Leaflet TEVIMBRA 100mg concentrate for solution for infusion

Tevimbra 100 mg concentrate for solution for infusion

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 antibodyproduced in recombinant Chinese hamster ovary cells.

Each ml of concentrate for solution for infusion contains 1.6 mg sodium and 0.2 mg polysorbate 20(E432).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

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.

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

Tevimbra, in combination with pemetrexed and platinum-containing chemotherapy, is indicated forthe first-line treatment of adult patients with non-squamous NSCLC whose tumours have PD-L1expression 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-basedchemoradiation, or

* metastatic NSCLC.

Tevimbra, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for thefirst-line treatment of adult patients with squamous NSCLC who have:

* locally advanced NSCLC and are not candidates for surgical resection or platinum-basedchemoradiation, or

* metastatic NSCLC.

Tevimbra as monotherapy is indicated for the treatment of adult patients with locally advanced ormetastatic 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-linetreatment 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 forthe first-line treatment of adult patients with HER-2-negative locally advanced unresectable ormetastatic 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 treatmentof 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, locallyadvanced 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 ofadult 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 ofcancer.

If specified in the indication, patient selection for treatment with Tevimbra based on the tumourexpression of PD-L1 should be assessed by a CE-marked IVD with the corresponding intendedpurpose. If the CE-marked IVD is not available, an alternative validated test should be used (seesections 4.1, pct. 4.4, and 5.1).

Tevimbra monotherapy

The recommended dose of Tevimbra is either 200 mg once every 3 weeks or 400 mg once every6 weeks administered by intravenous infusion.

For resectable NSCLC, during the adjuvant treatment phase, the recommended dose of Tevimbra is400 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 every6 weeks administered by intravenous infusion, in combination with chemotherapy.

When Tevimbra and chemotherapy are administered on the same day, Tevimbra should beadministered before chemotherapy. The Summary of Product Characteristics (SmPC) for thechemotherapy product should be referred to for dosing as well as for recommendations oncorticosteroid use as pre-medication for the prevention of chemotherapy-related adverse reactions.

Patients should be treated with Tevimbra until disease progression or unacceptable toxicity (seesection 5.1).

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

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 insection 4.4.

Table 1 Recommended treatment modifications for Tevimbra

Immune-related adverse Severity1 Tevimbra treatment modificationreaction2,3

Pneumonitis Grade 2 Withhold

Recurrent Grade 2; Grade 3 or 4 Permanently discontinue3

ALT or AST >3 to 8 x ULN or Withhold2,3

Hepatitis total bilirubin >1.5 to 3 x ULN

ALT or AST >8 x ULN or total Permanently discontinue3bilirubin >3 x ULN

Rash Grade 3 Withhold2,3

Grade 4 Permanently discontinue3

Withhold2,3

Suspected SCARs, including SJS For suspected SJS or TEN, do not

Severe cutaneous adverse or TEN resume unless SJS/TEN has beenreactions (SCARs) ruled out in consultation withappropriate specialist(s).

Confirmed SCARs, including SJS Permanently discontinueor TEN

Colitis Grade 2 or 3 Withold2,3

Recurrent Grade 3; Grade 4 Permanently discontinue32,3

Myositis/rhabdomyolysis Grade 2 or 3 Withhold

Recurrent Grade 3; Grade 4 Permanently discontinue3

Hypothyroidism may be managed

Hypothyroidism Grade 2, 3 or 4 with replacement therapy withouttreatment interruption.

Immune-related adverse Severity1 Tevimbra treatment modificationreaction

Withhold2

For Grade 3 or 4 that has improvedto Grade ≤2 and is controlled with

Hyperthyroidism Grade 3 or 4 anti-thyroid therapy, if indicatedcontinuation of Tevimbra may beconsidered after corticosteroidtaper. Otherwise, treatment shouldbe discontinued.

Grade 2 Consider withholding treatmentuntil controlled by HRT.

Withhold3

For Grade 3 or 4 that has improved

Adrenal insufficiency to Grade ≤2 and is controlled with

Grade 3 or 4 HRT, if indicated continuation of

Tevimbra may be considered aftercorticosteroid taper. Otherwise,treatment should be discontinued.3

Grade 2 Consider withholding treatmentuntil controlled by HRT.

Withhold2,3

For Grade 3 or 4 that has improved

Hypophysitis to Grade ≤2 and is controlled with

Grade 3 or 4 HRT, if indicated continuation of

Tevimbra may be considered aftercorticosteroid taper. Otherwise,treatment should be discontinued.3

Type 1 diabetes mellitus Withholdassociated with Grade ≥3 For Grade 3 or 4 that has improvedto Grade ≤2 with insulin therapy, if

Type 1 diabetes mellitus hyperglycaemia(glucose >250 mg/dl indicated continuation of Tevimbraor >13.9 mmol/l) or associated may be considered once metabolicwith ketoacidosis control is achieved. Otherwise,treatment should be discontinued.

Grade 2 (creatinine >1.5 to 3 x Withhold2,3baseline or >1.5 to 3 x ULN)

Nephritis with renal dysfunction Grade 3 (creatinine >3 x baseline Permanently discontinue3or >3 to 6 x ULN) or Grade 4(creatinine >6 x ULN)

Myocarditis Grade 2, 3 or 4 Permanently discontinue32,3

Neurological toxicities Grade 2 Withhold

Grade 3 or 4 Permanently discontinue3

Grade 3 pancreatitis or Grade 3 or Withhold2,3

Pancreatitis 4 serum amylase or lipase levelsincreased (>2 x ULN)

Grade 4 Permanently discontinue3

Other immune-related adverse Grade 3 Withhold2,3reactions Recurrent Grade 3; Grade 4 Permanently discontinue3

Immune-related adverse Severity1 Tevimbra treatment modificationreaction

Other adverse drug reactions

Consider pre-medication for

Grade 1 prophylaxis of subsequent infusionreactions.

Slow the rate of infusion by 50%.

Infusion-related reactions Interrupt infusion.

Grade 2 Resume infusion if resolved ordecreased to Grade 1, and slow rateof infusion by 50%.

Grade 3 or 4 Permanently discontinue

ALT = alanine aminotransferase, AST = aspartate aminotransferase, HRT= hormone replacement therapy, SJS= Stevens-Johnson syndrome, TEN = Toxic epidermal necrolysis, ULN = upper limit of normal1 Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for

Adverse Events Version 4.0 (NCI-CTCAE v4.0). Hypophysitis grade is in accordance with NCI-CTCAEv5.0.

2 Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper over at least1 month. Permanently discontinue if no complete or partial resolution within 12 weeks of initiatingcorticosteroids or inability to reduce prednisone to ≤10 mg/day (or equivalent) within 12 weeks of initiatingcorticosteroids.

3 Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper to ≤10 mg/day (or equivalent)over at least 1 month is recommended, except for pneumonitis, where initial dose of 2 to 4 mg/kg/day isrecommended.

The safety and efficacy of Tevimbra in patients aged below 18 years have not been established. Nodata are available.

No dose adjustment is needed for patients aged ≥65 years (see section 4.8).

No dose adjustment is needed for patients with mild or moderate renal impairment. Data from patientswith severe renal impairment are too limited to make dosing recommendations for this population (seesection 5.2).

