title: Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00087022.
authors: Department of Urology, David Geffen School of Medicine at University of California, Los Angeles2Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles3Institute of Urologic Oncology, David Geffen School of Medicine at University of California, Los Angeles.
authors: Karim
authors: K
authors: Chamie
authors: Department of Urology, David Geffen School of Medicine at University of California, Los Angeles3Institute of Urologic Oncology, David Geffen School of Medicine at University of California, Los Angeles.
authors: Nicholas M
authors: NM
authors: Donin
authors: Wilex AG, Munich, Germany5MorphoSys AG, Munich, Germany.
authors: Pia
authors: P
authors: Klöpfer
authors: Wilex AG, Munich, Germany.
authors: Paul
authors: P
authors: Bevan
authors: Wilex AG, Munich, Germany6Therawis Pharma GmbH, Munich, Germany.
authors: Barbara
authors: B
authors: Fall
authors: Wilex AG, Munich, Germany6Therawis Pharma GmbH, Munich, Germany.
authors: Olaf
authors: O
authors: Wilhelm
authors: Institute of Pathology, University of Witten/Herdeke and Helios Hospital, Wuppertal, Germany.
authors: Stephan
authors: S
authors: Störkel
authors: Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles.
authors: Jonathan
authors: J
authors: Said
authors: Central Ohio Urology Group, Columbus.
authors: Michael
authors: M
authors: Gambla
authors: Christie Hospital NHS Trust, University of Manchester, Manchester, England.
authors: Robert E
authors: RE
authors: Hawkins
authors: Clinical Oncology, Carlos G Durand Hospital, Buenos Aires, Argentina.
authors: Gustavo
authors: G
authors: Jankilevich
authors: Department of Clinical Oncology, McMaster University, Hamilton, Ontario, Canada.
authors: Anil
authors: A
authors: Kapoor
authors: State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russia.
authors: Evgeny
authors: E
authors: Kopyltsov
authors: Department of Urology, University Hospitals Munich, Campus Grosshadern, Munich, Germany.
authors: Michael
authors: M
authors: Staehler
authors: Department of Urology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
authors: Kimmo
authors: K
authors: Taari
authors: Faculty of Medical Sciences of Minas Gerais (FELUMA), Belo Horizonte, Brazil.
authors: Alberto J A
authors: AJA
authors: Wainstein
authors: Department of Urology, David Geffen School of Medicine at University of California, Los Angeles2Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles3Institute of Urologic Oncology, David Geffen School of Medicine at University of California, Los Angeles.
authors: Allan J
authors: AJ
authors: Pantuck
authors: Department of Urology, David Geffen School of Medicine at University of California, Los Angeles2Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles3Institute of Urologic Oncology, David Geffen School of Medicine at University of California, Los Angeles.
authors: Arie S
authors: AS
authors: Belldegrun
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009392:Nephrectomy; D016016:Proportional Hazards Models; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C106533:G250 monoclonal antibody; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX