Tevimbra

The concentrate for solution for infusion (sterile concentrate) is a clear to slightly opalescent, colourless to slightly yellowish solution.
The solution has a pH of approximately 6.5 and an osmolality of approximately 270 to 330 mOsm/kg.
Each ml of concentrate for solution for infusion contains 10 mg tislelizumab.
Each 10 ml vial contains 100 mg tislelizumab (100 mg/10 ml).
Tislelizumab is an Fc-engineered humanised immunoglobulin G4 (IgG4) variant monoclonal antibody produced in recombinant Chinese hamster ovary cells.
Excipient with known effect: Each ml of concentrate for solution for infusion contains 0.069 mmol (or 1.6 mg) sodium.
Excipients/Inactive Ingredients: Sodium citrate dihydrate, Citric acid monohydrate, L-histidine hydrochloride monohydrate, L-histidine, Trehalose dihydrate, Polysorbate 20, Water for injection.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates. ATC code: L01FF09.
Pharmacology: Pharmacodynamics: 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), 7^th 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), 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 median OS follow-up times by reverse Kaplan-Meier methodology were 9.9 months in the T+PP arm and 9.7 months in the PP arm.
The efficacy results of the final analysis (data cut-off date of 26-Oct-2020) were consistent with those of the interim analysis. At the final analysis, the median OS follow-up times by reverse Kaplan-Meier methodology were 18.4 months in the T+PP arm and 18.0 months in the PP arm.
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 1 and the Kaplan-Meier curve for PFS and OS is presented in Figures 1 and 2, respectively. (See Table 1 and Figures 1 and 2.)

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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), 7^th 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), 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 median OS follow-up times by reverse Kaplan-Meier methodology were 8.8 months in the T+PC arm, 8.8 months in the T+nPC arm, and 8 months in the PC arm.
The final analysis (data cut-off date of 30-Sep-2020) showed the consistent results from the interim analysis. At the final analysis, the median OS follow-up times by reverse Kaplan-Meier methodology were 18.8 months in the T+PC arm, 18.9 months in the T+nPC arm, and 18.1 months in the PC arm.
Efficacy results for the final analysis are shown in Table 2, Figure 3 and Figure 4. (See Table 2 and Figures 3 and 4.)

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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%.
Previously treated 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 PD-L1 (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), 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. The median follow-up times by reverse Kaplan-Meier methodology were 19.5 months in the tislelizumab arm and 17.0 months in the docetaxel arm. At the final analysis (data cutoff date 15-Jul-2021), 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 median follow-up time by reverse Kaplan-Meier methodology at the final analysis were 31.1 months in the tislelizumab arm and 27.9 months in the docetaxel arm.
The final analysis (data cut-off date 15-Jul-2021) showed consistent efficacy results in the ITT population compared to the interim analysis.
Table 3 and Figure 5 summarise the efficacy results for BGB-A317-303 (ITT analysis set) at the final analysis. (See Table 3 and Figure 5.)

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Prespecified subgroup analyses demonstrated a consistent OS treatment effect in favour of tislelizumab across major demographic and prognostic subgroups.
Table 4 summarises efficacy results of OS by tumour PD-L1 (<25% TC, ≥25% TC) expression in prespecified subgroup analyses. (See Table 4.)

