Fibroblast Activation Protein-Targeted Radioligand Therapy (FAP RLT) in Gastroenteropancreatic Malignancies: Biological Rationale, Clinical Evidence, and Future Directions

Abstract Gastroenteropancreatic (GEP) malignancies are a major cause of cancer-related mortality, with many patients presenting at advanced stages where curative options are limited. Outcomes remain suboptimal, particularly beyond first-line therapy, highlighting the need for novel approaches. Fibroblast activation protein (FAP)-targeted radioligand therapy (RLT) has emerged as a biologically rational strategy that exploits the stromal compartment of desmoplastic tumors. FAPI PET/CT enables noninvasive assessment of target expression and supports a theranostic framework for patient selection. This review summarizes current clinical evidence on Lutetium-177 (177Lu)-FAP RLT in GEP cancers, including pancreatic, biliary, gastric, and colorectal malignancies. Available data, largely from small and heterogeneous early-phase studies, demonstrate feasibility and acceptable short-term safety, with hematologic toxicity as the main concern. Objective responses are uncommon; however, disease stabilization and symptomatic benefit have been observed in selected patients. Key limitations include variable tumor retention, heterogeneous selection criteria, and the lack of standardized dosimetry and response assessment. Overall, 177Lu-FAP RLT remains investigational but represents a biologically compelling but still clinically unproven biomarker-driven strategy, whose current role is best confined to investigational settings and highly selected patients. Future progress requires optimized ligand design, standardized imaging and dosimetry, and prospective clinical trials to define its clinical role.