Safety, Maximum Tolerated Dose, and Patient-Specific Dosimetry of [177Lu]Lu-LNC1011 in metastatic Castration-Resistant Prostate Cancer Patients

Introduction: [¹⁷⁷Lu]Lu-LNC1011 ([¹⁷⁷Lu]Lu-D-Dan-Phe-PSMA) is a novel long-circulating PSMA therapeutic probe whose structure is based on albumin binder dansyl group. This study represents the first-in-human investigation, aiming to explore its maximum tolerated dose (MTD), safety, dosimetry, and initial treatment efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods: This study employed an open-label, non-randomized design, representing the first human trial of its kind. It adopted a dose-escalation approach, enrolling mCRPC patients who have passed pre-screening PSMA PET/CT. The treatment initiation occurred at a dose of 1.85 GBq over a 6-week period. Subsequent cohorts experienced sequential 50% dose escalations until the observation of dose-limiting toxicity (DLT).

Results: A total of 12 mCRPC patients received [¹⁷⁷Lu]Lu-LNC1011 at doses ranging from 1.85 GBq to 3.7 GBq. No life-threatening adverse events were observed during the dosing observation period. Following two treatment cycles, dose level 1 and level 2 groups exhibited no hematologic toxicity, dose level 3 group showed Grade 1 thrombocytopenia. Effective dose for total-body was 0.10 ± 0.02 mSv/MBq. The kidneys received the highest expected radiation dose, calculated to be 3.40 ± 0.98 mSv/MBq. Effective doses for salivary glands and red bone marrow were 1.54 ± 1.00 mSv/MBq and 0.11 ± 0.03 mSv/MBq，respectively. The average effective dose for tumors was 0.13 ± 0.02 mSv/MBq. According to the guidelines of the Prostate Cancer Clinical Trials Working Group-3 (PCWG3), PSA response in dose level 1 group showed SD (66.67%) and PR (16.67%), in dose level 2 group showed SD (66.67%), and in dose level 3 group showed SD (66.7%) and PR (66.7%). In comparison to PSMA-617, LNC1011 had similar salivary expected dose (1.54 ± 1.00 vs. 1.25 ± 0.51) while demonstrating a notably higher effective dose (0.13 ± 0.02 vs. 0.02 ± 0.003). When compared to an earlier long-acting PSMA formula EB-PSMA, which was based on Evans blue as albumin binder, LNC1011 showcases significantly lower salivary dose (1.54 ± 1.00 vs. 6.14 ± 1.40) but maintained a comparable tumor effective dose (0.13 ± 0.02 vs. 0.13 ± 0.04).

Conclusions: The administration of [¹⁷⁷Lu]Lu-LNC1011 at a dose of 3.7 GBq in the treatment of mCRPC patients is well tolerated and has minimal side effects. It exhibits low uptake in the salivary glands and achieves a high tumor absorbed dose. The preliminary therapeutic efficacy is notable, positioning it as a promising PSMA RLT drug. Future research should focus on higher doses and multiple cycles to further assess its value in the treatment of mCRPC patients.

• Download figure
• Open in new tab
• Download powerpoint