No dose adjustment is needed for patients with mild or moderate hepatic impairment. Data frompatients with severe hepatic impairment are too limited to make dosing recommendations for thispopulation (see section 5.2).

Tevimbra is for intravenous use only. It is to be administered as an infusion and must not beadministered as an intravenous push or single bolus injection. For instructions on dilution of themedicinal 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 welltolerated, the subsequent infusions may be administered over a period of 30 minutes. The infusionshould be given via an intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or0.22 micron in-line or add-on filter.

The infusion of an initial dose of Tevimbra 400 mg should be delivered over 120 minutes (over90 minutes if it is used as subsequent treatment after the dose of 200 mg once every 3 weeks). If welltolerated, the second infusion may be administered over 60 minutes. If the second infusion is welltolerated, 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.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

When assessing the PD-L1 status of the tumour, it is important that a well validated methodology ischosen 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 ofimmune-related adverse reactions during Tevimbra therapy (see also Package Leaflet).

The prescriber must discuss the risks of immune-related adverse reactions during Tevimbra therapywith the patient.

Immune-related adverse reactions have been reported, including fatal cases, during treatment withtislelizumab (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 alsobeen reported after the last dose of tislelizumab. Immune-related adverse reactions affecting more thanone body system can occur simultaneously.

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or excludealternative aetiologies, including infection, should be ensured. Based on the severity of the adversereaction, tislelizumab should be withheld and corticosteroids administered (see section 4.2). Based onlimited data from clinical studies, administration of other systemic immunosuppressants can beconsidered in patients whose immune-related adverse reactions are not controlled with corticosteroiduse (see sections 4.2 and 4.8). Upon improvement to Grade ≤1, corticosteroid taper should be initiatedand continued over at least 1 month.

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

Immune-related pneumonitis, including fatal cases, has been reported in patients receivingtislelizumab. Patients should be monitored for signs and symptoms of pneumonitis. Patients withsuspected 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 treatmentmodifications as recommended in Table 1 (see section 4.2).

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. Liverfunction tests should be performed at baseline and periodically during treatment.

Patients with immune-related hepatitis should be managed according to the treatment modifications asrecommended in Table 1 (see section 4.2).

Immune-related skin reactions

Immune-related skin rash or dermatitis have been reported in patients receiving tislelizumab. Patientsshould be monitored for suspected skin reactions and other causes should be excluded. Based on theseverity of the skin adverse reactions, tislelizumab should be withheld or permanently discontinued asrecommended 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 monitoredfor signs or symptoms of SCARs (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions orprogressive skin rash) and other causes should be excluded. For suspected SCAR, tislelizumab shouldbe 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, frequently associated with diarrhoea, has been reported in patients treated withtislelizumab. 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 asrecommended in Table 1 (see section 4.2).

Immune-related endocrinopathies, including thyroid disorders, adrenal insufficiency, hypophysitis andtype 1 diabetes mellitus, have been reported in patients treated with tislelizumab. These may requiresupportive treatment depending on the specific endocrine disorder. Long-term hormone replacementtherapy (HRT) may be necessary in cases of immune-related endocrinopathies.

Patients with immune-related endocrinopathies should be managed according to the treatmentmodifications as recommended in Table 1 (see section 4.2).

Thyroid disorders

Thyroid disorders, including thyroiditis, hypothyroidism and hyperthyroidism, have been reported inpatients treated with tislelizumab. Patients should be monitored (at the start of treatment, periodicallyduring treatment and as indicated based on clinical evaluation) for changes in thyroid function andclinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with HRT withouttreatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically(see section 4.2).

Adrenal insufficiency has been reported in patients treated with tislelizumab. Patients should bemonitored for signs and symptoms of adrenal insufficiency. Monitoring of adrenal function andhormone levels should be considered. Corticosteroids and HRT should be administered as clinicallyindicated (see section 4.2).

Hypophysitis

Hypophysitis has been reported in patients treated with tislelizumab. Patients should be monitored forsigns and symptoms of hypophysitis/hypopituitarism. Monitoring of pituitary function and hormonelevels 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 withtislelizumab. Patients should be monitored for hyperglycaemia and other signs and symptoms ofdiabetes. Insulin should be administered for type 1 diabetes. In patients with severe hyperglycaemia orketoacidosis (Grade ≥3), tislelizumab should be withheld and anti-hyperglycaemic treatment should beadministered (see section 4.2). Treatment with tislelizumab may be resumed when metabolic control isachieved.

Immune-related nephritis with renal dysfunction

Immune-related nephritis with renal dysfunction has been reported in patients treated withtislelizumab. 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 thetreatment modifications as recommended in Table 1 (see section 4.2).

Other clinically important immune-related adverse reactions were reported with tislelizumab:myositis, myocarditis, arthritis, polymyalgia rheumatica, pericarditis, cystitis noninfective, immunethrombocytopenia, encephalitis, myasthenia gravis, Sjögren’s syndrome and Guillain-Barré syndrome(see section 4.8).

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

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 organtransplant recipients. The benefit of treatment with tislelizumab versus the risk of possible organrejection should be considered in these patients.

Haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving tislelizumab (seesection 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 andsymptoms of HLH. For suspected HLH, tislelizumab must be interrupted for diagnostic workup andtreatment for HLH initiated. If HLH is confirmed, administration of tislelizumab should bediscontinued.

Severe infusion-related reactions (Grade 3 or higher) have been reported in patients receivingtislelizumab (see section 4.8). Cases of anaphylaxis, including anaphylactic reaction and anaphylacticshock, have been reported in the post-marketing setting. Patients should be monitored for signs andsymptoms of infusion-related reactions.

Infusion-related reactions should be managed as recommended in Table 1 (see section 4.2).

Patients with any of the following conditions were excluded from clinical studies: baseline ECOGperformance status greater than or equal to 2; active brain or leptomeningeal metastases; activeautoimmune disease or history of autoimmune disease that may relapse; any condition requiringsystemic treatment with either corticosteroids (>10 mg/day prednisone or equivalent) or otherimmunosuppressants within the 14 days prior to study treatment; active or untreated HIV; untreatedhepatitis B or hepatitis C carriers; history of interstitial lung disease; administration of live vaccinewithin the 14 days prior to study treatment; infection requiring systemic therapy within the 14 daysprior to study treatment; history of severe hypersensitivity to another monoclonal antibody. In theabsence of data, tislelizumab should be used with caution in these populations after carefulconsideration 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 productcontains 16 mg sodium per 10 ml vial, equivalent to 0.8% of the WHO recommended maximum dailyintake 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 betaken 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 isequivalent to 4 mg in two 10 ml vials of a single infusion of Tevimbra. Polysorbates may causeallergic 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 monoclonalantibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug-metabolisingenzymes, inhibition or induction of these enzymes by co-administered medicinal products is notanticipated to affect the pharmacokinetics of tislelizumab.

The use of systemic corticosteroids and other immunosuppressants at baseline, before startingtislelizumab, 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 andefficacy of tislelizumab. However, systemic corticosteroids and other immunosuppressants can beused 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 withchemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

Tislelizumab should not be used in women of childbearing potential not using effective contraceptionunless the clinical condition of the woman requires treatment with tislelizumab. Women ofchildbearing 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.

There are no available data on the use of tislelizumab in pregnant women. Based on its mechanism ofaction, tislelizumab can cause foetal harm when administered to a pregnant woman.

Animal reproduction studies have not been conducted with tislelizumab. However, in murine modelsof pregnancy, blockade of PD-1/PD-L1 signalling has been shown to disrupt tolerance to the foetusand 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 requirestreatment with tislelizumab.

It is unknown whether tislelizumab is excreted in human milk. Its effects on breast-fednewborns/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 afterthe last dose of Tevimbra.

No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive anddevelopment toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dosetoxicity study, there were no notable effects in the male and female reproductive organs incynomolgus monkeys when tislelizumab was given at doses of 3, 10 or 30 mg/kg every 2 weeks for13 weeks (7 dose administrations) (see section 5.3).

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

The safety of tislelizumab as monotherapy is based on pooled data in 1952 patients across multipletumour 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%), andalanine 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 patientsexperienced adverse reactions leading to death. The adverse reactions leading to death werepneumonia (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 totislelizumab 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 patientsacross multiple tumour types who received 200 mg tislelizumab every 3 weeks, with the exception ofstudy BGB A317-315 where patients also received tislelizumab at a dose of 400 mg once every6 weeks as adjuvant treatment after neoadjuvant therapy and surgery. The most common adversereactions (≥ 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 reactionsleading 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% wereexposed to tislelizumab for 6 months or longer, and 31.9% were exposed for 12 months or longer.

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. Adversereactions are listed according to system organ class in MedDRA. Within each system organ class, theadverse reactions are presented in decreasing frequency. The corresponding frequency category foreach 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 beestimated from available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

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

Tislelizumab Tislelizumab plusmonotherapy chemotherapy

N = 1952 N = 1950

Frequency category Frequency category (All

Adverse reactions (All grades) grades)

Pneumonia1 Common* Very common*

Anaemia2 Very common Very common

Thrombocytopenia3 Very common* Very common*

Neutropenia4 Common Very common

Lymphopenia5 Common Very common

Haemophagocytic lymphohistiocytosis Not known Rare

Sjögren’s syndrome # Uncommon

Hypothyroidism6 Very common Very common

Hyperthyroidism7 Common Common

Thyroiditis8 Common Uncommon

Adrenal insufficiency9 Uncommon Uncommon

Hypophysitis10 Uncommon Uncommon

Hyperglycaemia11 Common Very common

Hyponatraemia12 Common Very common

Hypokalaemia13 Common Very common*

Diabetes mellitus14 Uncommon Common

Guillain-Barré syndrome Rare Rare

Encephalitis15 # Rare

Myasthenia gravis # Rare

Uveitis16 Uncommon Uncommon

Myocarditis17 Uncommon Common*

Pericarditis Uncommon Rare

Hypertension18 Common Common

Cough Very common Very common

Dyspnoea Common* Common*

Pneumonitis19 Common* Common*

Nausea Very common Very common

Diarrhoea20 Very common Very common

Stomatitis21 Common Common

Pancreatitis22 Uncommon Common

Colitis23 Uncommon Common

Coeliac disease Rare #

Hepatitis24 Common* Common*

Rash25 Very common Very common

Pruritus Very common Very common

Vitiligo26 Uncommon Uncommon

Erythema multiforme Uncommon Rare

Stevens-Johnson syndrome Rare #

Toxic epidermal necrolysis27 Not known* Not known*

Arthralgia Common Very common

Myalgia Common Common

Myositis28 Uncommon Uncommon*

Arthritis29 Uncommon Common

Nephritis30 Uncommon Uncommon

Cystitis noninfective31 Rare #

Fatigue32 Very common Very common

Pyrexia33 Very common Very common

Decreased appetite Very common* Very common

Aspartate aminotransferase increased Very common Very common

Alanine aminotransferase increased Very common Very common

Blood bilirubin increased34 Very common Very common

Blood alkaline phosphatase increased Common Common

Blood creatinine increased Common Very common

Infusion-related reaction35 Common Common1 Pneumonia includes preferred terms (PTs) of pneumonia, lower respiratory tract infection, lower respiratorytract infection bacterial, pneumonia bacterial, pneumonia fungal, pneumocystis jirovecii pneumonia,bronchopulmonary aspergillosis, candida pneumonia, pneumonia mycoplasmal, pneumonia staphylococcaland pneumonia viral.

2 Anaemia includes PTs of anaemia and haemoglobin decreased.3 Thrombocytopenia includes PTs of thrombocytopenia, platelet count decreased and immunethrombocytopenia.4 Neutropenia includes PTs of neutropenia and neutrophil count decreased.5 Lymphopenia includes PTs of lymphopenia, lymphocyte count decreased and lymphocyte percentagedecreased.6 Hypothyroidism includes PTs of hypothyroidism, anti-thyroid antibody increased, immune-mediatedhypothyroidism, thyroid hormones decreased, thyroxine free decreased, tri-iodothyronine free decreased,tri-iodothyronine decreased, primary hypothyroidism, central hypothyroidism and thyroxine decreased.

7 Hyperthyroidism includes PTs of blood thyroid stimulating hormone decreased, hyperthyroidism, immune-mediated hyperthyroidism, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased,and tri-iodothyronine increased.

8 Thyroiditis includes PTs of thyroiditis, autoimmune thyroiditis, immune-mediated thyroiditis, silentthyroiditis and thyroiditis subacute.

9 Adrenal insufficiency includes PTs of Addison's disease, adrenal insufficiency, glucocorticoid deficiency,immune-mediated adrenal insufficiency, primary adrenal insufficiency, and secondary adrenocorticalinsufficiency.

10 Hypophysitis includes PTs of hypophysitis and hypopituitarism.11 Hyperglycaemia includes PTs of hyperglycaemia and blood glucose increased.12 Hyponatraemia includes PTs of hyponatraemia and blood sodium decreased.13 Hypokalaemia includes PTs of hypokalaemia and blood potassium decreased.14 Diabetes mellitus includes PTs of diabetes mellitus, diabetic ketoacidosis, diabetic ketosis, ketoacidosis,type 1 diabetes mellitus and latent autoimmune diabetes in adults.15 Encephalitis includes the PT of immune-mediated encephalitis.16 Uveitis includes PTs of chorioretinitis, iridocyclitis, uveitis and iritis.17 Myocarditis includes PTs of myocarditis, immune-mediated myocarditis and autoimmune myocarditis.18 Hypertension includes PTs of hypertension, blood pressure increased and essential hypertension.19 Pneumonitis includes PTs of pneumonitis, immune-mediated lung disease, interstitial lung disease andorganising pneumonia.20 Diarrhoea includes PTs of diarrhoea and frequent bowel movements.21 Stomatitis includes PTs of stomatitis, mouth ulceration, oral mucosa erosion and aphthous ulcer.22 Pancreatitis includes PTs of, amylase increased, lipase increased, pancreatitis and pancreatitis acute.23 Colitis includes PTs of autoimmune colitis, colitis, colitis ulcerative and immune-mediated enterocolitis.24 Hepatitis includes PTs of hepatitis, drug-induced liver injury, hepatotoxicity, hepatic function abnormal,immune-mediated hepatitis, liver injury and autoimmune hepatitis.25 Rash includes PTs of rash, rash maculo-papular, eczema, rash erythematous, dermatitis, acute febrileneutrophilic dermatosis, autoimmune dermatitis, dermatitis allergic, dermatitis exfoliative, rash papular,urticaria, erythema, skin exfoliation, drug eruption, rash macular, psoriasis, rash pustular, dermatitisacneiform, rash pruritic, lichenoid keratosis, hand dermatitis, immune-mediated dermatitis, rash follicular,erythema nodosum and pemphigoid.

