Phase 1 Trial: Next-Gen PSMA Radioligand 177Lu-LNC1011 Shows Favorable Results

¹⁷⁷Lu-D-Dan-Phe-PSMA, also called ¹⁷⁷Lu-LNC1011, represents a next-generation PSMA-targeted radioligand therapy designed to improve on existing options like Pluvicto for metastatic castration-resistant prostate cancer (mCRPC). Unlike Pluvicto, which clears rapidly through the kidneys and limits sustained tumor exposure, this agent incorporates a dansyl modification for prolonged intratumoral retention while preserving systemic clearance. Early phase 1 results highlight its potential, showing high tumor-absorbed doses and promising efficacy signals in heavily pretreated patients.

The phase 1 trial enrolled nine PSMA PET/CT-positive mCRPC patients with lesions exhibiting SUVmax of at least 20, treating them in a 3+3 dose-escalation design for two cycles spaced six weeks apart. No dose-limiting toxicities occurred during the 42-day observation, and no hepatic or renal issues emerged, with adverse events limited mostly to grade 1 anemia, leukopenia, and one case of grade 3 thrombocytopenia that stabilized without complications. Dosimetry revealed a tumor effective half-life of 128 hours versus 49 hours whole-body, delivering 12.29 Gy/GBq to tumors compared to lower retention seen with Pluvicto.

Efficacy stood out particularly in the highest 3.70 GBq cohort, where all three patients achieved PSA reductions after two cycles, with 66.7% experiencing at least a 50% decline, higher than the 46% PSA50 rate from Pluvicto’s VISION phase 3 trial across up to six cycles in 551 patients. Overall objective response rates reached 33.3% and disease control 66.7%, with 80% stable disease or better among those with measurable lesions by RECIST 1.1.

Pluvicto’s VISION study randomized post-taxane, PSMA-positive mCRPC patients to 7.4 GBq doses plus best standard care versus standard care alone, confirming radiographic progression-free survival and overall survival benefits alongside manageable cytopenias and xerostomia. LNC1011’s design addresses Pluvicto’s pharmacokinetic shortcoming, preclinical data showing 7-8 times greater tumor uptake, which translated to superior intratumoral radiation in this first-in-human evaluation.

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Clinical trial.