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Gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: First-line treatment of G/GEJ adenocarcinoma: BGB-A317-305 BGB-A317-305 is a randomised, multicentre, double-blind, placebo-controlled phase III study comparing the efficacy and safety of tislelizumab plus platinum and fluoropyrimidine-based chemotherapy versus placebo plus platinum and fluoropyrimidine-based chemotherapy as first-line treatment in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma.
The study included only patients with histologically confirmed adenocarcinoma and with no prior systemic therapy for advanced disease. Patients may have received prior neoadjuvant or adjuvant therapy as long as it was completed and have no recurrence or disease progression for at least 6 months.
Patients were enrolled regardless of their tumour PD-L1 expression level, which was evaluated prospectively at a central laboratory by Tumour Area Positivity (TAP) score, which is defined as total percentage of tumor area (tumor and any desmoplastic stroma) covered by tumor cells with PD-L1 membrane staining (any intensity), and tumor associated immune cells with PD-L1 staining (any intensity), visually estimated by pathologists using Ventana PD-L1 (SP263) assay.
The study excluded patients who had squamous cell or undifferentiated or other histological type G/GEJ cancer and patients who had known HER-2 positive tumours.
Randomisation was stratified by geographical region (China [including Taiwan] versus Japan and South Korea versus rest of the world [ROW, including US and Europe]), PD-L1 expression (PD-L1 TAP score ≥5% versus PD-L1 TAP score <5%), presence of peritoneal metastasis (yes versus no) and ICC option (oxaliplatin plus capecitabine versus cisplatin plus 5-FU).
Patients were randomised (1:1) to receive tislelizumab 200 mg or placebo every 3 weeks in combination with platinum and fluoropyrimidine-based chemotherapy on a 21-day cycle. Tislelizumab (or placebo) was administered until disease progression or unacceptable toxicity. After 24 months of treatment, study therapy could be continued beyond two years if the investigator considered this to be in the best interest of the patient based on an assessment of clinical benefit and potential risks.
Chemotherapy consisted of: oxaliplatin 130 mg/m² IV on day 1 and capecitabine 1,000 mg/m² orally twice daily for 14 consecutive days, repeated every 3 weeks. Oxaliplatin was administered for up to 6 cycles and capecitabine was administered as maintenance therapy at investigator's discretion until disease progression or unacceptable toxicity; or cisplatin 80 mg/m² IV on day 1, and 5-FU 800 mg/m²/day by continuous IV infusion over 24 hours daily on days 1 to 5, repeated every 3 weeks. Cisplatin and 5-FU were given for up to 6 cycles.
The primary efficacy endpoints were overall survival (OS) in the PD-L1 Positive Analysis Set (PD-L1 TAP score ≥5%) and ITT analysis set (all randomized patients). The secondary efficacy endpoints were PFS, ORR and DoR, as assessed by the investigator per RECIST v1.1, and health-related quality of life (HRQoL).
Tumour assessment was performed approximately every 6 weeks during the first 48 weeks and thereafter approximately every 9 weeks.
A total of 997 patients were randomised to either the tislelizumab + chemotherapy arm (n = 501) or the placebo + chemotherapy arm (n = 496). Of the 997 patients, 546 (54.8%) had PD-L1 TAP score ≥5% (tislelizumab + chemotherapy: n = 274; placebo + chemotherapy: n = 272), 931 (93.4%) received oxaliplatin + capecitabine treatment (tislelizumab + chemotherapy: n = 466; placebo + chemotherapy: n = 465).
In patients whose tumours expressed PD-L1 with a TAP score ≥5%, the baseline characteristics for the study population were: median age of 62 years (range: 23 to 84), 39.2% age 65 years or older; 72.2% male; 23.1% White and 73.8% Asian; 33.7% with ECOG PS of 0 and 66.3% with ECOG PS of 1. A total of 79.9% patients had primary tumour location of stomach; 98.5% of patients had metastatic disease at baseline; 43.6% and 39.7% and patients had liver metastasis and peritoneal metastasis, respectively.
At prespecified interim analysis, BGB-A317-305 demonstrated a statistically significant improvement in OS for patients randomised to the tislelizumab + chemotherapy arm as compared to the placebo + chemotherapy arm in patients with PD-L1 TAP score ≥5%. The stratified HR was 0.74 (95% CI: 0.59 to 0.94; 1-sided p-value of 0.0056), with a median OS of 17.2 months in the tislelizumab + chemotherapy arm compared to 12.6 months in the placebo + chemotherapy arm. The study also demonstrated a statistically significant improvement in PFS in patients with PD-L1 TAP score ≥5%. The stratified HR was 0.67 (95% CI: 0.55 to 0.83; 1-sided p-value < 0.0001), with a median PFS of 7.2 months for tislelizumab + chemotherapy compared to 5.9 months for placebo + chemotherapy.
At prespecified final analysis, BGB-A317-305 demonstrated a statistically significant improvement for all randomized patients. The stratified HR was 0.80 (95% CI: 0.70 to 0.92; 1-sided p-value of 0.0011), with a median OS of 15.0 months in the tislelizumab + chemotherapy arm compared to 12.9 months in the placebo + chemotherapy arm. The updated results of OS in patients with PD-L1 TAP score ≥5% were consistent with its primary analysis results.
The final analysis efficacy results from patients with PD-L1 TAP score ≥5% are shown in Table 5 and in Figure 6. (See Table 5 and Figure 6.)

