Evaluation of [68Ga]Ga-DOTA-CP04 imaging in Cholecystokinin-2 receptors (CCK-2R) positive tumors

Introduction: Cholecystokinin-2 receptor (CCK-2R) is expressed in various tumors including medullary thyroid cancer (MTC), small-cell lung cancer (SCLC), somatostatin receptor (SSTR)-negative neuroendocrine tumors (NET) and is a potential diagnostic and therapeutic (theranostic) molecular target for CCK-2R expressing tumors. PET/CT imaging using the diagnostic tracer [⁶⁸Ga]Ga-DOTA-CP04 (CP04) has been developed to detect tumors with CCK-2R expression. We report the imaging characteristics of patients (pts) who underwent CP04 PET/CT imaging.

Methods: Retrospective review of pts who underwent CP04 PET/CT imaging at our center from 2018-2022. Uptake of physiologic organs were measured. Detection of lesions were assessed on a per-patient basis (considered positive if any lesion uptake SUVmax >1.5 x SUVmean blood pool), per-lesion (SUVmax of the most intense lesion), and compared to [⁶⁸Ga]Ga-DOTA-TATE (GaTATE) or [¹⁸F]F-FDG (FDG) PET/CT if available.

Results: Thirty-three pts (12 MTC, 18 NET, 2 SCLC, 1 large cell neuroendocrine carcinoma NEC) underwent 42 CP04 studies. The stomach had the highest physiological uptake with average SUVmax 26.9 (8.7-79.4). Average renal SUVmax 4.9 (2.8-6.6). Uptake of other physiological organs (mediastinal blood pool, myocardium, lungs, brain, liver, spleen, pancreas, spine, gluteal muscle) was low, average SUVmax <2.7. CP04 uptake of the most intense lesion had average SUVmax 11.7 (2.2-39.4).

MTC group: CP04 positive disease was identified in 7/12 (58%) pts, with average lesion SUVmax 7.6. In 3 pts, sites of disease were localised on CP04 which were not seen on comparative GaTATE or FDG imaging. Comparative PET/CTs were not done for 3 pts. A positive CP04 study altered management in 4/7 pts (57%): lesion detection leading to surgical resection (n=3), lesion localisation for MRI follow-up (n=1).

NET group: 16/18 (89%) pts had CP04 positive disease by threshold criteria, but majority had relatively low and non-uniform disease uptake, average lesion SUVmax of 6.8 (lowest 2.2), and some with fewer avid lesions than comparative GaTate PET/CT (n=5) or FDG (n=6), considered insufficient for theranostic therapy. Two pts with sub-optimal SSTR disease and limited therapeutic options had significantly high CP04 uptake (SUVmax 34.1, and 39.4 respectively) were deemed suitable and proceeded with [¹⁷⁷Lu]Lu-DOTA-CP04 therapy.

Others: Pts with FDG-avid SCLC (n=2) and large cell NEC (n=1) had CPO4 negative disease, unsuitable for theranostic approach.

Conclusions: This series demonstrated the promising diagnostic utility of [⁶⁸Ga]Ga-DOTA-CP04 PET/CT in pts with MTC, and the potential theranostic application in pts with low SSTR-expressing NET. Imaging distribution suggests the stomach as the potential theranostic dose-limiting organ, but the minimal background physiologic uptake and specific tumor targeting in some pts warrant further investigation and development of CCK-2R targeting in prospective clinical trials.