharmacology Research & Perspectives Vol. 9, Issue 4, no. e00808
- Publisher Link
- http://dx.doi.org/10.1002/prp2.808
- Publisher
- John Wiley & Sons
- Resource Type
- journal article
- Date
- 2021
- Description
- Trial data support an absence of an exposure–survival relationship for pembrolizumab. As these relationships remain unexamined in a real-world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade naïve patients receiving 2 mg/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T-cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one-way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan–Meier progression-free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (n = 14) experienced substantially longer median OS (not reached vs. 48 months, p = .014), than the low exposure group (n = 14). A similar positive exposure PFS relationship was found (median not reached vs. 48 months, p = .045). The frequency of TIM-3 expression on CD4+ T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, p = .01) and partial response (12.4%, p = .05). There was a near doubling of CXCR6 and TIM-3 co-expression on CD4+ T cells in PD (mean 23.3%) versus CR (mean 11.4, p = .003) and partial response (9.8%, p = .0001). We describe positive exposure-PFS and exposure-OS relationships for pembrolizumab in metastatic melanoma. TIM-3, alongside co-expression of CXCR6 and TIM-3 on circulating CD4+ T cells are potential bio markers of treatment failure.
- Subject
- CXCR6; drug exposure; immune checkpoint blockade; metastatic melanoma; pembrolizumab; pharmacokinetics; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1462542
- Identifier
- uon:46496
- Identifier
- ISSN:2052-1707
- Rights
- © 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
- Language
- eng
- Full Text
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