FDA issues complete response letter for 89Zr-DFO-girentuximab in ccRCC

The FDA has issued a complete response letter (CRL) on the biologics license application (BLA) for ⁸⁹Zr-DFO-girentuximab (Zircaix; TLX250-CDx), an investigational agent for PET imaging of clear cell renal cell carcinoma (ccRCC), Telix announced in a news release.¹

Specifically, the CRL cites deficiencies relating to the Chemistry, Manufacturing, and Controls (CMC) package, and includes “notices of deficiency (Form 483) issued to two third-party manufacturing and supply chain partners that will require remediation prior to resubmission.”

The FDA has also requested additional data “to establish comparability between the drug product used in the ZIRCON phase 3 clinical trial and the scaled-up manufacturing process intended for commercial use.”

Telix has confirmed that they will be conducting submission remediation immediately. According to the news release, the company plans to schedule a Type A meeting with the FDA to develop a plan to address these concerns and determine an appropriate timeline for resubmission.

“TLX250-CDx breaks new ground as a highly novel biologic-based PET imaging agent using a first-in-class isotope,” said Christian Behrenbruch, Managing Director and Group CEO for Telix, in the news release.¹ “Like many radiopharmaceuticals, it has a complex supply chain, and as the field advances this creates new challenges around the regulatory framework applied to these products. We believe the outstanding matters are resolvable and that we can address the remaining FDA requests within a reasonable time frame.”

Data on ⁸⁹Zr-DFO-girentuximab

⁸⁹Zr-DFO-girentuximab a Zr-labelled monoclonal antibody that targets carbonic anhydrase 9 (CAIX), which is highly expressed in ccRCC. The agent was previously granted a Breakthrough Therapy designation and priority review status by the FDA.

The BLA was supported by data from the phase 3 ZIRCON trial (NCT03849118), which met all primary and secondary end points by demonstrating high specificity and sensitivity of ⁸⁹Zr-DFO-girentuximab in the detection and characterization of ccRCC.

In total, the open-label, multi-center ZIRCON study enrolled 300 adult patients who had an indeterminate renal mass suspicious for ccRCC and were scheduled for partial or total nephrectomy. Of those, 284 evaluable patients were included in the primary analysis. The mean age of participants in the trial was 61 years (SD, 12).

All patients included in the study were given a single dose of ⁸⁹Zr-DFO-girentuximab IV (37 MBq ±10%; 10 mg girentuximab) on day 0 and underwent abdominal PET/CT imaging on day 5 (± 2 days). The co-primary outcome measures were sensitivity and specificity of ⁸⁹Zr-DFO-girentuximab in detecting ccRCC in patients with an indeterminate renal mass (7 cm or smaller). Histopathological confirmation was used as a standard of truth.

Data from the trial, which were published in Lancet Oncology,² showed that the agent had an average sensitivity of 85.5% (95% CI, 81.5 to 89.6) and an average specificity of 87% (95% CI, 81.0 to 93.1) across 3 independent readers in detecting ccRCC in patients with an indeterminate renal mass. Further, the agent demonstrated a positive predictive value of 92.9% (95% CI, 90.2 to 95.7) for ccRCC, including in small and difficult to detect lesions.

A secondary outcome analysis of patients with small masses (defined as 4 cm or less; cT1a; n = 145) showed an average sensitivity of 85.0% (95% CI, 81.8 to 88.1) and an average specificity of 89.5% (95% CI, 84.2 to 94.8) with the agent across all 3 readers. For both primary and secondary end points, the lower bounds of the 95% confidence intervals exceeded the prespecified thresholds across all readers.

Regarding safety, there were 261 adverse events (AEs) experienced among 122 patients. Of these, 74% of AEs occurred during or after surgery, and 56% were mild in intensity. The most common AEs of grade 3 or higher were post-procedural hemorrhage (2%), urinary retention (1%), and hypertension (1%). In total, there were 52 serious AEs reported, of which 98% occurred after surgery.

REFERENCES

1. Telix provides regulatory update on TLX250-CDx. News release. Telix Pharmaceuticals. August 28, 2025. Accessed August 28, 2025. https://ir.telixpharma.com/static-files/6264a633-04e6-4eb2-81c5-f9fc40d113d2

2. Shuch B, Pantuck AJ, Bernhard JC, et al. [89Zr]Zr-girentuximab for PET–CT imaging of clear-cell renal cell carcinoma: a prospective, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024;25(10):1277-1287. doi:10.1016/S1470-2045(24)00402-9