Use of PPV of [ ¹⁸ F]FAPI-74 PET to identify FAP expression in gastrointestinal cancers: Results from a prospective multicenter phase 2 study.

292 Background: Fibroblast activation protein (FAP) has high expression in cancer associated fibroblasts (CAFs) in the tumor microenvironment of many solid tumor malignancies. [ 18 F]FAPI-74 is a fluorine-18 labeled FAP-targeting PET imaging tracer with promising characteristics for detection of malignant disease in a variety of cancers. In this multicenter prospective Phase 2 trial, we hypothesized that [ 18 F]FAPI-74 PET would have a high positive predictive value (PPV) for detecting FAP-expressing tumor tissue in a variety of gastrointestinal (GI) malignancies. Methods: This Phase 2 multicenter trial was conducted in the United States at MGH, MSKCC, BAMF, Northwell, UCLA and Mayo (NCT05641896). Eligible GI cancers in the study included hepatocellular carcinoma, cholangiocarcinoma, gastric, esophageal, pancreatic, and colorectal cancer. Each subject underwent one [ 18 F]FAPI-74 PET scan, and a tissue sample was obtained by biopsy and/or surgical resection. The imaging reads were performed centrally by experienced PET readers. The primary objective was to evaluate the PPV of [ 18 F]FAPI-74 PET in detecting FAP-expressing cells from patient collected tissues using centrally evaluated immunohistochemistry (IHC) with positivity defined by the sponsor as an H score higher than 50. The secondary objective was to evaluate the safety profile of [ 18 F]FAPI-74 and its PPV in detecting the presence of GI malignancies using histopathology as the standard of truth. Results: The trial was activated in May 2023, with the last patient imaged in Jan 2025. Of 103 subjects with GI malignancies, the primary site was gastroesophageal in 46 (45%), pancreatic in 22 (21%), colorectal in 17 (17%), hepatobiliary in 10 (10%) and of other GI origin in 8 (8%) cancers. 60 participants were male and 43 female. In total, 60 patients had viable and representative tissue data for efficacy analysis of primary and secondary endpoints. No serious adverse events were reported because of the investigational product. The PPV of [ 18 F]FAPI-74 PET to detect FAP-expressing cells using IHC was 100% (52/52). The sensitivity and specificity for the detection of FAP were 90% (52/58) and 100% (2/2) respectively. The PPVs of [ 18 F]FAPI-74 PET to detect cancer using histopathology as truth standard was 94% (49/52). The sensitivity for the detection of disease was 91% (49/54). Conclusions: The Phase 2 study in GI cancers demonstrates that [ 18 F]FAPI-74 PET detects FAP expression and presence of disease in cancers of the GI tract. PPV of 100% for primary objective and 94% for secondary objective were determined. These results support initiation of a Phase 3 study of [ 18 F]FAPI-74 PET in patients with GI cancers. In addition, [ 18 F]FAPI-74 PET’s reliability in visualizing FAP expression cells in the tumor microenvironment supports a further role in selection of patients for FAP-directed therapies. Clinical trial information: NCT05641896 .