TIZVENI Concentrate for solution for infusion Ref.[110144] Active ingredients: Tislelizumab

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

Non-small cell lung cancer

First-line treatment of non-squamous NSCLC: BGB-A317-304

BGB-A317-304 was a randomised, open-label, multicentre phase III study to investigate the efficacy and safety of tislelizumab in combination with platinum-pemetrexed versus platinum-pemetrexed alone as first-line treatment for chemotherapy-naïve patients with locally advanced non-squamous NSCLC who were not candidates for surgical resection or platinum-based chemoradiation, or metastatic non-squamous NSCLC.

The study excluded patients with active brain or leptomeningeal metastases, known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, active autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressants.

A total of 334 patients were randomised (2:1) to receive tislelizumab 200 mg combined with pemetrexed 500 mg/m² and carboplatin AUC 5 mg/ml/min or cisplatin 75 mg/m² (T+PP arm, n=223) or pemetrexed 500 mg/m² and carboplatin AUC 5 mg/ml/min or cisplatin 75 mg/m² (PP arm, n=111). The choice of platinum (cisplatin or carboplatin) was at the investigator’s discretion.

The treatment was administered on a 3-week cycle. After the administration of 4, 5 or 6 cycles of chemotherapy or tislelizumab combined with chemotherapy at the investigator’s discretion, patients in the T+PP arm received tislelizumab 200 mg combined with pemetrexed 500 mg/m² on a 3-week cycle until disease progression or unacceptable toxicity; patients in the PP arm received pemetrexed 500 mg/m² alone until disease progression or unacceptable toxicity, and those with disease progression confirmed by Independent Review Committee (IRC) were given the option to cross over to receive tislelizumab monotherapy on a 3-week cycle.

Randomisation was stratified by PD-L1 expression in tumour cells (TC) (<1% versus 1% to 49% versus ≥50%) and disease stage (IIIB versus IV), as classified according to American Joint Committee on Cancer (AJCC), 7th edition of Cancer Staging Manual. PD-L1 expression was evaluated at a central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1 staining on tumour cells. Tumour assessments were conducted every 6 weeks for the first 6 months, then every 9 weeks for the second 6 months, then every 12 weeks.

The baseline characteristics for patients in study BGB-A317-304 were: median age 61 years (range: 25 to 75), 29% age 65 years or older; 74% male; 100% Asian (all enrolled in China); 23.4% with ECOG PS of 0 and 76.6% with ECOG PS of 1; 18.3% with disease stage IIIB; 26.6% with unknown status for ALK rearrangement and 73.4% with negative ALK rearrangement; 36.2% never-smokers; 5.4% with brain metastases. The characteristics of age, sex, ECOG PS, stage, smoking status, PD-L1 TC score and prior anticancer treatments were balanced between the treatment arms.

The primary efficacy endpoint was progression-free survival (PFS) per RECIST v1.1 by IRC in the intent-to-treat (ITT) analysis. The secondary efficacy endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DoR) per IRC and per investigator.

The study met its primary endpoint at the interim analysis (data cut-off date of 23-Jan-2020 and a median duration of study follow-up of 9.8 months), showing a statistically significant improvement in PFS with T+PP compared with PP. The stratified hazard ratio was 0.65 (95% CI: 0.47, 0.91; p=0.0054) with a median PFS of 9.7 months with T+PP and 7.6 months with PP.

The efficacy results of the final analysis (data cut-off date of 26-Oct-2020 and a median duration of study follow-up of 16.1 months) were consistent with those of the interim analysis.

Amongst the 334 patients in study BGB-A317-304, 110 (33%) patients had tumour cell PD-L1 expression ≥50%. Of these, 74 patients were in the tislelizumab plus chemotherapy group and 36 patients were in the placebo plus chemotherapy group. Efficacy results of the patients with tumour cell PD-L1 expression ≥50% from the final analysis are shown in Table 3 and the Kaplan-Meier curve for PFS and OS is presented in Figures 1 and 2, respectively.

Table 3. Efficacy results in BGB-A317-304 in patients with PD-L1 expression ≥50%:

PFS = progression-free survival; CI = confidence interval; OS = overall survival; ORR = objective response rate; CR = complete response; PR = partial response; DoR = duration of response; NE = not estimable.
Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
^a Hazard ratio was estimated from stratified Cox model with pemetrexed+platinum group as reference group and stratified by disease stage (IIIB versus IV).
^b PFS was based on IRC assessment, and ORR/DoR was based on the confirmed response by IRC.
^c 95% CI was calculated using Clopper-Pearson method.

Figure 1. Kaplan Meier plot of PFS in BGB-A317-304 in patients with PD-L1 ≥50%:

Figure 2. Kaplan-Meier plot of OS in BGB-A317-304 in patients with PD-L1 ≥50%:

First-line treatment of squamous NSCLC: BGB-A317-307

BGB-A317-307 was a randomised, open-label, multicentre phase III study to compare the efficacy and safety of tislelizumab in combination with paclitaxel plus carboplatin or nab-paclitaxel plus carboplatin with that of paclitaxel plus carboplatin alone as first-line treatment for chemotherapy-naïve patients with locally advanced squamous NSCLC who were not candidates for surgical resection or platinum-based chemoradiation or metastatic squamous NSCLC.

