First-In-Human Results On The Biodistribution, Pharmacokinetics, And Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in Patients with Various End-stage Cancers

Abstract Purpose: The present study aimed to evaluate and compare the biodistribution, pharmacokinetics, dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers.Methods: The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2 were administered in two different groups of patients. Three patients (mean age; 50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2 – 3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age; 51 years) were treated with 1.48 GBq (IQR: 0.6 – 1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 hour and 168 hours post-injection (p.i.)The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Results: Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. The whole body effective dose for [177Lu]Lu-DOTAGA.(SA.FAPi)2 was significantly higher than [177Lu]Lu-DOTA.SA.FAPi [2.26E-01 ± 1.24E-01; vs. 6.22E-02 ± 9.96E-03 mSv/MBq, P-0.058). In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed dose were noted in the Kidneys (0.618 ± 0.015 Gy/GBq), followed by a colon (right colon: 0.472 Gy/GBq and left colon: 0.43 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.16 Gy/GBq and left colon: 2.87 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (P < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5 – 70.1) vs. 23.1 h (IQR: 17.8 – 31.5); P-0.0167]. The median absorbed doses to the lesions were 6.03E-01(IQR: 2.30E-01 - 1.81E+00) Gy/GBq and 6.70E+00 (IQR: 3.40E+00 - 4.9E+01) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. Conclusion: The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.