26 Vitiligo includes PTs of, leukoderma skin depigmentation, skin hypopigmentation and vitiligo.27 Post-marketing experience.28 Myositis includes PTs of myositis, rhabdomyolysis and immune-mediated myositis.29 Arthritis includes PTs of arthritis, polyarthritis and immune-mediated arthritis.30 Nephritis includes PTs of nephritis, focal segmental glomerulosclerosis, glomerulonephritis membranous,immune-mediated renal disorder, tubulointerstitial nephritis and immune-mediated nephritis.31 Cystitis noninfective includes PTs of cystitis noninfective and immune-mediated cystitis. Cases of immune-mediated cystitis have been reported in the post-marketing setting.

32 Fatigue includes PTs of fatigue, asthenia, malaise, physical deconditioning and lethargy.33 Pyrexia includes the PTs of body temperature increased and pyrexia.34 Blood bilirubin increased includes PTs of blood bilirubin increased, bilirubin conjugated increased, bloodbilirubin unconjugated increased and hyperbilirubinaemia.35 Infusion-related reaction includes PTs of anaphylactic reaction, chills, corneal oedema, dermatitis allergic,drug eruption, drug hypersensitivity, face oedema, gingival swelling, hypersensitivity, laryngealobstruction, laryngeal oedema, lip oedema, lip swelling, mouth swelling, pruritus allergic, rash, rasherythematous, rash macular, rash pruritic, rhinitis allergic, swelling face, tongue oedema, type Ihypersensitivity, urticaria, infusion-related reaction and infusion-related hypersensitivity reaction.

* Including fatal outcomes# Not reported in this pooled setting

The data below reflect information for significant adverse drug reactions for tislelizumab asmonotherapy in clinical studies. Details for the significant adverse reactions for tislelizumab whengiven in combination with chemotherapy are presented if clinically relevant differences were noted incomparison to tislelizumab monotherapy.

In patients treated with tislelizumab as monotherapy, immune-related pneumonitis occurred in 5.1% ofpatients, 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 wasinterrupted in 1.9% of patients. Pneumonitis resolved in 47.0% of patients.

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

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

In patients treated with tislelizumab as monotherapy, immune-related hepatitis occurred in 1.2% ofpatients, 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 wasinterrupted in 0.8% of patients for immune-related hepatitis. Hepatitis resolved in 60.9% of patients.

In patients treated with tislelizumab as monotherapy, immune-related skin adverse reactions occurredin 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 wasinterrupted 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).

In patients treated with tislelizumab as monotherapy, immune-related colitis occurred in 0.6% ofpatients, 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 to26.5 months), and the median duration from onset to resolution was 28.0 days (range: 9.0 days to26.7 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumabtreatment 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/rhabdomyolysisoccurred 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 to39.3 months), and the median duration from onset to resolution was 1.2 months (range: 5.0 days to5.2 months). Tislelizumab was permanently discontinued in 0.2% of patients and tislelizumabtreatment was interrupted in 0.5% of patients. Myositis/rhabdomyolysis resolved in 75.0% of patients.

Thyroid disorders

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 wasinterrupted in 0.6% of patients. Hypothyroidism resolved in 36.4% of patients.

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 to39.4 months). The median duration from onset to resolution was 1.4 months (range: 8.0 days to22.1 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumabtreatment was interrupted in 0.3% of patients. Hyperthyroidism resolved in 77.0% of patients.

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 to20.7 months). The median duration from onset to resolution was 2.0 months (range: 20.0 days to15.3 months). Tislelizumab was not permanently discontinued in any patient and tislelizumabtreatment was interrupted in 0.2% of patients. Thyroiditis resolved in 38.1% of patients.

In patients treated with tislelizumab as monotherapy, adrenal insufficiency occurred in 0.5% ofpatients, 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 to16.9 months). The median duration from onset to resolution was 1.9 months (range: 30.0 days to13.6 months). Tislelizumab was not permanently discontinued in any patient and tislelizumabtreatment 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% ofpatients.

The median time from first dose to onset of the event was 9.0 months (range: 22.0 days to16.2 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 notinterrupted 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% ofpatients, 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 to36.1 months). The median duration from onset to resolution was 22.0 days (range: 5.0 days to3.6 months). Tislelizumab was permanently discontinued in 0.2% of patients and tislelizumabtreatment was interrupted in 0.2% of patients. Type 1 diabetes mellitus resolved in 8.3% of patients.

In patients treated with tislelizumab as monotherapy, immune-related nephritis and renal dysfunctionoccurred 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 to12.1 months). The median duration from onset to resolution was 9.0 days (the same for 2 resolvedevents). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatmentwas interrupted in 0.1% of patients. Immune-related nephritis and renal dysfunction resolved in 50.0%of patients.

In patients treated with tislelizumab as monotherapy, immune-related myocarditis occurred in 0.8% ofpatients, 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 to33.6 months), and the median duration from onset to resolution was 1.2 months (range: 4.0 days to15.6 months). Tislelizumab was permanently discontinued in 0.4% of patients and tislelizumabtreatment 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 immunecheckpoint inhibitors which might also occur during treatment with tislelizumab: pancreatic exocrineinsufficiency.

In patients treated with tislelizumab as monotherapy, infusion-related reactions occurred in 3.0% ofpatients, including Grade 3 (0.1%) events. Tislelizumab was permanently discontinued in 0.1% ofpatients and tislelizumab treatment was interrupted in 0.1% of patients.

Cases of anaphylaxis, including anaphylactic reaction and anaphylactic shock, have been reported inthe post-marketing setting.

In patients treated with tislelizumab monotherapy, the proportion of patients who experienced a shiftfrom baseline to a Grade 3 or 4 laboratory abnormality was as follows: 0.1% for increasedhaemoglobin, pct. 4.4% for decreased haemoglobin, 0.9% for decreased leukocytes, 8.9% for decreasedlymphocytes, 0.2% for increased lymphocytes, 2.1% for decreased neutrophils, 1.3% for decreasedplatelets, 2.6% for increased alanine aminotransferase, 0.3% for decreased albumin, 2.7% forincreased alkaline phosphatase, pct. 4.8% for increased aspartate aminotransferase, 2.8% for increasedbilirubin, 1.9% for increased creatine kinase, 1.2% for increased creatinine, pct. 4.4% for increasedglucose, 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 whoexperienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 14.2% fordecreased haemoglobin, 23.3% for decreased leukocytes, 17.9% for decreased lymphocytes, 0.1% forincreased lymphocytes, 47.2% for decreased neutrophils, 14.1% for decreased platelets, 3.5% forincreased alanine aminotransferase, 0.5% for decreased albumin, 0.8% for increased alkalinephosphatase, 3.1% for increased aspartate aminotransferase, 2.0% for increased bilirubin, 2.3% forincreased creatine kinase, 1.8% for increased creatinine, 0.5% for decreased glucose, 1.2% forincreased glucose, 1.3% for increased potassium, 7.6% for decreased potassium, 0.3% for increasedsodium, 11.5% for decreased sodium.