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Oesophageal squamous cell carcinoma (OSCC): First-line treatment of OSCC: BGB-A317-306: BGB-A317-306 is a randomised, double-blind placebo-controlled, global phase III study to compare the efficacy of tislelizumab in combination with platinum-based chemotherapy versus placebo in combination with platinum-based chemotherapy in patients with unresectable, locally advanced recurrent or metastatic OSCC.
The study enrolled patients who were not amenable to chemoradiation or surgery with curative intent. 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 using TAP (tumour area positivity) score, defined as the total percentage of the tumour area (tumour and any desmoplastic stroma) covered by tumour cells with PD-L1 membrane staining at any intensity and tumour-associated immune cells with PD-L1 staining at any intensity, as visually estimated using the VENTANA PD-L1 (SP263) Assay.
Patients who had received prior systemic therapy for advanced or metastatic disease were excluded. A treatment-free interval of at least 6 months was required if the patient had received prior neoadjuvant/adjuvant therapy with platinum-based chemotherapy.
The study excluded patients who had evidence of fistula or complete oesophageal obstruction not amenable to treatment.
Randomisation was stratified by geographical region (Asia [excluding Japan] versus Japan versus rest of world [ROW]), prior definitive therapy (yes versus no) and investigator choice of chemotherapy (ICC; platinum with fluoropyrimidine or platinum with paclitaxel).
Patients were randomised (1:1) to receive either tislelizumab 200 mg or placebo every 3 weeks in combination with investigator's choice of chemotherapy (ICC) on a 21-day cycle. The chemotherapy doublet regimen consisted of: platinum (cisplatin [60 to 80 mg/m² IV on day 1] or oxaliplatin [130 mg/m² IV on day 1]) and a fluoropyrimidine (5-FU [750 to 800 mg/m² IV on days 1 to 5] or capecitabine [1000 mg/m² orally twice daily on days 1 to 14]), or platinum (cisplatin [60 to 80 mg/m² IV on day 1 or 2] or oxaliplatin [130 mg/m² IV on day 1 or 2]) and paclitaxel (175 mg/m² IV on day 1).
Patients were treated with tislelizumab in combination with chemotherapy or placebo in combination with chemotherapy until disease progression, as assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. After 24 months of treatment, study therapy could be continued beyond two years if the investigator considered this to be in the best interest of the patient based on an assessment of clinical benefit and potential risks.
The tumour assessments were conducted every 6 weeks for the first 48 weeks, and every 9 weeks thereafter.
The primary efficacy endpoint was overall survival (OS) in the intent-to-treat (ITT) population. Secondary efficacy endpoints were progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) as assessed by the investigator per RECIST v1.1, OS in the PD-L1 positive (PD-L1 TAP score ≥10%) subgroup and health-related quality of life (HRQoL).
A total of 649 patients were randomised to receive tislelizumab in combination with chemotherapy (n = 326) or placebo in combination with chemotherapy (n = 323). Of the 649 patients, 293 (45.1%) patients received platinum + fluoropyrimidine, 358 patients had PD-L1 TAP score ≥5%, 184 patients had PD-L1 TAP score <5% and 107 patients had PD-L1 status unknown.
In patients whose tumours expressed PD-L1 with a TAP score ≥5%, the baseline characteristics were: median age 63.0 years (range: 40 to 84), 44.7% age 65 years or older; 84.9% male; 20.9% White and 78.2% Asian. 87.7% had metastatic disease at study entry and 12.3% had locally advanced disease. All patients had histological confirmation of squamous cell carcinoma. Baseline ECOG performance status was 0 (29.9%) or 1 (70.1%).
As of the data cut-off date of interim analysis (28 February 2022), BGB-A317-306 showed a statistically significant improvement in OS for all randomised patients. The stratified HR was 0.66 (95% CI, 0.54-0.80, 1-sided p-value of < 0.0001), with a median OS of 17.2 months for the tislelizumab with chemotherapy arm vs. 10.6 months for the placebo with chemotherapy arm.
An updated analysis (up to 3-year follow-up; data cut-off date of 24 November 2023) showed consistent efficacy results with the interim analysis. The median follow-up times by reverse Kaplan-Meier methodology were 44.2 months in the tislelizumab in combination with chemotherapy arm and 43.8 months in the placebo in combination with chemotherapy arm.
Efficacy results for patients with PD-L1 TAP score ≥5%, at 3-year follow-up, are shown in Table 6 and Figure 7. (See Table 6 and Figure 7.)

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Previously treated 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/PD-L1 inhibitor treatment and tumour invasion into organs located adjacent to the oesophageal disease site (e.g. aorta or respiratory tract).
Randomisation was stratified by geographical 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 the PD-L1 Positive Analysis Set (PD-L1 score of visually-estimated Combined Positive Score, now known as Tumour Area Positivity [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 63 years (range: 35 to 86), 39.5% 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.
At the time of the prespecified final analysis, BGB-A317-302 showed a statistically significant improvement in OS for patients randomised to the tislelizumab arm as compared to the ICC arm. The stratified HR was 0.70 (95% CI: 0.57, 0.85; 1-sided p-value of 0.0001), with a median OS of 8.6 months (95% CI: 7.5, 10.4) in the tislelizumab arm compared to 6.3 months (95% CI: 5.3, 7.0) in 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.
An updated analysis with additional 24 months follow-up after the prespecified final analysis showed consistent efficacy results with the final analysis. The median follow-up times by reverse Kaplan-Meier methodology were 44.7 months in the tislelizumab arm and 44.0 months in the ICC arm.
Efficacy results of the updated analysis are shown in Table 7 and Figure 8. (See Table 7 and Figure 8.)

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Efficacy and PD-L1 subgroups (Updated analysis): At the updated analysis of OS in the PD-L1 positive subgroup (PD-L1 score ≥10%), the stratified HR for OS was 0.54 (95% CI: 0.36 to 0.79. The median survival was 10.2 months (95% CI: 8.5 to 14.5 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 0.86 (95% CI: 0.65 to 1.14), 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.
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 Dosage & Administration for information on paediatric use).
Pharmacokinetics: The pharmacokinetics (PK) of tislelizumab were assessed for Tevimbra both as monotherapy and in combination with chemotherapy.
The 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 body weight 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 [CL_Cr] ≥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 (CL_Cr 60 to 89 ml/min, n = 1,046) or moderate renal impairment (CL_Cr 30 to 59 ml/min, n = 320) and patients with normal renal function (CL_Cr ≥90 ml/min, n = 1,223). Mild and moderate renal impairment had no effect on the exposure of tislelizumab (see Dosage & Administration). 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 Dosage & Administration). 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.
Toxicology: Preclinical safety data: 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.

Non-small cell lung cancer (NSCLC): Tevimbra in combination with pemetrexed and platinum-containing chemotherapy is indicated for the first-line treatment of adult patients with non-squamous NSCLC whose tumours have PD-L1 expression on ≥50% of tumour cells with no EGFR or ALK positive mutations and who have: locally advanced NSCLC and are not candidates for surgical resection or platinum-based chemoradiation, or metastatic NSCLC.
Tevimbra in combination with carboplatin and either paclitaxel or nab-paclitaxel is indicated for the first-line treatment of adult patients with squamous NSCLC who have: locally advanced NSCLC and are not candidates for surgical resection or platinum-based chemoradiation, or metastatic NSCLC.
Tevimbra as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC after prior platinum-based therapy. Patients with EGFR mutant or ALK positive NSCLC should also have received targeted therapies before receiving tislelizumab.
Gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: Tevimbra, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line treatment of adult patients with HER-2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma whose tumours express PD-L1 with a tumour area positivity (TAP) score ≥5% (see Pharmacology: Pharmacodynamics under Actions).
Oesophageal squamous cell carcinoma (OSCC): Tevimbra, in combination with platinum-based chemotherapy, is indicated for the first-line treatment of adult patients with unresectable, locally advanced or metastatic OSCC whose tumours express PD-L1 with a TAP score ≥5% (see Pharmacology: Pharmacodynamics under Actions).
Tevimbra as monotherapy is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic OSCC after prior platinum-based chemotherapy.

Tevimbra treatment must be initiated and supervised by physicians experienced in the treatment of cancer.
PD-L1 testing: If specified in the indication, patient selection for treatment with Tevimbra based on the tumour expression of PD-L1 should be assessed by a CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used (see Indications/Uses, Precautions, and Pharmacology: Pharmacodynamics under Actions).
Posology: Tevimbra monotherapy: The recommended dose of Tevimbra is 200 mg administered by intravenous infusion once every 3 weeks.
Tevimbra combination therapy: The recommended dose of Tevimbra is 200 mg administered by intravenous infusion once every 3 weeks, in combination with chemotherapy.
When Tevimbra and chemotherapy are administered on the same day, Tevimbra should be administered before chemotherapy. The Summary of Product Characteristics (SmPC) for the chemotherapy product should be referred to for dosing as well as for recommendations on corticosteroid use as pre-medication for the prevention of chemotherapy-related adverse reactions.
Duration of treatment: Patients should be treated with Tevimbra until disease progression or unacceptable toxicity (see Pharmacology: Pharmacodynamics under Actions).
Dose delay or discontinuation (see also Precautions): Dose reductions of Tevimbra as monotherapy or in combination therapy are not recommended. Tevimbra should be withheld or discontinued based on safety and tolerability as described in Table 8. (See Table 8.)
Detailed guidelines for the management of immune-related adverse reactions are described in Precautions.

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Special populations: Paediatric population: The safety and efficacy of Tevimbra in patients aged below 18 years have not been established. No data are available.
Elderly: No dose adjustment is needed for patients aged ≥65 years (see Adverse Reactions).
Renal impairment: No dose adjustment is needed for patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to make dosing recommendations for this population (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is needed for patients with mild or moderate hepatic impairment. Data from patients with severe hepatic impairment are too limited to make dosing recommendations for this population (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: Tevimbra is for intravenous use only. It is to be administered as an infusion and must not be administered as an intravenous push or single bolus injection. For instructions on dilution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.
The first infusion should be administered over a period of 60 minutes. If this is well tolerated, the subsequent infusions may be administered over a period of 30 minutes. The infusion should be given via an intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on filter.
Other medicinal products must not be mixed or co-administered through the same infusion line.

