Tevimbra 100 mg/10 ml Infusion

Non-small cell lung cancer (NSCLC)

Tevimbra, in combination with platinum-containing chemotherapy as neoadjuvant treatment and then continued as monotherapy as adjuvant treatment, is indicated for the treatment of adult patients with resectable NSCLC at high risk of recurrence (for selection criteria, see section 5.1).

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.

Small Cell Lung Cancer (SCLC)

Tevimbra, in combination with etoposide and platinum chemotherapy, is indicated for the first-line treatment of adult patients with extensive-stage SCLC.

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 section 5.1).

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 section 5.1).

Tevimbra as monotherapy is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic OSCC after prior platinum-based chemotherapy.

Nasopharyngeal carcinoma (NPC)

Tevimbra, in combination with gemcitabine and cisplatin, is indicated for the first-line treatment of adult patients with recurrent, not amenable to curative surgery or radiotherapy, or metastatic NPC.

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 sections 4.1, 4.4, and 5.1).

Posology

Tevimbra monotherapy

The recommended dose of Tevimbra is either 200 mg once every 3 weeks or 400 mg once every 6 weeks administered by intravenous infusion.

For resectable NSCLC, during the adjuvant treatment phase, the recommended dose of Tevimbra is 400 mg administered by intravenous infusion once every 6 weeks.

Tevimbra combination therapy

The recommended dose of Tevimbra is either 200 mg once every 3 weeks or 400 mg once every 6 weeks administered by intravenous infusion, 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 section 5.1).

For the neoadjuvant and adjuvant treatment of resectable NSCLC, patients should be treated with neoadjuvant Tevimbra (200 mg every 3 weeks) in combination with chemotherapy for 3 or 4 cycles or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with Tevimbra (400 mg every 6 weeks) as monotherapy for up to 8 cycles or until disease recurrence, metastasis, or unacceptable toxicity.

Dose delay or discontinuation (see also section 4.4)

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 1.

Detailed guidelines for the management of immune‑related adverse reactions are described in section 4.4.

Table 1 Recommended treatment modifications for Tevimbra

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 section 4.8).

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 section 5.2).

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 section 5.2).

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 section 6.6.

The first infusion at 200 mg 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.

The infusion of an initial dose of Tevimbra 400 mg should be delivered over 120 minutes (over 90 minutes if it is used as subsequent treatment after the dose of 200 mg once every 3 weeks). If well tolerated, the second infusion may be administered over 60 minutes. If the second infusion is well tolerated, subsequent infusions may be administered over 30 minutes.

Other medicinal products must not be mixed or co-administered through the same infusion line.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 (see also Package Leaflet).

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 section 4.8). 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 section 4.2). 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 sections 4.2 and 4.8). Upon improvement to Grade ≤1, corticosteroid taper should be initiated and continued over at least 1 month.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

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 1 (see section 4.2).

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 1 (see section 4.2).

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 1 (see section 4.2).

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 section 4.8). 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 SCARs, 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 section 4.2).

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 1 (see section 4.2).

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 1 (see section 4.2).

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 section 4.2).

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 section 4.2).

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 section 4.2).

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 section 4.2). 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 1 (see section 4.2).

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, cystitis noninfective, and Guillain-Barré syndrome (see section 4.8).

Patients with other immune-related adverse reactions should be managed according to the treatment modifications as recommended in Table 1 (see section 4.2).

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.

Haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving tislelizumab (see section 4.8). HLH is a life-threatening syndrome characterised by fever, skin rash, lymphadenopathy, hepato- and/or splenomegaly and cytopenias. Patients should be monitored for clinical signs and symptoms of HLH. For suspected HLH, tislelizumab must be interrupted for diagnostic workup and treatment for HLH initiated. If HLH is confirmed, administration of tislelizumab should be discontinued.

Infusion-related reactions

Severe infusion-related reactions (Grade 3 or higher) have been reported in patients receiving tislelizumab (see section 4.8). 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 1 (see section 4.2).

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.

Tevimbra is to be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate 20 (E432)

This medicinal product contains 0.2 mg of polysorbate 20 in each ml of concentrate, which is equivalent to 4 mg in two 10 ml vials of a single infusion of Tevimbra. Polysorbates may cause allergic reactions. Patients with known allergies should be taken into consideration.

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 section 4.4). 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.

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 section 5.3).

Tevimbra has minor influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of tislelizumab (see section 4.8).

The safety of tislelizumab as monotherapy is based on pooled data in 1952 patients across multiple tumour types who received 200 mg tislelizumab every 3 weeks. The most common adverse reactions (≥ 20%) were anaemia (27.7%), aspartate aminotransferase increased (24.7%), fatigue (24.6%), and alanine aminotransferase increased (22.0%). The most common Grade 3/4 adverse reactions (≥ 2%) were anaemia (4.8%), aspartate aminotransferase increased (3.7%), pneumonia (3.6%), hyponatraemia (2.9%), blood bilirubin increased (2.8%), hypertension (2.4%), and fatigue (2.1%). 1.0% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.61%), pneumonitis (0.10%), hepatitis (0.10%), thrombocytopenia (0.05%), dyspnoea (0.05%) and decreased appetite (0.05%). Among the 1952 patients, 40.7% were exposed to tislelizumab for longer than 6 months, and 24.7% were exposed for longer than 12 months.

The safety of tislelizumab given in combination with chemotherapy is based on data in 1950 patients across multiple tumour types who received 200 mg tislelizumab every 3 weeks, with the exception of study BGB A317-315 where patients also received tislelizumab at a dose of 400 mg once every 6 weeks as adjuvant treatment after neoadjuvant therapy and surgery. The most common adverse reactions (≥ 20%) were neutropenia (71.6%), anaemia (67.2%), thrombocytopenia (48.7%), nausea (43.3%), fatigue (40.8%), decreased appetite (40.1%), alanine aminotransferase increased (30.6%), aspartate aminotransferase increased (30.3%), rash (21.4%) and diarrhoea (20.3%). The most common Grade 3/4 adverse reactions (≥ 2%) were neutropenia (45.2%), anaemia (14.5%), thrombocytopenia (14.1%), hyponatraemia (4.6%), hypokalaemia (4.5%), fatigue (4.2%), pneumonia (4.0%), lymphopenia (3.1%), rash (2.9%), decreased appetite (2.6%), aspartate aminotransferase increased (2.2%), alanine aminotransferase increased (2.1%). 1.3% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.50%), pneumonitis (0.30%), dyspnoea (0.20%), myocarditis (0.20%), hepatitis (0.05%), thrombocytopenia (0.05%), colitis (0.05%), hypokalaemia (0.05%), and myositis (0.05%). Among the 1950 patients, 56.5% were exposed to tislelizumab for 6 months or longer, and 31.9% 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= 1952) and in combination with chemotherapy (N = 1950) are presented in Table 2. 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.

Table 2 Adverse reactions with Tevimbra as monotherapy (N = 1952) and in combination with chemotherapy (N = 1950)

Description of selected adverse reactions

The data below 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 5.1% of patients, including Grade 1 (1.3%), Grade 2 (2.1%), Grade 3 (1.3%), Grade 4 (0.3%) and Grade 5 (0.1%) events.

The median time from first dose to onset of the event was 4.1 months (range: 1.0 day to 55.0 months), and the median duration from onset to resolution was 2.8 months (range: 7.0 days to 33.7 months). Tislelizumab was permanently discontinued in 1.8% of patients and tislelizumab treatment was interrupted in 1.9% of patients. Pneumonitis resolved in 47.0% of patients.

In patients treated with tislelizumab as monotherapy, pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.4%) than in patients who did not receive prior thoracic radiation (3.6%).

Pneumonitis occurred in 11.2% of patients with NSCLC treated with tislelizumab in combination with chemotherapy. In patients with NSCLC treated with tislelizumab as monotherapy, pneumonitis occurred in 8.3% of patients.

Immune-related hepatitis

In patients treated with tislelizumab as monotherapy, immune-related hepatitis occurred in 1.2% of patients, including Grade 1 (0.1%), Grade 2 (0.2%), Grade 3 (0.6%) and Grade 4 (0.3%) events.

The median time from first dose to onset of the event was 22.0 days (range: 1.0 day to 4.1 months), and the median duration from onset to resolution was 1.1 months (range: 6.0 days to 6.6 months). Tislelizumab was permanently discontinued in 0.3% of patients and tislelizumab treatment was interrupted in 0.8% of patients for immune-related hepatitis. Hepatitis resolved in 60.9% of patients.

Immune-related skin adverse reactions

In patients treated with tislelizumab as monotherapy, immune-related skin adverse reactions occurred in 12.6% of patients, including Grade 1 (7.7%), Grade 2 (3.7%), Grade 3 (1.0%) and Grade 4 (0.1%) events.

The median time from first dose to onset of the event was 1.5 months (range: 1.0 day to 36.1 months). The median duration from onset to resolution was 1.1 months (range: 1.0 day to 36.7 months). Tislelizumab was permanently discontinued in 0.1% of patients, and tislelizumab treatment was interrupted in 1.3% of patients. Skin adverse reactions resolved in 72.0% of patients.

Cases of SJS and TEN have been reported from post-marketing experience, some with fatal outcome (see section 4.2 and 4.4).

Immune-related colitis

In patients treated with tislelizumab as monotherapy, immune-related colitis occurred in 0.6% of patients, including Grade 2 (0.4%) and Grade 3 (0.2%) events.

The median time from first dose to onset of the event was 6.0 months (range: 6.0 days to 26.5 months), and the median duration from onset to resolution was 28.0 days (range: 9.0 days to 26.7 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.4% of patients. Colitis resolved in 81.8% of patients.

Immune-related myositis/rhabdomyolysis

In patients treated with tislelizumab as monotherapy, immune-related myositis/rhabdomyolysis 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 1.5 months (range: 15.0 days to 39.3 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 0.2% of patients and tislelizumab treatment was interrupted in 0.5% of patients. Myositis/rhabdomyolysis resolved in 75.0% of patients.

Immune-related endocrinopathies

Thyroid disorders

Hypothyroidism:

In patients treated with tislelizumab as monotherapy, hypothyroidism occurred in 13.8% of patients, including Grade 1 (6.4%), Grade 2 (7.3%), Grade 3 (0.1%) and Grade 4 (0.1%) events.

The median time from first dose to onset of the event was 4.0 months (range: 1.0 day to 29.9 months). The median duration from onset to resolution was 2.1 months (range: 2.0 days to 27.0 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.6% of patients. Hypothyroidism resolved in 36.4% of patients.

Hyperthyroidism:

In patients treated with tislelizumab as monotherapy, hyperthyroidism occurred in 5.1% of patients, including Grade 1 (4.4%) and Grade 2 (0.7%) events.

The median time from first dose to onset of the event was 2.1 months (range: 6.0 days to 39.4 months). The median duration from onset to resolution was 1.4 months (range: 8.0 days to 22.1 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.3% of patients. Hyperthyroidism resolved in 77.0% of patients.

Thyroiditis:

In patients treated with tislelizumab as monotherapy, thyroiditis occurred in 1.1% of patients, including Grade 1 (0.5%) and Grade 2 (0.6%) events.

The median time from first dose to onset of the event was 2.0 months (range: 14.0 days to 20.7 months). The median duration from onset to resolution was 2.0 months (range: 20.0 days to 15.3 months). Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.2% of patients. Thyroiditis resolved in 38.1% of patients.

Adrenal insufficiency

In patients treated with tislelizumab as monotherapy, adrenal insufficiency occurred in 0.5% of patients, including 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 10.3 months (range: 1.4 months to 16.9 months). The median duration from onset to resolution was 1.9 months (range: 30.0 days to 13.6 months). Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.4% of patients. Adrenal insufficiency resolved in 30.0% of patients.

