Covalent FAPI imaging-guided precision surgery in medullary thyroid carcinoma

Purpose: Medullary thyroid carcinoma (MTC) is curable only by complete resection of all malignant lesions; however, biochemical cure rates remain suboptimal due to imprecise lesion localization. We previously developed a covalent targeted radioligand fibroblast activation protein inhibitor (CTR-FAPI-30) with superior MTC detection rate and accuracy. This study evaluated whether [ 68 Ga]Ga-CTR-FAPI-30 PET-CT-guided surgery improves patient outcomes. Patients and methods: In this prospective, open-label phase II clinical trial, 50 MTC patients were enrolled and underwent [ 68 Ga]Ga-CTR-FAPI-30 PET-CT-guided surgery. Patients were stratified into 3 pre-defined arms: 1) newly-diagnosed MTC, R0 resection; 2) recurrent MTC, R0 resection; 3) unresectable disease or distant metastasis. The primary endpoint was the biochemical cure rate at 1-month postoperatively. Secondary endpoints included event free survival, the diagnostic accuracy of [ 68 Ga]Ga-CTR-FAPI-30, and surgical plan modification rate. Results: Baseline characteristics (demographics, T staging, N staging, preoperative calcitonin) of each arm were comparable to historical data from large-scale retrospective studies (p=0.120-0.948). The biochemical cure rates were higher under [ 68 Ga]Ga-CTR-FAPI-30-guided surgery compared to historical data, with 84.2% (95% CI, 60.4%-96.6%) vs. 57.9% (p=0.007) in Arm 1 (newly diagnosed, R0 resection) and 46.7% (95% CI, 21.3%-73.4%) vs. 16.2%-17.9% (p=0.038-0.049) in Arm 2 (persistent, R0 resection). No biochemical cure occurred in Arm 3. For 231 lesions with gold-standard pathology, [ 68 Ga]Ga-CTR-FAPI-30 demonstrated superior diagnostic accuracy (96.5% vs. 72.7%, p<0.0001), sensitivity (98.5% vs. 81.7%, p<0.0001), and specificity (85.3% vs. 20.6%, p<0.0001) compared to conventional imaging. Surgical plans were modified in 46% of patients based on [ 68 Ga]Ga-CTR-FAPI-30 PET-CT compared to investigator determined approaches, with 91% of these modifications were histopathologically justified. Conclusions: [ 68 Ga]Ga-CTR-FAPI-30-guided surgery achieved favorable biochemical cure rates for both newly diagnosed and recurrent MTC, enabling precision surgical resection through accurate lesion localization. Combined with its established diagnostic superiority over conventional imaging, [ 68 Ga]Ga-CTR-FAPI-30 PET-CT represents a promising standard-of-care tool for initial staging and surgical planning in MTC.