Implementing precision oncology in renal cell carcinoma (RCC): Prospective identification of clinical, tissue-based, and circulating factors to refine outcome prediction and support therapeutic choices (SIGNS-RCC TRIAL).

TPS617 Background: At diagnosis, 55% of RCC are localized, and 25% are locally advanced/metastatic (aRCC); an additional 30% develop metastases during follow-up. Prognosis is highly variable in both resectable and advanced disease. All patients’ stratification tools are based on clinical risk scores. For resected patients, only pembrolizumab has demonstrated OS benefit in the adjuvant setting. For metastatic disease, first-line combos (IO-IO and IO-TKI) have dramatically improved outcomes in intermediate/poor-risk patients but have shown no additional OS benefit over TKI in good-risk patients. Methods: We designed a multicentric trial to identify novel prognostic/predictive biomarkers to refine current therapeutic algorithms for systemic therapy in both early-stage and aRCC in three different cohorts of patients. Cohort (A) includes patients who underwent radical surgery for RCC (resected, rRCC). Cohort (B) is a retrospective cohort that reclutes aRCC treated with VEGFR TKI monotherapy in I line. The prospective cohort (C) enrolls aRCC patients who are candidate to receive current I-line IO-TKI combos. In the first part, we will correlate patient- and tumor-related factors with the risk of recurrence after surgery for rRCC and progression-free survival and overall survival for aRCC. Tissue-based signatures will be obtained using IHC (PD-L1 expression, tumor immune microenvironment - TiME - composition), an NGS custom panel (mutational profiling), and FISH (for recurrent RCC alterations, such as 9p loss). Multiplex IHC and RNA-ISH will assess cytokine production by specific TiME components. Correlations between the obtained signatures and clinical outcomes will be calculated. In cohort C, the prognostic role of circulating factors (serum cytokine levels and mononuclear cell subpopulations, focusing on MDSC and TReg) will also be evaluated in addition to clinical and tissue-based factors. Blood samples will be collected before and during I-line treatment at pre-planned timepoints. Biomarkers will be quantitatively analyzed to evaluate their relationship with outcomes. Enrollment is ongoing.