Clinical development updates with [18F]FAPI-74

Introduction: Fibroblast activation protein (FAP) is a type II transmembrane glycoprotein that has shown to have high expression in cancer associated fibroblasts (CAFs) in the tumor microenvironment of many malignancies. The FAPI (FAP inhibitor) family of radiopharmaceuticals targeting FAP have demonstrated favorable biodistribution and specificity as radiolabeled products for PET imaging with over 5000 reported patients imaged to date. [¹⁸F]FAPI-74 is a fluorine-18 labelled FAPI product with promising characteristics for detection of neoplastic diseases on PET.

Methods: [¹⁸F]FAPI-74 is in a Phase 2 clinical study in the United States for diagnosis of gastrointestinal (GI) cancers. The study includes two cohorts 1) Investigational Cohort and 2) Healthy Subjects Cohort for expanded pharmacokinetic (PK) study at various timepoints. In the Investigational Cohort, subjects will have confirmed GI cancer including hepatocellular carcinoma (HCC), cholangiocarcinoma, gastric, pancreatic, and colorectal cancer (NCT05641896). As part of the clinical protocol, each cancer subject undergoes one [¹⁸F]FAPI-74 PET/CT scan, and a tissue sample will be obtained in the form of biopsy and/or surgical resection from the cancer patients, with no treatment provided between the time of tissue collection and the [¹⁸F]FAPI-74 PET/CT. The primary objective is to evaluate the positive predictive value of [¹⁸F]FAPI-74 PET/CT images in detecting FAP-expressing cells using immunohistochemistry (IHC).

Results: The trial was activated in May 2023, and the first subject was imaged at MGH. Four clinical sites have been activated (MGH, MSKCC, Northwell Feinstein Institute, and BAMF Health) with two additional sites anticipated to be activated in 2024. Approximately 100 patients are expected to be enrolled in the study and as of January 2024, 22 patients have been imaged with an anticipated total of 50 patients expected by mid-2024. The PK study in 6 healthy subjects is earmarked for completion by June 2024 to provide additional tracer biodistribution insights. In support of the study, a proof-of-concept FAP IHC screening and scoring scheme was developed and sensitivity screening was performed in a total of 30 human cancer tissues as follows: gastric cancer (8), colon cancer (7), HCC (5), cholangiocarcinoma (5), and gastroesophageal cancer (5). Pancreatic cancer was evaluated in a separate proof of concept study in support of [⁶⁸Ga]-FAPI-46 and not included in this panel. Each tissue was evaluated by a board-certified pathologist for FAPα percentages for differential intensities of stromal staining to calculate Percent Scores [sum of percentages at different intensities ≥1+ with values ranging from 0 to 100] and H-Scores [sum of each percentage score (0-100%) multiplied by its corresponding intensity score (0, 1+, 2+, 3+) with values ranging from 0 to 300]. The average H-Scores (0-300) for each cancer indication were as follows: gastric cancer: 127.5, colon cancer: 176.4, HCC: 121.0, cholangiocarcinoma: 142.0, and gastroesophageal cancer: 164.0. The cancer evaluated in this panel had high levels of positive score, specifically, when evaluating average FAPα stromal staining H-scores by cancer indication, colon cancer samples averaged higher than the other four cancer indications tested. When evaluating average FAPα stromal Percent Scores of ≥1+ by cancer indication, gastric cancer samples averaged higher than the other cancer indications tested. However, colon cancer samples averaged the highest when evaluating average Percent Scores of ≥2+ and ≥3+.

Conclusions: [¹⁸F]FAPI-74 Phase 2 study in GI cancers is expected to be completed by the end of 2024, which will be followed by an end of Phase 2 submission to the FDA. Proof of concept FAP IHC indicated an overall high level of FAP expression in the tumors, specifically in gastric and colon cancer. Preliminary results suggest a valuable role for this radiotracer as a diagnostic tool in GI Cancers.