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TPS754 Background: Collecting duct carcinoma (CDC) is a rare type of non-clear cell renal cell carcinoma with an aggressive course and poor prognosis. The treatment of metastatic disease remains unsatisfactory as no standard-of-care has been established yet. The gap in the clinical management is certainly linked to the poor molecular characterization. To date, a comprehensive biological characterization of CDC and the identification of predictive biomarker is still lacking. Our previous studies proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signalling, metabolic and immune-related alterations and featured by a prognostic signature associating T cell immunity and angiogenesis with good clinical outcome and sensitivity to cabozantinib (Gargiuli et al, Cancers 2021 Jun 10;13(12):2903; Todoerti et al, J Clin Oncol 40, no. 16_suppl (June 01, 2022) e16507-e16507; Verzoni et al, Ann Oncol 33:S1218-S121). The aim of CICERONE trial is to change the paradigm of CDC management providing therapies in a biologically informed manner starting from our previous findings. Methods: First, we will define a molecular taxonomy of CDC through comprehensive transcriptomic profiling of 100 CDC samples retrospectively collected within 12 months from the Italian Group of Uropathology Network and the European Union Hub Center. Pathologic review by genitourinary pathologist was required. RNA-Seq will be performed. Results will be merged to that already obtained by the same methodology from the BONSAI dataset (NCT03354884) and evaluated by unsupervised clustering analysis. We will identify differentially expressed genes and pathways. The immune and angiogenic signatures will be searched validating our preliminary results to identify predictive signatures for the subsequent prospective phase II trial. RNA-seq data will be also explored to detect fusion transcripts, as potential source of novel CDC oncogenic drivers, and study immune tumor content through Cybersort deconvolution. RT-qPCR on RNA derived from tumor and normal tissue will be performed to determine tumor specific origin of the fusion transcripts. Immune infiltrate will be also characterized by IHC, together with PDL-1 scoring. Subsequently we will conduct a prospective phase II trial in order to optimize treatment choice and validate prospectively the biological data. In this phase, previously untreated patients with metastatic CDC will be treated according to baseline tumor signature. Moreover, we will assess whether a new concept of immune liquid biopsy that includes the assessment of immunosuppressive vs antitumor immune cells may represent an accessible and compliant tool to test systemic immunity and its implications in response to treatment. This study was supported by the Italian Ministry of health (RF-2019-12369602). Clinical trial information: NCT05372302 .