Calvary Mater Hospital Newcastle, Waratah, NSW, Australia.
Centre for Drug Repurposing and Medicines Research, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW, Australia.
Pharmacol Res Perspect. 2021 Aug;9(4):e00808. doi: 10.1002/prp2.808.
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.
试验数据支持 pembrolizumab 不存在暴露-生存关系。由于这些关系在真实环境中尚未得到检验，我们在一项观察性研究中前瞻性地确定了转移性黑色素瘤中的这些关系。转化目标包括确定进行性疾病（PD）的生物标志物。接受 2mg/kg Q3W pembrolizumab 的检查点阻滞-naive 患者收集了药代动力学和临床结果数据。使用 ELISA 评估了作为药物暴露有效替代物的低谷值。使用流式细胞术确定 T 细胞耗竭和趋化因子标志物。使用单向方差分析 (ANOVA) 检验了暴露和生物标志物的几何平均值与客观反应组的关系。根据中位数将队列分为高和低 pembrolizumab 暴露组。使用对数秩检验比较了高和低暴露组的Kaplan-Meier 无进展生存（PFS）和总生存（OS）曲线。高 pembrolizumab 暴露组（n=14）的中位 OS 显著延长（未达到与 48 个月，p=0.014），而低暴露组（n=14）的中位 OS 显著缩短（未达到与 48 个月，p=0.014）。发现了相似的阳性暴露 PFS 关系（中位数未达到与 48 个月，p=0.045）。PD 时 CD4 T 细胞上 TIM-3 表达的频率明显高于完全缓解（CR）（13.38%，p=0.01）和部分缓解（12.4%，p=0.05）。PD 时 CD4 T 细胞上 CXCR6 和 TIM-3 的共表达频率几乎翻了一番（23.3%，p=0.003），而 CR 时（11.4%，p=0.003）和部分缓解（9.8%，p=0.0001）时的频率较低。我们描述了 pembrolizumab 在转移性黑色素瘤中的阳性暴露-PFS 和暴露-OS 关系。TIM-3 以及循环 CD4 T 细胞上 CXCR6 和 TIM-3 的共表达是治疗失败的潜在生物标志物。
