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2632 Background: High-TMB was recently approved as an agnostic biomarker for pembrolizumab in advanced cancers. Still, several patients with high-TMB do not respond to ICI, while some patients with low-TMB benefit from immunotherapy. Methods: We collected genomic (MSK-IMPACTassay) and survival data from 1,661 patients and assessed OS (Kaplan-Meier method) according to the mutational status. To better qualify patients with TMB ≥ 10 mut/Mb (TMB-H) (N = 488, 29%) and TMB < 10 mut/Mb (TMB-L) (N = 1,173, 71%) for ICI treatment, we analyzed single gene alterations impacting OS (P < 0.05). For all genes exhibiting a correlation with OS, we conducted a Cox multivariate analysis stratified by median TMB, sex, median age, microsatellite instability (MSI) status, and histology. Results: Survival to ICI increased with higher TMB. Median OS was 42 and 15 months for TMB-H and TMB-L (P < 0.05), respectively. For TMB-H tumors, 5 genes ( STK11, KEAP1, CIC, E2F3, TP53) exhibited reduced OS on ICI, and 22 genes ( NTRK3, TERT, NOTCH3, RNF43, TET1, PTPRD, NCOA3, TENT5C, ZFHX3, RIT1, CCNE1, PPM1D, GATA2, ALK, DNMT1, PTPRT, MET, EPHA7, BCL6, SMO, CDK6, MED12) were associated with better OS, P < 0.05. Cox multivariate analysis confirmed a correlation between mutations in STK11 and E2F3 with worse OS, while mutations in NTRK, PTPRD, RNF43, TENT5C, TET1, and ZFHX3 were associated with better OS (P < 0.05). Histology did not play a relevant role in ICI response except for melanoma (better OS; P < 0.05). MSI status did not significantly affect OS. For TMB-L tumors, 20 genes were related with reduced OS ( TP53, H3C2, DAXX, SMARC4, STK11, SOX17, RB1, PIK3CA, CTNNB1, KMT2D, HLA-A, FBXW7, CDH1, RBM10, KEAP1, IGF1R, H3C11, EGFR, RUNX1, B2M), while 8 genes were associated with better OS ( VHL, SETD2, PBRM1, BRAF, KDM5C, MAP2K1, CSF1R, RET), P < 0.05. Cox multivariate analysis confirmed 15 genes associated with superior ( KDM5C, PBRM1, and VHL) and inferior ( CTNNB1, DAXX, FBXW7, H3C2, H3C1, IGF1R, KMT2D, PIK3CA , RB1, SMARC4, SOX17, TP53) OS (P < 0.05). In the TMB-L context, melanoma histology and MSI status (except among VHL-mutated tumors) were independently associated with better OS. Conclusions: This pan-cancer analysis demonstrates that genomic alterations in single cancer genes can help define outcomes of TMB-H and TMB-L patients treated with ICI. [Table: see text]

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This paper provides an overview of the H2020 Marine robotics research infrastructure network (EU Marine Robots) project. The overview is organized around the three main activities of infrastructure projects: i) Networking activities (NA); ii) Transnational access (TNA) in which access to marine robotic infrastructures from the partners is granted in competitive calls; iii) Joint research activities (JRA) aimed at making robotic infrastructures more operable and transitioning new systems and technologies to field operations. The strategic significance of the project and future developments are discussed as conclusions.

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