212Pb-VMT-α-NET Targeted Alpha Therapy in Metastatic Neuroendocrine Tumors: First in Human study on Safety and Efficacy

Introduction: Peptide Receptor Radioligand Therapy (PRRT) with alpha emitters has been to be an effective treatment option in patients with metastatic somatostatin receptor (SSTR) positive NETs. Alpha emitters such as Pb-212 have the potential to selectively kill tumour cells while preserving surrounding normal tissue. We present the safety and preliminary effectiveness of 212Pb-, a novel SSTR analogue for Targeted Alpha emitter Therapy (TAT), in SSTR(+) NET patients.

Methods: Twelve subjects, 7 men and 5 women, patients with unresectable or metastatic SSTR (+) NETs from different primary sites were enrolled in the study. Patients underwent a Pb203 VMT-α-NET ™ SPECT CT scan to demonstrate expression of somatostatin receptors, to look for biodistribution and predictive dosimetry. 212Pb-VMTwas administered at a fixed dose of 25MBq/Kg body weight at an interval of 8 weeks up to 6 cycles. Response to treatment was measured per RECIST 1.1 and the effect on quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Treatment-related side-effects were assessed every 2 weeks on the basis of physical examination, vital signs, laboratory results and adverse events graded according to the CTCAE v5.0.

Results: This exploratory first in human study was approved by the Institute Ethics Committee (IEC No:2023-002-EMP-40). By RECIST criteria 7 out of 12 subjects showed Partial response, 1 acheived complete response 3 showed progressive disease while one patient opted out of the trial. No clinically significant drug related toxicity was noted up to 13 months after treatment. There was significant improvement in quality of life in all the responders. The most common adverse effects (AEs) were nausea, alopecia, fatigue and appetite loss. These adverse effects excluding alopecia usually resolved about 7 - 10 days post infusion. None of the patients experienced grade 3 or 4 hemato-toxicity, renal insufficiencies or hepatotoxicity. There was no treatment related death.

Conclusions: Our results indicate 212Pb-VMT-α-NET therapy as an effective and safe with low and transient side-effects. 8 out of the 12 patients showed a marked reduction in functional tumour volume with a significant improvement in symptoms even at this rather low dose of therapy. None of the patients demonstrated a clinically significant grade 3 adverse event. This study is an ongoing trial and these are only the preliminary results. Based on these results treatment with Pb212 VMT -α-NET appears to be an effective therapeutic option for patients of unresectable NET with manageable adverse effects. There also appears to be large potential for dose escalation. If proven in larger cohorts this treatment may be a game changer in the management of metastatic neuroendocrine tumours.