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

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.

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.

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.

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.

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.

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.

clinicaltrials.gov Identifier: NCT00087022.

JAMA oncology. 2016 Oct 27 [Epub ahead of print]

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

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., 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., Wilex AG, Munich, Germany5MorphoSys AG, Munich, Germany., Wilex AG, Munich, Germany., Wilex AG, Munich, Germany6Therawis Pharma GmbH, Munich, Germany., Institute of Pathology, University of Witten/Herdeke and Helios Hospital, Wuppertal, Germany., Department of Pathology, David Geffen School of Medicine at University of California, Los Angeles., Central Ohio Urology Group, Columbus., Christie Hospital NHS Trust, University of Manchester, Manchester, England., Clinical Oncology, Carlos G Durand Hospital, Buenos Aires, Argentina., Department of Clinical Oncology, McMaster University, Hamilton, Ontario, Canada., State Institution of Healthcare Regional Clinical Oncology Dispensary, Omsk, Russia., Department of Urology, University Hospitals Munich, Campus Grosshadern, Munich, Germany., Department of Urology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Faculty of Medical Sciences of Minas Gerais (FELUMA), Belo Horizonte, Brazil.

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