Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Therapeutic radiopharmaceuticals, Other therapeutic radiopharmaceuticals, ATC code: V10XX04

Mechanism of action

Lutetium (177Lu) oxodotreotide has a high affinity for subtype 2 somatostatin receptors (SSTR2). It binds to malignant cells which overexpress SSTR2.

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), causing death of the targeted tumour cells with a limited effect on neighbouring normal cells.

Pharmacodynamic effects

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

Clinical efficacy and safety

NETTER-1
The NETTER-1 phase III study was a multicentre, stratified, open-label, randomised, comparator-controlled, parallel-group study comparing treatment with Lutathera (4 doses of 7 400 MBq, one dose every 8 weeks [±1 week]) co-administered with an amino acid solution and best supportive care (octreotide long-acting release [LAR] 30 mg after each Lutathera dose and every 4 weeks after completion of Lutathera treatment for symptom control, replaced by short-acting octreotide in the 4-week interval before Lutathera administration) to high-dose octreotide LAR (60 mg every 4 weeks) in patients with inoperable, progressive, somatostatin receptor-positive, midgut carcinoid tumours. The primary endpoint for the study was progression-free survival (PFS) evaluated by response evaluation criteria in solid tumours (RECIST v1.1), based on blinded independent review committee assessment. Secondary efficacy endpoints included objective response rate (ORR), overall survival (OS), time to tumour progression (TTP), safety and tolerability of the medicinal product, and health-related quality of life (HRQoL).

At the time of the primary analysis, 229 patients were randomised to receive either Lutathera (n=116) or high-dose octreotide LAR (n=113). Demographic and baseline disease characteristics were well balanced between the treatment arms with a median age of 64 years and 82.1% Caucasian in the general population.


At the time of the primary PFS analysis (cut–off date 24 July 2015), the number of centrally confirmed disease progressions or deaths was 21 events in the Lutathera arm and 70 events in the high-dose octreotide LAR arm (Table 6). PFS differed significantly (p<0.0001) between the treatment arms. The median PFS for the Lutathera arm was not reached at the cut-off date, whereas the median PFS for the high-dose octreotide LAR arm was 8.5 months. The hazard ratio (HR) for the Lutathera arm compared to the high-dose octreotide LAR arm was 0.18 (95% CI: 0.11; 0.29), indicating 82% reduction in the risk of disease progression or death in favour of the Lutathera arm.

Table 6 PFS observed in the NETTER-1 phase III study in patients with progressive midgut carcinoid tumours - cut-off date 24 July 2015 (full analysis set [FAS], N=229) 
Treatment
Lutathera and octreotide High-dose octreotide LAR
LAR
N                                116                           113
Patients with events                       21                            70 Censored patients                         95                            43 Median in months (95% CI)                Not reached                  8.5 (5.8; 9.1) p-value of Log-rank test                                <0.0001
Hazard ratio (95% CI)                            0.177 (0.108; 0.289) N: number of patients, CI: confidence interval.

The PFS Kaplan-Meier graph for the full analysis set (FAS) at the cut–off date 24 July 2015 is depicted in Figure 3.

Figure 3 PFS Kaplan-Meier curves for patients with progressive midgut carcinoid tumours - cut- off date 24 July 2015 (NETTER-1 phase III study; FAS, N=229)



At the cut-off date for post-hoc statistical analysis (cut-off date 30 June 2016) including two additional randomised patients (N=231), the number of centrally confirmed disease progressions or deaths was 30 events in the Lutathera arm and 78 events in the high-dose octreotide LAR arm (Table 7). PFS differed significantly (p<0.0001) between the treatment arms. The median PFS for the Lutathera arm was 28.4 months whereas the median PFS for the high-dose octreotide LAR arm was 8.5 months. The hazard ratio for the Lutathera arm compared to the high-dose octreotide LAR arm was 0.21 (95% CI: 0.14; 0.33), indicating 79% reduction in the risk of disease progression or death in favour of the Lutathera arm.


Table 7 PFS observed in the NETTER-1 phase III study in patients with progressive midgut carcinoid tumours - cut-off date 30 June 2016 (FAS, N=231)

Treatment
Lutathera and octreotide High-dose octreotide LAR
LAR
N                                 117                            114
Patients with events                        30                            78 Censored patients                          87                             36 Median in months (95% CI)               28.4 (28.4; NE)                8.5 (5.8; 11.0) p-value of Log-rank test                                  <0.0001
Hazard ratio (95% CI)                              0.214 (0.139; 0.330) N: number of patients, CI: confidence interval.

The PFS Kaplan-Meier graph for the FAS at the cut-off date 30 June 2016 is depicted in Figure 4.

Figure 4 PFS Kaplan-Meier curves for patients with progressive midgut carcinoid tumours cut-off date 30 June 2016 (NETTER-1 phase III study; FAS, N=231)



At the time of the interim OS analysis (cut-off date 24 July 2015), there were 17 deaths in the Lutathera arm and 31 deaths in the high-dose octreotide LAR arm, yielding a HR of 0.459 (99.9915% CI: 0.140; 1.506) in favour of the Lutathera arm. The median OS was not reached in the Lutathera arm at the cut-off date, while it was 27.4 months in the high-dose octreotide LAR arm. The interim OS results did not reach statistical significance. An update conducted about one year later (cut-off date 30 June 2016) including two additional randomised patients (N=231) showed a similar trend, with 28 deaths in the Lutathera arm and 43 deaths in the high-dose octreotide LAR arm, yielding a HR of
0.536 in favour of the Lutathera arm. The median OS was still not reached in the Lutathera arm at the cut-off date, while it was 27.4 months in the high-dose octreotide LAR arm.

At the time of the final OS analysis, which occurred 5 years after the last patient was randomised (N=231, cut-off date 18 January 2021), the median follow-up duration was 76 months in each study arm. There were 73 deaths in the Lutathera arm (62.4%) and 69 deaths in the high-dose octreotide LAR arm (60.5%), yielding a HR of 0.84 (95% CI: 0.60; 1.17; unstratified Log-rank test p=0.3039, two-sided) in favour of the Lutathera arm. The median OS was prolonged by a clinically relevant extent of 11.7 months in patients randomised to the Lutathera arm compared to patients randomised to high-dose octreotide LAR, with a median OS of 48.0 months (95% CI: 37.4; 55.2) and 36.3 months (95% CI: 25.9; 51.7), respectively. The final OS results did not reach statistical significance. In the high-dose octreotide LAR arm, 22.8% of patients received subsequent radioligand therapy (including lutetium (177Lu) oxodotreotide) within 24 months of randomisation, and 36% of patients received subsequent radioligand therapy by the final OS cut-off date, which along with other factors may have influenced the OS in this subset of patients.

The OS Kaplan-Meier graph for the FAS at the cut-off date 18 January 2021 is depicted in Figure 5.

Figure 5      OS Kaplan-Meier curves for patients with progressive midgut carcinoid tumours - cut-off date 18 January 2021 (NETTER-1 phase III study; FAS, N=231)



+○ Censoring times
++(a) Lutathera and octreotide LAR
○○(b) High-dose octreotide LAR



Number of subjects at risk                         Time from randomisation (months) (a)
(b)

In presence of non-proportional hazards, an additional sensitivity analysis (Restricted mean survival time) was performed at the time of the final OS analysis to further estimate the treatment effect (Table 8). At 60 months after randomisation, the average OS benefit was 5.1 months (95% CI: -0.5; 10.7) longer in the Lutathera arm compared to the high-dose octreotide LAR arm.

Table 8       OS by restricted mean survival time (RMST) observed in the NETTER-1 phase III study in patients with progressive midgut carcinoid tumours (FAS, N=231) 
Lutathera and             High-dose octreotide octreotide LAR N=117               LAR N=114
24 months       Deaths, n (%)                             26 (22.2)                    39 (34.2)
RMST (95% CI)                         21.2 (20.2; 22.3)            19.3 (18.0; 20.7) Difference (95% CI)                                   1.9 (0.1; 3.6)

36 months       Deaths, n (%)                             41 (35.0)                    51 (44.7) RMST (95% CI)                         29.7 (27.7; 31.6)            26.0 (23.7; 28.3) Difference (95% CI)                                   3.7 (0.7; 6.7)

48 months       Deaths, n (%)                             53 (45.3)                    58 (50.9)
RMST (95% CI)                         36.2 (33.4; 39.0)            31.5 (28.3; 34.8) Difference (95% CI)                                   4.6 (0.3; 8.9)

60 months       Deaths, n (%)                             65 (55.6)                    63 (55.3) RMST (95% CI)                         41.2 (37.6; 44.9)            36.1 (31.9; 40.4) Difference (95% CI)                                  5.1 (-0.5; 10.7) 

Health-Related Quality of Life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (generic instrument) and its neuroendocrine tumour module (EORTC QLQ-GI.NET-21).

The results indicate an improvement in the overall global health-related quality of life up to week 84, for patients in the Lutathera treatment arm as compared to patients in the high-dose octreotide LAR arm.

ERASMUS
The Erasmus phase I/II study was a monocentric single-arm open-label study to evaluate the efficacy of Lutathera (4 doses of 7 400 MBq each, one dose every 8 weeks) co-administered with amino acid solution in patients with somatostatin receptor-positive tumours. The median age of patients enrolled in the study was 59 years. Most patients were Dutch (811) with the remaining (403) residents of various European and non-European countries. The main analysis included 811 Dutch patients with different somatostatin receptor-positive neuroendocrine tumour types (NETs). The ORR (including complete response [CR] and partial response [PR] according to RECIST criteria) and duration of response (DoR) for the FAS Dutch population with gastroenteropancreatic (GEP) and bronchial NETs (360 patients) as well as per tumour type are presented in Table 9.
Table 9 Best response, ORR and DoR observed in the Erasmus phase I/II study in Dutch patients with GEP and bronchial NETs - (FAS, N=360)

N          CR           PR               SD                      ORR                          DoR (months) Tumour n    %       n        %      N      %          n      %          95%CI           Median         95%CI type
All NETs*       360    11    3% 151         42%     183    51%      162      45%       40%      50%        16.3     12.2       17.8 Bronchial        19    0     0% 7           37%      11    58%        7      37%       16%      62%        23.9      1.7       30.0 Pancreatic      133    7     5% 74          56%      47    35%       81      61%       52%      69%        16.3     12.1       21.8 Foregut**        12    1     8% 6           50%      4     33%        7      58%       28%      85%        22.3      0.0       38.0 Midgut          183    3     2% 58          32%     115    63%       61      33%       27%      41%        15.3     10.5       17.7 Hindgut          13    0     0% 6           46%      6     46%        6      46%       19%      75%        17.8      6.2       29.9 CR = Complete response; PR = Partial response; SD = Stable disease; ORR = Objective response rate (CR+PR); DoR = Duration of response * Includes foregut, midgut and hindgut; **Foregut NETs other than bronchial and pancreatic 
The overall median PFS and OS for the FAS Dutch population with GEP and bronchial NETs as well as per tumour type are presented in Table 10.
Table 10 PFS and OS observed in the Erasmus phase I/II study in Dutch patients with GEP and bronchial NETs - (FAS, N=360)


PFS                                      OS
Time (months)                           Time (months)
Median        95%CI                     Median        95%CI
All NETs*                                 360       28.5      24.8     31.4                 61.2     54.8      67.4 Bronchial                                  19       18.4      10.4     25.5                 50.6     31.3      85.4 Pancreatic                                133       30.3      24.3     36.3                 66.4     57.2      80.9 Foregut**                                  12       43.9      10.9     ND                   NR       21.3      ND Midgut                                    183       28.5      23.9     33.3                 54.9     47.5      63.2 Hindgut                                    13       29.4      18.9     35.0                 NR       ND        ND PFS = Progression free survival; OS = Overall survival; ND = Not detected, NR = Not reached * Includes foregut, midgut and hindgut; **Foregut NETs other than bronchial and pancreatic 
In the Erasmus phase I/II study 188 patients (52%) received and 172 (48%) did not receive concomitant octreotide LAR during Lutathera treatment. No statistically significant difference in PFS was observed between the subgroup of patients who did not receive octreotide LAR (25.4 months 
[95% CI 22.8; 30.6]) and the subgroup of patients who did receive concomitant treatment with octreotide LAR (30.9 months [95% CI 25.6; 34.8]) (p= 0.747).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
This medicinal product is administered intravenously and is immediately and completely bioavailable.

Distribution

An analysis performed with human plasma to determine the extent of plasma protein binding of non-radioactive compound (lutetium (175Lu) oxodotreotide) showed that about 50% of the compound is bound to plasmatic proteins.

Transchelation of lutetium-177 from lutetium (175Lu) oxodotreotide into serum proteins has not been observed.

Organ uptake

Within 4 hours after administration, the distribution pattern of lutetium (177Lu) oxodotreotide shows a rapid uptake in kidneys, tumour lesions, liver, and spleen, and in some patients, in the pituitary gland and in the thyroid. The co-administration of amino acid solution decreases the kidney uptake, enhancing the elimination of radioactivity (see section 4.4). Biodistribution studies show that lutetium (177Lu) oxodotreotide is rapidly cleared from the blood.

Biotransformation

There is evidence, from the analysis of urine samples of 20 patients included in the NETTER-1 phase III dosimetry, pharmacokinetic and ECG sub-study, that lutetium (177Lu) oxodotreotide is poorly metabolised and is excreted mainly as intact compound via the renal route.

The high performance liquid chromatography (HPLC) analyses performed on urine samples collected up to 48 hours post infusion showed unchanged lutetium (177Lu) oxodotreotide close to 100% in most of the analysed samples (with lowest value being greater than 92%), indicating that the compound is eliminated in urine mainly as intact compound.

This evidence confirms what was previously observed in the Erasmus phase I/II study, in which HPLC analysis of a urine specimen collected 1 hour post administration of lutetium (177Lu) oxodotreotide from one patient receiving 1.85 MBq of lutetium (177Lu) oxodotreotide indicated that the main portion (91%) was excreted unchanged.

These findings are supported by in vitro metabolism data in human hepatocytes, in which no metabolic degradation of lutetium (175Lu) oxodotreotide was observed.

Elimination

Based on the data collected during the Erasmus phase I/II and NETTER-1 phase III studies, lutetium (177Lu) oxodotreotide is primarily eliminated by renal excretion: about 60% of the medicinal product is eliminated in the urine within 24 hours, and about 65% within 48 hours following the administration.

Elderly

The pharmacokinetic profile in elderly patients (≥75 years) has not been established. No data are available.


In vitro evaluation of interaction potential
Metabolic and transporter based interaction
The absence of inhibition or significant induction of the human CYP450 enzymes, and the absence of specific interaction with P-glycoprotein (efflux transporter) or OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 and BCRP transporters in pre-clinical studies, suggest that Lutathera has a low probability of causing significant metabolism- or transporter-mediated interactions.