Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: L01FF09


Mechanism of action
Tislelizumab is a humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1 and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in T cells in in vitro cell-based assays.

Clinical efficacy and safety

Oesophageal squamous cell carcinoma (OSCC)
BGB-A317-302
BGB-A317-302 was a randomised, controlled, open-label, global phase III study to compare the efficacy of tislelizumab versus chemotherapy in patients with unresectable, recurrent, locally advanced or metastatic OSCC who progressed on or after prior systemic treatment. Patients were enrolled regardless of their tumour PD-L1 expression level. Where available, the archival/fresh tumour tissue specimens taken were retrospectively tested for PD-L1 expression status. PD-L1 expression was evaluated at a central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1 staining on both tumour and tumour-associated immune cells.

The study excluded patients with prior anti-PD-1 inhibitor treatment and tumour invasion into organs located adjacent to the oesophageal disease site (e.g. aorta or respiratory tract).

Randomisation was stratified by geographic region (Asia [excluding Japan] versus Japan versus USA/EU), ECOG PS (0 versus 1) and investigator choice of chemotherapy (ICC) option (paclitaxel versus docetaxel versus irinotecan). The choice of ICC was determined by the investigator before randomisation.

Patients were randomised (1:1) to receive tislelizumab 200 mg every 3 weeks or investigator’s choice of chemotherapy (ICC), selected from the following, all given intravenously:
•     paclitaxel 135 to 175 mg/m² on day 1, given every 3 weeks (also at doses of 80 to 100 mg/m2 on a weekly schedule according to local and/or country-specific guidelines for standard of care), or
•     docetaxel 75 mg/m2 on day 1, given every 3 weeks, or
•     irinotecan 125 mg/m2 on days 1 and 8, given every 3 weeks.

Patients were treated with Tevimbra or one of the ICC until disease progression as assessed by the investigator per RECIST version 1.1 or unacceptable toxicity.

The tumour assessments were conducted every 6 weeks for the first 6 months, and every 9 weeks thereafter.

The primary efficacy endpoint was overall survival (OS) in the intent-to-treat (ITT) population.
Secondary efficacy endpoints were OS in PD-L1 Positive Analysis Set (PD-L1 score of visually- estimated Combined Positive Score, now known as Tumour Area Positivity score [TAP] [PD-L1 score] ≥10%), objective response rate (ORR), progression-free survival (PFS) and duration of response (DoR), as assessed by the investigator per RECIST v1.1.

A total of 512 patients were enrolled and randomised to tislelizumab (n = 256) or ICC (n = 256; paclitaxel [n = 85], docetaxel [n = 53] or irinotecan [n = 118]). Of the 512 patients, 142 (27.7%) had PD-L1 score ≥10%, 222 (43.4%) had PD-L1 score <10% , and 148 (28.9%) had unknown baseline PD-L1 status.

The baseline characteristics for the study population were: median age 62 years (range: 35 to 86), 37.9% age 65 years or older; 84% male; 19% White and 80% Asian; 25% with ECOG PS of 0 and 75% with ECOG PS of 1. Ninety-five percent of the study population had metastatic disease at study entry. All patients had received at least one prior anti-cancer chemotherapy, which was a platinum- based combination chemotherapy for 97% of patients.

BGB-A317-302 showed a statistically significant improvement in OS for patients randomised to the tislelizumab arm as compared to the ICC arm. The median follow-up times by reverse Kaplan-Meier methodology were 20.8 months in the tislelizumab arm and 21.1 months in the ICC arm.

Efficacy results are shown in Table 3 and Figure 1.


Table 3                                Efficacy results in BGB-A317-302 
Endpoint                                                                                         Tevimbra                                          Chemotherapy (N = 256)                                           (N = 256)
OS
Deaths, n (%)                                                                                 197 (77.0)                     213 (83.2) Median (months)a (95% CI)                                                                   8.6 (7.5, 10.4)                 6.3 (5.3, 7.0) Hazard ratio (95% CI)b                                                                                    0.70 (0.57, 0.85) p-valuec                                                                                                     p = 0.0001 PFS assessed by investigatord
Disease progression or death, n (%)                                                              223 (87.1)                                           180 (70.3) Median (months) (95% CI)                                                                        1.6 (1.4, 2.7)                                       2.1 (1.5, 2.7) Hazard ratio (95% CI)                                                                                                0.83 (0.67, 1.01) ORR with confirmation by investigatord
ORR (%) (95% CI)                                                                           15.2 (11.1, 20.2)                                       6.6 (3.9, 10.4) CR, n (%)                                                                                       5 (2.0)                                                 1 (0.4) PR, n (%)                                                                                      34 (13.3)                                               16 (6.3) SD, n (%)                                                                                      81 (31.6)                                              90 (35.2) Median duration of response with                                                            10.3 (6.5, 13.2)                                        6.3 (2.8, 8.5) confirmation by investigator (months)
(95% CI)
OS = overall survival; CI = confidence interval; PFS = progression-free survival; ORR = objective response rate; CR = complete response; PR = partial response; SD = stable disease a
Estimated using Kaplan-Meier method.
b
Based on Cox regression model including treatment as covariate, and stratified by baseline ECOG status and investigator’s choice of chemotherapy.
c
Based on a one-sided log-rank test stratified by ECOG performance status and investigator’s choice of chemotherapy.
d
Based on ad hoc analysis.

Figure 1                               Kaplan-Meier plot of OS in BGB-A317-302 (ITT analysis set) 
1.0
1.0

0.9
0.9
Tislelizumab:
T islelizumab : nn==256
256,   events
, events    = 197
= 197    Median:,95%
Median:8.6  8.6, CI
95%7.5CI  7.5, 10.4
- 10.4
0.8
0.8                                                                     ICC: n = ICC 256,: events n = 256 =, events
213 Median:   6.3, 95% ,95%
= 213 Median:6.3  CI 5.3, 7.0 - 7.0
CI 5.3

0.7
0.7
HR HR
(95%(95%
CI) : CI): 0.70 -(0.57,
0.70(0.57    0.85) 0.85)
Probability probability



0.6
0.6                                                                                  Log-rank Log-rank test test p-value: p-value        0.0001
: 0.0001

0.5
0.5
Survival
Survival



0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0.0
0      2       4       6       8       10       12        14         16        18        20        22        24          26        28        30        32 T ime(months)
Time   (Months)
Number of patients at risk:
Number of Patients at Risk:
Time T ime:                        0   1   2   3   4   5   6   7   8   9 10 11     12   13   14    15   16   17   18   19   20   21   22   23   24     25   26   27   28   29   30   31   32 Tislelizumab
T islelizumab                   256 245 226 214 191 172 157 144 134 122 110 96   88   81   73    63   59   52   44   35   30   25   20   18   13     11    8   8    8     3    2    1    0 ICC         ICC                   256 235 219 191 167 143 124 105 93 83 77 59      51   42   36    34   29   26   21   19   15   11    7    6    5      4    4   2    2     1    1    0    0 

Efficacy and PD-L1 subgroups:
In a pre-specified analysis of OS in the PD-L1 positive subgroup (PD-L1 score ≥10%), the stratified hazard ratio (HR) for OS was 0.49 (95% CI: 0.33 to 0.74), with a 1-sided stratified log-rank test p- value of 0.0003. The median survival was 10.0 months (95% CI: 8.5 to 15.1 months) and 5.1 months (95% CI: 3.8 to 8.2 months) for the tislelizumab and ICC arms, respectively.


In the PD-L1 negative subgroup (PD-L1 score <10%), the stratified HR for OS was 0.83 (95% CI: 0.62 to 1.12), with median overall survival of 7.5 months (95% CI: 5.5 to 8.9 months) and 5.8 months (95% CI: 4.8 to 6.9 months) for the tislelizumab and ICC arms, respectively.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics (PK) of tislelizumab were characterised using population PK analysis with concentration data from 2 596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every 2 weeks, 2.0 and 5.0 mg/kg every 3 weeks, and 200 mg every 3 weeks.

The time to reach 90% steady-state level is approximately 84 days (12 weeks) after 200 mg doses once every 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately 2-fold.

Absorption

Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable.
Distribution

A population pharmacokinetic analysis indicates that the steady-state volume of distribution is 6.42 l, which is typical of monoclonal antibodies with limited distribution.

Biotransformation

Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Elimination

Based on population PK analysis, the clearance of tislelizumab was 0.153 l/day with an inter- individual variability of 26.3% and the geometrical mean terminal half-life was approximately 23.8 days with a coefficient variation (CV) of 31%.

Linearity/non-linearity

At the dosing regimens of 0.5 mg/kg to 10 mg/kg once every 2 or 3 weeks (including 200 mg once every 3 weeks), the PK of tislelizumab were observed to be linear and the exposure was dose proportional.

Special populations

The effects of various covariates on tislelizumab PK were assessed in population PK analyses. The following factors had no clinically relevant effect on the exposure of tislelizumab: age (range 18 to 90 years), weight (range 32 to 130 kg), gender, race (White, Asian and other), mild to moderate renal impairment (creatinine clearance [CLCr] ≥30 ml/min), mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST), and tumour burden.

Renal impairment
No dedicated studies of tislelizumab have been conducted in patients with renal impairment. In the population PK analyses of tislelizumab, no clinically relevant differences in the clearance of tislelizumab were found between patients with mild renal impairment (CLCr 60 to 89 ml/min, n = 1 046) or moderate renal impairment (CLCr 30 to 59 ml/min, n = 320) and patients with normal renal function (CLCr ≥90 ml/min, n = 1 223). Mild and moderate renal impairment had no effect on the exposure of tislelizumab (see section 4.2). Based on the limited number of patients with severe renal impairment (n = 5), the effect of severe renal impairment on the pharmacokinetics of tislelizumab is not conclusive.

Hepatic impairment
No dedicated studies of tislelizumab have been conducted in patients with hepatic impairment. In the population PK analyses of tislelizumab, no clinically relevant differences in the clearance of tislelizumab were found between patients with mild hepatic impairment (bilirubin ≤ ULN and AST >ULN or bilirubin >1.0 to 1.5 x ULN and any AST, n = 396) or moderate hepatic impairment (bilirubin >1.5 to 3 x ULN and any AST; n = 12), compared to patients with normal hepatic function (bilirubin ≤ ULN and AST = ULN, n = 2 182) (see section 4.2). Based on the limited number of patients with severe hepatic impairment (bilirubin >3 x ULN and any AST, n = 2), the effect of severe hepatic impairment on the pharmacokinetics of tislelizumab is unknown.