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Original Investigation
October 27, 2016

Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell CarcinomaThe ARISER Randomized Clinical Trial

Author Affiliations
  • 1Department of Urology, David Geffen School of Medicine at University of California, Los Angeles
  • 2Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles
  • 3Institute of Urologic Oncology, David Geffen School of Medicine at University of California, Los Angeles
  • 4Wilex AG, Munich, Germany
  • 5MorphoSys AG, Munich, Germany
  • 6Therawis Pharma GmbH, Munich, Germany
  • 7Institute of Pathology, University of Witten/Herdeke and Helios Hospital, Wuppertal, Germany
  • 8Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles
  • 9Central Ohio Urology Group, Columbus
  • 10Christie Hospital NHS Trust, University of Manchester, Manchester, England
  • 11Clinical Oncology, Carlos G Durand Hospital, Buenos Aires, Argentina
  • 12Department of Clinical Oncology, McMaster University, Hamilton, Ontario, Canada
  • 13State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russia
  • 14Department of Urology, University Hospitals Munich, Campus Grosshadern, Munich, Germany
  • 15Department of Urology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 16Faculty of Medical Sciences of Minas Gerais (FELUMA), Belo Horizonte, Brazil
JAMA Oncol. Published online October 27, 2016. doi:10.1001/jamaoncol.2016.4419
Key Points

Question  Does adjuvant weekly girentuximab following complete resection of clinically localized, high-risk clear cell renal cell carcinoma improve disease-free and overall survival when compared with placebo?

Findings  In this randomized clinical trial of 864 patients, there was no difference in disease-free or overall survival between patients receiving girentuximab and those receiving placebo. Girentuximab was well tolerated, and there was a nonsignificant disease-free survival benefit in patients with high carbonic anhydrase IX scores.

Meaning  Adjuvant girentuximab failed to improve disease-free or overall survival vs placebo in a cohort of patients with fully resected, high-risk clear cell renal cell carcinoma.

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

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