Prognostic significance of VISTA expression in patients with malignant pleural mesothelioma treated with nivolumab: Results of a retrospective multi-institutional analysis (HOT1901).

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8083 Background: Nivolumab as a second-line treatment for pleural mesothelioma (PM) has demonstrated efficacy in the MERIT phase 2 trial in Japan and the CONFIRM phase 3 trial in the UK. However, the response rate and survival outcomes were modest. Therefore, the exploration of biomarkers that can determine its efficacy and prognosis is crucial. Recently, V-domain immunoglobulin suppressor of T cell activation (VISTA), and other coinhibitory or costimulatory molecules which are expressed on T cells and tumor cells, have attracted attention as novel therapeutic targets and predictors of clinical outcomes beyond PD-L1 for immunotherapy against various solid tumors. However, few studies have explored the efficacy of nivolumab by examining these molecules, as well as specific gene mutation profiles, in patients with PM. Thus, we aimed to identify biomarkers associated with survival in our cohort. Methods: This retrospective, multi-institutional cohort study included patients with PM who received nivolumab monotherapy as a second-line or later treatment at 18 hospitals in Japan between August 2018 and October 2019. We investigated the association of progression-free survival (PFS) and overall survival (OS) with clinical variables, expression of CD4, CD8, OX40, PD-L1, Tim-3, LAG-3, and VISTA in tumor tissues via immunohistochemistry (IHC), and gene expression profiles using next-generation sequencing (NGS). Results: Fifty-five patients were enrolled in this study. IHC and NGS were performed in 42 and 33 patients, respectively. The median survival follow-up time for all patients was 12.3 months (range, 0.2–47.0 months). The median PFS was 4.8 months (95% confidence interval [CI], 3.6–6.0), and the median OS was 12.3 months (95% CI, 10.3–14.4). No differences in OS or PFS were observed based on histological type. The IHC analysis revealed that high VISTA expression in tumor cells was significantly associated with improved PFS and OS compared with low VISTA expression (PFS, median: 5.1 months [95% CI, 3.5–6.7] vs. 2.4 months [95% CI, 0.0–5.1], p = 0.001; OS, median: 12.8 months [95% CI, 11.0–14.6] vs. 4.3 months [95% CI, 1.2–7.3], p = 0.007). Multivariate analysis confirmed that high VISTA expression in tumor cells was an independent predictor of prolonged PFS and OS (PFS: hazard ratio [HR], 0.14; p < 0.001; OS: HR, 0.38; p = 0.044). NGS data showed that gene alterations commonly reported in PM, such as mutations in CDKN2A , BAP1 , and NF2 , were not associated with PFS or OS. Conclusions: For PM patients with low VISTA expression in tumor cells, nivolumab may not be the optimal treatment choice, and alternative therapies should be considered. These findings provide a basis for further biomarker exploration in combination therapies, such as nivolumab-ipilimumab or chemoimmunotherapy, for patients with PM.

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