First-in-human study of dosimetry, safety and efficacy for [¹⁷⁷Lu]Lu-P15-073: a novel bisphosphonate-based radioligand therapy (RLT) agent for bone metastases.

Abstract

Bisphosphonates are pivotal in managing bone tumors by inhibiting bone resorption. This study investigates the therapeutic potential of [¹⁷⁷Lu]Lu-P15-073, a novel bisphosphonate, for radioligand therapy (RLT) in bone metastases. Ten patients (age 35 to 75) with confirmed bone metastases underwent therapy with a single dose of [¹⁷⁷Lu]Lu-P15-073 (1,225 ± 84 MBq, or 33 ± 2 mCi). Prior to treatment, bone metastases were verified via [^99mTc]Tc-MDP bone scans. Serial planar whole-body scans monitored biodistribution over a 14-day period. Dosimetry was assessed for major organs and tumor lesions, while safety was evaluated through blood biomarkers and pain scores. Serial planar whole-body scans demonstrated rapid and substantial accumulation of [¹⁷⁷Lu]Lu-P15-073 in bone metastases, with minimal uptake in blood and other organs. The absorbed dose in the critical organ, red marrow, was measured at (0.034 ± 0.010 mSv/MBq), with a notably low normalized effective dose (0.013 ± 0.005 mSv/MBq) compared to other ¹⁷⁷Lu-labeled bisphosphonates. Persistent high uptake in bone metastases was observed, resulting in elevated tumor doses (median 3.12 Gy/GBq). Patients exhibited favorable tolerance to [¹⁷⁷Lu]Lu-P15-073 therapy, with no new instances of side effects. Additionally, 87.5% (7/8) of patients experienced a significant reduction in pain scale (numerical rating scale, NRS, from 5.1 ± 2.3 to 3.0 ± 1.8). The tumor-background ratio (TBRmean) of [^99mTc]Tc-MDP correlated significantly with [¹⁷⁷Lu]Lu-P15-073 uptake (P < 0.01), indicating its potential for prediction of absorbed dose. This study demonstrates the safety, dosimetry, and efficacy of a single therapeutic dose of [¹⁷⁷Lu]Lu-P15-073 in bone metastases. The treatment was well-tolerated with no severe adverse events. These findings suggest that [¹⁷⁷Lu]Lu-P15-073 holds promise as a novel RLT agent for bone metastases.