Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study

Abstract

Purpose: Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC).

Patients and methods: This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed.

Results: 177Lu-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 ± 0.04 mSv/MBq. Intense 177Lu-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 ± 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 ± 7.68 and 92.46 ± 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively.

Conclusions: FAP-targeted radioligand therapy with 177Lu-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.

Figure 1.

A representative example of a patient who underwent ¹⁷⁷Lu-LNC1004 therapy. A, A 36-year-old man with progressive metastatic radioiodine-refractory differentiated thyroid cancer began treatment with multi-kinase inhibitors but still experienced disease progression. ⁶⁸Ga-FAPI-46 PET/CT was performed for patient screening before ¹⁷⁷Lu-LNC1004 therapy and revealed intense ⁶⁸Ga-FAPI-46 uptake in metastatic lesions. B, After administrating 3.33 GBq of ¹⁷⁷Lu-LNC1004, intense radiotracer uptake was observed in the metastatic lesions (arrows) on post-therapeutic whole-body scintigraphy (WBS; anterior views) from 1 to 168 hours after injection, which was consistent with ⁶⁸Ga-FAPI-46 uptake presented in the PET/CT.

Figure 2.

Kinetics and dosimetry results of normal organs and metastases and comparative results from metastases (bone, lymph node, and other) in patients treated with ¹⁷⁷Lu-LNC1004: A, Uptakes in the percentage of administered activity (%); B, Effective half-life (h); C, Residence time (h); D, Kinetics of various types of metastases; E, Effective half-life of various types of metastases (h); F, Residence time of various types of metastases (h); and G, Absorbed dose of various types of metastases. les, lesions; LN, lymph node; met, metastases. Other involved recurrences, subcutaneous and visceral metastases.

Figure 3.

Two representative patients with a favorable therapeutic response after 2 cycles of ¹⁷⁷Lu-LNC1004. A, A 36-year-old man with disease progression after TKI treatment received ¹⁷⁷Lu-LNC1004 RLT at 3.3 GBq/cycle. Baseline ⁶⁸Ga-FAPI-46 PET/CT revealed intense ⁶⁸Ga-FAPI-46 uptake in most metastatic lesions, including lymph node, vertebral, and clavicular metastases (left, arrows). Obstructive pneumonia was also observed in the left lung due to the enlarged lymph nodes. After 2 treatment cycles, restaging ⁶⁸Ga-FAPI-46 PET/CT revealed a significant reduction in tumor size and radiotracer uptake in most of the metastatic lesions (right, arrows). Furthermore, the non-target lesion of obstructive pneumonia resolved. B, A 42-year-old man with disease progression after TKI treatment underwent ¹⁷⁷Lu-LNC1004 therapy. Baseline ⁶⁸Ga-FAPI-46 demonstrated intense uptake in multiple bone metastases, left hilar lymph node, and liver metastases (left, arrows). Follow-up ⁶⁸Ga-FAPI-46 PET/CT revealed a significant reduction in tumor size and radiotracer uptake in these metastatic lesions (right, arrows) after 2 cycles of ¹⁷⁷Lu-LNC1004 therapy.

Figure 4.

Best percentage of changes from baseline in the sum of the largest diameter of target lesions (n = 12). ATC, anaplastic thyroid cancer; DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer; PD, progressive disease; PR, partial response; SD, stable disease.