| Abstract: |
Purpose: Avelumab (anti-PD-L1) became the first approved treatment for metastatic Merkel cell carcinoma (mMCC) based on results from the phase II JAVELIN Merkel 200 trial. In this study, 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. We conducted analyses on somatic mutations, mutational signatures, and tumor mutational burden using paired whole-exome sequencing. Additionally, we examined gene and gene set expression, immune content from RNA sequencing profiles, as well as tumor PD-L1 and CD8 statuses from IHC 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 seemed 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 seemed to be associated with response to avelumab. 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 IFNγ-related pathways. Levels of activated dendritic cells in responding patients were higher in patients assessed after versus before chemotherapy. Conclusions: Exploratory analyses provide insights into mMCC biology and potential associations with response to avelumab. Chemotherapy seems to negatively modulate the immune microenvironment. © 2024 The Authors. |
| Keywords: |
adult; treatment outcome; aged; aged, 80 and over; middle aged; gene mutation; major clinical study; overall survival; genetics; mutation; clinical trial; cisplatin; cd8 antigen; cd8+ t lymphocyte; biological marker; quality control; metabolism; dna damage; progression free survival; phase 2 clinical trial; gene expression; skin neoplasms; cell infiltration; cohort analysis; drug effect; pathology; angiogenesis; tumor marker; monoclonal antibody; skin tumor; immunology; immune response; gamma interferon; merkel cell carcinoma; merkel cell polyomavirus; carcinoma, merkel cell; visceral metastasis; cell density; drug therapy; macrophage; immunosuppressive treatment; rna sequence; programmed death 1 ligand 1; tumor microenvironment; antibodies, monoclonal, humanized; very elderly; humans; human; male; female; article; exome sequencing; whole exome sequencing; biomarkers, tumor; avelumab; cd274 protein, human; immunological antineoplastic agent; antineoplastic agents, immunological; b7-h1 antigen
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