C-reactive protein at 1 month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma
C-reactive protein at 1 month after treatment of nivolumab as a predictive marker of efficacy in advanced renal cell carcinoma
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DOI：
10.1007/s00280-020-04088-y
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发表时间：
2020-06-14
影响因子：
3
通讯作者：
Yao, Masahiro
中科院分区：
文献类型：
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作者：
Noguchi, Go;Nakaigawa, Noboru;Yao, Masahiro
目的Nivolumab是mRCC标准治疗的一部分。虽然在一些患者中观察到深度和持久的反应，但治疗的益处仅限于一些患者，大多数患者将经历疾病进展。PD-L1作为预测性生物标志物仍在评估中，迫切需要建立用于治疗纳武单抗的生物标志物。在这里，我们研究了nivolumab治疗后1个月的C反应蛋白（CRP）作为预测转移性肾细胞癌（mRCC）患者对nivolumab的反应的目标。方法在我们的机构审查委员会批准该研究后，招募了64名在神奈川癌症中心和横滨市立大学医院接受纳武利尤单抗治疗的mRCC患者。评价患者特征、纳武利尤单抗治疗开始时和治疗后1个月的血液检查数据、对治疗的反应和无进展生存期（PFS）。根据实体瘤疗效评价标准（RECIST）1.1和免疫RECIST（iRECIST）标准评估肿瘤缓解。此外，在12名同意进行额外血液检查的患者中，研究了几种血清炎症因子，并检查了它们与CRP水平的相关性。结果随访0.2-29.8个月，中位8.3个月。中位PFS为4.5个月，中位免疫PFS（iPFS）为5.3个月。RECIST 1.1标准在4例（6.4%）病例中低估了nivolumab的获益。多变量分析显示，治疗开始时的东部肿瘤协作组体力状态（>= 2）和治疗后1个月的CRP水平（>= 1.5 mg/dL）是nivolumab iPFS较差的独立风险因素。基线CRP水平不是iPFS的独立预后因素。治疗后1个月，无应答组（iPD）的CRP水平显著高于应答组（iCR + iPR + iSD）（p < 0.001）。在应答者组中，与基线相比，纳武利尤单抗治疗后CRP水平显著降低（p = 0.002），而在非应答者组中显著增加（p = 0.019）。即使基线CRP高（>= 1.5 mg/dL）的患者，如果治疗后1个月CRP降低（< 1.5 mg/dL），也可获得良好的iPFS。此外，格拉斯哥预后评分（GPS）分类是基于CRP和白蛋白的累积预后评分，是iPFS的重要预测因子。强相关性（|R|> 0.7）与治疗后1个月的CRP水平相比，观察到sCD 163、IL-34、MMP-1、MMP-2、骨桥蛋白、sTNF-R1和sTNF-R2。其中，MMP-1和MMP-2在基线时不相关。结论我们的结果表明，纳武利尤单抗治疗后1个月的CRP水平似乎是mRCC患者对纳武利尤单抗治疗反应的一个有希望的预测生物标志物。能够在短时间内预测效果在临床上是有用的。需要进一步的前瞻性试验来证明这些初步发现。
Purpose Nivolumab is part of the standard therapy for mRCC. Although deep and long-lasting responses are seen in some patients, the benefit of treatment is limited to some patients and the majority of patients will experience disease progression. PD-L1 is still under evaluation as a predictive biomarker and there is an urgent need to establish biomarkers for the treatment of nivolumab. Here, we investigate C-reactive protein (CRP) at 1 month after treatment of nivolumab as a target to predict the response of patients with metastatic renal cell carcinoma (mRCC) to nivolumab. Methods After approval of the study by our institutional review board, 64 patients with mRCC who underwent nivolumab treatment at Kanagawa Cancer Center and Yokohama City University Hospital were enrolled. The patient characteristics, blood examination data at start of nivolumab treatment and 1 month after treatment, response to treatment and progression-free survival (PFS) were evaluated. Tumour responses were assessed according to both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the immune RECIST (iRECIST) criteria. Moreover, in 12 patients who agreed to an additional blood examination, several serum inflammatory factors were investigated and their correlation with CRP level was examined. Results The median follow-up was 8.3 months (range 0.2-29.8 months). The median PFS period was 4.5 months and the median immune-PFS (iPFS) period was 5.3 months. RECIST 1.1 criteria underestimated the benefits of nivolumab in four (6.4%) cases. Multivariate analyses showed that an Eastern Cooperative Oncology Group performance status (>= 2) at start of treatment and CRP level at 1 month after treatment (>= 1.5 mg/dL) were independent risk factors for a poor iPFS of nivolumab. The CRP level at baseline was not an independent prognostic factor for iPFS. When compared with the responder group (iCR + iPR + iSD), the non-responder group (iPD) had a significantly higher CRP levels at 1 month after treatment (p < 0.001). In the responder group, there was significant decrease in the CRP level after nivolumab treatment when compared with the baseline (p = 0.002), whereas there was a significant increase in the non-responder group (p = 0.019). Even patients with high baseline CRP (>= 1.5 mg/dL) obtained good iPFS if CRP was decreased (< 1.5 mg/dL) 1 month after treatment. In addition, the classification of Glasgow prognostic score (GPS), which is a cumulative prognostic score based on CRP and albumin, was a significant predictor for iPFS. A strong correlation (|r| > 0.7) with CRP level at 1 month after treatment was seen for sCD163, IL-34, MMP-1, MMP-2, osteopontin, sTNF-R1 and sTNF-R2. Of these, MMP-1 and MMP-2 were not correlated at baseline. Conclusion Our results indicated that the CRP level at 1 month after treatment with nivolumab appears to be a promising predictive biomarker for response to nivolumab treatment in patients with mRCC. It is clinically useful to be able to predict the effect within a short period. Further prospective trials are needed to prove these preliminary findings.