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. Populationpharmacokinetic analysis showed that ADA status was a statistically significant covariate onclearance; however, the presence of treatment-emergent ADA against tislelizumab appears to have noclinically relevant impact on pharmacokinetics or efficacy.

Among ADA-evaluable patients receiving 200 mg once every 3 weeks monotherapy or in combinationwith chemotherapies (including adjuvant 400 mg once every 6 weeks in resectable NSCLC) thefollowing rates of adverse events (AEs) have been observed for the ADA-positive populationcompared to the ADA-negative population, respectively: Grade ≥3 AEs 52.5% vs. 42.1%, seriousadverse 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 totislelizumab treatment discontinuation 13.6% vs 13.5% (for combination therapy).

Patients who developed treatment-emergent ADAs tended to have overall poorer health and diseasecharacteristics at baseline which can confound the interpretation of the safety analysis. Available datado not allow firm conclusions to be drawn on possible patterns of adverse drug reactions.

No overall differences in safety were observed with tislelizumab as monotherapy or in combinationwith chemotherapy between patients aged <65 years and patients aged between 65 and 74 years. Datafor patients aged 75 years and above are too limited to draw conclusions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, ATC code: L01FF09.

Tislelizumab is a humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1,binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in

T-cells in in vitro cell-based assays.

Based on modelling and simulation of the exposure-response relationships for efficacy and safety fortislelizumab, there are no clinically significant differences in efficacy or safety between the doses of200 mg once every 3 weeks and 400 mg once every 6 weeks.

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 theefficacy and safety of neoadjuvant treatment with tislelizumab plus platinum-based doubletchemotherapy followed by adjuvant tislelizumab versus neoadjuvant treatment with placebo plusplatinum-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 8th) NSCLCwith ECOG PS of 0 or 1 and no known EGFR mutations or ALK gene translocations and confirmedeligibility for R0 resection with curative intent. Patients with Stage IIIB were not included in thestudy.

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of the patient population with Stage II - IIIA according to the8th 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 partor all of the lung or involve a mainstem bronchus regardless of distance to the carina, or invadesvisceral 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 eithercisplatin 75 mg/m2 or carboplatin AUC of 5 mg/mL/min and pemetrexed 500 mg/m2 orpaclitaxel 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 orcarboplatin 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 wasadministered every 6 weeks for up to 8 cycles.

Patients with non-squamous histology received pemetrexed while patients with squamous histologyreceived paclitaxel, whereby the choice of cisplatin or carboplatin was decided by the investigators forall patients. If indicated, patients received postoperative adjuvant radiation therapy prior to adjuvanttislelizumab or placebo. Administration of tislelizumab and chemotherapy continued until treatmentcompletion, disease progression, unacceptable AE, death, or patient and/or investigator’s decision todiscontinue 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. Thebaseline characteristics for all 453 randomised patients were: median age of 62 years (range 30 to80 years); 40% of patients were ≥65 years of age; 3.3% of patients were ≥75 years of age; 90.5% ofpatients 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 IIIAdisease; 57.8% had PD-L1 expression ≥1%.

There were 84.1% of patients in the tislelizumab in combination with platinum-containingchemotherapy 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 patientsrandomised 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 byreverse Kaplan-Meier methodology were 43.3 months (95% CI: 41.2, 44.6) in the tislelizumab armand 41.6 months (95% CI: 39.9, 43.8) in the placebo arm.

Table 3 Efficacy results in BGB-A317-3151

Tislelizumab arm Placebo arm(N=226) (N=227)

Event-Free Survival

Events, n (%) 72 (31.9) 98 (43.2)

Median (months) (95% CI) NR (50.3, NE) 30.6 (16.6, 45.3)

HR (95% CI)a 0.58 (0.43, 0.79)

Major Pathological Responsen (%) 127 (56.2) 34 (15)95% CIc (49.5, 62.8) (10.6, 20.3)

Difference, % (95% CI)d 41.1 (33.2, 49.1)p-valuee <0.0001

Overall Survival

Deaths, n (%) 52 (23.0) 70 (30.8)

Median (months) (95% CI) NR (NE, NE) NR (NE, NE)

HR (95% CI)a 0.65 (0.45, 0.93)p-valueb 0.0093

CI = confidence interval; HR = hazard ratio; NE = not estimable; NR = not reached

Patients without surgery or pathological results were considered as non-responders.

1The prespecified final analysis of MPR was based on the data with cut-off date of 20-Feb-2023 and theprespecified final analysis of EFS and OS was based on the data with cut-off date of 07-Mar-2025.

a Hazard ratio and 95% CIs were estimated using a stratified Cox regression model stratified by histology,disease stage and PD-L1 expression from interactive response technology (IRT).

b The p-value was calculated using a log-rank test stratified by histology, disease stage and PD-L1 expressionfrom IRT.

c The 95% CI was estimated using the Clopper-Pearson method.d Mantel-Haenszel common risk difference was estimated along with its 95% CIs constructed by a normalapproximation and Sato's variance estimator stratified by histology, disease stage and PD-L1 expressionfrom IRT.

e The p-value was obtained using the Cochran-Mantel-Haenszel method stratified by histology, disease stageand PD-L1 expression from IRT.

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

Events Median Hazard Ratio(%) (95% CI) (95% CI)tislelizumab arm 72 (31.9) NR (50.3, NE) 0.58 (0.43, 0.79)placebo arm 98 (43.2) 30.6 (16.6, 45.3)tislelizumab armplacebo arm

Time (Months)

Number At Risktislelizumab arm 226 196 176 161 152 143 136 128 123 121 117 101 92 69 49 39 21 17 2 0placeboarm 227 187 149 128 117 105 98 91 88 83 79 69 59 47 29 22 11 11 0 0

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

Events Median Hazard Ratio p-Value(%) (95% CI) (95% CI)tislelizumab arm 52 (23.0) NR (NE, NE) 0.65 (0.45, 0.93) 0.0093placebo arm 70 (30.8) NR (NE, NE)

Time (Months)

Number At Risktislelizumab arm 226 218 212 209 206 202 195 189 188 183 176 163 143 121 91 69 47 36 15 0placeboarm 227 214 207 199 186 180 172 165 161 157 148 131 117 98 73 51 34 26 9 0

Overall Survival Probability (%) Event-Free Survival Probability (%)

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 notevaluable/indeterminate) (tislelizumab arm [n=89; 39%] vs. placebo arm [n=84; 37%]). The EFS HRwas 0.53 (95% CI: 0.35, 0.79) in patients with PD-L1 ≥ 1% and 0.70 (95% CI: 0.43, 1.14) in patientswith 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 efficacyand safety of tislelizumab in combination with platinum-pemetrexed versus platinum-pemetrexedalone 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, ormetastatic non-squamous NSCLC.

