Feasibility, Biodistribution, and Preliminary Dosimetry in Peptide-Targeted Radionuclide Therapy of Diverse Adenocarcinomas Using 177Lu-FAP-2286: First-in-Humans Results

Abstract

Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-humans results using ¹⁷⁷Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). Methods: PTRT using ¹⁷⁷Lu-FAP-2286 was performed on 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary after prior confirmation of uptake on ⁶⁸Ga-FAP-2286 or ⁶⁸Ga-FAPI-04 PET/CT. Results: Administration of ¹⁷⁷Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4-9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective dose was 0.07 ± 0.02 Gy/GBq (range, 0.04-0.1 Gy/GBq). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range, 0.4-2.0 Gy/GBq) and 0.05 ± 0.02 Gy/GBq (range, 0.03-0.09 Gy/GBq), respectively. Significant uptake and long tumor retention of ¹⁷⁷Lu-FAP-2286 resulted in high absorbed tumor doses, such as 3.0 ± 2.7 Gy/GBq (range, 0.5-10.6 Gy/GBq) in bone metastases. No grade 4 adverse events were observed. Grade 3 events occurred in 3 patients-1 with pancytopenia, 1 with leukocytopenia, and 1 with pain flare-up; 3 patients reported a pain response. Conclusion:¹⁷⁷Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well tolerated, with acceptable side effects, and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.

Keywords: 177Lu-FAP-2286; adenocarcinoma; fibroblast activation protein; first-in-humans; peptide-targeted radionuclide therapy.

Graphical abstract

FIGURE 1.

(A and B) Patient 4 had adenocarcinoma of pancreatic body, as well as hepatic, peripancreatic lymph node, and osseous metastases, which demonstrated high FAP expression on maximum-intensity-projection ⁶⁸Ga-FAP-2286 PET image (A) and transverse ⁶⁸Ga-FAP-2286 PET/CT image (B). (C and D) Significant uptake and late retention of ¹⁷⁷Lu-FAP-2286 were noted in liver metastases on posttherapeutic whole-body scintigraphy in anterior and posterior views at 48 h after injection (C) and on transverse SPECT/CT image (D). Because of low resolution of ¹⁷⁷Lu for imaging, as compared with ⁶⁸Ga for PET/CT, not all tumor sites seen on ⁶⁸Ga-FAP-2286 PET/CT are apparent on ¹⁷⁷Lu-FAP-2286 images.

FIGURE 2.

(A) Patient 6, with breast cancer, presented predominantly with diffuse FAP-positive bone and bone marrow metastases (but also lymph node metastases) on ⁶⁸Ga-FAP-2286 PET/CT. (B, C, D, E, G, H, and I) Serial whole-body scintigraphy in anterior and posterior views at 3 h (B), 20 h (C), 44 h (D), 68 h (E), 92 h (G), 7 d (H), and 10 d (I) after PTRT using 2.4 GBq of ¹⁷⁷Lu-FAP-2286 demonstrated uptake and retention in metastases. (F) ⁶⁸Ga-FAP-2286 PET/CT after 8 wk demonstrated mixed response: regression of bone and bone marrow lesions but overall progressive disease with new evidence of liver metastases. (J) Axial ⁶⁸Ga-FAP-2286 PET/CT images before (left) and after (right) PTRT show FAP-positive metastases in ribs and vertebrae, and occurrence of a new liver metastasis on the right side.