Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other therapeutic radiopharmaceuticals, ATC code: V10XX04 Mechanism of action
Lutetium-177-labeled oxodotreotide ([177Lu]DOTA-TATE) has a high affinity for subtype 2 somatostatin receptors (sst2). It binds to malignant cells which overexpress sst2 receptors.
Lutetium-177 is a β- emitting radionuclide with a maximum penetration range in tissue of 2.2 mm (mean penetration range of 0.67 mm), which is sufficient to kill targeted tumor cells with a limited effect on neighboring normal cells.

Pharmacodynamic effects

At the concentration used (about 10 μg/mL in total, for both free and radiolabeled forms), the peptide oxodotreotide does not exert any clinically relevant pharmacodynamic effect.

Clinical efficacy and safety
LuNET-SRY has been produced in Israel for over four years, enabling treatment of several hundred patients with various NETs on compassionate grounds. Under these circumstances, non-clinical and clinical studies were not performed. Non-clinical and clinical studies evaluating the pharmacokinetic, pharmacodynamic, safety and efficacy characteristics of [177Lu]DOTA-TATE have been reported and are public knowledge. A brief summary of these data is provided herein, followed by clinical information (progression-free survival (PFS), overall survival (OS) and dosimetry data) of patients treated with LuNET-SRY in a single medical center in Israel between May 2018 and Sept 2020.
• In a Phase-III multi-centric, active-controlled randomized clinical trial including GEP-NET patients,
[177Lu]DOTA-TATE (7,400 MBq every 8 weeks, four cycles) plus intramuscular long-acting octreotide 30 mg was compared to high dose octreotide LAR (60 mg every 4 weeks). The results of this study demonstrated increased median PFS of 28.4 months in the [177Lu]DOTA-TATE treatment arm, with a hazard ratio (HR) of 0.18 (95% CI 0.11 - 0.29 p<0.0001). Following a median follow-up of 76.3 months, the median OS of the [177Lu]DOTA-TATE treatment arm was higher by 11.7 months, albeit the difference in OS was not statistically significant. Furthermore, improved health related quality of life (HRQoL) was reported for [ 177Lu]DOTA-TATE up to week 84 from randomization compared to octreotide LAR.
• In another monocentric phase I/II single-arm study, the efficacy of [177Lu]DOTA-TATE (7,400 MBq every 8 weeks, four cycles) was assessed in patients with SSTR-positive bronchial/ pancreatic, foregut, midgut or hindgut tumors. In the full analysis set (FAS), which included 360 patients, the median PFS was 28.5 months (95% CI 24.8 - 31.4 months) and the reported median OS was 61.2 months (95% CI 54.8 - 67.4 months). The median PFS of a subgroup of patients (52%, n = 188) who received concomitant treatment with octreotide LAR was 25.4 months (95% CI 22.8 - 30.6) compared to a median PFS of 30.9 months (95% CI 25.6 - 34.8) in the subgroup of patients, who did not receive concomitant octreotide LAR treatment (p = 0.747).
• LuNET-SRY survival data and tumor responses were reviewed retrospectively after the treatments were given on compassionate grounds, in accordance to the literature and the published guidelines. Patient eligibility for LuNET-SRY treatment included the following: (1) high expression of SSTR in tumors as indicated by [68Ga]DOTA-TATE PET/CT, wherein tumor uptake was greater than the background liver activity, (2) evidence of progressive disease in the past 12 months, as assessed by combination of increasing biochemical marker (chromogranin A), and new or enlarging lesions on SSTR PET/CT imaging, contrast-enhanced CT, or magnetic resonance imaging (MRI), or (3) persistence of symptoms despite conventional management. Treatment was excluded in case of: (i) low SSTR expression in tumor, (ii) renal impairment (CrCL <50 mL/min), (iii) hypoalbuminemia (<25 g/L), (iv) thrombocytopenia (<70 × 109/L), (v) pancytopaenia (hemoglobin <10 g/dL and white cell count <3 × 109/L), (vi) Eastern Cooperative Oncology Group (ECOG) performance status score of 4, (vii) expected survival of less than 3 months, or (viii) in case of confirmed pregnancy.
Data of 70 patients (42 males) who received 212 LuNET-SRY treatments between May 2018 and Sept 2020 in a single medical center were available for the efficacy (PFS and OS) analyses (Table 4). Of these, 45 (64%) had GEP-NETs, whilst 25 (36%) had other NETs (including neuroblastoma, pheochromocytoma/ paraganglioma, and/or NET of unknown origin). The average age of patients was 62.1 ± 14.8 years, including three adolescents (12, 13, and 18 years old). The total number of treatments per patient ranged between 1 and 6 (Table 4), and the average time between treatments was 49 ± 19 days.