Hypophysitis

In patients treated with tislelizumab as monotherapy, hypophysitis (Grade 2) occurred in 0.3% of patients.

The median time from first dose to onset of the event was 9.0 months (range: 22.0 days to 16.2 months). The median duration from onset to resolution was 2.3 months (only 1 resolved event). Tislelizumab was not permanently discontinued in any patients and tislelizumab treatment was not interrupted in any patients. Hypophysitis resolved in 20.0% of patients.

Type 1 diabetes mellitus

In patients treated with tislelizumab as monotherapy, type 1 diabetes mellitus occurred in 0.6% of patients, including Grade 1 (0.1%), 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 6.5 months (range: 1.1 months to 36.1 months). The median duration from onset to resolution was 22.0 days (range: 5.0 days to 3.6 months). Tislelizumab was permanently discontinued in 0.2% of patients and tislelizumab treatment was interrupted in 0.2% of patients. Type 1 diabetes mellitus resolved in 8.3% of patients.

Immune-related nephritis and renal dysfunction

In patients treated with tislelizumab as monotherapy, immune-related nephritis and renal dysfunction occurred in 0.2% 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 9.0 days (the same for 2 resolved events). 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 (0.4%), Grade 2 (0.2%), 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 33.6 months), and the median duration from onset to resolution was 1.2 months (range: 4.0 days to 15.6 months). Tislelizumab was permanently discontinued in 0.4% of patients and tislelizumab treatment was interrupted in 0.4% of patients. Myocarditis resolved in 60.0% of patients.

Myocarditis occurred in 1.2% of patients treated with tislelizumab in combination with chemotherapy, including Grade 5 (0.2%) events.

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 3.0% of patients, including Grade 3 (0.1%) events. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% 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, 4.4% for decreased haemoglobin, 0.9% for decreased leukocytes, 8.9% for decreased lymphocytes, 0.2% for increased lymphocytes, 2.1% for decreased neutrophils, 1.3% for decreased platelets, 2.6% for increased alanine aminotransferase, 0.3% for decreased albumin, 2.7% for increased alkaline phosphatase, 4.8% for increased aspartate aminotransferase, 2.8% for increased bilirubin, 1.9% for increased creatine kinase, 1.2% for increased creatinine, 4.4% for increased glucose, 0.5% for decreased glucose, 0.9% for increased potassium, 2.9% for decreased potassium, 0.1% for increased sodium, 6.5% 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: 14.2% for decreased haemoglobin, 23.3% for decreased leukocytes, 17.9% for decreased lymphocytes, 0.1% for increased lymphocytes, 47.2% for decreased neutrophils, 14.1% for decreased platelets, 3.5% for increased alanine aminotransferase, 0.5% for decreased albumin, 0.8% for increased alkaline phosphatase, 3.1% for increased aspartate aminotransferase, 2.0% for increased bilirubin, 2.3% for increased creatine kinase, 1.8% for increased creatinine, 0.5% for decreased glucose, 1.2% for increased glucose, 1.3% for increased potassium, 7.6% for decreased potassium, 0.3% for increased sodium, 11.5% for decreased sodium.

Immunogenicity

Of 3614 antidrug antibodies (ADA)-evaluable patients, 21.1% of patients tested positive for treatment-emergent ADA, and neutralising antibodies (NAbs) were detected in 0.9% 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 monotherapy or in combination with chemotherapies (including adjuvant 400 mg once every 6 weeks in resectable NSCLC) 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 52.5% vs. 42.1%, serious adverse events (SAEs) 39.0% vs. 31.8%, AEs leading to tislelizumab treatment discontinuation 12.3% vs 11.4% (for monotherapy); Grade ≥ 3 AEs 80.0% vs. 78.6%, SAEs 43.3% vs. 41.0%, AEs leading to tislelizumab treatment discontinuation 13.6% vs 13.5% (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 on this population.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Pharmacotherapeutic group: Antineoplastic agents, 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

Based on modelling and simulation of the exposure-response relationships for efficacy and safety for tislelizumab, there are no clinically significant differences in efficacy or safety between the doses of 200 mg once every 3 weeks and 400 mg once every 6 weeks.

