Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177Lu-Satoreotide Tetraxetan

Abstract

Purpose: Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of neuroendocrine tumors (NETs). We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist ¹⁷⁷Lu-satoreotide tetraxetan.

Patients and methods: Twenty patients with advanced SSTR2-positive NETs were treated with ¹⁷⁷Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with ¹⁷⁷Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered 3 months apart. The maximum activity was 7.4 GBq per cycle.

Results: Of 20 patients with NETs (one lung, seven small bowel, nine pancreatic, one gastric, one rectal, one kidney; mean prior treatments: three), six received one cycle of ¹⁷⁷Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in four of seven (57%) patients after cycle 2 of ¹⁷⁷Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1 Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% [5% complete response (1/20), 40% partial response (8/20)]; with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI, 13.6-NR).

Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of ¹⁷⁷Lu-satoreotide tetraxetan. Additional studies are ongoing to determine optimal therapeutic dose/schedule.

Figure 1

Study Design Dose modification occurred after trial suspension. Trial was modified so that the dose of cycle 2 was reduced by an additional 50%.

Figure 2

Planar whole-body scans of four patients with metastatic NETs after injection of ¹⁷⁷Lu-satoreotide tetraxetan at the indicated times. Intense tracer uptake was observed in liver, lymph node, and osseous metastases.

Figure 3

Relationship between estimated absorbed radiation dose to red marrow (all administrations combined) and development of G4 thrombocytopenia. Red: G4 thrombocytopenia after two cycles (3 months apart). Green: no G4 thrombocytopenia after two cycles (≤ 3 months apart). Blue: no G4 thrombocytopenia after two cycles (> 3 months apart). Black: no G4 thrombocytopenia after one cycle (did not have second cycle).

Figure 4

Progression-free survival and overall survival: Median follow-up of 32 months. Note: two patients (ID# 14,18) died early on had non-measurable disease (peritoneum and bone) are included in PFS at the time of death