6 Antitumor Activity of 177Lu-PSMA-617 in PSMA-Positive Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): Results from a Phase 2 Trial (LASER)

Background There is an unmet need for therapeutic targets beside tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI) and HIF inhibitors in ccRCC. PSMA (prostate-specific membrane antigen) is expressed on the neovasculature of solid tumors, including ccRCC. 177Lu-PSMA-617 (LuPSMA) is a beta-emitting PSMA-targeting radiopharmaceutical that has proven efficacy in PSMA-positive prostate cancer. We sought to evaluate the efficacy and safety of LuPSMA in advanced, PSMA-positive ccRCC. Methods LASER is a single-center, investigator-initiated open-label trial conducted at Dana-Farber Cancer Institute, Boston. Eligible patients had metastatic ccRCC who had previously received ≥1 TKI and ≥1 ICI, unless they had a significant contraindication to ICI. Participants were required to have PSMA-positive disease on screening PSMA-PET/CT, with ≥1 lesion with uptake > liver and no or limited PSMA-negative lesions (≤25% of lesions with uptake < liver). LuPSMA was administered at a standard dose of 7.4GBq every 6 weeks for up to 6 cycles; interim PSMA-PET/CT was performed prior to cycle 3 and dosing continued if ≥ 1 avid lesion was seen. The primary endpoint was objective response rate (ORR), as defined per RECIST1.1. A two-stage design was used, with 9 patients enrolled in stage 1 and a further 15 patients planned to accrue to stage 2 if ≥ 1 partial or complete response was observed in stage 1. The design assumed a 5% ORR as unacceptably low and 25% ORR as clinically meaningful; there was 90% power to detect an ORR of 25% with 1-sided a = 0.1 and 63% probability of early discontinuation if true ORR is 5%. Results A total of 21 patients were screened between July 2025 and February 2026; 9 patients were eligible and received therapy in stage 1. Median age was 73 and participants had received a median of 4 prior lines of therapy. The median number of LuPSMA cycles received was 1, with 4 patients receiving 2 or more cycles. There were no radiographic responses (ORR 0%). 2 patients had stable disease, 3 had progressive disease and 4 patients discontinued therapy after 1 cycle due to clinical progression; 1 patient completed all 6 cycles with ongoing stable disease. Median progression-free survival was 2.3 months (95% CI 0.5-5.3), and 3 deaths have been reported to date with a 6-month overall survival rate of 62% (95% CI 21-86). Therapy was well tolerated with no grade ≥3 treatment-related adverse events (TRAEs); the most common grade 1-2 TRAEs were dry mouth (44%, all grade 1) and fatigue (44%). Data pertaining to imaging characteristics of treated patients will be presented. The trial was halted for futility at stage 1. Conclusions LuPSMA was well-tolerated but had no single-agent activity in heavily-pretreated patients with PSMA-positive advanced ccRCC. Future work evaluating radiopharmaceuticals in RCC should focus on alternative targets as well as combinations with standard therapies.