[⁶⁸Ga]Ga-FAP-2286 versus [¹⁸F]FDG PET/CT in lung cancer: lesion-based comparison across primary tumors and metastatic sites

Accurate delineation of disease extent is essential for lung cancer staging. 18 F-fluorodeoxyglucose ([¹⁸F]FDG) PET/CT has limitations, including high physiologic brain uptake and non–tumor-specific uptake in infection/inflammation. [⁶⁸Ga]Ga-FAP-2286 targets fibroblast activation protein (FAP) in tumor stroma, but lesion-level evidence in lung cancer remains limited. In this retrospective cohort (March 2023–September 2025), 72 patients underwent [¹⁸F]FDG and [⁶⁸Ga]Ga-FAP-2286 PET/CT within 1 week. Both tracers detected all primary/recurrent pulmonary lesions (55/55). [⁶⁸Ga]Ga-FAP-2286 showed lower maximum standardized uptake value (SUVmax) than [¹⁸F]FDG across all three histologic subtypes, whereas pooled tumor-to-background ratio (TBR) was comparable between tracers; TBR was significantly lower with [⁶⁸Ga]Ga-FAP-2286 in pulmonary neuroendocrine tumors (NETs). FAP-positive tumor volume and [¹⁸F]FDG metabolic tumor volume (MTV) were comparable. Among 218 nodal metastases, the lesion-based detection rate was lower for [⁶⁸Ga]Ga-FAP-2286 than for [¹⁸F]FDG (89.0% vs. 97.7%, P < 0.001), driven by NETs (55.6% vs. 100%, P < 0.001); the detection rates were similar in adenocarcinoma ( P = 0.774) and not significantly different in squamous cell carcinoma ( P = 0.063). For 158 bone metastases, the lesion-based detection rates were comparable ( P = 0.238) and SUVmax was similar, whereas TBR was higher with [⁶⁸Ga]Ga-FAP-2286 ( P < 0.001). In pooled analyses, [⁶⁸Ga]Ga-FAP-2286 detected numerically more liver metastases than [¹⁸F]FDG, although the difference did not reach statistical significance ( P = 0.07); TBR was higher with [⁶⁸Ga]Ga-FAP-2286 ( P = 0.03). For pleural/peritoneal metastases ( n = 38), SUVmax and TBR were higher with [⁶⁸Ga]Ga-FAP-2286 ( P = 0.009 and P < 0.001, respectively). For pulmonary metastases ( n = 66; median diameter, 8.4 mm), [⁶⁸Ga]Ga-FAP-2286 showed a lower detection rate ( P = 0.004), SUVmax, and TBR than [¹⁸F]FDG. In an exploratory analysis of seven brain metastases from four patients, [⁶⁸Ga]Ga-FAP-2286 detected six lesions versus one with [¹⁸F]FDG, with higher TBR despite low absolute uptake. [⁶⁸Ga]Ga-FAP-2286 PET/CT may complement [¹⁸F]FDG PET/CT in lung cancer: performance was comparable for primary/recurrent lesions and bone metastases, while exploratory findings suggested potentially favorable lesion-to-background contrast for liver and brain metastases and greater lesion conspicuity for pleural/peritoneal metastases. However, detectability was lower for pulmonary metastases, and nodal detectability was reduced mainly in pulmonary NETs.