¹⁷⁷Lu-3BP-227 for Neurotensin Receptor 1–Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results

Abstract

Neurotensin receptor 1 (NTR1) is overexpressed in ductal pancreatic adenocarcinoma, which is still one of the deadliest cancers, with a very poor prognosis. Eligible patients were offered salvage radiopharmaceutical therapy with the novel NTR1 antagonist Lu-3BP-227. Six patients with confirmed ductal pancreatic adenocarcinoma who had exhausted all other treatment options received Lu-3BP-227 for evaluation of NTR1 expression in vivo. Three patients received treatment activities of 5.1-7.5 GBq. Administration of Lu-3BP-227 was well tolerated by all patients. The kidneys were identified as the dose-limiting organ. The most severe adverse event was reversible grade 2 anemia. One patient achieved a partial response and experienced significant improvement of symptoms and quality of life. This patient survived 13 mo from diagnosis and 11 mo from the start ofLu-3BP-227 therapy. This initial report provides clinical evidence of the feasibility of treatment of ductal pancreatic adenocarcinoma usingLu-3BP-227.

The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review

“…Pancreatic ductal adenocarcinoma overexpresses NTSR1 and NT, whilst normal pancreatic tissue does not [28,29]. The intensity of NTSR1 increases with the stage of pancreatic cancer and metastases express NTSR1 at the same level as the primary tumour [30]. Preliminary studies showed that NTSR1 is a promising target for therapeutic and diagnostic purposes [31,32].…”

“…Preliminary studies showed that NTSR1 is a promising target for therapeutic and diagnostic purposes [31,32]. Baum and colleagues tested the use of radiopharmaceutical therapy, using an NTSR1 antagonist, in 6 patients with advanced pancreatic adenocarcinoma [30]. They used 177 Lu-3BP-227 as an intravenous agent to assess uptake and then one of the patients proceeded to have 3 further intraperitoneal doses.…”

“…They used 177 Lu-3BP-227 as an intravenous agent to assess uptake and then one of the patients proceeded to have 3 further intraperitoneal doses. Tumor uptake was observed in 5 out of 6 patients and one of the patients achieved a partial remission with improved quality of life and 11-month survival despite a very poor prognosis [30]. There is currently an ongoing phase I and II trial, in evaluating 177 Lu-3BP-227's safety and efficacy in various cancers including pancreatic cancer [33].…”

Fibroblast-Activating Protein: Targeting the Roots of the Tumor Microenvironment

“…Besides safety and efficacy considerations, regulatory and reimbursement issues require increased attention for any theranostic approach to come. Besides well-established and exciting new theranostic approaches in thyroid diseases, neuroendocrine tumors, and prostate cancers, an increasing armamentarium of novel radiotheranostic agents is about to enter clinical evaluation-for example, neurotensin receptor 1 in pancreatic cancer, as recently reported (19). Thus, harmonization of requirements from the various stakeholders and regulatory agencies will be just as important as continued research along the lines of clinical development and evaluation to bring the best possible theranostic approaches to patients.…”

GPCRs in pancreatic adenocarcinoma: Contributors to tumour biology and novel therapeutic targets

“…Radiolabelled neurotensin targeted compounds may be potential therapeutics. Baum et al (2018) treated six pancreatic adenocarcinoma patients with a NTS 1 receptor antagonist, 3 BP ‐227, labelled with 177 Lu. The compound was well tolerated.…”