# Comparative Evaluation of [68Ga]Ga-Fibroblast Activation Protein Inhibitor vs. [18F]FDG as a Novel Radiotracer for Biology-Guided Image Radiotherapy

## TL;DR

This study compares two radiotracers for biology-guided radiotherapy, finding that [68Ga]Ga-FAPI-04 outperforms [18F]FDG in several cancers.

## Contribution

The first comparison of [68Ga]Ga-FAPI-04 and [18F]FDG for biology-guided radiotherapy, showing FAPI-04's superior performance.

## Key findings

- NNA and NTS for [68Ga]Ga-FAPI-04 met BgRT requirements for all cancer types.
- NNAFAPI was significantly higher than NNAFDG for pancreatic, H&N, and cervical cancer.
- NTSFAPI was significantly higher than NTSFDG for pancreatic, liver, and lung cancer.

## Abstract

Biology-guided radiotherapy (BgRT) uses PET radiotracer emissions as image guidance to deliver adaptive targeted radiation to tumors. Due to limitations of the PET radiotracer 18F-Fluorodeoxyglucose ([18F]FDG), there is significant interest in developing alternative radiotracers for BgRT. Fibroblast activation protein (FAP) is a transmembrane protein that is overexpressed in cancer-associated fibroblasts within multiple tumor types with minimal expression in normal tissues. Fibroblast activation protein inhibitors (FAPIs) bind avidly to FAP and can be labeled with a radiotracer such as Gallium-68 (68Ga). Multiple studies have compared [68Ga]Ga-FAPI-04 vs. [18F]FDG for diagnostic imaging, but no one has compared the utility of [68Ga]Ga-FAPI-04 vs. [18F]FDG for BgRT. This study was designed to compare calculated parameters from [68Ga]Ga-FAPI-04 vs. [18F]FDG PET-CT to determine if FAPI-04 can be a useful biological fiducial for BgRT. The findings from this work could have a significant impact on the field by providing evidence that [68Ga]Ga-FAPI-04 is a superior agent for image-guided adaptive radiation therapy.

Background/Objectives: Biology-guided radiotherapy (BgRT) is a novel technology utilizing PET radiotracer emissions to deliver image-guided adaptive RT. 18F-Fluorodeoxyglucose ([18F]FDG) is the most common PET radiotracer but has background in the liver and brain because it is taken up by viable tumor cells as well as inflammatory cells. Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts with minimal expression in normal tissues. FAP inhibitors (FAPIs) bind to FAP, and a FAPI labeled with Gallium-68 (68Ga) is a novel radiotracer with high tumor selectivity. Multiple studies have compared [68Ga]Ga-FAPI-04 vs. [18F]FDG for diagnostic imaging, but [68Ga]Ga-FAPI-04 vs. [18F]FDG have never been compared in terms of their utility for BgRT. Purpose: This study was designed to assess the utility of [68Ga]Ga-FAPI-04 vs. [18F]FDG for BgRT used to treat pancreatic, liver, lung, head and neck, and cervical cancers. Methods: A radiation oncologist specializing in each cancer contoured the gross tumor volume (GTV) on [18F]FDG PET-CT and [68Ga]Ga-FAPI-04 PET-CT images. Auto-contours were generated using an auto-threshold of 40% of the maximum Standardized Uptake Value (SUV). The suitability of [68Ga]Ga-FAPI-04 vs. [18F]FDG for BgRT was evaluated by comparing Normalized Net Activity Concentration (NNA) and Normalized Target Signal (NTS) for each cancer. Results: NNA and NTS for [68Ga]Ga-FAPI-04 and [18F]FDG met the requirements for [18F]FDG-guided BgRT (NNA > 5.0 kBq/mL, NTS > 2.7) for all disease sites. NNAFAPI was significantly greater than NNAFDG for pancreatic, H&N, and cervical cancer. NTSFAPI was significantly greater than NTSFDG for pancreatic, liver, and lung cancer. Conclusions: [68Ga]Ga-FAPI-04 is a novel radiotracer for BgRT and has the greatest potential impact in the treatment of pancreatic cancer.