Novel Fibroblast Activation Protein Inhibitor-Based Targeted Theranostics for Radioiodine-Refractory Differentiated Thyroid Cancer Patients: A Pilot Study

Thyroid. 2022 Jan;32(1):65-77. doi: 10.1089/thy.2021.0412. Epub 2021 Dec 31.


Background: This exploratory study was meant to assess clinical and safety data with a novel fibroblast activation protein inhibitor-based targeted theranostics as a salvage treatment option in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients who had progressed on tyrosine kinase inhibitors. Methods: Patients with metastatic RR-DTC who progressed on sorafenib/lenvatinib were prospectively recruited. If [68Ga]Ga-DOTA.SA.FAPi positron emission tomography/computed tomography scan demonstrated moderate-to-excellent uptake in metastases, and patients had given informed consent, they received intravenous [177Lu]Lu-DOTAGA.(SA.FAPi)2 as therapy at eight-weekly intervals. The primary endpoints were thyroglobulin (Tg) response and functional imaging response. The secondary endpoints were visual analog score (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status. The grading of toxicities was performed by using Common Terminology Criteria for Adverse Events (CTCAEV5.0). The sequential images were acquired by a dual-headed gamma camera, and dosimetric calculations were performed by using OLINDA/EXM V2.1. Results: Fifteen patients were recruited [age: 55 ± 9 years (range: 39-67)]. [177Lu]Lu-DOTAGA.(SA.FAPi)2 had median whole-body Teff of 88.06 hours (interquartile range [IQR]: 86.6-99). The colon was identified as a critical organ. The whole-body effective dose was 1.62E-01 ± 1.53E-02 mSv/MBq. A total of 45 cycles were administered, and the median cumulative administered activity was 8.2 ± 2.7 GBq (range 5.5-14 GBq). The median absorbed doses to the tumor lesions were 1.08E+01 (IQR: 4.16E+00 to 8.97E+01) mSv/MBq per cycle. The Serum Tg level significantly decreased after treatment [(median Tg: baseline-10,549 ng/mL (IQR: 3066.5-39,450) versus at the time of assessment: 5649 ng/mL (IQR: 939.5-17,099), p = 0.0005)]. Molecular response assessment revealed no complete response; however, partial response was documented in four, and stable disease in three patients. The VASmax scores [pre-therapy: 9 (IQR: 8-10) versus follow-up: 6 (3-6) (p-0.0001)], and ECOG [3, (IQR: 2-3 vs. 2, (IQR: 2-3) (p-0.0078)] performance scores significantly improved after treatment. None of the patients experienced grade III/IV hematological, renal, or hepatotoxicity. Conclusion: These preliminary data suggest that the novel molecule [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe, seems effective, and, most importantly, opens up a new avenue for the treatment of aggressive RR-DTC patients who have exhausted all standard line of treatments.

Keywords: [177Lu]Lu-DOTAGA.(SA.FAPi)2,; fibroblast activation protein inhibitors; radioiodine-refractory differentiated thyroid cancer.

MeSH terms

  • Adult
  • Aged
  • Female
  • Humans
  • India
  • Male
  • Middle Aged
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use
  • Pilot Projects
  • Positron Emission Tomography Computed Tomography / methods
  • Positron Emission Tomography Computed Tomography / statistics & numerical data
  • Precision Medicine / methods*
  • Precision Medicine / statistics & numerical data
  • Prospective Studies
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Quinolines / pharmacology
  • Quinolines / therapeutic use
  • Sorafenib / pharmacology
  • Sorafenib / therapeutic use
  • Thyroid Neoplasms / diagnostic imaging
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / physiopathology


  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Quinolines
  • Sorafenib
  • lenvatinib