Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial
Karim Chamie, Nicholas M Donin, Pia Klöpfer, Paul Bevan, Barbara Fall, Olaf Wilhelm, Stephan Störkel, Jonathan Said, Michael Gambla, Robert E Hawkins, Gustavo Jankilevich, Anil Kapoor, Evgeny Kopyltsov, Michael Staehler, Kimmo Taari, Alberto J A Wainstein, Allan J Pantuck, Arie S Belldegrun, Karim Chamie, Nicholas M Donin, Pia Klöpfer, Paul Bevan, Barbara Fall, Olaf Wilhelm, Stephan Störkel, Jonathan Said, Michael Gambla, Robert E Hawkins, Gustavo Jankilevich, Anil Kapoor, Evgeny Kopyltsov, Michael Staehler, Kimmo Taari, Alberto J A Wainstein, Allan J Pantuck, Arie S Belldegrun
Abstract
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.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Chamie receives research support from and serves as a consultant for UroGen Pharma, receives grant support from Phase 1 Organization, Stop Cancer Foundation, and is a consultant for Cold Genesys and a scientific advisory board member of Altor. Drs Klöpfer, Bevan, Fall, and Wilhelm are employees of Wilex, AG. Dr Staehler receives honoraria and research support from, and serves as an advisor to Pfizer, Roche, Bayer, GlaxoSmithKline, Bristol-Myers Squibb, Novartis, and Wilex. Dr Taari receives honoraria from Abbvie, receives research support from Medivation, and receives travel and accommodation support from Orion and Astellas. Dr Wainstein receives travel and accommodation support, speakers bureau compensation, and compensation for consulting in an advisory role from MDS, Bristol-Myers Squibb, and Roche. Dr Pantuck receives compensation as a consultant and advisor for Kite Pharma. Dr Belldegrun is president and CEO of Kite Pharma, serves on the scientific advisory board of UroGen Pharma, and is a consultant for Teva Pharmaceutical. No other disclosures are reported.
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Source: PubMed