Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but current clinical practice fails to localize the disease in 29% to 60% of patients. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]fluorodeoxyglucose ([18F]FDG) PET-CT in 50 patients with MTC. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, P = 0.0002). This improved detection was attributed to increased tumor uptake (maximum standardized uptake value = 11.71 ± 9.16 vs. 2.55 ± 1.73, P < 0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared with [18F]FDG (96.7% vs. 43.3%, P < 0.0001). Notably, the management of 32% of patients was altered following [68Ga]Ga-CTR-FAPI PET-CT, and the surgical plan was changed for 66.7% of patients. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared with [18F]FDG PET-CT, enabling precision management of patients with MTC.

Significance:

In this first-in-class clinical trial of CTR, [68Ga]Ga-CTR-FAPI demonstrated an improved patient-based detection rate (98%), tumor uptake (maximum standardized uptake value = 11.71 ± 9.16), and pathology-validated diagnostic accuracy (96.7%) compared with the currently approved method in MTC treatment. It directly altered management in 32% of patients, enabling precision diagnosis and management of MTC.

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©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
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Supplementary data

Clinical Protocol

Clinical Protocol

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Notification to AttendingPhysician

Notification to Attending Physician

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Supplementary Table 1

Baseline characteristics of the enrolled patients

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Supplementary Table 2

Detection rate of patients with calcitonin <500 pg/ml

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Supplementary Table 3

Detection rate of patients with calcitonin 500 to 2000 pg/ml

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Supplementary Table 4

Detection rate of patients with calcitonin >2000 pg/ml

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Supplementary Table 5

Inter-reader agreement

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Supplementary Table 6

Tumor uptake in lesions avid on both imaging

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Supplementary Table 7

Tumor uptake stratified by calcitonin levels

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Supplementary Table 8

Tumor uptake stratified by CEA levels

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Supplementary Table 9

Tumor uptake stratified by newly diagnosed or persistent MTC

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Supplementary Table 10

Presurgical imaging identification of the 60 lesions

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Supplementary Table 11

Accuracy of [68Ga]Ga-CTR-FAPI PET-CT and traditional imaging in identifying MTC or non-MTC lesions

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Supplementary Table 12

Pre- and post-surgical calcitonin level of surgical patients

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Supplementary Table 13

Safety of the PET-CT regimens

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Supplementary Table 14

Representativeness of study participants

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Supplementary Figure 1

Patient-based and region-based detection rates

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Supplementary Figure 2

Lesion uptake of [18F]FDG and [68Ga]Ga-CTR-FAPI

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Supplementary Figure 3

Correlation between [68Ga]Ga-CTR-FAPI uptake and FAP expression

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