Table 4. Efficacy of LuNET-SRY in NET patients treated at a single medical center 
Patient          No. of       Average dose per       Response to           PFS            OS No.          treatments       treatment (MBq)        treatment          (months)       (months) 1                4                7262.9               SD                18.1           18.1            2              3                 7396.3                LFU                -              -
3              1                 7217.8                LFU                -              -            4              1                 7015.1                PD                0.0           13.8
5              4                 6959.6                SD                8.9            8.9 
6       4        6974.2        LFU    -      -
7       4        7327.9        SD    3.0    3.0
#
8      3         7949.7        PD    5.2    8.4
9       3        6996.1        PD    1.9    1.9
#
10     3         7217.5        LFU    -      -
#
11     1         6847.9        PD    3.5    3.5
12      4        7254.3        SD    2.8    2.8
13      4        7357.6        PD    7.5    7.5
#
14     2         7297.1        SD    19.1   19.1
#
15     4         7703.6        LFU    -      -
16      4        7291.3        PD    15.7   15.7
17      3        7514.8        LFU    -      -
18      4        7311.8        SD    9.1    9.1
19      4        7293.5        SD    3.2    3.2
#
20     1         7309.7        PD    8.4    8.4
21      4        7434.7        SD    28.0   28.0
22      3        7333.0        SD    23.3   23.3
23      4        7479.1        SD    22.3   22.3
24      3        7073.9        SD    20.0   20.0
25      4        7461.1        SD    4.1    4.1
26      4        7180.4        SD    7.1    7.1
27      1        7511.6        PD    1.3    1.3
#
28     4         7320.5        SD    11.8   11.8
29      2        7378.3        SD    18.8   21.8
30      5        7484.4        OT     -     0.0
31      2        3364.0        SD    0.0    0.0
32      4        7360.9        LFU    -      -
#
33     4         7200.4        PR    4.4    4.4
34      5        7444.2        SD    20.2   20.2
35      3        7232.5        SD    11.5   11.5
36      1        7504.3        SD    7.8    7.8
#
37     3         7579.9        PR    2.3    2.3
38      4        7337.9        SD    24.6   24.6
39      1        7602.5        SD    2.6    2.6
40      3        7495.8        LFU    -      -
41      1        7208.3        SD    9.5    10.5
42      1        6791.6        LFU    -      -
#
43   4 (3+1 )    7411.4        ST    2.8    8.3
44      3        7660.2        ST    3.4    6.9
45      2        7450.2        SD    28.9   28.9
46      1        7085.2        LFU    -      -
47     6#        7656.4        PD    6.1    12.6
48      4        7193.7        SD    15.5   15.5
49      3        7331.3        SD    26.1   26.1
50      2        7425.8        ST    10.1   10.1
#
51     4         7486.8        LFU    -      -
#
52     1         7573.5        ST    1.6    1.6
53      3        7363.7        SD    21.3   21.3

54               4                  7227.3                   SD                12.0             12.2 55               6                  7528.6                   SD                 8.2             20.2 56               4                  7324.6                   SD                13.3             13.3 57               3                  7307.8                   SD                 6.9              6.9 58               1                  7209.2                   LFU                 -                - 59               4                  7062.7                   SD                22.1             22.1 #
60               3                  7345.8                   SD                 7.5             12.0 61               4                  7493.8                   SD                 0.0              0.0 62               4                  7537.8                   LFU                 -                - 63               3                  7338.1                   SD                21.8             21.8 64               3                  7596.1                   SD                10.1             10.1 65               3                  7677.9                   LFU                 -                - 66               1                  7054.0                   LFU                 -                - 67               3                  7205.8                   SD                17.7             17.7 68               1                  7386.6                   PD                 0.6              1.0 69               4                  7453.8                   PR                 8.0              8.0 70               1                 7177.7                     PD               0.8              6.3 Assessed             Assessed                 Assessed            Assessed        Assessed patients: 70/70      patients: 70/70          patients: 50/70     patients:       patients: SD:
54/70           55/70
Total                7400 MBq ±10%:           Tumor treatments: 212      69                       response:           Censored:       Censored: CR 0 (0%)           35              38
#
Salvage             3700 MBq ±10%:           SD: 36 (72%)        Events: 16      Events: 14 treatments: 40       1                        PR: 3 (6%)          Excluded:       Excluded: 3 PD: 11 (22%)        3

Excluded: 20/70
LFU: 15*
ST: 4**
OT: 1*** stable disease, PR: partial response, NR: no response, PD: progressive disease, LFU: lost to follow-up, ST: stopped treatment, OT: ongoing treatment, PFS: progression-free survival, OS: overall survival.

The analyzed data contained 212 treatments given to 70 patients. Of those, *15 patients were lost to follow-up (LFU) and excluded from further PFS and OS analyses. **4 patients had died and treatment was stopped (ST) before the 4th cycle. In all cases death was related to NET, but unrelated to PRRT. *** Treatment was ongoing (OT) in one patient, for whom the reference date for calculating OS was that of the first treatment. This patient was excluded from the PFS analysis.

At the time of data analysis, the median PFS and OS of LuNET-SRY-treated patients were not yet reached.
However, the estimated rates of PFS and OS at 25 months were 60.3% and 56.0%, respectively (Figure 2). This suggests that the LuNET-SRY survival rates are in line with those reported in the literature. It should be noted that the calculated PFS and OS rates for LuNET-SRY were slightly underestimated, as they were determined from the time of the last treatment rather than the time of the first treatment or time of randomization (as in the aforementioned clinical studies). Moreover, LuNET-SRY treatment was given for treating NETs of all types and of all grades, in adults and in adolescents. In a similar manner, tumor responses following LuNET-SRY treatment were also determined from the time of the last treatment. The calculated response rates of complete response (CR): 0 (0%), stable disease (SD): 36 (72%), partial response (PR): 3 (6%) and PD: 11 (22%) were in line with those reported in the literature.


Figure 2.   Kaplan-Meier survival plots for PFS and OS of a patient cohort treated at a single medical center, as measured from the last treatment with LuNET-SRY



• LuNET-SRY treatments were also administered in a second medical center, wherein 38 patients with high SSTR-expressing were given a total of 80 treatments between May 2018 and Feb 2019. The various patients have received between 1-4 treatments, and the average time between treatments was 77 ± 39 days. Only distribution and dosimetry data were available in this patient population, as described under section 8.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The pharmacokinetic (PK) properties of LuNET-SRY have not been studied. The PK characteristics of a similar [177Lu]DOTA-TATE drug product have been investigated in vitro and in vivo, including evaluation of distribution, metabolism and excretion, and are publically available. A brief summary of the PK of [177Lu]DOTA-TATE is provided herein.
• [177Lu]DOTA-TATE is administered intravenously and is fully bioavailable upon administration.
• [177Lu]DOTA-TATE is rapidly cleared from blood and accumulates in the kidneys, tumor lesions, liver and spleen, and in certain cases, in the pituitary and the thyroid. Co-administration of the amino acid infusion decreases the uptake in kidneys and enhances the renal clearance of the drug product. About 50% of the product is bound to plasma proteins.
• [177Lu]DOTA-TATE is poorly metabolized, and most of the activity excreted in the urine up to 48 h after administration represents the unchanged drug product. These findings are in line with in vitro studies using human hepatocytes, in which no metabolites of [177Lu]DOTA-TATE were detected.
• The primary elimination route of [177Lu]DOTA-TATE is renal clearance, with about 60% and 65% of the injected dose being eliminated unchanged in the urine within 24 h and 48 h, respectively. No data are available regarding the PK profile in elderly patients (>75 y).