Status:
Recruiting
Clinicaltrials.gov identifier:
Sponsor:
National Cancer Institute/CTEP via the National Clinical Trials Network (Lead group: ECOG);
Enrollment:
766
Study Design:
PROSPER RCC (EA8143) is a global, un-blinded, phase 3 study which will examine if perioperative nivolumab in combination with radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology will be enrolled. T1 tumors are allowed if signs of clinical node positivity. Tumor biopsy prior to randomization is mandatory to ensure RCC but also permits unparalleled correlative science. Randomization is 1:1. Patients are stratified by clinical T stage, node positivity, and histology. Patients on the investigational arm receive two doses of nivolumab prior to surgery followed by adjuvant nivolumab for 9 months. The adjuvant dosing will be every 2 weeks for 3 months then transition to every 4 weeks x 6 months for enhanced quality of life. The control arm will receive standard of care surgical resection followed by observation. The primary endpoint is recurrence-free survival. The study is also powered to evaluate a significant increase in overall survival with the addition of perioperative PD-1 blockade. Safety, feasibility, and quality of life endpoints critical to adjuvant therapy considerations will be evaluated. PROSPER RCC exemplifies team science with a wealth of embedded correlative work aimed at investigating the impact of the baseline immune milieu, the changes induced by neoadjuvant anti-PD-1 priming, and how both correlate with clinical outcomes.
Rationale:
As of 2018, there remains no standard adjuvant systemic therapy that increases overall survival over nephrectomy alone for patients with non-metastatic RCC. Nivolumab is an antibody against PD-1 that can improve overall survival in metastatic RCC and is well tolerated. Moving this agent earlier in the disease course to improve clinical outcomes makes sense but requires a thoughtful approach. Within the primary tumor and its microenvironment, there is an ongoing but unsuccessful anti-tumor immune response. Work in murine models has shown that post-PD-1 blockade, anti-tumor CD8 T cells may preferentially expand in these areas and traffic to distant sites, developing into memory cells (Woo Cancer Research 2012). Nephrectomy may remove the majority of these effector cells and cytokines thereby inducing a less potent immune response. Mouse solid tumor models have revealed an overall survival benefit with a short course of neo-adjuvant PD-1 blockade compared to adjuvant therapy alone (Liu Cancer Discovery 2016). In humans, ongoing phase 2 studies of perioperative nivolumab in M0 RCC patients are showing preliminary feasibility and safety with no surgical delays or complications (NCT02575222; NCT02595918).
Comments:
The success of PROSPER RCC requires a thoughtful disruption of the current practice of upfront surgery followed by consideration of adjuvant systemic therapy. Given the mechanism of action of nivolumab, it makes sense to engage the patient’s immune system by priming with nivolumab prior to surgery when there is significant target (i.e., tumor antigen) in place. This change in practice has strong potential to increase cures, delay time to recurrence and improve overall survival in patients with high risk non-metastatic RCC.
