Multi-omics analysis of atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma.

Abstract

e21539 Background: A multicenter, open-label, single-arm phase II study has demonstrated that atezolizumab plus bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma, with an ORR of 45.0%. Here, we report the multi-omics analysis results with the aim of identifying potential biomarkers of response to this combination therapy. Methods: Patients with available samples were included in this study. The FFPE tissue was performed for DNA and RNA co-extraction and underwent whole exome sequencing (WES) and transcriptome sequencing. The responses were classified as complete response (CR) and partial response (PR) for responders and stable disease (SD) and progressive disease (PD) for non-responders per RECIST v1.1. Mutational signature, SNVs clonality, copy-number variations, differential expression genes, GSEA, and the immune microenvironment analysis were performed and analyzed for correlation with clinical benefits. Results: A total of 29 patients with FFPE samples underwent WES and/or transcriptome sequencing, including 1 CR, 15 PR, 9 SD, and 4 PD. As of January 11, 2023, the median follow-up time was 31 months (range, 5.0 to 37.0 months). Compared with non-reponders, responders had a significantly longer PFS (median 14.0, 95% CI 9.1 to 16.9 months vs 2.0, 95% CI 1.5 to 2.5 months, P< 0.001) and OS (median 35.0, 95% CI 20.4 to 49.6 months vs 14.0, 95% CI 5.5 to 22.5 months, P =0.005). Of the patients who underwent WES analysis, TMB and TNB were not associated with response, PFS or OS; but 53.3% (8/15) of responders harbored NRAS/PKHDL1 mutation, whereas only 16.7% (2/12) of non-reponders harbored NRAS/PKHDL1 mutation ( P= 0.112). Transcriptome analysis revealed that compared with non-reponders, responders displayed more significant angiogenesis, T cell cytotoxicity and interferon gamma response gene expression signatures. CIBERSORT analysis showed that responsders had higher proportions of cytotoxic immune cells, and non-responders had higher a higher proportion of B cells. The expression of CD274 was not associated with the response, and the expression of CD276 was significantly higher in responders than that in non-responders ( P =0.014). Weighted gene co-expression network analysis showed that the high expression of genes associated with the p38 MAPK pathway presented in cold tumor environments ( P =0.052) and was negatively correlated to the PFS ( P< 0.001) and OS ( P< 0.001). Conclusions: These molecular profiles indicated that the inflammatory cell infiltration and tumor angiogenic status was associated with response to anti-PD-L1 and anti-VEGF combination treatments, and targeting p38 MAPK pathway may further improve the survival of patients with mucosal melanoma.