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SAN FRANCISCO — A novel, noninvasive method was able to accurately and noninvasively identify clear cell renal carcinoma (ccRCC,), and shows promise for differentiating indeterminant renal masses, say researchers reporting the phase 3 ZIRCON study with radiolabeled 89Zr-DFO-girentuximab (TLX250-CDx, Telix).

Detection of renal masses can present a considerable patient management challenge. Diagnostic options include cross-sectional imaging, which cannot reliably differentiate between benign and malignant renal masses, and tissue biopsy, can xanax and diazepam be taken together which is invasive and subject to sampling errors.

The new imaging agent showed high sensitivity and specificity thresholds for PET/CT imaging of ccRCC.

 “89Zr-DFO-girentuximab improves the identification of clear cell RCC compared to conventional cross-sectional metrics,” said lead author Brian M. Shuch, MD, director of the Kidney Cancer Program and endowed chair in kidney cancer research at the University of California, Los Angeles.

“It has the potential to improve care, as this ‘molecular biopsy’ may select appropriate patients for treatment or suggest when further imaging, biopsy, or surveillance could be considered.”

He added that girentuximab holds promise to improve clear cell RCC staging and treatment, as well as image other solid tumor types. “These are all ongoing initiatives,” he said.

Shuch presented the findings here at the 2023 American Society of Clinical Oncology  Genitourinary Cancers Symposium.

Diagnosis Is Challenging

“Clear cell RCC accounts for 75% of RCC and causes about 90% of deaths,” he said. “Renal mass biopsy is invasive and anatomic imaging cannot reliably distinguish between benign/malignant renal masses.”

Shuch noted that 20%-30% of resected small renal masses are benign. “I’m tired of removing benign tumors,” he commented. “Having an accurate, noninvasive method that helps pretreatment risk stratification would really change the field, akin to what prostate-specific membrane antigen can do with prostate cancer.”

Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme that is highly expressed in ccRCC. Radiolabeled 89Zr-DFO-girentuximab is highly specific for carbonic anhydrase IX and can help differentiate between malignant cells and other types of renal lesions.

All Key Endpoints Met

The ZIRCON study involved 300 adult patients with indeterminate renal masses (≤ 7 cm; tumor stage cT1) who were scheduled for partial nephrectomy within 90 days from planned 89Zr-DFO-girentuximab administration.

Each patient received a single dose of 89Zr-DFO-girentuximab (37 MBq ± 10%; 10 mg girentuximab) on day 0 and then underwent PET/CT imaging on day 5 (± 2 days) before their scheduled surgery.

A partial/radical nephrectomy with central histology review was performed within 90 days of receiving 89Zr-DFO-girentuximab.

A total of 288 patients had available central histopathology of surgical samples, and of those, 193 (67%) had ccRCC, and 95 (33%) other renal lesions.

The co-primary objectives were to evaluate both the sensitivity and specificity of 89Zr-DFO-girentuximab PET/CT imaging in detecting ccRCC in patients with indeterminate renal masses, using histology as “the standard of truth.”

The sensitivity and specificity for the key secondary endpoints was 85% and 90%. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%.

There were minimal adverse events. Shuch pointed out that there were no unexpected safety signals and the side effect patterns were consistent with post-resection complications related to nephrectomy. Most were mild, and only 18 patients (6%) experienced grade 3 or higher treatment emergent adverse events.

“The ZIRCON phase 3 pivotal study met its primary endpoint exceeding the sensitivity and specificity thresholds,” Shuch concluded. “Key secondary endpoints were met, demonstrating similar performance in small masses, exceeding the sensitivity and specificity thresholds.”

Based on these results, the “favorable safety and tolerability profile of 89Zr-DFO-girentuximab was confirmed,” he added.

Use Needs to Be Contextualized

Approached by Medscape Medical News for an independent comment, Robert Uzzo, MD, MBA, president and CEO of Fox Chase Cancer Center, Philadelphia, Pennsylvania,  explained that the ZIRCON trial is the second open-label, multi-centered clinical validation trial evaluating the radiolabeled monoclonal antibody against the CAIX antigen that is found in the majority of clear cell carcinomas.

The REDECT trial was a smaller study with 195 patients, that Fox Chase helped lead, he explained. That study showed superior sensitivity (86.2%) and specificity (85.9%) for iodine-124 (124I) girentuximab PET/CT in the detection of ccRCC when compared with contrast enhance CT (sensitivity of 75.5% and specificity of 46.8%). (J Clin Oncol. 2013; 31:187-194)

These new results from the ZIRCON trial are “very similar and confirmatory, albeit in a larger cohort,” Uzzo said. “But as with the REDECT trial, the question that arises from ZIRCON relate to the clinical utility of this new potential diagnostic study.”  

“If current practice was to biopsy all cT1 renal mass and only treat those with ccRCC, this new diagnostic would save a lot of biopsies,” he continued.  “For example, if you obtained a 89Zr-DFO-girentuximab PET/CT on every patient in lieu of a biopsy and treated only those with a positive scan, you would properly treat 92% of patients for ccRCC and only treat 8% of patients without ccRCC.”

Only patients with a negative 89Zr-DFO-girentuximab scan would be biopsied, because of the negative predictive value. “In this scenario, you would find about 26% of those with a negative scan who had ccRCC and therefore needed treatment,” Uzzo said, “And many patients would be spared the risks and limitations of renal mass biopsy and potentially the risks of surgery.”

However, current practice is not to biopsy every cT1 mass and only treat those with ccRCC.  “Therefore, not all G250 positive scans go to surgery and not all G250 negative scans get monitored or biopsied,” he explained. “Depending on the clinical circumstances, other histologies that are G250 negative may require treatment and moreover, the risks of biopsy in most patients are acceptably low.”

Overall, like most new diagnostic tests, the utility of 89Zr-DFO-girentuximab CT/PET needs to be contextualized in the care of specific patients.  “The sensitivity and specificity demonstrated here are clinically meaningful but unlikely to change the evaluation of most patients with cT1 renal masses based on current practice,” Uzzo said. “In the otherwise healthy patient with a good life expectancy and a tumor anatomically amenable to biopsy if clinically warranted, a G250 PET/CT scan is unlikely to change clinical decision-making since a positive scan will confirm what is most likely and lead to treatment, and a negative scan doesn’t obviate a biopsy and/or treatment, since 1 or more in 4 negative scans may still need treatment.”

The study was sponsored by Telix Pharmaceuticals, manufacturer of 89Zr-DFO-girentuximab. Shuch reported receiving honoraria from Exelixis, as well as consulting or advisory roles with Bristol-Myers Squibb, Genentech/Roche, HistoSonics, Johnson & Johnson/Janssen, Merck, and Veracyte. Uzzo reports that he on a steering committee for Merck’s clinical trial in adjuvant kidney cancer.

2023 Genitourinary Cancers Symposium: Abstract LBA602. Presented February 18, 2023

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