The ITALIC-RCC: A Randomized Trial on Clinical and Humoral Impact of Primary Tumor Ablation by Surgery or Radiotherapy in Metastatic Renal Cell Carcinoma Treated with Checkpoint Inhibitors.

Background: Immunotherapy-based combinations have improved overall survival (OS) in metastatic renal cell carcinoma (mRCC), but recent evidence suggests a therapeutic plateau, underscoring the need for more personalized strategies. Many patients start systemic therapy with the primary kidney tumor still in situ, and the role of cytoreductive nephrectomy (CN) in the immunotherapy era remains uncertain after CARMENA and SURTIME trials. In parallel, stereotactic body radiotherapy (SBRT) has emerged as a noninvasive option that achieves local control of primary RCC with limited toxicity. The ITALIC-RCC study evaluates whether local ablation of the primary tumor-by deferred CN or SBRT-improves outcomes in patients with mRCC who derive early benefit from anti-PD-1-based standard-of-care (SOC) therapy. Study design: ITALIC-RCC is a phase 4, randomized, multicenter trial. Patients with tumors ≤4 cm are randomized 1:1:1 to CN + SOC, radiotherapy (RT) + SOC, or SOC alone; those with tumors >4 cm are randomized 1:1 to CN + SOC or SOC alone. End points: The primary end point is OS comparing CN + SOC versus SOC alone from the time of randomization. Secondary end points include OS from systemic therapy initiation and progression-free survival (PFS) in the CN+SOC cohort versus the SOC-alone cohort, OS and PFS in the SBRT cohort, safety and complications of local treatments, and changes in quality of life. Exploratory end points include proteomic and tissue-based biomarkers associated with OS and PFS. Patients and methods: The study plans to enroll 409 adults with predominantly clear-cell mRCC, Eastern Cooperative Oncology Group performance status 0-1, a primary tumor in situ, and no progression after 24-52 wk of first-line anti-PD-1-based SOC (axitinib + pembrolizumab, cabozantinib + nivolumab, lenvatinib + pembrolizumab, or nivolumab after ipilimumab + nivolumab). Systemic therapy continues until progression by RECIST v1.1 or unacceptable toxicity. Imaging is performed every 12 ± 2 wk. Safety is assessed by CTCAE v5.0 and Clavien-Dindo; quality of life by EQ-5D-5L and FKSI-19. Blood samples at randomization and 8 ± 2 wk after intervention undergo proteomic profiling.Trial registrationClinicalTrials.gov identifier: NCT06903312.