Integrin α _V β ₃ -targeted imaging for identification of lung cancer and mapping of lymph-node metastases: A prospective, multicenter, self-controlled phase 3 trial (TRIIL study).

8017 Background: Integrin α V β 3 mediates tumor formation, invasion, metastasis and angiogenesis. 99m Tc-3PRGD2, a first-in-class radiopharmaceutical targeting integrin α V β 3 , was advanced into a phase 3 clinical trial for evaluation of lung cancer via single photon emission computed tomography (SPECT)/computed tomography (CT), with mapping the lymph-node metastases as the primary objective. Methods: A prospective, multicenter, phase 3 trial of 99m Tc-3PRGD2 SPECT/CT enrolled 409 patients with solid lung lesions ≥ 1.5×1.0 cm in high suspicion of lung cancer (TRIIL; ClinicalTrials.gov identifier: NCT04233476; chinadrugtrials.org.cn identifier: CTR20191465). A self-controlled design was used for a head-to-head comparison with the conventional metabolic imaging via F-18 fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/CT. The primary outcome was to define the superiority of diagnostic specificity of 99m Tc-3PRGD2 SPECT/CT over that of 18 F-FDG PET/CT in assessment of lymph-node metastases of lung cancer. The secondary outcomes included the other diagnostic values and safety. Results: No severe adverse event was observed in 407 patients with complete safety data. In 268 patients with pathological diagnosis of the lung tumors, no significant difference was found between 99m Tc-3PRGD2 SPECT/CT and 18 F-FDG PET/CT for detection of lung malignancies (sensitivity, 96% vs 98%, P = 0.083). In 259 patients with pathological diagnosis of 1601 lymph-node stations, 99m Tc-3PRGD2 SPECT/CT demonstrated superiority over 18 F-FDG PET/CT in the diagnostic specificity (74% vs 50%, P < 0.001) and accuracy (70% vs 55%, P < 0.001) for mapping the lymph-node metastases station-by-station, with a relatively lower sensitivity (55% vs 75%, P < 0.001) mainly due to spatial resolution limitation of the current SPECT systems. In a semi-quantitative analysis of the tumor-to-background ratios in each method, the areas under the receiver operating characteristic curves were 0.69 for 99m Tc-3PRGD2 SPECT/CT and 0.63 for 18 F-FDG PET/CT ( P = 0.13), respectively, for discriminating lymph-node stations with and without metastasis. In a case-by-case analysis, the integrin α V β 3 -targeting 99m Tc-3PRGD2 SPECT/CT corrected the false-positive diagnosis of 18 F-FDG PET/CT in 344 lymph-node stations from 152 (59%) of the 259 patients, providing more accurate evaluation of lymph-node metastasis in 116 (45%) patients, whereas 18 F-FDG PET/CT held better diagnosis of the lymph-node involvement only in 40 (15%) patients. Conclusions: This trial substantiates the advantages of the integrin imaging for mapping the lymph-node metastases of lung cancer, and paves the way for 99m Tc-3PRGD2 SPECT/CT to be evolved into a universally accessible and cost-efficient technique for tumor diagnosis and staging, and further towards precise therapy. Clinical trial information: NCT04233476 .