FAPI-CUP: A prospective cohort study of patients with cancer of unknown primary (CUP) to evaluate a novel radiotracer, fibroblast activated protein (FAPI), targeting cancer-associated fibroblasts for primary site detection.

Abstract

3072 Background: Cancer of unknown primary (CUP) represents a heterogeneous group of metastatic tumours for which standardised diagnostic work-up fails to identify the site of origin at diagnosis. 18 F-FDG-PET/CT aids in identifying a putative primary site in ~30-50% of CUP patient (pts); however, has limited sensitivity for detecting cancers with high stromal content. Fibroblast activation protein (FAP) is a type II transmembrane serine protease and highly expressed by cancer-associated fibroblasts abundant in desmoplastic tumours such as CUP. 68 Ga-FAPI-46 is a FAP-targeting PET tracer but has not been directly compared to 18 F-FDG-PET/CT in CUP. Aims: We aimed to determine if the addition of 68 Ga-FAPI-46 detects more primary sites compared with 18 F-FDG-PET/CT and CT CAP (standard of care; SoC) in CUP pts and if there is an association between the level of FAPI avidity and response to systemic treatment. Methods: A prospective cohort study recruiting CUP pts across four sites in Australia. Key inclusion criteria: 1) pts considered CUP after diagnostic work-up, pathological review and gender appropriate tests; 2) adequate haematologic and organ function; 3) not commenced current line of systemic treatment (exception palliative radiotherapy for symptom control); 4) ECOG ≤ 2 and life expectancy > 3months. 5) ≤1 prior line of systemic treatment. Pts undergo SoC imaging (CT CAP, 18 F-FDG-PET/CT) and 68 Ga-FAPI-46 PET/CT scan which are reviewed at a multidisciplinary meeting to determine primary site. Clinicopathological review and genomic analysis (if available) were used to determine final primary site. Pts start systemic treatment and have SoC follow-up with data regarding RECIST 1.1 response, survival outcome and further lines of treatment for 12 months. Results: At interim analysis 60 pts were recruited from 03/2022 to 06/2025. Median age was 68 years [30-83] with 89% being ECOG 0-1 and 80% classified as having an unfavourable CUP subtype. A primary site was detected in 37/60 (62%) and 33/60 (55%) pts with 68 Ga-FAPI-46 PET/CT and SoC and SoC alone, respectively. Cholangiocarcinoma (9/37; 24%) and lung (7/37; 19%) were the commonest primary sites detected. 46/60 (77%) pts commenced systemic treatment with a best overall response rate of 9/38 (24%) in RECIST evaluable pts. There was no association between RECIST response and baseline FAPI avidity for either average SUVmax top 3 lesions (p=0.653) or highest SUVmax (p=0.416). Conclusions: 68 Ga-FAPI-46 PET/CT in addition to SoC detected a primary site in more patients compared to SoC imaging alone. There was no association between RECIST response and baseline FAPI avidity. Clinical trial information: NCT05263700 .