The study excluded patients with active brain or leptomeningeal metastases, known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, active autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive treatments.

A total of 360 patients were randomised (1:1:1) to receive tislelizumab 200 mg combined with paclitaxel 175 mg/m² and carboplatin AUC 5 mg/ml/min (T+PC arm, n = 120), or tislelizumab 200 mg combined with nab-paclitaxel 100 mg/m² and carboplatin AUC 5 mg/ml/min (T+nPC arm, n=119), or paclitaxel 175 mg/m² and carboplatin AUC 5 mg/ml/min (PC arm, n=121).

The treatment was administered on a 3-week cycle, until the patient completed administration of 4 to 6 cycles of chemotherapy or tislelizumab combined with chemotherapy at the investigator’s discretion. Patients in the T+nPC and T+PC arms received tislelizumab until disease progression or unacceptable toxicity. Patients in the PC arm with disease progression were given the option to cross over to receive tislelizumab monotherapy on a 3-week cycle.

Randomisation was stratified by PD-L1 expression in tumour cells (TC) (<1% versus 1% to 49% versus ≥50%) and tumour staging (IIIB versus IV), as classified according to American Joint Committee on Cancer (AJCC), 7th edition of Cancer Staging Manual. PD-L1 expression was evaluated at a central laboratory using the Ventana PD-L1(SP263) assay that identified PD-L1 staining on tumour cells. Tumour assessments were conducted every 6 weeks for the first 6 months, then every 9 weeks for the remainder of the first year, then every 12 weeks until disease progression.

The baseline characteristics for the study population were: median age 62.0 years (range: 34 to 74), 35.3% age 65 years or older; 91.7% male; 100% Asian (all enrolled in China), 23.6% with ECOG PS of 0 and 76.4% with ECOG PS of 1; 33.9% diagnosed with stage IIIB and 66.1% with stage IV at baseline; 16.4% never-smokers; 38.3% with PD-L1 TC score <1%, 25.3% with PD-L1 TC score ≥1% and ≤49%, 34.7% with PD-L1 TC score ≥50%. The characteristics of age, sex, ECOG PS, stage, smoking status, PD-L1 TC score and prior anticancer treatments were balanced between the treatment arms.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by IRC per RECIST v1.1 in the ITT analysis which was to be tested sequentially in arms T+PC versus PC and arms T+nPC versus PC. The secondary efficacy endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DoR) per IRC and per investigator.

The study met its primary endpoint at the interim analysis (data cut-off date of 06-Dec-2019 and a median duration of study follow-up of 8.4 months), showing statistically significant improvements in PFS with tislelizumab in combination with paclitaxel and carboplatin (T+PC arm) and tislelizumab in combination with nab-paclitaxel and carboplatin (T+nPC arm) compared with paclitaxel and carboplatin alone (PC arm). The stratified HR (T+PC arm versus PC arm) was 0.48 (95% CI: 0.34, 0.69; p <0.0001). The stratified HR (T+nPC arm versus PC arm) was 0.45 (95% CI: 0.32, 0.64; p <0.0001). Median PFS was 7.6 months in the T+PC arm, 7.6 months in the T+nPC arm and 5.4 months in the PC arm.

The final analysis (data cut-off date of 30-Sep-2020 and a median duration of study follow-up of 16.7 months) showed the consistent results from the interim analysis.

Efficacy results for the final analysis are shown in Table 4, Figure 3 and Figure 4.

Table 4. Efficacy results in BGB-A317-307:

PFS = progression-free survival; CI = confidence interval; OS = overall survival; ORR = objective response rate; CR = complete response; PR = partial response; DoR = duration of response; NE = not estimable.
^a Stratified by stratification factors: disease stage (IIIB versus IV) and PD-L1 expression in tumour cell (≥50% TC versus 1% to 49% TC versus <1% TC).
^b PFS was based on IRC assessment, and ORR/DoR was based on the confirmed response by IRC.

Figure 3. Kaplan-Meier plot of PFS in BGB-A317-307 by IRC:

T+PC arm versus T+nPC arm versus PC arm

CI = Confidence interval; T+PC = tislelizumab+paclitaxel+carboplatin; T+nPC = tislelizumab+nab-paclitaxel+carboplatin; PC = paclitaxel+carboplatin.

Figure 4. Kaplan-Meier plot of OS in BGB-A317-307:

T+PC arm versus T+nPC arm versus PC arm

CI = Confidence interval; T+PC = tislelizumab+paclitaxel+carboplatin; T+nPC = tislelizumab+nab-paclitaxel+carboplatin; PC = paclitaxel+carboplatin; NE = not estimable.

Subgroup analyses demonstrated consistent PFS treatment effect across major demographic and prognostic subgroups, including PD-L1 expression <1%, 1 to 49% and ≥50% and disease stages IIIB and IV:

• for T+PC, with PFS HR of 0.57 (95% CI, HR = 0.34, 0.94) for PD-L1 <1%, 0.40 (95% CI, HR = 0.21, 0.76) for 1 to 49% and 0.44 (95% CI, HR = 0.26, 0.75)) for ≥50%
• for T+nPC, with PFS HR of 0.65 (95% CI, HR = 0.40, 1.06) for PD-L1 <1%, 0.40 (95% CI, HR = 0.22, 0.74) for 1 to 49% and 0.33 (95% CI, HR = 0.18, 0.59)) for ≥50%

Second-line treatment of NSCLC: BGB-A317-303

BGB-A317-303 was a randomised, open-label, multicentre phase III study to investigate the efficacy and safety of tislelizumab compared with docetaxel in patients with locally advanced or metastatic NSCLC (squamous or non-squamous), who had experienced disease progression on or after a prior platinum-based regimen.

The study excluded patients with known EGFR mutation or ALK rearrangement, prior PD-(L)1 inhibitor or CTLA-4 inhibitor treatment, active autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive treatments.

A total of 805 patients were randomised (2:1) ratio to receive tislelizumab 200 mg intravenously every 3 weeks (n=535) or docetaxel 75 mg/m² intravenously every 3 weeks (n=270). Randomisation was stratified by histology (squamous versus non-squamous), lines of therapy (second- versus third-line), and PD-L1 expression in tumour cells (TC) (≥25% versus <25%). Administration of docetaxel and tislelizumab continued until disease progression, as assessed by investigator per RECIST v1.1, or unacceptable toxicity. PD-L1 expression was evaluated at a central laboratory using the Ventana PDL1 (SP263) assay that identified PD-L1 staining on tumour cells. Tumour assessments were conducted every 9 weeks for 52 weeks after randomisation and continued every 12 weeks thereafter. Survival status was followed every 3 months after discontinuation of the study treatment.

The baseline characteristics for the study population were: median age 61 years (range: 28 to 88), 32.4% age 65 years or older, 3.2% age 75 years or older; 77.3% male; 17.0% White and 79.9% Asian; 20.6% with ECOG PS of 0 and 79.4% with ECOG PS of 1; 85.5% with metastatic disease; 30.3% never-smokers; 46.0% with squamous and 54.0% non-squamous histology; 65.8% with wild-type and 34% with unknown EGFR status; 46.1% with wild-type and 53.9% with unknown ALK status; 7.1% with previously treated brain metastases.

57.0% of the patients had a PD-L1 TC score <25% and 42.5% had a PD-L1 TC score ≥25%. All patients had received prior therapy with a platinum-doublet regimen: 84.7% patients received one prior therapy, 15.3% had received two prior therapies.

The dual-primary efficacy endpoints were OS in the ITT and PD-L1 TC score ≥25% analysis sets. Additional efficacy endpoints included investigator-assessed PFS, ORR and DoR.

BGB-A317-303 met both dual-primary endpoints of OS in the ITT analysis and PD-L1 ≥25% analysis sets. At the prespecified interim analysis (data cut-off date 10-Aug-2020 with a median duration of follow-up time of 11.7 months), a statistically significant improvement in OS was observed in the ITT population. Results favoured the tislelizumab arm (HR = 0.64; 95% CI: 0.53, 0.78; p<0.0001). Median OS was 17.2 months for the tislelizumab arm and 11.9 months for the docetaxel arm. At the final analysis (data cutoff date 15-Jul-2021 with a median duration of follow-up of 14.2 months), a statistically significant improvement in OS was observed in the PD-L1 ≥25% analysis set favouring the tislelizumab arm (stratified HR = 0.53; 95% CI: 0.41, 0.70; p<0.0001) with median OS being 19.3 months for the tislelizumab arm and 11.5 months for the docetaxel arm.

The final analysis (data cut-off date 15-Jul-2021 and a median duration of follow-up of 14.2 months) showed consistent efficacy results in the ITT population compared to the interim analysis.

Table 5 and Figure 5 summarise the efficacy results for BGB-A317-303 (ITT analysis set) at the final analysis.

Table 5. Efficacy results in BGB-A317-303:

OS = overall survival; CI = confidence interval; PFS = progression-free survival; ORR = objective response rate; CR = complete response; PR = partial response; DoR = duration of response.
Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
^a Hazard ratio was estimated from stratified Cox model with docetaxel group as reference group.
^b Stratified by stratification factors: histology (squamous versus non-squamous), lines of therapy (second versus third), and PD-L1 expression in tumour cells (≥25% PD-L1 score versus <25% PD-L1 score).
^c Confirmed by investigator.

Figure 5. Kaplan-Meier plot of OS in BGB-A317-303 (ITT Analysis Set):

Prespecified subgroup analyses demonstrated a consistent OS treatment effect in favour of tislelizumab across major demographic and prognostic subgroups.

Table 6 summarises efficacy results of OS by tumour PD-L1 (<25% TC, ≥25% TC) expression in prespecified subgroup analyses.

Table 6. Efficacy results of OS by tumour PD-L1 expression (<25% TC, ≥25% TC) in BGBA317-303:

^a Hazard ratio and its 95% CI were estimated from unstratified Cox model.

Paediatric population

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).