Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward

Abstract

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Keywords: EA8143; PD-1 blockade; PROSPER RCC; Renal cell carcinoma; adjuvant; neoadjuvant; nephrectomy; nivolumab; priming; recurrence-free survival.

Fig.1

Rationale to prime the immune system with PD-1 blockade prior to nephrectomy. At baseline, it is thought that there is an ongoing but ineffective inflammatory T cell response against the primary tumor. Preclinical work suggests PD-1 blockade may induce proliferation of anti-tumor T cells in the tumor, tumor microenvironment, and lymph nodes supporting the tumor. These antigen specific T cells can then traffic to distant sites through the lymphatic and circulatory system where they can eliminate metastatic disease. They can transform to memory cells capable of continual suppression or elimination of metastatic disease or new primaries. Removal of the kidney tumor by nephrectomy before priming would eliminate the majority of tumor antigen as well as nearby effector cells, which produce the necessary immunomodulatory cytokines, and could result in a less potent response to adjuvant PD-1 pathway blockade alone.

Fig.2

Schema of The PROSPER RCC Study. A phase III randomized study comparing perioperative nivolumab vs. observation in patients with localized renal cell carcinoma undergoing nephrectomy (PROSPER RCC) NCT 03055013.