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

Abstract

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. <b>Methods:</b> 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. <b>Conclusion:</b> 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.