Comparison of Baseline 68Ga-FAPI and 18F-FDG PET/CT for Prediction of Response and Clinical Outcome in Patients with Unresectable Hepatocellular Carcinoma Treated with PD-1 Inhibitor and Lenvatinib

Fibroblast activation protein contributes to immunosuppression and resistance to immunotherapies. This study aimed to compare baseline ⁶⁸Ga-labeled fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) PET/CT and ¹⁸F-FDG PET/CT in response and survival prediction in unresectable hepatocellular carcinoma (uHCC) patients treated with the combination of programmed cell death 1 (PD-1) inhibitor and lenvatinib. Methods: In this prospective cohort study, 22 patients with uHCC who underwent baseline ¹⁸F-FDG and ⁶⁸Ga-FAPI PET/CT and soon began taking a combination of PD-1 inhibitor and lenvatinib were recruited. Semiquantitative indices of baseline PET/CT were measured as ¹⁸F-FDG SUV_max, metabolic tumor volume, total lesion glycolysis, ⁶⁸Ga-FAPI SUV_max, ⁶⁸Ga-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The primary endpoint was durable or nondurable clinical benefit after treatment, and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The overall response rate of the combination therapy was 41% (9/22). Fifty percent of patients had durable clinical benefit. Median PFS and OS were 4.8 and 14.4 mo, respectively. Patients with nondurable clinical benefit showed a significantly higher FTV and TLF than those with durable clinical benefit, whereas ¹⁸F-FDG parameters overlapped. A higher ⁶⁸Ga-FAPI-avid tumor burden (FTV > 230.46 cm³ or TLF > 961.74 SUV_{body weight}⋅cm³) predicted both shorter PFS (4.0 vs. 13.5 mo, P = 0.016) and shorter OS (7.8 mo vs. not reached, P = 0.030). Patients with a higher metabolic tumor burden (metabolic tumor volume > 206.80 cm³ or total lesion glycolysis > 693.53 SUV_{body weight}⋅cm³) showed a shorter OS although the difference did not reach statistical significance (P = 0.085). In multivariate analysis, a higher ⁶⁸Ga-FAPI-avid tumor burden (hazard ratio [HR], 3.88 [95% CI, 1.26-12.01]; P = 0.020) and macrovascular invasion (HR, 4.00 [95% CI, 1.06-15.14]; P = 0.039) independently predicted a shorter PFS, whereas a higher ⁶⁸Ga-FAPI-avid tumor burden (HR, 5.92 [95% CI, 1.19-29.42]; P = 0.035) and bone metastases (HR, 5.88 [95% CI, 1.33-25.93]; P = 0.022) independently predicted a shorter OS. Conclusion: Volumetric indices on baseline ⁶⁸Ga-FAPI PET/CT were potentially independent prognostic factors to predict durable clinical benefit, PFS, and OS in uHCC patients treated with a combination of PD-1 and lenvatinib. Baseline ⁶⁸Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy.