As the biological half-life of FAPI-46 is relatively short (24 h), it is better aligned with isotypes with similar half-life, such as ⁹⁰Y (64 h) to get optimal radiation dose delivery to the target tissue. Fendler et al. administered up to four cycles of [⁹⁰Y]Y-FAPI-46 to a cohort of 21 patients with advanced solid malignancies (5). Treatment-related grade 3 or 4 adverse events were observed in 8 patients (38%), with thrombocytopenia and anemia being the most frequently reported toxicities. Among the 16 evaluable patients, response assessment according to PERCIST criteria revealed disease control in 8 patients (50%), comprising 1 partial response (PR) and 7 stable disease (SD) (5). Moreover, median overall survival (OS) was significantly longer for RECIST responders, stratified by response category: partial response (not reached), stable disease (14.4 months), progressive disease (6.6 months), nonavailable response status (2.2 months). Notably, the observed clinical benefits (PR and SD) were predominantly confined to patients with sarcoma, particularly those with solitary fibrous tumor (SFT) (5). Based on these findings, a subsequent study by the same group focused exclusively on SFT, where immunohistochemistry demonstrated FAP expression predominantly localized to tumor cell membranes. In this follow-up investigation, 11 patients with SFT received a total of 34 cycles of [⁹⁰Y]Y-FAPI-46 (median: 3 cycles per patient), resulting in disease control in 9 patients (82%), including 3 PR and 6 SD, and a median progression-free survival (PFS) of 227 days (6). In a recent case report study, 3 patients with metastatic SFT who were exhausted standard treatments received 4 cycles of [⁹⁰Y]Y-FAPI-46 with a cumulative dose of approximately 26 GBq (7). Treatment was well tolerated, with only minor adverse events observed. RECIST assessment indicated 2 PR and 1 SD. Of note, PERCIST assessment revealed one patient with a complete metabolic response, with complete resolution of ¹⁸F-FDG uptake in measurable target lesions (7).

However, the biological half-life of FAPI-46 (24 h) is still shorter than that of ⁹⁰Y (64 h), limiting optimal radiation dose delivery to the target tissue. To better match the pharmacokinetics of FAPI-46, Kratochwil et al. labeled FAPI-46 with short physical half-life (46.3 h) ¹⁵³Sm and tested its feasibility in a patient with metastatic soft tissue sarcoma (8). Emission scans during therapy demonstrated tumor targeting up to 44 h p.i. and rapid clearance from normal organs. Three cycles with cumulative 20 GBq [¹⁵³Sm]Sm- and 8 GBq [⁹⁰Y]Y-FAPI-46 were well tolerated and achieved stable disease for 8 months (8). However, the utilization of ¹⁵³Sm is challenging so far as it is inevitably contaminated with ¹⁵⁴Eu during manufacturing process (9). An alternative option is to conjugate FAPI-46 with ²¹³Bi, an α-emitter with a half-life of 46 min. Recently, Helisch et al. conducted a pilot study of [²¹³Bi]Bi-FAPI-46 in 6 patients with progressive metastatic solid tumors (10). A mean of 1,609 MBq of [²¹³Bi]Bi-FAPI-46, fractionated into 53 single administrations (range, 5–12 RLT administrations per patient) was well tolerated without adverse side effects, resulting in 1 PR, 1 SD and 4 progressive disease (PD). This study demonstrated that fractionated [²¹³Bi]Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the ¹⁷⁷Lu- or ⁹⁰Y-labeled compounds (10).

To enhance tumor retention, Moon et al. (11) and Martin et al. (12) developed bivalent FAP inhibitors such as DOTAGA.(SA.FAPi)₂, which exhibited prolonged tumor residence time and increased uptake compared to the monomeric DOTA.SA.FAPi (effective half-life, 86.6 h vs. 14 h) (13). [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ demonstrated effective half-lives of 46.2 h and 86.6 h in the whole body and tumor lesions, respectively (13). In a prospective exploratory study involving 15 patients with radioiodine-refractory differentiated thyroid carcinoma (RR-DTC), administration of [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ was well tolerated, with no reported grade 3/4 hematologic, renal, or hepatic toxicities. Molecular imaging-based response assessment revealed PR in 4 patients and SD in 3 patients (14).

A retrospective analysis was subsequently conducted in 19 patients with metastatic breast cancer who received 2–6 cycles of [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ (15). Treatment was well tolerated, with no grade ≥3 adverse events. Response assessment using PERCIST criteria via [⁶⁸Ga]Ga-DOTA.SA.FAPi PET/CT revealed PR in 25% of patients and PD in 37.5%, with an overall clinical benefit rate of 84%. According to the visual analog score (VAS), 26.3% of patients achieved complete response (CR), 15.7% PR, 42% minimal response, 11% SD, and 5% exhibited no response. At the time of analysis, median overall survival (OS) was 12 months, and median PFS was 8.5 months (15). More recently, long-term outcomes of [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ therapy in patients with radioiodine-resistant follicular cell-derived thyroid cancer were reported in another retrospective study (16). A median cumulative activity of 22.2 GBq (range: 4–55.5 GBq) was administered over 1–9 treatment cycles (median: 3 cycles). Four patients (5.4%) encountered grade 3 anemia, primarily linked to bone metastasis in three cases and neck tumor mass bleed in one. Grade 3 thrombocytopenia occurred in three patients (4%). No grade ≥ 3 renal or hepatic toxicity was reported. Among 36 evaluable patients, PERCIST-based molecular response assessment demonstrated PR in 50%, SD in 25%, and PD in 25%. Median OS and PFS were 32 months and 29 months, respectively (16).

Serum albumin functions as a highly versatile endogenous carrier for therapeutic agents, enabling reversible binding with drug molecules to form albumin-drug complexes that serve as circulating reservoirs. This interaction enhances both systemic distribution and bioavailability of the therapeutic payload (17). To exploit this mechanism, Wen and colleagues developed [¹⁷⁷Lu]Lu-EB-FAPI (designated as [¹⁷⁷Lu]Lu-LNC1004) by conjugating FAPI-02 with Evans blue (EB) (18), an albumin-binding moiety known for its strong affinity toward binding site 1 on serum albumin (19, 20). This modification significantly improved tumor uptake and retention, with sustained tumor accumulation observed up to 96 h post-injection (18). In a first-in-human dose-escalation study involving 12 patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC), 3.33 GBq/cycle of [¹⁷⁷Lu]Lu-LNC1004 was well tolerated with one patient experienced grade 4 thrombocytopenia and three with no dose-limiting toxicities (21). Dose escalation to 4.99 GBq per cycle resulted in grade 3 and 4 hematologic toxicities in two patients. The effective half-lives of [¹⁷⁷Lu]Lu-LNC1004 were estimated at 90.20 h for whole-body and 92.46 h within tumor lesions. Based on RECIST v1.1 criteria, PR, SD, and PD were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively, resulting in an objective response rate (ORR) of 25% and disease control rate (DCR) of 83% (21).

Subsequently, in a phase II investigator-initiated trial, 28 patients with progressive metastatic solid tumors received 2–4 cycles of [¹⁷⁷Lu]Lu-LNC1004 at a fixed dose of 3.33 GBq every six weeks (22). The mean absorbed radiation dose to tumors was 4.69 ± 3.83 Gy/GBq (range: 1.18–25.03 Gy/GBq). Treatment-related grade 3/4 hematotoxicities occurred in 21% (n = 6) of patients, predominantly involving thrombocytopenia, leukopenia, and neutropenia. No grade ≥ 3 hepatotoxicity or nephrotoxicity was observed. Disease control as per RECIST criteria was achieved in 13 of 28 patients (46%), including 4 PR and 9 SD, which was significantly associated with prolonged PFS and OS (P < 0.001) (22).

FAP-2286 is a cyclic FAP-binding peptide linked to DOTA, allowing radionuclide chelation for imaging or therapeutic applications (23–25). In preclinical HEK-FAP mouse models, [¹⁷⁷Lu]Lu-FAP-2286 demonstrated prolonged tumor retention time (≥ 72 h) compared to FAPI-46 (24 h) after injection (23). In its first-in-human trial for treatment of 11 patients with advanced solid tumors, [¹⁷⁷Lu]Lu-FAP-2286 was administrated at a mean dose of 5.8 ± 2.0 GBq per cycle (26). The treatment was well tolerated, with prolonged tumor retention observed for up to 10 days post-injection. The effective half-lives of [¹⁷⁷Lu]Lu-FAP-2286 were estimated at 35 h for whole body and 44 h for bone metastases. No grade 4 adverse events were reported. Grade 3 adverse events occurred in three patients, comprising pancytopenia (n = 1), leukocytopenia (n = 1), and pain flare (n = 1). Notably, three patients reported symptomatic pain relief following therapy. According to RECIST 1.1 criteria, two patients achieved SD, while the remaining nine experienced PD (26).

Building upon these findings, a phase I/II clinical trial (LuMIERE study; NCT04939610) was initiated to further evaluate the safety, dosimetry, and preliminary antitumor activity of [¹⁷⁷Lu]Lu-FAP-2286 in patients with advanced solid tumors. In its phase I portion, 27 patients were recruited, with pancreatic (n = 9), colorectal (n = 4), and head and neck cancers (n = 3) being the most common tumor types (27). Treatment-related adverse events were observed in 14 patients with two experienced grade ≥ 3 events. dose-limiting toxicities included grade 4 lymphopenia at a dose of 5.55 GBq and grade 3 hemoptysis at 9.25 GBq. Importantly, no grade ≥ 3 reductions in neutrophil counts, hemoglobin levels, or platelet counts were noted. RECIST 1.1 evaluation revealed PR in one patient and SD in nine patients (27). Based these favourable safety and activity profiles, a phase II trial is underway to further evaluate the safety and efficacy of [¹⁷⁷Lu]Lu-FAP-2286 as monotherapy and combination regimens with chemotherapy in selected solid tumors (NCT04939610).

More recently, two prospective studies further investigated the therapeutic potential of [¹⁷⁷Lu]Lu-FAP-2286 (28, 29). In one study, five patients with advanced metastatic sarcoma received four cycles of [¹⁷⁷Lu]Lu-FAP-2286 (doses ranging from 6,660 to 7,400 MBq) (28). Treatment was well tolerated, with no grade 3 or 4 toxicities reported. Quantitative imaging and volumetric analysis demonstrated a 52.37% mean reduction in primary tumor volume, along with substantial decreases in SUVmax and tumor-to-background ratio (TBR) of metastatic lesions (29.67% and 43.66%, respectively), particularly in pulmonary metastases. RECIST 1.1 assessment revealed PR in 4/5 (80%) patients and PD in 1/5 (20%) patient (28). Another study assessed safety and efficacy in nine patients with advanced lung cancer who received 2–6 cycles (7.4 GBq per cycle) of [¹⁷⁷Lu]Lu-FAP-2286 (29). No grade 3 or 4 toxicities were observed throughout the follow-up period. Based on RECIST 1.1 and PERCIST 1.0 criteria, PR, SD, and PD were documented in 44%, 33.3%, and 22.2% of patients, respectively. The highest observed metabolic response reached a 66.89% reduction in tumor metabolic activity, and the ORR was 77.78%. Median OS and PFS were 10 and 6 months, respectively. The most significant improvements in clinical symptoms were noted in dyspnea and cancer-associated pain (29).

The heterodimeric radioligand FAPI-RGD, which simultaneously targets FAP and integrin αvβ3 (RGD), has demonstrated superior tumor uptake and retention compared to its monomeric counterparts (36). In a first-in-human dosimetry study involving nine patients with advanced solid malignancies, administration of [¹⁷⁷Lu]Lu-DOTA-FAPI-RGD was well tolerated, with no observed adverse clinical symptoms or pharmacological effects of concern (37). The whole-body effective radiation dose was estimated at 0.06 ± 0.03 Gy/GBq. The mean absorbed doses of red marrow, liver, spleen and kidneys were 0.04 ± 0.02 Gy/GBq, 0.56 ± 0.44 Gy/GBq, 0.28 ± 0.13 Gy/GBq, 0.34 ± 0.27 Gy/GBq, respectively. The agent exhibited substantial tumor localization and prolonged retention, resulting in high absorbed tumor doses 4.3 ± 0.7 Gy/GBq in pulmonary metastases and 4.0 ± 1.8 Gy/GBq in peritoneal metastases. According to RECIST criteria, PR was achieved in 2 patients (22.2%), SD in 6 patients (66.7%), and PD in 1 patient (11.1%). The ORR was 22.2%, and the DCR was 88.9% (37).