Methods: ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [89Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET–CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [89Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [89Zr]Zr-girentuximab PET–CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET–CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment.
Findings: Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [89Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5–89·6) and mean specificity was 87·0% (81·0–93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [89Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths.
Interpretation: Our results suggest that [89Zr]Zr-girentuximab PET–CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing.
Brian Shuch, MDa ∙ Allan J Pantuck, MDa ∙ Jean-Christophe Bernhard, MDb ∙ Michael A Morris, MDc ∙ Viraj Master, MDd ∙ Andrew M Scott, MDe,f,g,h ∙ Charles van Praet, MDi ∙ Clement Bailly, MDj ∙ Bülent Önal, MDk ∙ Tamer Aksoy, MDl ∙ Robin Merkx, MDm ∙ David M Schuster, MDn ∙ Sze Ting Lee, MDe,f,g,h ∙ Neeta Pandit-Taskar, MDo,p ∙ Alice C Fan, MDq ∙ Phillip Allman, PhDr ∙ Karl Schmidts ∙ Libuse Tauchmanova, MDt ∙ Michael Wheatcroft, PhDt ∙ Christian Behrenbruch, DPhilt ∙ Colin R W Hayward, MBBSt ∙ Peter Mulders, MDu
- Institute of Urologic Oncology, University of California Los Angeles, Los Angeles, CA, USA
- Department of Urology, Centre Hospitalier Universitaire de Bordeaux—Groupe Hospitalier Pellegrin, Bordeaux, France
- United Theranostics, Glen Burnie, Baltimore, MD, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
- Department of Urology, Ghent University Hospital, Ghent, Belgium
- Department of Nuclear Medicine, Nantes University Hospital, Nantes, France
- Department of Urology, Istanbul University-Cerrahpasa, Istanbul, Turkey
- Department of Nuclear Medicine, Istanbul Training and Research Hospital, Istanbul, Turkey
- Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA
- Premier Research, Morrisville, NC, USA
- ABX-CRO Advanced Pharmaceutical Services Forschungsgesellschaft, Dresden, Germany
- Telix Pharmaceuticals, Melbourne, VIC, Australia
- Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands