Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Data Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2019 Oct 15;25(20):6080-6088. doi: 10.1158/1078-0432.CCR-19-1135. Epub 2019 Aug 1.
Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents.
IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR ( = 306) and CABOSUN ( = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated.
Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1-positive TC had poorer PFS and OS than patients with PD-L1-negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients ( = 0.034) and for patients treated with cabozantinib only ( = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression.
Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy.
免疫组化（IHC）检测程序性死亡配体 1（PD-L1）状态对转移性肾细胞癌（mRCC）具有预后价值，其作为潜在预测生物标志物的作用正在研究中。本研究使用来自 METEOR（NCT01865747）和 CABOSUN（NCT01835158）临床试验的肿瘤组织，探讨 PD-L1 表达和免疫细胞浸润程度是否可以作为卡博替尼和其他靶向药物的预后和/或预测生物标志物。
对 METEOR（n=306）和 CABOSUN（n=110）临床试验的肿瘤组织进行 PD-L1 和 CD45/CD163（免疫细胞标志物）的双重免疫组化染色。还分析了免疫细胞密度和 MET 表达水平。我们的主要目的是通过独立的中心评估，将患者的无进展生存期（PFS）与接受卡博替尼、依维莫司（METEOR）或舒尼替尼（CABOSUN）治疗的患者的 PD-L1 状态相关联。还研究了总生存期（OS）。
在 METEOR 和 CABOSUN 试验中，分别有 29%和 23%的患者肿瘤细胞（TC）PD-L1 表达（≥1%截断值）阳性。在单变量分析中，在两项试验中，无论治疗方法如何，PD-L1 阳性 TC 患者的 PFS 和 OS 均比 PD-L1 阴性 TC 患者差。在多变量分析和两项试验合并时，TC PD-L1 表达与所有患者（p=0.034）和仅接受卡博替尼治疗的患者（p=0.038）的 OS 之间存在统计学显著关联。与依维莫司和舒尼替尼相比，卡博替尼与 PFS（HR<0.70）和 OS（HR<0.85）的改善相关，无论 PD-L1 表达如何。
在接受靶向治疗的 mRCC 患者中，较高的 PD-L1 表达导致更差的临床结局。此外，PD-L1 表达不能预测卡博替尼治疗的反应。