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

A total of 334 patients were randomised (2:1) to receive tislelizumab 200 mg combined withpemetrexed 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 ofchemotherapy or tislelizumab combined with chemotherapy at the investigator’s discretion, patients inthe T+PP arm received tislelizumab 200 mg combined with pemetrexed 500 mg/m2 on a 3-week cycleuntil disease progression or unacceptable toxicity; patients in the PP arm received pemetrexed500 mg/m2 alone until disease progression or unacceptable toxicity, and those with disease progressionconfirmed by Independent Review Committee (IRC) were given the option to cross over to receivetislelizumab 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 Committeeon Cancer (AJCC), 7th edition of Cancer Staging Manual. PD-L1 expression was evaluated at a centrallaboratory 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 thesecond 6 months, then every 12 weeks.

The baseline characteristics for patients in study BGB-A317-304 were: median age 61 years (range: 25to 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% withbrain metastases. The characteristics of age, sex, ECOG PS, stage, smoking status, PD-L1 TC scoreand 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 theintent-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), showinga statistically significant improvement in PFS with T+PP compared with PP. The stratified hazardratio was 0.65 (95% CI: 0.47, 0.91; p = 0.0054) with a median PFS of 9.7 months with T+PP and7.6 months with PP. The median OS follow-up times by reverse Kaplan-Meier methodology were9.9 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 thoseof the interim analysis. At the final analysis, the median OS follow-up times by reverse Kaplan-Meiermethodology 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-L1expression ≥50%. Of these, 74 patients were in the tislelizumab plus chemotherapy group and36 patients were in the placebo plus chemotherapy group. Efficacy results of the patients with tumourcell PD-L1 expression ≥50% from the final analysis are shown in Table 4 and the Kaplan-Meier curvefor 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%

Endpoint Tislelizumab + Pemetrexed + Platinum

Pemetrexed + Platinum (n = 36)(n = 74)

PFS

Events, n (%) 33 (44.6) 22 (61.1)

Median PFS (months) (95% CI) 14.6 (11.5, NE) 4.6 (3.5, 9.7)

Stratified hazard ratioa (95% CI) 0.31 (0.18, 0.55)

OS

Deaths, n (%) 24 (32.4) 20 (55.6)

Median OS (months) (95% CI) NE (NE, NE) 13.1 (5.6, NE)

Stratified hazard ratioa (95% CI) 0.39 (0.22, 0.71)

Best overall response, n (%)b

ORRb, n (%) 52 (70.3) 11 (30.6)95% CIc (58.5, 80.3) (16.3, 48.1)

DoRb

Median DoR (months) (95% CI) NE (13.2, NE) 8.5 (3.3 NE)

PFS = progression-free survival; CI = confidence interval; OS = overall survival; ORR = objective responserate; DoR = duration of response; NE = not estimable.

Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyerand Crowley.a Hazard ratio was estimated from stratified Cox model with pemetrexed+platinum group as referencegroup and stratified by disease stage (IIIB versus IV).b PFS was based on IRC assessment, and ORR/DoR was based on the confirmed response by IRC.c 95% CI was calculated using Clopper-Pearson method.

Figure 3 Kaplan‑Meier plot of PFS in BGB‑A317‑304 in patients with PD-L1 ≥50%100 Events Median Hazard ratio(%) (95% CI) (95% CI)90 T+PP 33(44.6) 14.6(11.5-NE) 0.313[0.178- 0.547]

PP 22(61.1) 4.6(3.5-9.7)

T+PP0 PP0 3 6 9 12 15 18 21 24 27

Time (M onths)

No. at Risk

T+PP 74 64 53 45 36 21 9 3 2 0

PP 36 18 9 7 4 1 1 0 0 0

Figure 4 Kaplan-Meier plot of OS in BGB-A317-304 in patients with PD-L1 ≥50%

Events Median Hazard ratio(%) (95% CI) (95% CI)

T+PP 24 (32.4) NE (NE - NE) 0.39 [0.22 - 0.71]

PP 20 (55.6) 13.1 (5.6 - NE)

No. at risk Time (months)

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 andsafety of tislelizumab in combination with paclitaxel plus carboplatin or nab-paclitaxel pluscarboplatin versus of paclitaxel plus carboplatin alone as first-line treatment for chemotherapy-naïvepatients with locally advanced squamous NSCLC who were not candidates for surgical resection orplatinum-based chemoradiation or metastatic squamous NSCLC.

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

A total of 360 patients were randomised (1:1:1) to receive tislelizumab 200 mg combined withpaclitaxel 175 mg/m2 and carboplatin AUC 5 mg/ml/min (T+PC arm, N = 120), or tislelizumab200 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).

Overall survival probability (%) PPrrooggrreessssiioonn--FFrreeee SSuurrvviivvaall PPrroobbaabbiilliittyy((%%))

The treatment was administered on a 3-week cycle, until the patient completed administration of 4 to6 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 unacceptabletoxicity. Patients in the PC arm with disease progression were given the option to cross over to receivetislelizumab monotherapy on a 3-week cycle.

Randomisation was stratified by PD-L1 expression in tumour cells (TC) (<1% versus 1% to 49%versus ≥50%) and tumour staging (IIIB versus IV), as classified according to American Joint

Committee on Cancer (AJCC), 7th edition of Cancer Staging Manual. PD-L1 expression was evaluatedat a central laboratory using the Ventana PD-L1(SP263) assay that identified PD-L1 staining ontumour cells. Tumour assessments were conducted every 6 weeks for the first 6 months, then every9 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 PSof 0 and 76.4% with ECOG PS of 1; 33.9% diagnosed with stage IIIB and 66.1% with stage IV atbaseline; 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 treatmentarms.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by IRC per RECISTv1.1 in the ITT analysis which was to be tested sequentially in arms T+PC versus PC and arms T+nPCversus 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), showingstatistically significant improvements in PFS with tislelizumab in combination with paclitaxel andcarboplatin (T+PC arm) and tislelizumab in combination with nab-paclitaxel and carboplatin (T+nPCarm) 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 monthsin 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 inthe PC arm.

The final analysis (data cut-off date of 30-Sep-2020) showed the consistent results from the interimanalysis. At the final analysis, the median OS follow-up times by reverse Kaplan-Meier methodologywere 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 5, Figure 5 and Figure 6.

Table 5 Efficacy results in BGB-A317-307

Endpoint Tislelizumab + Tislelizumab + Paclitaxel +

Paclitaxel + nab-Paclitaxel + Carboplatin

Carboplatin Carboplatin (N = 121)(N = 120) (N = 119)

PFS

Events, n (%) 80 (66.7) 79 (66.4) 86 (71.1)

Median PFS (months) (95% 7.7 (6.7, 10.4) 9.6 (7.4, 10.8) 5.5 (4.2, 5.6)

CI)

Stratified hazard ratioa (95% 0.45 (0.33, 0.62) 0.43 (0.31, 0.60) -

CI)

OS

Deaths, n (%) 48 (40.0) 47 (39.5) 52 (43.0)

Median OS (months) (95% CI) 22.8 (19.1, NE) NE (18.6, NE) 20.2 (16.0, NE)

Stratified hazard ratio (95% CI) 0.68 (0.45, 1.01) 0.752 (0.50, 1.12) -

ORRb

ORR, n (%) 74 (61.7) 74 (62.2) 45 (37.2)95% CI (52.4, 70.4) (52.8, 70.9) (28.6, 46.4)

DoRb

Median DoR (months) (95% 13.2 (7.85, 18.79) 10.4 (8.34, 17.15) 4.8 (4.04, 5.72)

CI)

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

Figure 5 Kaplan-Meier plot of PFS in BGB-A317-307 by IRC

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

T+PC: Events (%) = 80 (66.7) Median (95% CI): 7.7 (6.7,10.4)

T+nPC: Events (%) = 79 (66.4) Median (95% CI): 9.6 (7.4,10.8)

PC: Events (%) = 86 (71.1) Median (95% CI): 5.5 (4.2,5.6)

HR (95% CI) T+PC vs. PC = 0.45 [0.33-0.62]

HR (95% CI) T+nPC vs. PC = 0.43 [0.31-0.60]

Number of patients still at risk Time (months)

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

Progression-free survival probability (%)

Figure 6 Kaplan-Meier plot of OS in BGB-A317-307

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

HR (95% CI) T+PC vs. PC = 0.68 [0.46-1.01]

HR (95% CI) T+nPC vs. PC = 0.75 [0.50-1.12]

T+PC: Events (%) = 48 (40.0) Median (95% CI): 22.8 (19.1,NE)

T+nPC: Events (%) = 47 (39.5) Median (95% CI): NE (18.6,NE)

PC: Events (%) = 52 (43.0) Median (95% CI): 20.2 (16.0,NE)

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 andprognostic subgroups, including PD-L1 expression <1%, 1 to 49% and ≥50% and disease stages IIIBand 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 efficacyand 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 priorplatinum-based regimen.

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

A total of 805 patients were randomised (2:1) ratio to receive tislelizumab 200 mg intravenously every3 weeks (N = 535) or docetaxel 75 mg/m2 intravenously every 3 weeks (N = 270). Randomisation wasstratified 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 andtislelizumab continued until disease progression, as assessed by investigator per RECIST v1.1, orunacceptable 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 wereconducted 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 ALKstatus; 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%. Allpatients had received prior therapy with a platinum-doublet regimen: 84.7% patients received oneprior 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% analysissets. At the prespecified interim analysis (data cut-off date 10-Aug-2020), a statistically significantimprovement 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 and11.9 months for the docetaxel arm. The median follow-up times by reverse Kaplan-Meiermethodology were 19.5 months in the tislelizumab arm and 17.0 months in the docetaxel arm. At thefinal analysis (data cutoff date 15-Jul-2021), a statistically significant improvement in OS wasobserved 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 and11.5 months for the docetaxel arm. The median follow-up time by reverse Kaplan-Meier methodologyat 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 ITTpopulation compared to the interim analysis.

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

Table 6 Efficacy results in BGB-A317-303

Endpoint Tislelizumab Docetaxel(N = 535) (N = 270)

OS

Deaths, n (%) 365 (68.2) 206 (76.3)

Median OS (months) (95% CI) 16.9 (15.24, 19.09) 11.9 (9.63, 13.54)

Hazard ratio (95% CI)a, b 0.66 (0.56, 0.79)

PFS

Events, n (%) 451 (84.3) 208 (77.0)

Median PFS (months) (95% CI) 4.2 (3.88, 5.52) 2.6 (2.17, 3.78)

Hazard ratioa (95% CI) 0.63 (0.53, 0.75)

ORR (%) (95% CI)c 20.9 (17.56, 24.63) 3.7 (1.79, 6.71)

DoR c

Median DoR (months) (95% CI) 14.7 (10.55, 21.78) 6.2 (4.11, 8.31)

OS = overall survival; CI = confidence interval; PFS = progression-free survival; ORR = objective responserate; DoR = duration of response.

Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyerand Crowley.a Hazard ratio was estimated from stratified Cox model with docetaxel group as reference group.b Stratified by stratification factors: histology (squamous versus non‑squamous), lines of therapy (secondversus third), and PD-L1 expression in tumour cells (≥25% PD-L1 score versus <25% PD-L1 score).c Confirmed by investigator.

Figure 7 Kaplan-Meier plot of OS in BGB-A317-303 (ITT Analysis Set)

Arm A (tislelizumab): n= 535, events= 365; Median 16.9, 95% CI: 15.24,19.09

Arm B (docetaxel): n=270, events= 206; Median 11.9, 95% CI: 9.63, 13.54

HR (95% CI): 0.66 (0.56 - 0.79)

Time (months)

Number of patients at risk

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

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

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

A317-303

Tislelizumab arm Docetaxel arm

N = 535 N = 270

PD‑L1 expression in tumour cells <25%, n 307 152

Events, n (%) 223 (72.6) 117 (77.0)

Median OS (months) (95% CI) 15.2 (13.4, 17.6) 12.3 (9.3, 14.3)

Hazard ratio a (95% CI) 0.79 (0.64, 0.99)

PD‑L1 expression in tumour cells ≥25%, n 227 115

Events, n (%) 141 (62.1) 86 (74.8)

Median OS (months) (95% CI) 19.3 (16.5, 22.6) 11.5 (8.2, 13.5)

Hazard ratio a (95% CI) 0.54 (0.41, 0.71)a Hazard ratio and its 95% CI were estimated from unstratified Cox model.

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 efficacyand safety of tislelizumab in combination with cisplatin or carboplatin plus etoposide versus placeboin combination with cisplatin or carboplatin plus etoposide as first-line treatment in patients withextensive-stage small cell lung cancer (ES-SCLC).

The study included patients with histologically or cytologically confirmed diagnosis of ES-SCLC whohad 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:

Survival probability

* Arm tislelizumab + chemotherapy: tislelizumab 200 mg plus carboplatin AUC 5 mg/mL/minor cisplatin 75 mg/m2 on Day 1 and etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 ofeach 21-day cycle for a maximum of 4 cycles.

* Arm placebo + chemotherapy: placebo plus carboplatin AUC 5 mg/mL/min or cisplatin75 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, lossof clinical benefit, unacceptable toxicity.

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

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

Demographics and baseline characteristics were generally balanced between the 2 treatment arms. Thebaseline characteristics for all 457 randomised patients were: median age of 62 years (range: 31 to78 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’schoice; 62.6% were current smokers; and 89.3% had disease Stage IV defined by AJCC 7th Edition.

At the time of the prespecified final analysis (data cut-off 19 April 2023), BGB-A317-312 showed astatistically significant improvement in OS for patients randomised to the tislelizumab pluschemotherapy 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 tislelizumabplus 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 resultswith the final analysis. The median OS follow-up times by reverse Kaplan-Meier methodology were39.8 months (95% CI: 36.2 to 41.4 months) in the tislelizumab plus chemotherapy arm and36.4 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 brainmetastases are too limited to draw conclusions on this population.

