The novel long-circulating prostate-specific membrane antigen (PSMA) therapeutic radioligand [177Lu]Lu-D-Dan-Phe-PSMA (Lu177 Lu-LNC1011) was well tolerated across all dose levels and delivered high tumor-absorbed radiation doses with prolonged tumor retention in patients with metastatic castration-resistant prostate cancer (mCRPC), according to results from a phase 1 dose-escalation study (NCT06250244) published in Theranostics.1
In the 3.70 GBq–cohort (n = 3), all 3 patients experienced 100% prostate specific antigen (PSA) reduction after 2 treatment cycles, with 66.7% achieving at least a 50% PSA decline. The partial response (PR) rate was 66.7% and the stable disease (SD) rate was 33.3%, yielding a disease control rate of 100% and an objective response rate of 66.7%.
“[177Lu]Lu-D-Dan-Phe-PSMA demonstrated early tumor uptake with high tumor absorbed dose and long tumor retention," Jiarou Wang, MD, PhD, candidate at Peking Union Medical College Hospital in Beijing, China, and colleagues wrote in the publication.
Key Takeaways From the Phase 1 Study
- The novel long-circulating PSMA therapeutic radioligand [177Lu]Lu-D-Dan-Phe-PSMA was well tolerated across all dose levels and delivered high tumor-absorbed radiation doses with prolonged tumor retention in patients with mCRPC.
- In the 3.70 GBq-cohort (n = 3), all 3 patients experienced PSA reduction after 2 treatment cycles, with 66.7% achieving at least a 50% PSA decline.
- No DLTs were observed in any activity group during the 42-day observation period, and no immediate or life-threatening serious adverse effects were reported.
What was the rationale for the phase 1 study?
In March 2022, the FDA approved lutetium Lu 177 vipivotide tetraxetan (Pluvicto) for the treatment of adult patients with PSMA-positive mCRPC who received prior anticancer therapies.2 The decision represented the first approval of a targeted radioligand therapy for the treatment of patients with progressive PSMA-positive mCRPC. In March 2025, the FDA expanded the indication to include adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibitor therapy and are considered appropriate to delay taxane-based chemotherapy.3
However, lutetium Lu 177 vipivotide tetraxetan’s pharmacokinetic profile is characterized by rapid renal clearance of unbound radioligand, which can reduce off-target radiation exposure but may concurrently limit sustained intratumoral radiation delivery.1 This feature underscores the importance of developing next-generation agents that optimize the balance between tumor retention and systemic clearance.
How was the phase 1 trial designed?
The open-label, non-randomized, phase 1 dose-escalation trial enrolled patients with PSMA-positive mCRPC confirmed by PSMA PET/CT between May 2023 and December 2024. Patients were not required to have received prior docetaxel, but needed at least 1 lesion with a PSMA PET maximum standardized uptake value of at least 20 and could not have had FDG PET-positive/PSMA-negative lesions.
The study employed a standard 3 + 3 dose-escalation design. Treatment was planned for up to 2 cycles with an inter-cycle time interval of 6 weeks. A follow-up Gallium 68 Ga-PSMA-11 PET/CT scan occurred 6 weeks following treatment. Patients included in the publication were treated with [177Lu]Lu-D-Dan-Phe-PSMA at 1.85 GBq (n = 3), 2.78 GBq (n = 3), and 3.70 GBq (n = 3).
The primary end point was safety. Secondary end points included efficacy after 2 treatment cycles and treatment dosimetry. PSA responses were evaluated per Prostate Cancer Clinical Trials Working Group 3 criteria, and imaging assessments were conducted per RECIST 1.1 and RECIP 1.0 criteria.
At baseline, the median ages in the 1.85-GBq, 2.78-GBq, and 3.70-GBq groups were 72 years (range, 69-74), 74 years (range, 64-81), and 72 years (range, 65-78), respectively. The respective baseline Gleason scores were 9 (range, 8-9), 9 (range, 9-10), and 9 (range, 9-10). Baseline PSA levels were 44.88 ng/mL (range, 10.23-100), 37.31 ng/mL (range, 5.27-100), and 366.67 ng/mL (range, 21.10-1001.00), respectively.
What were the additional efficacy and safety data that were reported?
After 2 cycles, 3 patients (33.3%) exhibited disease progression, 2 in the 1.85-GBq cohort and 1 in the 2.78-GBq cohort. Three patients (33.3%) achieved SD, distributed across all three activity groups, and 3 patients achieved PR, including 1 in the 2.78-GBq cohort and 2 in the 3.70-GBq cohort. Among 5 patients with measurable disease at baseline by RECIST 1.1 criteria, 4 (80%) achieved SD and 1 (20%) attained a PR.
In terms of safety, no dose-limiting toxicities (DLTs) were observed in any activity group during the 42-day observation period, and no immediate or life-threatening serious adverse effects were reported. No hepatic or renal toxicity was detected across any cohort.
In the 1.85-GBq group, 1 patient developed grade 1 anemia after 2 cycles, and 2 patients developed grade 1 leukopenia after 1 cycle. In the 2.78-GBq group, grade 1 anemia was present at baseline in all 3 patients, with 1 patient returning to normal levels during treatment; 1 patient developed grade 1 leukopenia after 1 cycle.
In the 3.70-GBq group, 1 patient developed grade 1 thrombocytopenia after the first cycle, which progressed to grade 3 at an additional 42-day follow-up, with platelet counts declining from 143 × 10⁹/L at baseline to 32 × 10⁹/L by week 8. The patient exhibited no significant signs of hemorrhage, and platelet count subsequently stabilized at 40 × 10⁹/L at 12-week follow-up.
“Considering its safety, dosimetric characteristics, and therapeutic efficacy, the 3.70-GBq [dose level] is deemed suitable for further exploration in large-cohort, multi-cycle treatment studies,” Wang and colleagues wrote.
References
- Wang J, Wang R, Xiang J, et al. Phase I dose-escalation study of [¹⁷⁷Lu]Lu-LNC1011, a long-circulating dansyl-modified PSMA theranostics, in metastatic castration-resistant prostate cancer. Theranostics. 2026;16(10):5175-5184. doi:10.7150/thno.128143
- Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. News release. Novartis. March 23, 2022. Accessed May 8, 2026. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer
- FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed May 8, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication
