Efficacy of [177Lu]Lu-PSMA-617 in Patients with Metastatic Clear-cell Renal Cell Carcinoma: The Multicentre, Single-arm, Phase 2 RENALUT Trial.

Background and objective: Angiogenesis-targeting tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are standard treatments for metastatic clear-cell renal cell carcinoma (ccRCC). However, therapeutic options remain limited after progression on these agents. Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of endothelial cells in ccRCC, making radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 a promising approach.

Clinical trial design and timeframe: RENALUT (NCT06783348) is a single-arm, open-label, phase 2 trial investigating the safety and efficacy of [¹⁷⁷Lu]Lu-PSMA-617 in metastatic ccRCC after TKI and ICI failure. Eligible patients must have PSMA-positive lesions on PSMA positron emission tomography imaging. Patients will receive four cycles of [¹⁷⁷Lu]Lu-PSMA-617 every 6 wk, with up to two additional cycles in cases with stable disease or a partial response.

Endpoints: The primary endpoint is the objective response rate according to Response Evaluation Criteria in Solid Tumours version 1.1.

Data sources and statistical analysis plan: Assuming a PSMA negativity rate of 15%, a total of 56 patients will be screened to achieve the target enrolment of 48 patients. European centres from three countries (Belgium, France, and Spain) will participate. First patient enrolment is expected in September 2025.

Strengths and limitations: This is the first multicentre trial to assess PSMA-targeted radioligand therapy for patients with metastatic ccRCC selected on the basis of PSMA expression, which may be a potential biomarker in this setting.

Funding: RENALUT is funded by Novartis and is being conducted as a research collaboration trial. The trial is sponsored by the EORTC.

Ethics and trial registration: The trial has been approved by the ethics committee of the coordinating institution in the lead country (Belgium) and is registered on ClinicalTrials.gov as NCT06783348. Twelve centres across three countries will be participating. Regulatory submissions are ongoing at all participating sites in compliance with national requirements. Enrolment will begin only after all required approvals are in place.

Patient summary: This trial is looking at a new treatment, called [¹⁷⁷Lu]Lu-PSMA-617, for patients with advanced kidney cancer that has spread and no longer responds to standard inhibitor and immunotherapy treatments. [¹⁷⁷Lu]Lu-PSMA-617 is a radioactive agent that targets a molecule called PSMA (prostate-specific membrane antigen). Patients who have PSMA detected on a PET (positron emission tomography) scan will receive the treatment every 6 weeks for up to four cycles, with the possibility of two extra cycles if their cancer is stable or shrinking. The aim of the trial is to test a new treatment option for patients who have few remaining alternatives.