Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials
Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials
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DOI：
10.1634/theoncologist.2020-0518
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发表时间：
2020-09-18
期刊：
影响因子：
5.8
通讯作者：
Curigliano, Giuseppe
中科院分区：
文献类型：
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作者：
Criscitiello, Carmen;Marra, Antonio;Curigliano, Giuseppe
背景：外周血参数与实体瘤（如黑色素瘤和非小细胞肺癌）中免疫检查点抑制剂的疗效相关。目前关于这些免疫炎症生物标志物对其他实体瘤和免疫治疗组合的预后作用的数据很少。材料和方法从2014年8月至2019年5月，153例转移性实体瘤患者参加了I期临床试验，测试免疫治疗作为单一药物和组合药物。主要终点是评估基线血液参数对无进展生存期（PFS）和总生存期（OS）的影响。结果肿瘤类型以胃肠道、乳腺和妇科肿瘤最多见，分别占22.9%、22.2%和15.0%。较高的乳酸脱氢酶（LDH）和衍生的嗜中性粒细胞/淋巴细胞比率（dNLR）与PFS降低独立相关（风险比[HR]，1.97; 95%置信区间[CI]，1.30-2.99;p= .001，HR，2.29; 95% CI，1.39-3.77;p= .001）和OS降低（HR，2.04; 95% CI，1.26-3.28;p= 0.004; HR，2.06; 95% CI，1.12-3.79;p= 0.02）。在亚组分析中（单药与联合用药），“良好”（dNLR 3和/或LDH > ULN）风险患者的PFS分别较高和较低（相互作用p = .002）。相反，根据风险组，接受单药治疗的患者的OS存在统计学显著性差异，而联合治疗的患者未观察到这种效应（相互作用p = 0.004）。结论LDH和dNLR升高与I期临床试验中接受免疫治疗的患者的生存结局较差相关，无论肿瘤类型如何。这些参数代表了一种简单的工具，可以被认为是基于免疫治疗的临床试验中的分层因素。在这项回顾性队列研究中，153例转移性实体瘤患者在I期临床试验的背景下接受免疫治疗，基线乳酸脱氢酶升高和衍生的嗜中性粒细胞/淋巴细胞比率与生存率降低相关，无论肿瘤亚型如何。如果进行前瞻性验证，这些参数可能代表低成本和简单的生物标志物，可以帮助患者选择早期免疫治疗试验，并作为分层因素应用于随机研究测试免疫治疗药物。
Background Peripheral blood parameters are correlated to immune-checkpoint inhibitor efficacy in solid tumors, such as melanoma and non-small cell lung cancer. Few data are currently available on the prognostic role of these immune-inflammatory biomarkers for other solid tumors and immunotherapy combinations. Material and Methods From August 2014 to May 2019, 153 patients with metastatic solid tumors were enrolled in phase I clinical trials testing immunotherapy both as single agents and as combinations. Primary endpoint was to evaluate the impact of baseline blood parameters on progression-free survival (PFS) and overall survival (OS). Results The most common tumor types were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Higher lactate dehydrogenase (LDH) and derived neutrophil-to-lymphocyte ratio (dNLR) were independently associated with reduced PFS (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.30-2.99;p= .001, and HR, 2.29; 95% CI, 1.39-3.77;p= .001, respectively) and reduced OS (HR, 2.04; 95% CI, 1.26-3.28;p= .004, and HR, 2.06; 95% CI, 1.12-3.79;p= .02, respectively). In the subgroup analysis, (single agent vs. combination), patients at "good" (dNLR 3 and/or LDH > ULN) risk had higher and lower PFS, respectively (pfor interaction = .002). Conversely, patients receiving monotherapy presented statistically significant difference in OS according to the risk group, whereas this effect was not observed for those treated with combinations (pfor interaction = .004). Conclusion Elevated LDH and dNLR are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type. These parameters represent an easy tool that might be considered as stratification factors in immunotherapy-based clinical trials. Implications for Practice In this retrospective cohort study of 153 patients with metastatic solid tumors treated with immunotherapy in the context of phase I clinical trials, elevated baseline lactate dehydrogenase and derived neutrophil-to-lymphocyte ratio were associated with reduced survival regardless of tumor subtype. If prospectively validated, these parameters might represent low-cost and easy biomarkers that could help patient selection for early phase immunotherapy trials and be applied as a stratification factor in randomized studies testing immunotherapy agents.