FAP-Targeted Radiopeptide Therapy using 177Lu-, 225Ac- and 90Y-labeled 3BP-3940 in Diverse Advanced Solid Tumors: First-in-Humans Results

Introduction: Fibroblast activating protein (FAP) is a transmembrane serine protease rarely expressed in normal adult connective tissue, but abundant on cancer associated fibroblasts (CAFs) and expressed in 90% of epithelial cancers. The purpose of this study was to determine the feasibility of using a novel FAP-targeted cyclic peptide 3BP-3940 for peptide targeted radionuclide therapy (PTRT) and present first-in-humans results using ¹⁷⁷Lu, ⁹⁰Y and ²²⁵Ac labeled 3BP-3940 in end-stage cancer patients.

Methods: 28 patients (16 men and 12 women; mean age 59.4 ± 10.5 years) with advanced metastatic cancers of the pancreas (PDAC), breast, lung, esophagus, hepatocellular, colon, appendix, ovary, and bowel sarcoma presented with disease progression after previous treatments and were treated with PTRT between March 2021 and December 2022. Pre-treatment PET/CT imaging was done with Ga-68 3BP-3940 to determine tumor uptake. CTCA v.5.0. was used to grade toxicity. Treatment response was evaluated according to RECIST and EORTC. Kaplan–Meier survival analysis was performed to calculate overall survival (OS), defined from the start of PTRT.

Results: Cumulative activity was for ¹⁷⁷Lu 12.6 ± 11.5 GBq (n=21; up to 43.1 GBq), ⁹⁰Y 9.8 ± 7.2 GBq (n=10; up to 25.7 GBq), and ²²⁵Ac 15.2 ± 8.5 MBq (n=23; up to 33 MBq). Visual analysis of posttherapy whole-body scans and SPET/CT scans demonstrated significant uptake and retention of 3BP-3940 in tumor lesions on delayed imaging in all patients, with very high tumor-to-background ratio. After 1-5 cycles of PTRT, responses were complete remission (n=1, 4%), partial remission (n=4, 14%), mixed pattern (n=3, 11%), stable disease (n=3, 11%), progressive disease (n=9, 32%), and to-be evaluated (n=8, 29%). 12/28 patients passed away due to disease progression. One patient died due to sepsis following check-point inhibitor therapy. One patient died post bowel bypass surgery. Two patients withdrew from the study before their 2^nd cycle due to disease progress. For the entire cohort from the start of PTRT (n = 28), the median OS was 9.0 months. In the subgroup of patients with advanced pancreatic adenocarcinoma (n = 8), the median OS was 8.3 months.

Conclusions: 3BP-3940 PTRT is feasible with ¹⁷⁷Lu/⁹⁰Y/²²⁵Ac either alone or as TANDEM treatment of end-stage cancer patients. Treatments were well-tolerated without significant adverse effects. 3BP-3940 PTRT demonstrated a favorable biodistribution, significant uptake and retention in tumor lesions with very high tumor-to-background ratio, and should objective responses in advanced metastatic adenocarcinomas and sarcomas. The survival benefit for PDAC patients seems to be very promising.

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