Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial.

IMPORTANCE: Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). Its safety and activity in phase 2 studies prompted investigation into its use as adjuvant monotherapy in participants with high-risk ccRCC. OBJECTIVE: To evaluate the safety and efficacy of adjuvant girentuximab on disease-free survival (DFS) and overall survival (OS) in patients with localized completely resected high-risk ccRCC. DESIGN, SETTING, AND PARTICIPANTS: The ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC) was a randomized, double-blind, placebo-controlled phase 3 clinical trial that took place between June 10, 2004, and April 2, 2013, at 142 academic medical centers in 15 countries in North and South America and Europe. Eligible adult patients had undergone partial or radical nephrectomy for histologically confirmed ccRCC and fell into 1 of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater. Patients were assigned via central computerized double-blind 1:1 randomization to receive either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region. The data were analyzed from March 31, 2012, to April 2, 2013. MAIN OUTCOMES AND MEASURES: Co-primary end points were DFS and OS, based on imaging studies assessed by independent radiological review committee. Secondary end points included safety, assessed as the rate and grade of adverse events. RESULTS: A total of 864 patients (66% male; median [interquartile range] age, 58 [51-65] years) were randomized to girentuximab (n = 433) or placebo (n = 431). Compared with placebo, participants treated with girentuximab had no statistically significant DFS (hazard ratio, 0.97; 95% CI, 0.79-1.18) or OS advantage (hazard ratio, 0.99; 95% CI, 0.74-1.32). Median DFS was 71.4 months (interquartile range, 3 months to not reached) for girentuximab and never reached for placebo group. Median OS was never reached regardless of treatment. Drug-related adverse events occurred in 185 patients (21.6%), reported comparably between arms. Serious adverse events occurred in 72 patients (8.4%), reported comparably between arms. One drug-related serious adverse event occurred in a patient receiving placebo. CONCLUSIONS AND RELEVANCE: Girentuximab had no clinical benefit as adjuvant treatment for patients with high-risk ccRCC. The surprisingly long DFS and OS in these patients represent a challenge to adjuvant ccRCC drug development. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00087022.

Body Mass Index and Survival in a Prospective Randomized Trial of Localized High-Risk Renal Cell Carcinoma.

BACKGROUND: The relationship between adiposity and renal cell carcinoma is poorly understood. Prior studies have suggested body mass index (BMI) may be associated with indolent disease. METHODS: We reviewed the clinicopathologic records of 845 patients across 14 countries who were enrolled in a prospective, placebo-controlled study of adjuvant girentuximab treatment for high-risk renal cell carcinoma. Clinical features analyzed included age, gender, race, BMI, and performance status. BMI was stratified into <25 kg/m(2), 25.0-29.9 kg/m(2), 30.0-34.9 kg/m(2), and ≥35 kg/m(2) We examined the association of BMI with stage and survival using logistic and Cox regression analyses, respectively. RESULTS: 845 patients were included for analysis. The majority (72%) were overweight/obese. There was an inverse relationship between BMI and lymph node involvement (P = 0.04). Obesity was associated with improved disease-free and overall survival (log rank <0.01 for both). When compared with normal weight subjects, those with a BMI 30-34.9 [HR 0.50; 95% confidence interval (CI) 0.31-0.81] and BMI ≥35 (HR 0.24; 95% CI 0.09-0.60) had significantly improved overall survival. A trend towards improved disease-free survival was found among subjects with BMI 30-34.9 (HR 0.77; 95% CI 0.56-1.05) and ≥35 (HR 0.74; 95% CI, 0.48-1.15). CONCLUSIONS: In a prospective cohort of nephrectomized patients with high-risk disease, obesity is associated with lower risk of lymphatic spread and improved overall survival. IMPACT: This is the first study utilizing data from a prospective randomized trial reporting an association between obesity and improved overall survival for patients with clear cell renal cell carcinoma. Cancer Epidemiol Biomarkers Prev; 25(9); 1326-32. ©2016 AACR.

Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial.

INTRODUCTION AND OBJECTIVE: With a limited number of prognostic and predictive biomarkers available, carbonic anhydrase-IX (CAIX) has served as an important prognostic biomarker for patients with clear cell renal cell carcinoma (ccRCC). However, studies have recently called into question the role of CAIX as a biomarker for ccRCC. To investigate this uncertainty, we quantified the association of CAIX with lymphatic involvement and survival using data from ARISER study (WX-2007-03-HR)--a prospective trial involving subjects with high-risk nonmetastatic ccRCC. METHODS AND MATERIALS: We reviewed the records of 813 patients enrolled in the ARISER study. Central review of histology, grade, and CAIX staining (frequency and intensity) was performed. CAIX score was derived by multiplying the staining intensity (1-3) by percent positive cells (0%-100%), yielding a range of 0 to 300. We quantified the association of CAIX expression and score with lymphatic spread and survival (disease-free survival [DFS] and overall survival [OS]) using Kaplan-Meier and multivariable propensity score adjusted Cox regression analyses. RESULTS: Median follow-up of the cohort was 54.2 months. Although 56% of subjects with lymphatic involvement had CAIX>85%, only 33% had CAIX score ≥ 200. On multivariable analysis, CAIX>85% was not a statistically significant predictor of DFS and OS (P = 0.06 and P = 0.15, respectively). However, CAIX score ≥ 200, when compared with CAIX score ≤ 100, was associated with improved DFS and OS (P = 0.01 and P = 0.01, respectively) on multivariable analysis. CONCLUSIONS: The largest, multicenter, prospective analysis of patients with high-risk nonmetastatic ccRCC demonstrates the utility of CAIX score as a statistically significant prognostic biomarker for survival. We recommend that CAIX score be quantified for all patients with high-risk disease after nephrectomy.