Non-small cell lung cancer

Neoadjuvant and adjuvant treatment of resectable NSCLC: BGB-A317-315

BGB-A317-315 was a phase 3 randomised, placebo-controlled, double-blind study to compare the efficacy and safety of neoadjuvant treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab versus neoadjuvant treatment with placebo plus platinum-based doublet chemotherapy followed by adjuvant placebo in patients with resectable Stage II or IIIA NSCLC.

The study included patients who had histologically confirmed Stage II or IIIA (AJCC 8^th) NSCLC with ECOG PS of 0 or 1 and no known EGFR mutations or ALK gene translocations and confirmed eligibility for R0 resection with curative intent. Patients with Stage IIIB were not included in the study.

The following selection criteria define patients with high risk of recurrence who are included in the therapeutic indication and are reflective of the patient population with Stage II – IIIA according to the 8^th edition AJCC staging system:
 • Tumour size > 4 cm; or tumours of any size that are either accompanied by N1 or N2 status;
 • Tumours that invade thoracic structures (directly invade the visceral pleura, parietal pleura, chest wall, main bronchus, phrenic nerve, mediastinal pleura, parietal pericardium);
 • Tumours > 4 cm that cause obstructive atelectasis that extends to the hilar region, involving part or all of the lung or involve a mainstem bronchus regardless of distance to the carina, or invades visceral pleura (PL1 or PL2) for N0 status;
 • Tumours with separate nodule(s) in the same lobe as the primary lung cancer.

A total of 453 patients were randomised (1:1) to receive:
 • Tislelizumab arm: neoadjuvant tislelizumab 200 mg on Day 1 in combination with either cisplatin 75 mg/m² or carboplatin AUC of 5 mg/mL/min and pemetrexed 500 mg/m² or paclitaxel 175 mg/m² on Day 1 of each 21-day cycle for 3 to 4 cycles. Following surgery, adjuvant tislelizumab 400 mg was administered every 6 weeks for up to 8 cycles.
 • Placebo arm: neoadjuvant placebo on Day 1 in combination with either cisplatin 75 mg/m² or carboplatin AUC of 5 mg/mL/min and pemetrexed 500 mg/m² or paclitaxel 175 mg/m² on Day 1 of each 21-day cycle for 3 to 4 cycles. Following surgery, adjuvant placebo was administered every 6 weeks for up to 8 cycles.

Patients with non-squamous histology received pemetrexed while patients with squamous histology received paclitaxel, whereby the choice of cisplatin or carboplatin was decided by the investigators for all patients. If indicated, patients received postoperative adjuvant radiation therapy prior to adjuvant tislelizumab or placebo. Administration of tislelizumab and chemotherapy continued until treatment completion, disease progression, unacceptable AE, death, or patient and/or investigator's decision to discontinue study treatment.

The dual primary endpoints were event-free survival (EFS) by blinded independent central review (BICR) and major pathological response (MPR) rate by blinded independent pathological review (BIPR). The secondary efficacy endpoints included pathological complete response (pCR) rate by BIPR, and overall survival (OS).

Demographics and baseline characteristics were generally balanced between the 2 treatment arms. The baseline characteristics for all 453 randomised patients were: median age of 62 years (range 30 to 80 years); 40% of patients were ≥65 years of age; 3.3% of patients were ≥75 years of age; 90.5% of patients were male; 100% Asian (all enrolled in China), 65.3% had an ECOG PS score of 0; 84.5% were current or former smokers; 78.1% had diagnosed squamous histology; 58.5% had stage IIIA disease; 57.8% had PD-L1 expression ≥1%.

There were 84.1% of patients in the tislelizumab in combination with platinum-containing chemotherapy arm who had definitive surgery compared to 76.2% of patients in the platinum-containing chemotherapy arm.

The study demonstrated statistically significant improvement in MPR, EFS, pCR and OS for patients randomised to tislelizumab arm compared with placebo arm.

