Purpose: Avelumab (anti–PD-L1) became the first approved treatment for metastatic Merkel cell carcinoma (mMCC) based on results from the phase 2 JAVELIN Merkel 200 trial. We report exploratory biomarker analyses from the trial. Patients and methods: Patients with mMCC (n=88) with or without prior first-line chemotherapy received avelumab 10 mg/kg every 2 weeks. Analyses included: somatic mutations, mutational signatures, and tumor mutation burden from paired whole exome sequencing; gene, gene set, and immune content from RNAseq profiles; tumor PD-L1 and CD8 status from immunohistochemistry; and CD8 status from digital pathology. Results: Tumors positive for Merkel cell polyomavirus (MCPyV) were characterized by an absence of driver mutations and a low tumor mutational burden, consistent with previous studies. A novel MCPyV-specific host gene expression signature was identified. MCPyV+ tumors had increased levels of immunosuppressive M2 macrophages in the tumor microenvironment, which appeared to correlate with PD-L1 expression; high CD8+ T-cell density in these tumors did not predict response to avelumab. Conversely, in patients with MCPyV− tumors, higher CD8+ T-cell density appeared to be associated with response. Mutations in several genes were associated with treatment outcomes. Compared with tumors sampled before chemotherapy, tumors sampled after chemotherapy had downregulated gene signatures for immune responses, including reduced expression of IFN-γ–related pathways. Levels of activated dendritic cells in responding patients were higher in patients assessed after vs before prior chemotherapy. Conclusions: Exploratory analyses provide insights into mMCC biology and potential associations with response to avelumab. Chemotherapy seems to negatively modulate the immune microenvironment.

中文翻译：

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生物标志物分析调查疾病生物学以及与 avelumab 治疗转移性默克尔细胞癌的 JAVELIN Merkel 200 试验结果的关联


目的：根据 2 期 JAVELIN Merkel 200 试验的结果，Avelumab（抗 PD-L1）成为首个获批治疗转移性 Merkel 细胞癌 (mMCC) 的治疗方法。我们报告了试验中的探索性生物标志物分析。患者和方法：患有 mMCC 的患者 (n=88)，无论是否接受过一线化疗，每 2 周接受 10 mg/kg avelumab 治疗。分析包括：来自配对全外显子组测序的体细胞突变、突变特征和肿瘤突变负荷； RNAseq 配置文件中的基因、基因集和免疫内容；免疫组织化学检测肿瘤 PD-L1 和 CD8 状态；和来自数字病理学的 CD8 状态。结果：默克尔细胞多瘤病毒（MCPyV）阳性的肿瘤的特点是不存在驱动突变和低肿瘤突变负荷，这与之前的研究一致。鉴定出一种新的 MCPyV 特异性宿主基因表达特征。 MCPyV+ 肿瘤在肿瘤微环境中免疫抑制性 M2 巨噬细胞水平增加，这似乎与 PD-L1 表达相关；这些肿瘤中的高 CD8+ T 细胞密度并不能预测对 avelumab 的反应。相反，在 MCPyV− 肿瘤患者中，较高的 CD8+ T 细胞密度似乎与反应相关。一些基因的突变与治疗结果相关。与化疗前取样的肿瘤相比，化疗后取样的肿瘤免疫反应的基因特征下调，包括 IFN-γ 相关途径的表达减少。与化疗前相比，在有反应的患者中，在化疗后评估的患者中活化的树突状细胞水平更高。结论：探索性分析提供了对 mMCC 生物学以及与 avelumab 反应的潜在关联的见解。 化疗似乎会对免疫微环境产生负面影响。