Prospective Phase II Trial of [Ga]Ga-NODAGA-E[c(RGDyK)] PET/CT Imaging of Integrin αβ for Prognostication in Patients with Neuroendocrine Neoplasms.

Integrin αβ, a subtype of the arginine-glycine-aspartate (RGD)-recognizing cell surface integrins, is upregulated on endothelial cells during angiogenesis and on tumor cells. Because of involvement in tumor growth, invasiveness and metastases, and angiogenesis, integrin αβ is an attractive target in cancers. In this study, we applied Ga-NODAGA-E[c(RGDyK)] for imaging of integrin αβ in patients with neuroendocrine neoplasms (NENs) and its potential use for prognostication. We hypothesized that Ga-NODAGA-E[c(RGDyK)] PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Between December 2017 and November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for Ga-NODAGA-E[c(RGDyK)] PET/CT. The scan was acquired 45 min after injection of 200 MBq of Ga-NODAGA-E[c(RGDyK)] Board-certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUV in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUV for each patient was used as a predictor of outcome. Patients were followed for at least 1 y to assess progression-free survival and overall survival. Of 113 patients enrolled in the trial, 99 underwent Ga-NODAGA-E[c(RGDyK)] PET/CT, with 97 patients having evaluable lesions. The patients predominantly had small intestinal (64%) or pancreatic (20%) NEN and most had metastatic disease (93%). Most patients had low-grade tumors (78%), whereas 22% had high-grade tumors. During a median follow-up of 31 mo (interquartile range, 26-38 mo), 62 patients (64%) experienced disease progression and 25 (26%) patients died. In total, 76% of patients had positive tumor lesions, and of the patients with high-grade tumors 91% had positive tumor lesions. High integrin αβ expression, defined as an SUV of at least 5.25, had a hazard ratio of 2.11 (95% CI, 1.18-3.78) and 6.95 (95% CI, 1.64-29.51) for progression-free survival and overall survival, respectively ( = 0.01 for both). Tumor lesion uptake of Ga-NODAGA-E[c(RGDyK)] was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish whether Ga-NODAGA-E[c(RGDyK)] PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin αβ