There is no information on overdose with tislelizumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse drug reactions, and appropriate symptomatic treatment should be instituted immediately.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Assessment of PD-L1 status: When assessing the PD-L1 status of the tumour, it is important that a well validated methodology is chosen to minimise false negative or false positive determinations.
Patient Card: Patients treated with Tevimbra must be given the Patient Card to be informed about the risks of immune-related adverse reactions during Tevimbra therapy.
The prescriber must discuss the risks of immune-related adverse reactions during Tevimbra therapy with the patient.
Immune-related adverse reactions: Immune-related adverse reactions have been reported, including fatal cases, during treatment with tislelizumab (see Adverse Reactions). The majority of these events improved with interruption of tislelizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also been reported after the last dose of tislelizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously.
For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or exclude alternative aetiologies, including infection, should be ensured. Based on the severity of the adverse reaction, tislelizumab should be withheld and corticosteroids administered (see Dosage & Administration). Based on limited data from clinical studies, administration of other systemic immunosuppressants can be considered in patients whose immune-related adverse reactions are not controlled with corticosteroid use (see Dosage & Administration and Adverse Reactions). Upon improvement to Grade ≤1, corticosteroid taper should be initiated and continued over at least 1 month.
Immune-related pneumonitis: Immune-related pneumonitis, including fatal cases, has been reported in patients receiving tislelizumab. Patients should be monitored for signs and symptoms of pneumonitis. Patients with suspected pneumonitis should be evaluated with radiographic imaging and infectious or disease-related aetiologies should be ruled out.
Patients with immune-related pneumonitis should be managed according to the treatment modifications as recommended in Table 8 (see Dosage & Administration).
Immune-related hepatitis: Immune-related hepatitis, including fatal cases, has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of hepatitis and changes in liver function. Liver function tests should be performed at baseline and periodically during treatment.
Patients with immune-related hepatitis should be managed according to the treatment modifications as recommended in Table 8 (see Dosage & Administration).
Immune-related skin reactions: Immune-related skin rash or dermatitis have been reported in patients receiving tislelizumab. Patients should be monitored for suspected skin reactions and other causes should be excluded. Based on the severity of the skin adverse reactions, tislelizumab should be withheld or permanently discontinued as recommended in Table 8 (see Dosage & Administration).
Cases of severe cutaneous adverse reactions (SCARs) including erythema multiforme (EM), Stevens-Johnson Syndrome (SJS) and Toxic epidermal necrolysis (TEN), some of them with fatal outcome, have been reported in patients receiving tislelizumab (see Adverse Reactions). Patients should be monitored for signs or symptoms of SCARs (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash) and other causes should be excluded. For suspected SCAR, tislelizumab should be withheld and the patient should be referred to specialised care for assessment and treatment. If SCAR is confirmed, tislelizumab should be permanently discontinued (see Dosage & Administration).
Immune-related colitis: Immune-related colitis, frequently associated with diarrhoea, has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of colitis. Infectious and disease-related aetiologies should be ruled out.
Patients with immune-related colitis should be managed according to the treatment modifications as recommended in Table 8 (see Dosage & Administration).
Immune-related endocrinopathies: Immune-related endocrinopathies, including thyroid disorders, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, have been reported in patients treated with tislelizumab. These may require supportive treatment depending on the specific endocrine disorder. Long-term hormone replacement therapy (HRT) may be necessary in cases of immune-related endocrinopathies.
Patients with immune-related endocrinopathies should be managed according to the treatment modifications as recommended in Table 8 (see Dosage & Administration).
Thyroid disorders: Thyroid disorders, including thyroiditis, hypothyroidism and hyperthyroidism, have been reported in patients treated with tislelizumab. Patients should be monitored (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) for changes in thyroid function and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with HRT without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically (see Dosage & Administration).
Adrenal insufficiency: Adrenal insufficiency has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of adrenal insufficiency. Monitoring of adrenal function and hormone levels should be considered. Corticosteroids and HRT should be administered as clinically indicated (see Dosage & Administration).
Hypophysitis: Hypophysitis has been reported in patients treated with tislelizumab. Patients should be monitored for signs and symptoms of hypophysitis/hypopituitarism. Monitoring of pituitary function and hormone levels should be considered. Corticosteroids and HRT should be administered as clinically indicated (see Dosage & Administration).
Type 1 diabetes mellitus: Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients treated with tislelizumab. Patients should be monitored for hyperglycaemia and other signs and symptoms of diabetes. Insulin should be administered for type 1 diabetes. In patients with severe hyperglycaemia or ketoacidosis (Grade ≥3), tislelizumab should be withheld and anti-hyperglycaemic treatment should be administered (see Dosage & Administration). Treatment with tislelizumab may be resumed when metabolic control is achieved.
Immune-related nephritis with renal dysfunction: Immune-related nephritis with renal dysfunction has been reported in patients treated with tislelizumab. Patients should be monitored for changes in renal function (elevated serum creatinine), and other causes of renal dysfunction should be excluded.
Patients with immune-related nephritis with renal dysfunction should be managed according to the treatment modifications as recommended in Table 8 (see Dosage & Administration).
Other immune-related adverse reactions: Other clinically important immune-related adverse reactions were reported with tislelizumab: myositis, myocarditis, arthritis, polymyalgia rheumatica, pericarditis, immune thrombocytopenia, encephalitis, myasthenia gravis, Sjögren's syndrome and Guillain-Barré syndrome (see Adverse Reactions).
Patients with other immune-related adverse reactions should be managed according to the treatment modifications as recommended in Table 8 (see Dosage & Administration).
Solid organ transplant rejection: Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with tislelizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with tislelizumab versus the risk of possible organ rejection should be considered in these patients.
Infusion-related reactions: Severe infusion-related reactions (Grade 3 or higher) have been reported in patients receiving tislelizumab (see Adverse Reactions). Cases of anaphylaxis, including anaphylactic reaction and anaphylactic shock, have been reported in the post-marketing setting. Patients should be monitored for signs and symptoms of infusion-related reactions.
Infusion-related reactions should be managed as recommended in Table 8 (see Dosage & Administration).
Patients excluded from clinical studies: Patients with any of the following conditions were excluded from clinical studies: baseline ECOG performance status greater than or equal to 2; active brain or leptomeningeal metastases; active autoimmune disease or history of autoimmune disease that may relapse; any condition requiring systemic treatment with either corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressants within the 14 days prior to study treatment; active or untreated HIV; untreated hepatitis B or hepatitis C carriers; history of interstitial lung disease; administration of live vaccine within the 14 days prior to study treatment; infection requiring systemic therapy within the 14 days prior to study treatment; history of severe hypersensitivity to another monoclonal antibody. In the absence of data, tislelizumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Patients on controlled sodium diet: Each ml of this medicinal product contains 0.069 mmol (or 1.6 mg) sodium. This medicinal product contains 16 mg sodium per 10 ml vial, equivalent to 0.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on ability to drive and use machines: Tevimbra has minor influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of tislelizumab (see Adverse Reactions).

Women of childbearing potential/Contraception: Tislelizumab should not be used in women of childbearing potential not using effective contraception unless the clinical condition of the woman requires treatment with tislelizumab. Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment and for at least 4 months following the last dose of tislelizumab.
Pregnancy: There are no available data on the use of tislelizumab in pregnant women. Based on its mechanism of action, tislelizumab can cause foetal harm when administered to a pregnant woman.
Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in increased foetal loss.
Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing foetus. Women should be advised of the potential risk to a foetus.
Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab.
Breast-feeding: It is unknown whether tislelizumab is excreted in human milk. Its effects on breast-fed newborns/infants and on milk production are also unknown.
Because of the potential for serious adverse drug reactions in breast-fed newborns/infants from Tevimbra, women should be advised not to breast-feed during treatment and for at least 4 months after the last dose of Tevimbra.
Fertility: No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10 or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations) (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The safety of tislelizumab as monotherapy is based on pooled data in 1,534 patients across multiple tumour types who received 200 mg tislelizumab every 3 weeks. The most common adverse reactions were anaemia (29.8%), fatigue (23.9%) and aspartate aminotransferase increased (21.3%). The most common Grade 3/4 adverse reactions were anaemia (5.1%), pneumonia (4.4%), hyponatraemia (2.9%), aspartate aminotransferase increased (2.6%), hypertension (2.3%), blood bilirubin increased (2.1%), pneumonitis (2.0%) and fatigue (2.0%). 1.1% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.72%), hepatitis (0.07%), abnormal hepatic function (0.07%), pneumonitis (0.07%), dyspnoea (0.07%), decreased appetite (0.07%) and decreased platelet count (0.07%). Among the 1,534 patients, 40.8% were exposed to tislelizumab for 6 months or longer, and 24.0% were exposed for 12 months or longer.
The safety of tislelizumab given in combination with chemotherapy is based on data in 1,319 patients with G/GEJ adenocarcinoma, OSCC or NSCLC. The most common adverse reactions were neutropenia (65.6%), anaemia (63.6%), thrombocytopenia (48.8%), nausea (44.0%), fatigue (43.1%), decreased appetite (41.8%), aspartate aminotransferase increased (31.7%), alanine aminotransferase increased (30.4%), diarrhoea (22.7%), and rash (20.8%). The most common Grade 3/4 adverse reactions were neutropenia (38.4%), thrombocytopenia (13.3%), anaemia (13.3%), fatigue (5.0%), hypokalaemia (4.4%), hyponatraemia (3.9%), pneumonia (3.8%), decreased appetite (3.3%), rash (2.6%), lymphopenia (2.5%), alanine aminotransferase increased (2.4%), aspartate aminotransferase increased (2.4%), diarrhoea (2.4%), pneumonitis (2.0%), and hepatitis (2.0%). 1.1% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.5%), pneumonitis (0.2%), dyspnoea (0.2%), myocarditis (0.2%), colitis (0.1%), hypokalaemia (0.1%), and myositis (0.1%). Among the 1,319 patients, 57.1% were exposed to tislelizumab for 6 months or longer, and 29.7% were exposed for 12 months or longer.
Tabulated list of adverse reactions: Adverse reactions reported in the pooled dataset for patients treated with Tevimbra monotherapy (N = 1,534) and in combination with chemotherapy (N = 1,319) are presented in Table 9. Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in decreasing frequency. The corresponding frequency category for each adverse reaction is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Tables 9a and 9b.)

