Klümper Niklas, Sikic Danijel, Saal Jonas, Büttner Thomas, Goldschmidt Franziska, Jarczyk Jonas, Becker Philippe, Zeuschner Philip, Weinke Maximilian, Kalogirou Charis, Breyer Johannes, Burger Maximilian, Nuhn Philipp, Tully Karl, Roghmann Florian, Bolenz Christian, Zengerling Friedemann, Wirtz Ralph M, Muders Michael, Kristiansen Glen, Bald Tobias, Ellinger Jörg, Wullich Bernd, Hölzel Michael, Hartmann Arndt, Erben Philipp, Ritter Manuel, Eckstein Markus
Department of Urology, University Medical Center Bonn (UKB), Bonn, Germany; Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany; Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Germany.
Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany, Erlangen.
Eur J Cancer. 2022 May;167:13-22. doi: 10.1016/j.ejca.2022.02.022. Epub 2022 Mar 30.
Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response.
We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS).
Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P < 0.001). CRP flare response was associated with prolonged PFS and OS (P < 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07-0.48, P < 0.001).
CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.
转移性尿路上皮癌（mUC）中预测免疫检查点阻断（ICB）反应的可靠生物标志物仍有待开发。最近，早期C反应蛋白（CRP）动力学，尤其是新发现的CRP flare反应现象与免疫治疗反应相关。
我们开展了一项多中心观察性研究，纳入了154例接受ICB治疗的mUC患者，以评估先前描述的治疗期间CRP动力学的预测价值：CRP flare反应者（ICB开始后第一个月内基线CRP至少翻倍，随后在三个月内降至基线以下）、CRP反应者（三个月内基线CRP下降≥30%且无先前flare）以及其余患者作为CRP无反应者。CRP动力学组与基线参数、PD-L1状态、无进展生存期（PFS）和总生存期（OS）相关。
CRP反应者中有57.1%观察到客观反应，CRP flare反应者中有45.8%，CRP无反应者中有17.9%（P<0.001）。CRP flare反应与延长的PFS和OS相关（P<0.001）。在多变量Cox回归分析中，与CRP无反应者相比，CRP flare反应者肿瘤进展和死亡风险降低约70%。CRP flare反应者的亚组分析显示，长flare反应（治疗期间完成flare反应动力学≥6周）的患者在ICB后预后更有利（HR=0.18，95%CI：0.07-0.48，P<0.001）。
CRP（flare）反应能可靠预测mUC患者的免疫治疗反应和结局，且与PD-L1状态无关。因此，早期治疗期间的CRP动力学是一种有前景的低成本且易于实施的生物标志物，可优化接受ICB治疗的mUC患者的治疗监测。