At a prespecified interim analysis of EFS (data cut-off date 21‑Aug‑2023), the EFS HR was 0.56 (95% CI: 0.40, 0.79; 1-sided p-value of 0.0003) and the median OS follow-up times by reverse Kaplan-Meier methodology were 24.6 months in the tislelizumab arm and 22.7 months in the placebo arm.

Table 3, Figure 1 and Figure 2 summarise the efficacy results.

At a pre-specified final analysis (data cut-off date 07‑Mar‑2025), the median OS follow-up times by reverse Kaplan-Meier methodology were 43.3 months (95% CI: 41.2, 44.6) in the tislelizumab arm and 41.6 months (95% CI: 39.9, 43.8) in the placebo arm.

Table 3 Efficacy results in BGB-A317-315¹

Figure 1 Kaplan-Meier Plot for Event-Free Survival in BGB-A317-315

Figure 2 Kaplan-Meier Plot for Overall Survival in BGB-A317-315

A subgroup analysis was performed in study BGB-A317-315 in patients who had PD‑L1 ≥ 1% (tislelizumab arm [n=130; 58%] vs. placebo arm [n=132; 58%]) and PD‑L1 < 1% (which excludes not evaluable/indeterminate) (tislelizumab arm [n=89; 39%] vs. placebo arm [n=84; 37%]). The EFS HR was 0.53 (95% CI: 0.35, 0.79) in patients with PD‑L1 ≥ 1% and 0.70 (95% CI: 0.43, 1.14) in patients with PD‑L1 < 1%. The OS HR was 0.61 (95% CI: 0.38, 0.98) in patients with PD‑L1 ≥ 1% and 0.91 (95% CI: 0.50, 1.64) in patients with PD‑L1 < 1%.

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 and a median duration of study follow-up of 9.0 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 4 and the Kaplan-Meier curve for PFS and OS is presented in Figures 3 and 4, respectively.

Table 4 Efficacy results in BGB-A317-304 in patients with PD-L1 expression ≥50%

Figure 3 Kaplan‑Meier plot of PFS in BGB‑A317‑304 in patients with PD-L1 ≥50%

Figure 4 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 versusof 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 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 5, Figure 5 and Figure 6.

Table 5 Efficacy results in BGB-A317-307

Figure 5 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 6 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%

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% Caucasian 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 6 and Figure 7 summarise the efficacy results for BGB-A317-303 (ITT analysis set) at the final analysis.

Table 6 Efficacy results in BGB-A317-303

Figure 7 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 7 summarises efficacy results of OS by tumour PD-L1 (<25% TC, ≥25% TC) expression in prespecified subgroup analyses.

Table 7 Efficacy results of OS by tumour PD-L1 expression (<25% TC, ≥25% TC) in BGB-A317-303

Small cell lung cancer

First-line treatment of extensive-stage SCLC: BGB-A317-312

BGB-A317-312 was a randomised, double-blind, multicentre phase III study to compare the efficacy and safety of tislelizumab in combination with cisplatin or carboplatin plus etoposide versus placebo in combination with cisplatin or carboplatin plus etoposide as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC).

The study included patients with histologically or cytologically confirmed diagnosis of ES-SCLC who had not received any prior systemic treatment for ES-SCLC and ECOG performance status 0 or 1.

A total of 457 patients were randomised (1:1) to receive:
 • Arm tislelizumab + chemotherapy: tislelizumab 200 mg plus carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m² on Day 1 and etoposide 100 mg/m² intravenously on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles.
 • Arm placebo + chemotherapy: placebo plus carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m² on Day 1 and etoposide 100 mg/m² intravenously on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles.

The choice of platinum agent (cisplatin or carboplatin) was at the investigator's discretion. Tislelizumab 200 mg monotherapy or placebo continued every 3 weeks until disease progression, loss of clinical benefit, unacceptable toxicity.

Randomisation was stratified by ECOG performance status (0 versus 1), investigator-chosen chemotherapy (carboplatin versus cisplatin), and brain metastasis (yes versus no).

