Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities

Abstract

Purpose: We report efficacy and safety of 90Y-FAPI-46-RLT in patients with advanced sarcoma, pancreatic cancer (PDAC) and other cancer entities. Experimental Design: Up to four cycles of RLT were offered to patients with (a) progressive metastatic malignancy, (b) exhaustion of approved therapies, and (c) high fibroblast activation protein (FAP) expression, defined as SUVmax≥10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival, dosimetry and safety of FAP-RLT. Results: Among n=119 screened patients, n=21 (18%) were found eligible (n=16/3/1/1 sarcoma/PDAC/prostate/gastric cancer; 38% ECOG≥2) and received n=47 90Y-FAPI-46-RLT cycles; n=16/21 (76%) patients underwent repeat RLT. By RECIST disease control was confirmed in n=8/21 patients (38%; 8/16 [50%] of evaluable patients). There were 1 partial response and 7 stable diseases after RLT. Disease control was associated with prolonged overall survival (p=0.013). PERCIST response was noted in n=8/21 patients (38%; 8/15 [53%] of evaluable patients). Dosimetry was acquired in n=19 (90%) patients. Mean absorbed dose was 0.53Gy/GBq in kidney, 0.04Gy/GBq in bone marrow and <0.14Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in n=8 (38%) patients with thrombocytopenia (n=6) and anemia (n=6) being most prevalent. Conclusion: 90Y-FAPI-46-RLT was safe and led to RECIST partial response in one case as well as stable disease in about one third of patients with initially progressive sarcomas, PDAC and other cancers. Discontinuation after the first cycle and a low rate of partial response require for future improvement of FAP-RLT.

Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies

“…Since compassionate care programs differ across the world, with some countries having a liberal policy, there is reported literature of more than 100 patients that have received TRT using FAP tracers. At present, the most promising clinical data of FAP TRT was reported in advanced sarcoma, breast, thyroid, and pancreatic cancer [30,33]. In these end-stage patients, there is an unmet need for novel anti-cancer therapies.…”

“…Median absorbed dose for tumor lesions after the first cycle was 1.28 Gy/GBq (IQR, 0.83-1.71 Gy/GBq) per cycle for target lesions. In July 2022, the third and latest published study using [ 90 Y]Y-FAPI-46 was reported by Fendler et al (which potentially included patients of the prior study) [30]. The effectiveness (following RECIST) and safety (following CTCAE 5.0) of [ 90 Y]Y-FAPI-46 were reported in in 16, 3, 1, and 1 patient(s) with sarcoma, pancreatic, prostate, and gastric cancer.…”

Preliminary Findings of the Role of FAPi in Prostate Cancer Theranostics

“…Finally, in the work by Fendler et al [ 24 ], up to four cycles of [ 90 Y]DOTA-FAPi-46 RLT were administered to patients with progressive metastatic malignancy with adequate haematopoiesis and high FAP expression levels (defined as [ 68 Ga]Ga-DOTA-FAPi-46 SUV max ≥ 10 in >50% of the tumour). Twenty-one patients, including 1 patient with mCRPCa, were found to be eligible for the treatment and received 47 [ 90 Y]FAPi-DOTA-46-RLT cycles.…”

“…Among the FAPi molecules that have been explored so far in PCa, FAPi-46 showed a longer retention time than FAPi-04 did, making it a more suitable ligand for RLT. The authors showed the feasibility of FAPi theranostics using a beta probe ([ 90 Y]DOTA-FAPi-46) [ 24 ] and a probe with a longer half-life ([ 177 Lu]Lu-FAPi-46) [ 23 ].…”

“…FAP overexpression increases the risk of tumour invasion, lymph node metastasis and the decreased overall survival (OS) [ 12 , 13 , 14 , 15 ] of many solid cancers, including mCRPCa [ 16 ], especially if the cancer exhibits neuroendocrine (NE) differentiation [ 17 ]. It thus represents a potential target for theranostics applications for aggressive (and often, low-PSMA-expressing) PCa [ 13 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. In this systematic review, we provide an overview of clinical applications using FAPi ligands in the PCa theranostics scenario by summarising the main preliminary results.…”