Kidney absorbed radiation doses for [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T determined by 3D clinical dosimetry

Purpose For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [177Lu]Lu-PSMA-I&T compared to [177Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [177Lu]Lu-PSMA-617 or [177Lu]Lu-PSMA-I&T, using an identical dosimetry protocol. We evaluated the absorbed doses of both 177Lu-labelled radioligands in human kidneys. Methods 3D SPECT/computed tomography (CT) imaging of the kidneys was performed after PSMA-RLT in cancer patients with PSMA-positive disease and an adequate glomerular filtration rate (≥50 mL/min). Ten metastatic hormone-sensitive prostate cancer patients (mHSPC) were treated with [177Lu]Lu-PSMA-617 and 10 advanced salivary gland cancer (SGC) patients were treated with [177Lu]Lu-PSMA-I&T. SPECT/CT imaging was performed at five timepoints (1 h, 24 h, 48 h, 72 h, and 168 h post-injection). In mHSPC patients, SPECT/CT imaging was performed after cycles 1 and 2 (cumulative activity: 9 GBq) and in SGC patients only after cycle 1 (activity: 7.4 GBq). Kidney absorbed dose was calculated using organ-based dosimetry. Results The median kidney absorbed dose was 0.49 Gy/GBq (range: 0.34–0.66) and 0.73 Gy/GBq (range: 0.42–1.31) for [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T, respectively (independent samples t test; P = 0.010). Conclusion This study shows that the kidney absorbed dose for [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T differs, with a ~1.5x higher median kidney absorbed dose for [177Lu]Lu-PSMA-I&T. This difference in the clinical setting is considerably smaller than observed in preclinical studies and may not hamper treatments with [177Lu]Lu-PSMA-I&T.

Although [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T have the identical PSMA binding motif (glutamate-urea-lysine), they differ with respect to the linker and chelator resulting in different chemical properties [5]. In humans, [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T have not been compared head-to-head. Unfortunately, the intestines, salivary glands, and proximal tubule of the kidneys also show high uptake of PSMA ligands, possibly resulting in significant radiation doses to these healthy organs following PSMA-RLT. Moreover, [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are renally excreted, which may increase the radiation exposure to the kidneys even further. The European Guidelines also identified the kidneys as the most important dose-limiting organ for PSMA-RLT [6].
While kidney failure due to PSMA-RLT is rarely seen, this might also be the result of the poor overall survival of the end-stage patients that currently received PSMA-RLT. However, the number of trials that investigate PSMA-RLT in early-stage cancer patients is increasing (e.g. NCT04720157, NCT04430192, and NCT04443062) [7,8]. In these patients, late toxicities may become apparent during longer follow-ups, such as kidney-related toxicities. Moreover, doses to the healthy organs such as the kidneys are important as organ toxicities could reduce the quality of life of patients and preclude patients from qualifying for the following treatment lines. Furthermore, in contrast to these preclinical findings, several clinical dosimetry studies found a comparable mean kidney-absorbed radiation dose for 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T [11][12][13][14][15][16][17][18]. Unfortunately, these studies applied varying dosimetry protocols, often only using planar scans, and are therefore difficult to compare. Thus, it is presently unclear if patients receiving [ 177 Lu] Lu-PSMA-I&T are exposed to higher kidney radiation doses compared to [ 177 Lu]Lu-PSMA-617. In this study, we compared the kidney dosimetry results of [ 177 Lu] Lu-PSMA-I&T and [ 177 Lu]Lu-PSMA-617 which were acquired from two prospective clinical trials, following an identical 3D dosimetry protocol.

Patients
In a third-line academic institute (Radboudumc, the Netherlands), two prospective clinical studies were conducted on PSMA-RLT in cancer patients with PSMApositive disease and an adequate glomerular filtration rate (GFR) (≥50 mL/min). Both studies used an identical dosimetry protocol. One study applied a first cycle of 3 GBq and a second cycle (after 6 weeks) of ~6 GBq [ 177 Lu]Lu-PSMA-617 in ten low-volume metastatic hormone-sensitive prostate cancer (mHSPC) patients, thus in total a cumulative activity of ~9 GBq [7]. The other used ~7.4 GBq [ 177 Lu]Lu-PSMA-I&T in 10 advanced SGC patients (NCT04291300). The dosimetry protocol of both trials consisted of five time points (1 h, 24 h, 48 h, 72 h, and 168 h) 3D SPECT/CT imaging post [ 177 Lu]Lu-PSMA injection. All scans were acquired on a Symbia T16 or Symbia Intevo Bold system (Siemens Healthineers, Erlangen, Germany) using a medium-energy low-penetration collimator, a 20% photon energy window at 208 keV with dual-energy window for Compton scattering, 64 projections per detector and 14 s per projection, matrix size 128 × 128 and zoom 1. Data were reconstructed using ordered subsets maximization expectation reconstruction (Flash 3D with collimator detector response) using four iterations, eight subsets and a smoothing Gaussian filter of 8.4 mm.

