LASER: A Phase 2 Trial of 177Lu-PSMA-617 as Systemic Therapy for RCC.

Renal cell carcinoma is one of the most common malignancies in the United States, with clear cell renal cell carcinoma (ccRCC) comprising approximately 70% of all cases. ccRCC remains therapeutically challenging, particularly in patients whose disease progresses after therapy with immune checkpoint inhibitors and tyrosine kinase inhibitors. Prostate-specific membrane antigen (PSMA), expressed in the tumor neovasculature of ccRCC, offers a potential therapeutic target for radiopharmaceutical therapy with 177Lu-PSMA-617, a well-established therapy in the management of prostate cancer. Methods: This is a single-center, open-label, single-arm, phase 2 clinical trial designed to evaluate the safety and efficacy of 177Lu-PSMA-617 in patients with advanced PSMA-positive ccRCC. Eligible participants must have measurable disease, have received at least 1 immune checkpoint inhibitor and 1 tyrosine kinase inhibitor, and demonstrate PSMA-avid disease in the majority of lesions on baseline 68Ga-PSMA-11 PET/CT. Patients will receive up to 6 cycles of 177Lu-PSMA-617 every 6 wk. A 2-stage design is used: 9 patients will be enrolled in stage 1, with trial continuation dependent on at least 1 objective response. If criteria are met, 15 additional patients will be enrolled, for a total of 24. The primary endpoint is the objective response rate in accordance with RECIST 1.1. Secondary endpoints include safety, progression-free survival, and overall survival. Exploratory objectives include the correlation of imaging biomarkers, circulating cell-free DNA, and genomic alterations with clinical outcomes. Conclusion: This prospective trial aims to evaluate the safety and preliminary efficacy of 177Lu-PSMA-617 in patients with advanced PSMA-positive ccRCC. The results of this study may support the clinical development of PSMA-targeted radiopharmaceutical therapy as a novel treatment option for patients whose disease has progressed after standard systemic therapies.