Phase 1 Study of [ 177 Lu]Lu-NeoB in Patients with Advanced Solid Tumors Overexpressing Gastrin-Releasing Peptide Receptor: Preliminary Safety and Dosimetry Results

Year: 2025

Type: article

Abstract: Gastrin-releasing peptide receptor (GRPR) is overexpressed in a range of tumor types, making it an attractive candidate for novel treatment approaches. NeoB binds to GRPR with high affinity and can be radiolabeled with 68Ga ([68Ga]Ga-NeoB) for imaging or 177Lu ([177Lu]Lu-NeoB, hereafter 177Lu-NeoB) for therapy, making it suitable for theranostics. Methods: NeoRay is a prospective, phase 1/2a, open-label, multicenter, first-in-human study of 177Lu-NeoB. Patients with selected advanced solid tumors with GRPR expression (confirmed by [68Ga]Ga-NeoB lesion uptake) were enrolled. Here, we report preliminary data (cutoff, April 29, 2024) from phase 1, which aimed to identify the maximum tolerated dose and/or recommended phase 2 dose of 177Lu-NeoB. Patients were scheduled to receive at least 3 cycles of 177Lu-NeoB at an interval of at least 6 wk. A Bayesian optimal interval design was used, with dose-escalation decisions based on dose-limiting toxicities (DLTs) during cycle 1 of each dose level. The primary endpoint was the incidence and nature of DLTs. Safety was assessed before and throughout each cycle. Dosimetry was assessed after the first administration. Results: Seventeen patients (median age, 65 y; 71% male) with advanced gastrointestinal stromal tumors, prostate cancer, glioblastoma, or breast cancer received 177Lu-NeoB activities of 1.85 GBq (cycle 1) and then 5.55 GBq (cycles 2–4) (n = 3), 9.25 GBq (n = 9), or 11.1 GBq (n = 5). Four DLTs were observed in 3 patients who received 11.1 GBq: grade 3 anemia (n = 2), grade 4 neurologic decline (n = 1), and grade 3 encephalopathy (n = 1). No DLTs were observed at lower administered activities. Overall, 4 of 17 patients (23.5%) had treatment-related adverse events of grade 3 or higher. Among patients with at least 1 evaluable dosimetry measurement (n = 16), the mean absorbed dose coefficient was 0.10 Gy/GBq (SD, 0.056 Gy/GBq) in the kidneys, 0.055 Gy/GBq (SD, 0.039 Gy/GBq) in the pancreas, and 0.018 Gy/GBq (SD, 0.0076 Gy/GBq) in the red marrow. Conclusion:177Lu-NeoB has a favorable organ dosimetry profile in patients with advanced solid tumors expressing GRPR, with a large safety margin compared with accepted external beam radiation therapy thresholds for organ toxicity. The maximum tolerated dose of 177Lu-NeoB was identified as 9.25 GBq, and the recommended phase 2 dose for the phase 2a dose expansion is 9.25 GBq.

Source: Journal of Nuclear Medicine

DOI: 10.2967/jnumed.125.270411

Authors: Erik S. Mittra, Lilja B. Solnes, Astrid A.M. van der Veldt, Jeffrey Wong, Luigi Aloj, Michael C. Heinrich, Christopher T. Chen, Steven P. Rowe, Tessa Brabander, Simon Pacey, Paola Aimone, Dhrubajyoti Pathak, Lars Blumenstein, Yongmin Liu, Andrei Iagaru

Institutions: Oregon Health & Science University, Johns Hopkins University, Johns Hopkins Medicine, Erasmus MC, City Of Hope National Medical Center, City of Hope, University of Cambridge, Portland VA Medical Center, VA Portland Health Care System, Stanford Medicine, Stanford University, University of North Carolina at Chapel Hill, Novartis (Switzerland), Novartis Institutes for BioMedical Research, Novartis (China)

Language: English

Topic: Radiopharmaceutical Chemistry and Applications

Subfield: Radiology, Nuclear Medicine and Imaging

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Awards: G139696651, G1960665002, Functional profiling of germline SDH variants associated with cancer susceptibility, G2493601830, G2537968379, Novel models for functional profiling of germline SDH variants associated with cancer, G3584577881, G370598735, G4291216142, G4655236649, G515689015, G5167650663, G544954095, G5739028346, G5741036609, G6077662935, G6887062956, G7782972677, G8683158713

OpenAlex ID: W4416998599