Evaluation safety, dosimetry and efficacy of [177Lu]Lu-P15-073 for therapy of bone metastases

Introduction: Prolonged cancer survival increases bone metastasis risk, surpassing 50% in advanced breast, prostate, and lung cancer, causing pain, fractures, and hypercalcemia, impacting patient quality of life. Previously, a bone imaging agent, ([⁶⁸Ga]Ga-HBED-CC-BP, [⁶⁸Ga]Ga-P15-041), containing a bisphosphonate group was prepared and it showed excellent bone uptake and efficient detection of bone metastasis in cancer patients. By adding an additional DOTA chelator P15-041 was converted to P15-073, which can accommodate different α- or β- emitting metals, ie., ⁶⁸Ga(III) or ¹⁷⁷Lu(III), for formation of stable complexes as bone seeking drugs. The preclinical evaluation of [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-P15-073 indicated high specific binding and long retention in bone metastasis with fast wash-out in untargeted organs. Herein, we investigate the pharmacokinetic, dosimetry biodistribution and toxicity of [¹⁷⁷Lu]Lu-P15-073 in human.

Methods: Nine male patients (mean age ± SD, 60.7 ± 3.8 y; range, 35-75 y) with histologically proven malignant tumors and adequate bone marrow function were enrolled. The presence of multiple or disseminated bone metastasis was verified by [^99mTc]Tc-MDP bone scan within 2 weeks before therapy. Patients received 1237 ± 78 MBq (33 ± 2 mCi) [¹⁷⁷Lu]Lu-P15-073 intravenously for radiotherapy and dosimetry study. Planar whole-body SPECT scans were acquired at 1.5±0.5h, 24±2h, 7d and at 14d after injection, with additional SPECT/CT imaging performed at 24h time-point. Venous blood samples of 3 mL were taken at 30 ± 5 min, 1 ± 0.5h, 2 ± 0.5h, 4 ± 0.5h, 24 ± 1h after injection. Dosimetry calculations for [¹⁷⁷Lu]Lu-P15-073 were carried out using the Xeleris® workstation (GE Healthcare, Milwaukee, USA) equipped with the Dosimetry Toolkit® and OLINDA/EXM® V2.0. Safety was monitored through blood biomarkers at 2, 4, and 6 weeks, graded according to CTCAE v5.0.

Results: [¹⁷⁷Lu]Lu-P15-073 exhibited rapid blood clearance, with 4h and 24h blood retention of 1.0 ± 0.3 %ID/g and 0.8 ± 0.1%ID/g, respectively. The highest absorbed dose was in red marrow (0.03 ± 0.01 mSv/MBq), significantly lower than other bisphosphonates ([¹⁷⁷Lu]Lu-DOTAZOL 0.46 ± 0.06 mSv/MBq and [¹⁷⁷Lu]Lu-DOTA-IBA 0.47 ± 0.19 mSv/MBq). Liver and kidneys also showed high absorbed doses (0.035 ± 0.03 and 0.016 ± 0.024 mSv/MBq, respectively). [¹⁷⁷Lu]Lu-P15-073 demonstrated rapid uptake and prolonged retention in bone metastases, with a tumor absorbed dose of 4.8 ± 3.9 Gy/GBq. No uptake occurred in other organs except the kidneys and bladder. The highest TBR was observed at 72 hours post-injection. Furthermore, [¹⁷⁷Lu]Lu-P15-073 and [^99mTc]Tc-MDP exhibited a strong correlation in TBRs. Relative to baseline, only one patient experienced hematotoxicity, escalating from grade 2 to 4. The [¹⁷⁷Lu]Lu-P15-073 therapy exhibited no statistically significant impact on bone marrow hematopoietic function, liver function, or kidney function during follow-up. Pain relief was achieved in 55% (5/9) of patients, stability in 22% (2/9), and 22% (2/9) patients reported no baseline pain.

Conclusions: [¹⁷⁷Lu]Lu-P15-073 is safe and has a favorable therapeutic index compared with other radiopharmaceuticals used in the treatment of osteoblastic bone metastases. It provides a set of potential theranostic radiopharmaceuticals and may have a good prospect for the management of bone metastasis.