Adjuvant therapy for high-risk localized renal cell carcinoma patients following radical neprectomy has been a controversial topic – conflicting results using tyrosine-kinase inhibitors (TKI’s) have resulted in uncertainty into their use. One study (S-TRAC) demonstrated DFS benefit, while three other studies (ASSURE, PROTECT and the soon to be reported ATLAS) demonstrated no benefit. So, while sunitinib is FDA-approved in this setting, utilization has been limited. In fact, guidelines primarily recommend clinical trial enrollment.
To that effect, this is one such clinical trial. In this study, they assess perioperative nivolumab (Nivo) as a neoadjuvant/adjuvant agent. The theory is that a single-dose pre-operatively may prime the system and adjuvant therapy may help complete therapy for micrometastatic disease.
Nivo is an antibody against PD-1, which has been shown to improve overall survival in metastatic RCC and is well tolerated. Mouse solid tumor models have revealed an OS benefit to a short course of PD-1 blockade when given neoadjuvantly compared to adjuvantly. Two ongoing phase 2 studies of perioperative nivo in M0 RCC patients are showing preliminary feasibility and safety with no surgical delays (NCT02575222; NCT02595918). There is also promising neoadjuvant use of pembrolizumab and nivolumab in breast and lung cancer – 3X rate of CR in patients treated with neoadjuvant pembro in triple-negative breast cancer, 45% major pathologic response with 2 doses nivolumab before surgery for M0 lung cancer.
Study Design: Unblinded Phase III randomized trial
Inclusion Criteria:
Patients with cT2+ or cN+ renal cell carcinoma (but must be cM0) – localized or locally advanced RCC only.
Tumor biopsy prior to randomization is necessary to confirm histology – will also enable correlative science.
Treatment:
Investigation arm (Nivo arm): two doses of nivo prior to surgery followed by adjuvant nivo for 9 months (q2 wks x 3 mo followed by q4 wks x 6 mo).
Control arm: standard of care surgical resection followed by observation
Randomization will be stratified by clinical T stage, node positivity, and histology.
Enrollment:
Planned enrollment of 766 patients. 84.2% power to detect a 14% absolute benefit in recurrence-free survival (RFS) at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is also powered to evaluate a significant increase in overall survival (HR 0.67).
Safety, feasibility, and quality of life endpoints critical to adjuvant therapy considerations will be evaluated
Many centers are joining – 158 sites approved, 399 in process!
This will be an exciting addition to the adjuvant space if positive.
Presented by: Lauren Christine Harshman, MD
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA