177Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with medullary thyroid cancer.

Introduction: The study aimed to assess the safety and efficacy of [¹⁷⁷Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with advanced-stage medullary thyroid cancer (MTC), taking into account the significant presence of tumor stroma observed in various types of thyroid cancers, including MTC.

Methods: In this study from June 2021 to December 2023, 21 MTC patients pretreated with standard treatment options were enrolled. Patients were offered [¹⁷⁷Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy if they exhausted standard line treatment options, and demonstrated high fibroblast activation protein (FAP) expression on the [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT scan. Six females and fifteen males with a mean age of 44 years (range:14 -74 years) were enrolled and treatment cycles were repeated every 8 to 12 weekly intervals over a median follow-up duration of 24 months (mo) (range:4 to 28 mo). Endpoints included molecular response assessment as per PERCIST 1 criteria, overall survival, progression-free survival, and safety assessment according to Common Terminology Criteria for Adverse Events (CTCAEV5.0).

Results: The study involved a total of 85 cycles of [¹⁷⁷Lu]Lu-DOTAGA.FAPi dimer therapy, with a median of 3 cycles (range: 2 - 8) and a median administered activity per cycle of 5.5 GBq (range: 2.0 GBq – 9.3 GBq). Molecular response assessment based on [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT imaging in eight patients revealed a partial response in 46.6% (7/15), stable disease in 46.6% (7/15), and disease progression in 6.8% (1/15). During the median follow-up duration of 24 months, 14.3% (3/21) deaths occurred. The 24-month progression-free survival probability was 55%, and the overall survival probability was 77%. Notably, no grade III/IV hematological, renal, or hepatotoxicities were observed.

Conclusions: [¹⁷⁷Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, and safe and improves survival in advanced stage MTC patients. [¹⁷⁷Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy opens a new scope for the treatment of aggressive MTC patients who have exhausted the available standard line of treatments.