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

Demographics and baseline characteristics were generally balanced between the 2 treatment arms. The baseline characteristics for all 457 randomised patients were: median age of 62 years (range: 31 to 78 years); 37.2% were ≥65 years of age; 81.4% male; 100% Asian (all enrolled in China), 84.9% with ECOG PS of 1; 1.1% had a history of brain metastases; 79% received carboplatin per investigator's choice; 62.6% were current smokers; and 89.3% had disease Stage IV defined by AJCC 7^th Edition.

At the time of the prespecified final analysis (data cut-off 19 April 2023), BGB-A317-312 showed a statistically significant improvement in OS for patients randomised to the tislelizumab plus chemotherapy arm as compared to the placebo plus chemotherapy arm. The stratified HR was 0.75 (95% CI: 0.61, 0.93; 1-sided p-value of 0.004), with a median OS of 15.5 months in the tislelizumab plus chemotherapy arm compared to 13.5 months in the placebo plus chemotherapy arm.

A descriptive updated analysis (data cut-off 29 December 2023) showed consistent efficacy results with the final analysis. The median OS follow-up times by reverse Kaplan-Meier methodology were 39.8 months (95% CI: 36.2 to 41.4 months) in the tislelizumab plus chemotherapy arm and 36.4 months (95% CI: 35.0 to 40.9 months) in the placebo plus chemotherapy arm.

Efficacy results of the updated analysis are shown in Table 8 and Figure 8. Data for patients with brain metastases are too limited to draw conclusions on this population.

Table 8 Efficacy results in BGB-A317-312 – Updated analysis

Figure 8 Kaplan-Meier plot of OS in BGB-A317-312

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 randomised 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 randomised 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 9 and in Figure 9.

Table 9 Efficacy results in BGB-A317-305 patients with PD-L1 TAP score ≥ 5% (final analysis)

Figure 9 Kaplan-Meier plot of OS in BGB-A317-305 patients with PD-L1 TAP score ≥ 5% (final analysis)

T+C = Tislelizumab + Chemotherapy, P+C = Placebo + Chemotherapy

Both log-rank and Cox regression model were stratified by regions (east Asia versus US, Europe) and presence of peritoneal metastasis.

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, 290(44.7%) 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 10 and Figure 10.

Table 10 Efficacy results in BGB‑A317‑306 patients with PD-L1 TAP score ≥ 5% - 3-year follow-up (data cut-off 24 November 2023)

Figure 10 Kaplan-Meier plot of OS in BGB‑A317‑306 patients with PD-L1 TAP score ≥ 5% - 3-year follow-up (data cut-off 24 November 2023)

Hazard ratio was based on a stratified Cox regression model.

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

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

Efficacy results of the updated analysis are shown in Table 11 and Figure 11.

Table 11 Efficacy results in BGB-A317-302 – Updated analysis

Figure 11 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 p-value of 0.0003. The median survival was 10.0 months (95% CI: 8.5 to 15.1 months) and 5.1 months (95% CI: 3.8 to 8.2 months) for the tislelizumab and ICC arms, respectively.

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

Nasopharyngeal carcinoma (NPC)

First-line treatment of recurrent or metastatic NPC: BGB-A317-309

BGB-A317-309 was a randomised, multicentre, double-blind, placebo-controlled phase III study to compare the efficacy and safety of tislelizumab in combination with gemcitabine and cisplatin versus placebo in combination with gemcitabine and cisplatin as first-line treatment in patients with recurrent or metastatic NPC.

Patients were treatment-naive for recurrent or metastatic NPC. A treatment-free interval of at least 6 months was required if the patient had received prior neoadjuvant chemotherapy, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for nonmetastatic disease. The study excluded patients with local recurrence suitable for curative surgery or radiotherapy, and patients who received prior therapies targeting PD-1 or PD-L1.

Patients were randomised (1:1) to receive either tislelizumab 200 mg every 3 weeks or placebo in combination with cisplatin 80 mg/m² on Day 1 plus gemcitabine 1 g/m² on Day 1 and Day 8 of each 21-day cycle for 4 to 6 cycles. Randomised patients were stratified by gender and liver metastasis status.

