Nectin-4 and Trop-2 expression as potential therapeutic target in collecting duct carcinoma: Preliminary results from the CICERONE trial (NCT05372302).

587 Background: Collecting Duct Carcinoma (CDC) represents 1% of all renal cell carcinomas (RCC) and is characterized by aggressive clinical behavior and a particularly dismal prognosis. Cabozantinib and platinum-based chemotherapy are active therapeutic options, but survival remains poor with no novel agents approved for the treatment of metastatic disease. Antibody-Drug Conjugate (ADC) targeting Nectin-4 and TROP-2 are dramatically changing the therapeutic landscape of Urothelial Carcinoma (UC). Given the biological and clinical similarities between CDC and UC, we evaluated Nectin-4 and TROP-2 expression in CDC. Methods: CDC tissue samples were collected from patients enrolled in the CICERONE study (NCT05372302), a multicentric trial that aims to define the transcriptomic profile of CDC with the goal of changing the paradigm of CDC management by using biology-driven treatments. Nectin-4 and TROP-2 are surface proteins involved in cell adhesion and proliferation. Their expression was assessed by immunohistochemistry (IHC) using a validated assay with a Nectin-4 antibody (clone M22-321b41.1) and a TROP-2 antibody (Ab227689 by Abcam).Staining area was quantified as a percentage (0–100%) and considered positive if >10% of the tumor surface was stained. Staining intensity was dichotomized into positive and weakly positive, based on a clear distinction from the negative control. Results: 59 tissue samples from patients with diagnosis of CDC were considered eligible after centralized histological review. Fresh or archival tumor tissue was collected from either primary lesion or metastatic sites biopsies at baseline before the start of systemic therapy. Preliminary results demonstrated that Nectin-4 was expressed in 24 out of 59 samples (41%), while TROP-2 positivity was observed in 58/59 cases (98%). Conclusions: CDC appears to be a unique kidney tumor, which lies between UC and RCC clinically and biologically. Here we report for the first time the expression of two potential therapeutic targets in metastatic CDC, Nectin-4 and TROP-2, confirming the similarities between CDC and UC.Based on this encouraging data, along with the interesting results from EV-302 trial, we hypothesize that pembrolizumab in combination with Antibody-Drug Conjugate (ADC) could be active in mCDC and this combo will be assessed in the phase II RePRINT trial (NCT06302569). Clinical trial information: NCT05372302 .