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Description of selected adverse reactions: The following data reflect information for significant adverse drug reactions for tislelizumab as monotherapy in clinical studies. Details for the significant adverse reactions for tislelizumab when given in combination with chemotherapy are presented if clinically relevant differences were noted in comparison to tislelizumab monotherapy.
Immune-related pneumonitis: In patients treated with tislelizumab as monotherapy, immune-related pneumonitis occurred in 5.4% of patients, including Grade 1 (1.3%), Grade 2 (2.2%), Grade 3 (1.6%), Grade 4 (0.3%) and Grade 5 (0.1%) events.
The median time from first dose to onset of the event was 3.3 months (range: 1.0 day to 26.2 months), and the median duration from onset to resolution was 6.1 months (range: 1.0+ day to 33.9+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 2.0% of patients and tislelizumab treatment was interrupted in 1.9% of patients. Pneumonitis resolved in 48.2% of patients.
In patients treated with tislelizumab as monotherapy, pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (7.8%) than in patients who did not receive prior thoracic radiation (3.8%).
Pneumonitis occurred in 9.1% of patients with NSCLC treated with tislelizumab in combination with chemotherapy. In patients with NSCLC treated with tislelizumab as monotherapy, pneumonitis occurred in 6.0% of patients.
Immune-related hepatitis: In patients treated with tislelizumab as monotherapy, immune-related hepatitis occurred in 1.1% of patients, including Grade 1 (0.1%), Grade 2 (0.2%), Grade 3 (0.5%), Grade 4 (0.3%) and Grade 5 (0.1%) events.
The median time from first dose to onset of the event was 22.0 days (range: 4.0 days to 2.7 months), and the median duration from onset to resolution was 1.9 months (range: 6.0 days to 6.6 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.6% of patients for immune-related hepatitis. Hepatitis resolved in 64.7% of patients.
Immune-related skin adverse reactions: In patients treated with tislelizumab as monotherapy, immune-related skin adverse reactions occurred in 13.4% of patients, including Grade 1 (9.0%), Grade 2 (3.7%), Grade 3 (0.7%) and Grade 4 (0.1%) events.
The median time from first dose to onset of the event was 1.6 months (range: 1.0 day to 25.8 months). The median duration from onset to resolution was 1.7 months (range: 1.0 day to 35.4+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients, and tislelizumab treatment was interrupted in 0.8% of patients. Skin adverse reactions resolved in 68.9% of patients.
Cases of SJS and TEN have been reported from post-marketing experience, some with fatal outcome (see Dosage & Administration and Precautions).
Immune-related colitis: In patients treated with tislelizumab as monotherapy, immune-related colitis occurred in 0.5% of patients, including Grade 1 (0.1%), Grade 2 (0.3%) and Grade 3 (0.1%) events.
The median time from first dose to onset of the event was 10.1 months (range: 12.0 days to 28.2 months), and the median duration from onset to resolution was 27.0 days (range: 2.0 days to 6.5 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.2% of patients. Colitis resolved in 87.5% of patients.
Immune-related myositis/rhabdomyolysis: In patients treated with tislelizumab as monotherapy, immune-related myositis/rhabdomyolysis occurred in 0.9% of patients, including Grade 1 (0.3%), Grade 2 (0.3%) and Grade 3 (0.3%) events.
The median time from first dose to onset of the event was 1.5 months (range: 15.0 days to 11.7 months), and the median duration from onset to resolution was 1.2 months (range: 5.0 days to 5.2 months). Tislelizumab was permanently discontinued in 0.3% of patients and tislelizumab treatment was interrupted in 0.5% of patients. Myositis/rhabdomyolysis resolved in 71.4% of patients.
Immune-related endocrinopathies: Thyroid disorders: Hypothyroidism: In patients treated with tislelizumab as monotherapy, hypothyroidism occurred in 14.3% of patients, including Grade 1 (6.6%), Grade 2 (7.6%) and Grade 4 (0.1%) events.
The median time from first dose to onset of the event was 3.5 months (range: 1.0 day to 29.0 months).
The median duration from onset to resolution was 12.5 months (range: 1.0+ day to 37.3+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.5% of patients. Hypothyroidism resolved in 33.6% of patients.
Hyperthyroidism: In patients treated with tislelizumab as monotherapy, hyperthyroidism occurred in 5.0% of patients, including Grade 1 (4.4%) and Grade 2 (0.6%) events.
The median time from first dose to onset of the event was 2.1 months (range: 6.0 days to 25.6 months). The median duration from onset to resolution was 1.4 months (range: 5.0 days to 29.0+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Hyperthyroidism resolved in 76.3% of patients.
Thyroiditis: In patients treated with tislelizumab as monotherapy, thyroiditis occurred in 1.2% of patients, including Grade 1 (0.6%) and Grade 2 (0.6%) events.
The median time from first dose to onset of the event was 2.1 months (range: 20.0 days to 20.7 months). The median duration from onset to resolution was 4.9 months (range: 20.0 days to 26.1+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.1% of patients. Thyroiditis resolved in 50.0% of patients.
Adrenal insufficiency: In patients treated with tislelizumab as monotherapy, adrenal insufficiency occurred in 0.4% of patients, including Grade 2 (0.2%), Grade 3 (0.1%) and Grade 4 (0.1%) events.
The median time from first dose to onset of the event was 7.9 months (range: 1.3 months to 16.9 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 1.0 month to 18.2+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.3% of patients. Adrenal insufficiency resolved in 33.3% of patients.
Hypophysitis: In patients treated with tislelizumab as monotherapy, hypophysitis (Grade 2) occurred in 0.2% of patients.
The median time from first dose to onset of the event was 8.3 months (range: 22.0 days to 9.0 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 13.0+ months to 23.3+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was neither interrupted nor permanently discontinued in any patient. Hypophysitis did not resolve in any patient.
Type 1 diabetes mellitus: In patients treated with tislelizumab as monotherapy, type 1 diabetes mellitus occurred in 0.9% of patients, including Grade 1 (0.1%), Grade 2 (0.5%) and Grade 3 (0.3%) events.
The median time from first dose to onset of the event was 5.3 months (range: 8.0 days to 33.2 months). The median duration from onset to resolution was 3.3 months (range: 5.0 days to 30.1+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Type 1 diabetes mellitus resolved in 28.6% of patients.
Immune-related nephritis and renal dysfunction: In patients treated with tislelizumab as monotherapy, immune-related nephritis and renal dysfunction occurred in 0.3% of patients, including Grade 1 (0.1%), Grade 2 (0.1%) and Grade 3 (0.1%) events.
The median time from first dose to onset of the event was 1.5 months (range: 15.0 days to 12.1 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 9.0 days to 16.2+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Immune-related nephritis and renal dysfunction resolved in 50.0% of patients.
Immune-related myocarditis: In patients treated with tislelizumab as monotherapy, immune-related myocarditis occurred in 0.8% of patients, including Grade 1 (0.3%), Grade 2 (0.3%), Grade 3 (0.2%) and Grade 4 (0.1%) events.
The median time from first dose to onset of the event was 1.6 months (range: 14.0 days to 6.1 months), and the median duration from onset to resolution was 5.1 months (range: 4.0 days to 26.4+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.5% of patients and tislelizumab treatment was interrupted in 0.4% of patients. Myocarditis resolved in 53.8% of patients.
Myocarditis occurred in 1.2% of patients treated with tislelizumab in combination with chemotherapy, including Grade 5 (0.2%).
Immune checkpoint inhibitor class effects: There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with tislelizumab: pancreatic exocrine insufficiency.
Infusion-related reactions: In patients treated with tislelizumab as monotherapy, infusion-related reactions occurred in 2.9% of patients, including Grade 3 (0.13%) events. Tislelizumab was permanently discontinued in 0.07% of patients and tislelizumab treatment was interrupted in 0.07% of patients.
Cases of anaphylaxis, including anaphylactic reaction and anaphylactic shock, have been reported in the post-marketing setting.
Laboratory abnormalities: In patients treated with tislelizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 0.1% for increased haemoglobin, 4.8% for decreased haemoglobin, 0.9% for decreased leukocytes, 9.7% for decreased lymphocytes, 0.07% for increased lymphocytes, 1.9% for decreased neutrophils, 1.2% for decreased platelets, 2.2% for increased alanine aminotransferase, 0.7% for decreased albumin, 2.5% for increased alkaline phosphatase, 3.4% for increased aspartate aminotransferase, 2.3% for increased bilirubin, 2.1% for increased creatine kinase, 0.9% for increased creatinine, 0.9% for increased potassium, 2.5% for decreased potassium, 0.1% for increased sodium, 6.0% for decreased sodium.
In patients treated with tislelizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 12.9% for decreased haemoglobin, 18.8% for decreased leukocytes, 14.8% for decreased lymphocytes, 0.1% for increased lymphocytes, 39.8% for decreased neutrophils, 13.2% for decreased platelets, 4.4% for increased alanine aminotransferase, 0.6% for decreased albumin, 0.9% for increased alkaline phosphatase, 4.0% for increased aspartate aminotransferase, 2.1% for increased bilirubin, 2.1% for increased creatine kinase, 2.4% for increased creatinine, 0.4% for decreased glucose, 1.8% for increased glucose, 1.8% for increased potassium, 8.6% for decreased potassium, 0.4% for increased sodium, 11.7% for decreased sodium.
Immunogenicity: Of 2,686 antidrug antibodies (ADA)-evaluable patients treated at the recommended dose of 200 mg once every 3 weeks with tislelizumab as monotherapy or in combination with chemotherapies, 19.5% of patients tested positive for treatment-emergent ADA, and neutralising antibodies (NAbs) were detected in 1.0% of patients. Population pharmacokinetic analysis showed that ADA status was a statistically significant covariate on clearance; however, the presence of treatment-emergent ADA against tislelizumab appears to have no clinically relevant impact on pharmacokinetics or efficacy.
Among ADA-evaluable patients receiving 200 mg once every 3 weeks, the following rates of adverse events (AEs) have been observed for the ADA-positive population compared to the ADA-negative population, respectively: Grade ≥3 AEs 51.7% vs. 41.2%, serious adverse events (SAEs) 37.9% vs. 31.0%, AEs leading to tislelizumab treatment discontinuation 12.1% vs 10.7% (for monotherapy); Grade ≥3 AEs 78.5% vs. 74.5%, SAEs 44.7% vs. 41.5%, AEs leading to tislelizumab treatment discontinuation 14.4% vs 13.8% (for combination therapy).
Patients who developed treatment-emergent ADAs tended to have overall poorer health and disease characteristics at baseline which can confound the interpretation of the safety analysis. Available data do not allow firm conclusions to be drawn on possible patterns of adverse drug reactions.
Elderly: No overall differences in safety were observed with tislelizumab as monotherapy or in combination with chemotherapy between patients aged <65 years and patients aged between 65 and 74 years. Data for patients aged 75 years and above are too limited to draw conclusions.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the local reporting mechanism.