Tislelizumab or placebo was administered until disease progression or unacceptable toxicity. Patients in the placebo arm were given the option to crossover to receive tislelizumab monotherapy after IRC-confirmed disease progression.

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

A total of 263 patients were randomised to receive either tislelizumab in combination with gemcitabine and cisplatin (N=131) or placebo in combination with gemcitabine and cisplatin (N=132).

The baseline characteristics for the study population were: median age of 50 years (range: 23 to 74 years), 91.6% of patients were younger than 65 years old; 78.3% of patients were male; 63.1% had ECOG PS score of 1; 100% were Asian (from China, Thailand, and Taiwan); and 46.7% were current or former smokers. 95.1% of the study population had metastatic disease at randomisation, with histological subtypes of NPC including 86.3% non-keratinised, 6.5% keratinised squamous carcinoma, and 7.2% unclassified NPC. The majority (76%) of patients had Epstein-Barr virus (EBV) DNA level ≥ 500 IU/mL. The baseline characteristics were generally balanced between the 2 arms.

At the time of the prespecified interim analysis (data cut-off date of 26-Mar-2021), BGB-A317-309 demonstrated a statistically significant improvement in PFS for patients randomised to tislelizumab in combination with gemcitabine and cisplatin arm compared with the placebo plus gemcitabine and cisplatin arm. The stratified HR was 0.52 (95% CI: 0.38, 0.73; 1 sided p-value of < 0.0001), with a median PFS of 9.2 months in the tislelizumab plus chemotherapy arm compared to 7.4 months in the placebo plus chemotherapy arm.

An updated analysis (data cut-off date of 08-Dec-2023) showed consistent efficacy results with the interim analysis (Table 12 and Figure 12). At this time, 52.3% of patients in the control arm had crossed over to receive tislelizumab monotherapy. The median OS follow-up times by reverse Kaplan-Meier method were 41.4 months in the tislelizumab plus chemotherapy arm and 40.8 months in the placebo plus chemotherapy arm.

Data from NPC patients aged 65 years or older are too limited to draw conclusions in this population.

Table 12 Efficacy results in BGB-A317-309 (ITT Analysis Set) – Updated Analysis

Figure 12 Kaplan-Meier plot of PFS in BGB-A317-309 by IRC (ITT Analysis Set) – Updated Analysis

* Chemotherapy = Gemcitabine + Cisplatin.

Paediatric population

The Licensing Authority 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 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 2596 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) and at 400 mg once every 6 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 section 4.2). Based on the limited number of patients with severe renal impairment (n = 5), the effect of severe renal impairment on the pharmacokinetics of tislelizumab is not conclusive.

Hepatic impairment

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

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.

Sodium citrate dihydrate

Citric acid monohydrate

L-histidine hydrochloride monohydrate

L-histidine

Trehalose dihydrate

Polysorbate 20 (E 432)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial

3 years.

After opening

Once opened, the medicinal product should be diluted and infused immediately (see section 6.6 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 10 days (240 hours) at 2°C to 8°C. The 10 days (240 hours) include storage of the diluted solution under refrigeration (2°C to 8°C), 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.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

10 ml of Tevimbra concentrate is provided in a clear Type 1 glass vial, with a grey chlorobutyl stopper with FluroTec coating and seal cap with a flip-off button.

Tevimbra is available in unit packs containing 1 vial and in multipacks containing 2 (2 packs of 1) vials.

The diluted solution for infusion should be prepared by a healthcare professional using aseptic technique.

Preparation of solution for infusion

• Remove the required number of 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 required volume from the vial(s) 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.

• For 200 mg once every 3 weeks, the first infusion should be delivered over 60 minutes. If well tolerated, subsequent infusions may be administered over 30 minutes.

The infusion of an initial dose of Tevimbra 400 mg should be delivered over 120 minutes (over 90 minutes if it is used as subsequent treatment after the dose of 200 mg once every 3 weeks). If well tolerated, the second infusion may be administered over 60 minutes. If the second infusion is 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.