Dosimetry analysis
The absorbed doses for both cohorts were calculated in a similar way, as previously described [19]. In short, volumetric organ-based dosimetry was performed according to the scheme defined by the Committee on Medical Internal Radiation Dose [20] using Hermes HybridViever/Dosimetry (Hermes Medical Solutions, Stockholm, Sweden). All SPECT/CT images were co-registered per patient, followed by drawing volumes of interest of the kidneys. Kidney absorbed radiation dose was determined in Olinda 2.1 (Hermes Medical Solutions, Stockholm, Sweden) using gender-specific human kidney weights based on the ICRP Publication 89 [21], corresponding S-values and a mono-exponential fit.

Statistical analysis
To test for baseline differences between study populations, the independent samples t test was used for continuous variables and Fisher's exact test was used for categorical variables. The independent samples t test was used to compare the kidney absorbed radiation dose between [ 177 Lu]Lu-PSMA-617 treated mHSPC patients and [ 177 Lu]Lu-PSMA-I&T treated SGC patients. A P value <0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 25.0 (IBM Corp, Armonk, New York, USA). Table 1.

Patient characteristics
Per protocol, all 20 patients had adequate kidney function at baseline (see Table 2). The kidney uptake on baseline 68 Ga-PSMA-11 PET was also comparable between the two populations. The SGC patients had a significantly higher tumour burden than the low-volume mHSPC patients (P ≤ 0.001). Figure 1 illustrates the baseline disease burden of four patients (two mHSPC and two SGC). Furthermore, other baseline patient characteristics are presented in Table 2.  [16]. However, this retrospective study is impaired by its alternating dosimetry protocol and by relying on planar imaging, which can significantly affect the accuracy of the dosimetry outcomes [23][24][25]. With our results using an elaborate and identical dosimetry protocol, we can confirm the previous preclinical and retrospective study outcomes. However, the observed differences in kidney radiation doses are considerably lower than the preclinical work suggested and more in line with the retrospective study of Schuchardt et al. Therefore, the risk for kidney toxicity with [ 177 Lu] Lu-PSMA-I&T may be of less concern in a real-life setting.

Kidney-absorbed radiation doses
To date, the longest follow-up has been reported for [ 177 Lu]Lu-PSMA-617 with a median of 30.4 months. At this time, the authors did not observe a grade >3 of kidney toxicity [26]. Neither did the recently published pivotal 'VISION' trial of [ 177 Lu]Lu-PSMA-617 (median follow-up 20.9 months) [2]. However, the median follow-up in both these studies of end-stage mCRPC patients was rather short due to the poor survival in most of the patients. In addition, there is no mature data on adverse events following [ 177 Lu]Lu-PSMA-I&T yet as the results of the pivotal trial of [ 177 Lu]Lu-PSMA-I&T are awaited (NCT04647526) [1,27]. Therefore, the clinical consequences of a higher radiation dose for [ 177 Lu] Lu-PSMA-I&T in the kidneys are to be determined.
The European guidelines suggest that the threshold dose of [ 177 Lu]Lu-PSMA is 40 Gy in Biological Effective Dose (BED) before kidney-related toxicity occurs [6]. This threshold dose is mostly based on 177 Lu-DOTATATE studies and on data from external beam radiotherapy studies. We, therefore, urge the need to include dosimetry in trials to adequately correlate adverse events to   absorbed doses to the organs at risk. This will also pave the way for the broad adoption of targeted radionuclide therapies particularly in earlier-stage cancer patients and for more than a fixed amount of (4-6) cycles. After all, the dosimetry of radionuclide therapies allows for personalized dosing schemes [28].
Although it is yet unknown why the kidney uptake differs between  [29]. However, the degree of renal doses is also related to the structure, size, binding and circulation time of the radioligand complex [29]. Therefore, more studies are needed to elucidate the exact cause of the higher kidney doses of