Efficacy of [67Cu]Cu-EB-TATE Theranostic Against Somatostatin Receptor Subtype-2-Positive Neuroendocrine Tumors

Abstract

β^--emitting ¹⁷⁷Lu-octreotate is an approved somatostatin receptor subtype 2 (SSTR2)-directed peptide receptor radionuclide therapy for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). However,¹⁷⁷Lu-octreotate has fast pharmacokinetics, requiring up to 4 treatment doses. Moreover, ¹⁷⁷Lu is less than ideal for theranostics because of the low branching ratio of its γ-emissions, which limits its SPECT imaging capability. Compared with ¹⁷⁷Lu, ⁶⁷Cu has better decay properties for use as a theranostic. Here, we report the preclinical evaluation of a long-lived somatostatin analog, [⁶⁷Cu]Cu-DOTA-Evans blue-TATE (EB-TATE), against SSTR2-positive NETs. Methods: The in vitro cytotoxicity of [⁶⁷Cu]Cu-EB-TATE was investigated on 2-dimensional cells and 3-dimensional spheroids. In vivo pharmacokinetics and dosimetry were studied in healthy BALB/c mice, whereas ex vivo biodistribution, micro-SPECT/CT imaging, and therapy studies were done on athymic nude mice bearing QGP1.SSTR2 and BON1.SSTR2 xenografts. Therapeutic efficacy was compared with [¹⁷⁷Lu]Lu-EB-TATE. Results: Projected human effective doses of [⁶⁷Cu]Cu-EB-TATE for male (0.066 mSv/MBq) and female (0.085 mSv/MBq) patients are tolerable. In vivo micro-SPECT/CT imaging of SSTR2-positive xenografts with [⁶⁷Cu]Cu-EB-TATE showed tumor-specific uptake and prolonged accumulation. Biodistribution showed tumor accumulation, with concurrent clearance from major organs over a period of 72 h. [⁶⁷Cu]Cu-EB-TATE was more effective (60%) at eliminating tumors that were smaller than 50 mm³ within the first 15 d of therapy than was [¹⁷⁷Lu]Lu-EB-TATE (20%) after treatment with 2 doses of 15 MBq administered 10 d apart. Mean survival of [⁶⁷Cu]Cu-EB-TATE-treated groups was 90 d and more than 90 d, whereas that of [¹⁷⁷Lu]Lu-EB-TATE was more than 90 d and 89 d against vehicle control groups (26 d and 53 d), for QGP1.SSTR2 and BON1.SSTR2 xenografts, respectively. Conclusion: [⁶⁷Cu]Cu-EB-TATE exhibited high SSTR2-positive NET uptake and retention, with favorable dosimetry and SPECT/CT imaging capabilities. The antitumor efficacy of [⁶⁷Cu]Cu-EB-TATE is comparable to that of [¹⁷⁷Lu]Lu-EB-TATE, with [⁶⁷Cu]Cu-EB-TATE being slightly more effective than [¹⁷⁷Lu]Lu-EB-TATE for complete remission of small tumors. [⁶⁷Cu]Cu-EB-TATE therefore warrants clinical development.

Keywords: PRRT; SPECT/CT imaging; SSTR2; [67Cu]Cu-EB-TATE; dosimetry.