72: SWOG S1931 (PROBE): Phase III randomized trial of Immune checkpoint inhibitor (ICI) combination regimen with or without Cytoreductive Nephrectomy (CN) in Advanced Renal Cancer [NCT04510597]

Background: Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no overall survival (OS) benefit with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary tumor.

Methods: Eligible patients with primary tumor and metastases are treated with one of the 5 FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab/avelumab, cabozantinib + nivolumab or Lenvatinib + pembrolizumab. Urology evaluation prior to randomization to decide whether patient is surgical candidate is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy.