Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: BeiGene Ireland Limited, 10 Earlsfort Terrace, Dublin 2, D02 T380, Ireland, Tel. +353 1 566 7660, E-mail: bg.ireland@beigene.com
Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates
ATC code: L01FF09
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.
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:
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 visuallyestimated 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 platinumbased 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 (N=256) | Chemotherapy (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 confirmation by investigator (months) (95% CI) | 10.3 (6.5, 13.2) | 6.3 (2.8, 8.5) |
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):
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 pvalue 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.
The European Medicines Agency has waived the obligation to submit the results of studies with tislelizumab in all subsets of the paediatric population in the treatment of malignant neoplasms (except central nervous system, haematopoietic and lymphoid tissue) (see section 4.2 for information on paediatric use).
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.
Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable.
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.
Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Based on population PK analysis, the clearance of tislelizumab was 0.153 l/day with an interindividual variability of 26.3% and the geometrical mean terminal half-life was approximately 23.8 days with a coefficient variation (CV) of 31%.
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.
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.
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.
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.
In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations), no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.
No developmental and reproductive toxicity studies or animal fertility studies have been conducted with tislelizumab.
No studies have been performed to assess the potential of tislelizumab for carcinogenicity or genotoxicity.
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