Introduction:

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

Methods:

Patient and Methods:

Eligible RCC patients with metastatic disease and with the primary tumor in place are treated with one of the FDA approved ICI-based combinations: ipilimumab/nivolumab, axitinib/pembrolizumab, or axitinib/avelumab. Urology evaluation and response assessment is required.  Patients are randomized within 10-14 weeks, 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy.  Correlative studies involving quality of life, radiomics, microbiome and genomic testing, are planned.

Statistical Design:

The primary endpoint is OS. We estimate the median OS from time of randomization for the non-surgical arm will be 25 months. The study hypothesis is that CN will result in improvement in OS in advanced synchronous RCC post initial systemic ICI-based combination therapy. With a sample size of 302 eligible randomized participants (151 per arm) and a one-sided alpha=0.025, the study has 85% power to detect a 47% improvement in median OS (HR=0.68; 1/0.68 = 1.47).

Results:

Conclusion:

Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820