Covalent FAPI Imaging-Guided Precision Surgery in Patients with Medullary Thyroid Carcinoma: A Phase II Clinical Trial

Abstract

Purpose: Medullary thyroid carcinoma (MTC) is curable only by complete resection of all malignant lesions; however, biochemical cure rates remain suboptimal because of 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 [68Ga]Ga-CTR-FAPI-30 positron emission tomography-computed tomography (PET-CT)-guided surgery improves patient outcomes.

Patients and methods: In this prospective, open-label phase II clinical trial, 50 patients with MTC were enrolled and underwent [68Ga]Ga-CTR-FAPI-30 PET-CT-guided surgery. Patients were stratified into three predefined arms: (i) newly diagnosed MTC, R0 resection; (ii) recurrent MTC, R0 resection; and (iii) 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 [68Ga]Ga-CTR-FAPI-30, and surgical plan modification rate.

Results: The biochemical cure rates were favorable under [68Ga]Ga-CTR-FAPI-30-guided surgery, with 84.2% [95% confidence interval (CI), 60.4%-96.6%] in arm 1 (newly diagnosed, R0 resection) and 46.7% (95% CI, 21.3%-73.4%) in arm 2 (recurrent, R0 resection), both of which exceeded historical data (P = 0.007-0.049). For 231 lesions with gold-standard pathology, [68Ga]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 with conventional imaging. Surgical plans were modified in 46% of patients based on [68Ga]Ga-CTR-FAPI-30 PET-CT compared with investigator-determined approaches, with 91% of these modifications histopathologically justified.

Conclusions: [68Ga]Ga-CTR-FAPI-30-guided surgery achieved favorable biochemical cure rates for both newly diagnosed MTC and recurrent MTC, enabling precision surgical resection through accurate lesion localization.