(UroToday.com) The 2023 European Association of Urology (EAU) annual congress held in Milan, Italy between March 10th and 13th, 2023 was host to a game changing session. Professor Peter Mulders presented results from the phase 3 ZIRCON study, which evaluated 89Zr-DFO-girentuximab for PET/CT imaging of clear cell renal cell carcinoma.
The increasing detection of renal masses presents a significant patient management challenge. Diagnostic options include cross-sectional imaging, which cannot reliably differentiate benign and malignant renal masses, and biopsy, which is invasive and subject to sampling errors. Furthermore, 20-30% of resected small renal masses are benign, and clear cell RCC is 75% of RCC and causes ~90% of deaths. These limitations highlight the unmet need for an accurate noninvasive methods for pre-treatment risk stratification, similar to the recent advancements in PSMA imaging in prostate cancer. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX, a cell surface, transmembrane protein whose expression is upregulated by hypoxia or VHL loss, but minimally expressed in normal tissue.
Radiolabeled 89Zr-DFO-girentuximab (TLX250-CDx) is highly specific for carbonic anhydrase IX and can aid differentiation between clear cell RCCs and other renal lesions:
The ZIRCON study evaluated the performance of TLX250-CDx PET/CT for the detection of clear cell RCC in adult patients with indeterminate renal masses.
ZIRCON was an open-label, multicenter clinical trial. Patients with indeterminate renal masses (≤ 7 cm; tumor stage cT1) who were scheduled for partial/radical nephrectomy within 90 days from planned TLX250-CDx administration were eligible. Enrolled patients received a single dose of TLX250-CDx IV (37 MBq ± 10%; 10 mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (± 2 days) prior to surgery:
Blinded central histology review determined clear cell RCC status. The co-primary objectives were to evaluate both the sensitivity and specificity of TLX250-CDx PET/CT imaging in detecting clear cell RCC in patients with indeterminate renal masses, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with indeterminate renal masses ≤ 4 cm (cT1a). Other secondary objectives included positive and negative predictive values, safety, and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be > 70% and 68% respectively for ≥ 2 independent readers to declare the study successful.
There were 300 patients enrolled between August 2019 and August 2022 among 36 sites in 9 countries that received TLX250-CDx:
The median patient age was 62 years (range: 27-87), and 71% of patients were male.
Among patients with evaluable histology on surgical samples, the median lesion size was 3.7 cm (range: 0.9 – 7.7 cm), with cT1a lesions accounting for 62%. Overall, 67% of lesions excised with clear cell in etiology.
As clear cell histology is generally considered one of the more aggressive variants of renal cell carcinoma, it was not surprising that as the size of the renal lesions increased, the proportion of clear cell histology among renal masses increased:
The overall sensitivity and specificity of TLX250-CDx PET/CT were 86% and 87%, respectively. The positive and negative predictive values were 93% and 75%, respectively. The overall accuracy was calculated at 86%.
Very few adverse events were considered possible or related to 89Zr-DFO-girentuximab. Most AEs were mild, with only 18 patients (6%) having a Grade >= 3 treatment emergent adverse event. The adverse event pattern was consistent with post-surgical complications related to the nephrectomy, and no unexpected safety signals were observed.
Next, the investigators calculated an SUV maximum cut-off point for each reader to determine the optimal Youden index. The optimal SUVmax cut-off point was determined to be between 24.1 and 25.2, which was associated with a sensitivity of ~80% and specificity ~95%. The AUC for all three readers was ~0.92.
As expected, patients with PET positive clear cell RCC had higher CAIX expression compared to patients with PET negative clear cell RCC (i.e. false negative cohort). Among the 12 patients with false positive findings on PET, the following were the histologic findings:
- Papillary RCC: 9
- Undefined cancer: 1
- Oncocytoma: 1
- Sarcomatoid/spindle cell: 1
Professor Mulders concluded his presentation as follows:
- ZIRCON phase II pivotal study with 89Zr-DFO-girentuximab has met its primary endpoint, exceeding the sensitivity and specificity targets
- The study met its key secondary endpoint of sensitivity and specificity in small masses (cT1a)
- The favorable safety and tolerability profile of 89Zr-DFO-girentuximab was confirmed
- These positive results suggest that 89Zr-DFO-girentuximab improves the identification of primary RCC compared to cross-sectional imaging
- 89Zr-DFO-girentuximab has the potential to improve management by aiding risk stratification, selecting appropriate patients for treatment or suggesting where further imaging/biopsy could be indication
- 89Zr-DFO-girentuximab holds promise to improve staging in clear cell RCC, therapeutic target (radiopharmaceuticals), or image other solid tumors (true hypoxia) all of which are ongoing initiatives
Presented by: Professor Peter Mulders, Professor and Chairman of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Association of Urology (EAU) 38th annual congress held in Milan, Italy between March 10-13, 2023