Tislelizumab is a humanised monoclonal antibody, cleared from the circulation through catabolism. As such, formal pharmacokinetic interaction studies have not been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug-metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of tislelizumab.
The use of systemic corticosteroids and other immunosuppressants at baseline, before starting tislelizumab, except for low doses of systemic corticosteroid (10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of tislelizumab. However, systemic corticosteroids and other immunosuppressants can be used after starting tislelizumab to treat immune-related adverse reactions (see Precautions).
Corticosteroids can also be used as pre-medication when tislelizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in Special precautions for disposal and other handling as follows.
Special precautions for disposal and other handling: The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique.
Preparation of solution for infusion: Two Tevimbra vials are required for each dose.
Remove the vials from the refrigerator, taking care not to shake them.
Inspect each vial visually for particulate matter and discolouration prior to administration. The concentrate is a clear to slightly opalescent, colourless to slightly yellowish solution. Do not use a vial if the solution is cloudy, or if visible particles or discolouration are observed.
Invert the vials gently without shaking. Withdraw the solution from the two vials (a total of 200 mg in 20 ml) into a syringe and transfer into an intravenous infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection, to prepare a diluted solution with a final concentration ranging from 2 to 5 mg/ml. Mix diluted solution by gentle inversion to avoid foaming or excessive shearing of the solution.
Administration: Administer the diluted Tevimbra solution by infusion through an intravenous administration line with a sterile, non-pyrogenic, low-protein-binding 0.2 micron or 0.22 micron in-line or add-on filter with a surface area of approximately 10 cm².
The first infusion should be delivered over 60 minutes. If well tolerated, subsequent infusions may be administered over 30 minutes.
Other medicinal products should not be co-administered through the same infusion line.
Tevimbra must not be administered as an intravenous push or single bolus injection.
The intravenous line must be flushed at the end of the infusion.
Discard any unused portion left in the vial.
Tevimbra vials are for single use only.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Shelf life: After opening: Once opened, the medicinal product should be diluted and infused immediately (see Special precautions for disposal and other handling under Cautions for Usage for instructions on dilution of the medicinal product before administration).
After preparation of solution for infusion: Tevimbra does not contain a preservative. Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C. The 24 hours include storage of the diluted solution under refrigeration (2°C to 8°C) for no more than 20 hours, time required for returning to room temperature (25°C or below) and time to complete the infusion within 4 hours.
From a microbiological point of view, once diluted, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the user. The diluted solution must not be frozen.
Special precautions for storage: Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.

Targeted Cancer Therapy / Cancer Immunotherapy

L01FF09 - tislelizumab ; Belongs to the class of PD-1/PD-L1 (Programmed cell death protein 1/death ligand 1) inhibitors. Used in the treatment of cancer.

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