Prospective Phase II Trial of [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ PET/CT Imaging of Integrin α_vβ₃ for Prognostication in Patients with Neuroendocrine Neoplasms

Abstract

Integrin α_vβ₃, 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 α_vβ₃ is an attractive target in cancers. In this study, we applied ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂ for imaging of integrin α_vβ₃ in patients with neuroendocrine neoplasms (NENs) and its potential use for prognostication. We hypothesized that ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂ PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Methods: Between December 2017 and November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂ PET/CT. The scan was acquired 45 min after injection of 200 MBq of ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂. Board-certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUV_max in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUV_max 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. Results: Of 113 patients enrolled in the trial, 99 underwent ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂ 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 α_vβ₃ expression, defined as an SUV_max 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 (P = 0.01 for both). Conclusion: Tumor lesion uptake of ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂ was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish whether ⁶⁸Ga-NODAGA-E[c(RGDyK)]₂ PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin α_vβ_3.