16LASER—a phase 2 trial of 177Lu-PSMA-617 as systemic therapy for renal cell carcinoma (NCT06964958)

Abstract Background There is an unmet need for therapeutic targets beyond immune checkpoint (IO), VEGF and HIF inhibition in advanced clear cell renal cell carcinoma (ccRCC). PSMA (prostate-specific membrane antigen) is highly expressed on the cell surface of prostate cancer as well as the neovasculature of other tumors, including RCC. A high degree of PSMA expression has been noted with RNA-sequencing and immunohistochemistry (IHC) in ccRCC and a high rate of detection of ccRCC has been seen with use of PSMA-PET/CT, confirming the validity of PSMA as a therapeutic target. 177Lu-PSMA-617 (LuPSMA) is a beta-emitting PSMA-targeting radiopharmaceutical with proven efficacy in advanced prostate cancer. There is therefore a clear biologic and clinical rationale for evaluating LuPSMA in PSMA-positive advanced ccRCC. Methods NCT06964958 is an investigator-initiated, single-arm, single-center phase 2 trial at Dana-Farber Cancer Institute. The primary objective is to evaluate the objective response rate (ORR) per RECIST 1.1 of LuPSMA in patients with PSMA-positive, advanced ccRCC. Key secondary objectives include safety, progression-free (PFS) and overall survival (OS). Exploratory objectives include imaging, blood and tissue-based biomarkers of response and resistance to therapy, with optional baseline and on-therapy biopsies to be performed in up to 10 patients. Correlative investigations will focus on evaluating SUV thresholds on PSMA-PET/CT associated with response, IHC for DNA damage repair markers in tissue, and spatial transcriptomic and single-nucleus RNA-seq (sNuc-seq) to characterize the inflammatory and immune milieu and understand the interplay between the immune system and response to LuPSMA. Key eligibility criteria include prior receipt of ≥ 1 IO and ≥1 VEGF-TKI, the presence of PSMA-positive disease (≥1 lesion with avidity liver) and the absence of PSMA-negative measurable lesions. Eligible patients will receive 2 cycles of LuPSMA and undergo an interim PSMA-PET, with the option of receiving up to 4 further cycles if there is continued presence of PSMA-avid disease. Radiographic assessment by CT/MRI will occur every 12 weeks. The study will employ a Simon’s optimal two-stage design, with the aim of detecting an ORR of 25% (similar to ORR of belzutifan in the post-IO/TKI setting). 9 patients will be enrolled in stage 1, and the study will proceed to stage 2 and enrol a further 15 patients (for a total of 24 patients overall) if ≥ 1 response is seen in stage 1. If ≥ 3 responses are seen among 24 evaluable patients, the treatment will be declared effective. The probability of concluding that the treatment is effective is 0.9 if the true rate is ≥ 25%, and ≤0.1 if the true rate is ≤ 5%. There is a 63% chance of stopping early with a true ORR of 5%. The trial is due to activate in June 2025. Trial Schema Significance & Vision LASER is one of the first trials of radiopharmaceutical therapy (RPT) in advanced ccRCC and evaluates a novel therapeutic target in this disease. Should promising activity be observed, this study would pave the way for a larger, randomized phase 2/3 study in the post-IO and post-TKI setting. Insights from this study will also inform future RPT trials evaluating other targets including CAIX. Furthermore, the planned imaging, blood and tissue correlatives will provide unique scientific insights into the mechanisms of response and resistance to LuPSMA in RCC, and potentially lead to identification of other therapeutic targets and inform future clinical and translational research evaluating RPT in RCC.