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

Tislelizumab + Placebo +

Chemotherapy Chemotherapy(N = 227) (N = 230)

Overall Survival

Deaths, n (%) 175 (77.1) 195 (84.8)

Median (months) (95% CI)a 15.5 (13.5, 17.1) 13.5 (12.1, 14.9)

Stratified Hazard Ratio (95% CI)b 0.78 (0.63, 0.95)

Progression-Free Survival

Events, n (%) 178 (78.4) 207 (90.0)

Median (months) (95% CI)a 4.7 (4.3, 5.5) 4.3 (4.2, pct. 4.4)

Stratified Hazard Ratio (95% CI)b 0.65 (0.53, 0.80)

Overall Response Ratec, (%) (95% CI)d 68.3 (61.8, 74.3) 61.7 (55.1, 68.0)

Median Duration of Response (Months)c (95% CI)a 4.3 (4.1, 5.6) 3.7 (3.0, 4.1)a Median was estimated using Kaplan-Meier method with 95% CIs estimated using the method of

Brookmeyer and Crowley with log-log transformation.b Hazard ratio and 95% CI were estimated using a Cox regression model stratified by ECOG performance

Tislelizumab + Placebo +

Chemotherapy Chemotherapy(N = 227) (N = 230)(1 vs 0) and platinum (Carboplatin vs Cisplatin) with placebo + chemotherapy as the reference group.

c Objective responses were confirmed per RECIST v1.1.d The 95% CI was estimated using the Clopper-Pearson method.

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

Events Median Hazard Ratio(%) (95% CI) (95% CI)tislelizumab + etoposide + platinum 175 (77.1) 15.5 (13.5, 17.1) 0.78 (0.63, 0.95)placebo + etoposide + platinum 195 (84.8) 13.5 (12.1, 14.9)tislelizumab + etoposide + platinumplacebo + etoposide + platinum

Time (Months)

Number At Risk:tislelizumab+ etoposide+ platinum 227 211 198 166 141 118 95 82 73 62 55 51 33 28 16 10 7 1 0placebo +etoposide 230 221 197 165 132 98 78 62 49 45 33 27 17 12 7 2 0 0 0+ platinum

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 studycomparing the efficacy and safety of tislelizumab plus platinum and fluoropyrimidine-basedchemotherapy versus placebo plus platinum and fluoropyrimidine-based chemotherapy as first-linetreatment in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma.

The study included only patients with histologically confirmed adenocarcinoma and with no priorsystemic therapy for advanced disease. Patients may have received prior neoadjuvant or adjuvanttherapy as long as it was completed and have no recurrence or disease progression for at least 6months.

Patients were enrolled regardless of their tumour PD-L1 expression level, which was evaluatedprospectively at a central laboratory by Tumour Area Positivity (TAP) score, which is defined as totalpercentage of tumor area (tumor and any desmoplastic stroma) covered by tumor cells with PD-L1membrane staining (any intensity), and tumor associated immune cells with PD-L1 staining (anyintensity), 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

Overall Survival Probability (%)

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 incombination 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 oftreatment, study therapy could be continued beyond two years if the investigator considered this to bein 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 for14 consecutive days, repeated every 3 weeks. Oxaliplatin was administered for up to 6 cyclesand capecitabine was administered as maintenance therapy at investigator’s discretion untildisease progression or unacceptable toxicity.

or

* cisplatin 80 mg/m² IV on day 1, and 5-FU 800 mg/m2/day by continuous IV infusion over24 hours daily on days 1 to 5, repeated every 3 weeks. Cisplatin and 5-FU were given for up to6 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 endpointswere PFS, ORR and DoR, as assessed by the investigator per RECIST v1.1, and health-related qualityof life (HRQoL).

Tumour assessment was performed approximately every 6 weeks during the first 48 weeks andthereafter approximately every 9 weeks.

A total of 997 patients were randomised to either the tislelizumab + chemotherapy arm (n = 501) orthe 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%) receivedoxaliplatin + 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 forthe 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 of1. A total of 79.9% patients had primary tumour location of stomach; 98.5% of patients had metastaticdisease 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 improvementin 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: 0.59to 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 alsodemonstrated 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 of7.2 months for tislelizumab + chemotherapy compared to 5.9 months for placebo + chemotherapy.

At prespecified final analysis, BGB-A317-305 demonstrated a statistically significant improvement forall 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 inthe 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 andin Figure 9.

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

Tislelizumab + chemotherapy Placebo + chemotherapy(n = 274) (n = 272)

Patients with PD-L1 score ≥ 5%

Median study follow-up (months)a 32.5 32.2

OS

Death, n (%) 192 (70.1) 219 (80.5)

Medianb (months) (95% CI) 16.4 (13.6, 19.1) 12.8 (12.0, 14.5)

Hazard ratioc (95% CI) 0.71 (0.58, 0.86)p-valuec,d 0.0003e

PFS

Disease progression or death, n(%) 189 (69.0) 216 (79.4)

Medianb (months) (95% CI) 7.2 (5.8, 8.4) 5.9 (5.6, 7.0)

Hazard ratioc (95% CI) 0.68 (0.56, 0.83)

ORR (%) (95% CI) 51.5 (45.4, 57.5) 42.6 (36.7, 48.8)

OS = overall survival; CI = confidence interval; PFS = progression-free survival; ORR = objective response rate.

a Median follow-up time was estimated by the reverse Kaplan-Meier method.b Medians were estimated using Kaplan-Meier method with 95% CIs estimated using the method of

Brookmeyer and Crowley.c Stratified by regions (east Asia versus US, Europe) and peritoneal metastasis.d One-sided p-value from stratified log-rank test.e Nominal p-value.

Figure 9 Kaplan-Meier plot of OS in BGB-A317-305 patients with PD-L1 TAP score ≥ 5%(final analysis)1.10. 00.09. 9

TA+rCm: An =: n2 7=4 ,2 e7v4e n, tesv =e n1t9s2 =, m19ed2i a, nM: 1e6d.i4an, 9:156%.4 C ,I 9 153%.6 ,C 1I9 1.13). 6 - 19.10.08. 8 PA+rCm: Bn =: n2 7=2 2, 7ev2e ,n tesv =en 2t1s9 =, m21e9di a, nM: e1d2i.a8n, :9152%.8 C , I9 152%.0 C, 1I4 1.52). 0 - 14.50.07. 7

HR (95% CI) : 0.71 (0.58 - 0.86)

HR (95% CI): 0.71 (0.58, 0.86)0.06. 60.05. 50.04. 40.03. 30.02. 20.01. 10.00. 00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

TTimimee ( m(Monotnhtsh) s)

NNumumbebre ro fo pf aPtiaetnietsn atst raits kR isk:

T imTeim: e 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

ArmT A+C 274 263 247 228 199 178 156 145 133 120 109 102 97 84 68 50 38 34 27 19 14 9 7 3 1 0

ArmP +BC 272 261 236 215 190 168 148 120 99 83 69 59 53 51 39 29 23 16 14 9 7 3 2 1 0 0

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 ofperitoneal metastasis.

SSuurrvviivvaall pPrroobbaabbiilliittyy

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 comparethe efficacy of tislelizumab in combination with platinum-based chemotherapy versus placebo incombination with platinum-based chemotherapy in patients with unresectable, locally advancedrecurrent 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, thearchival/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 totalpercentage 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 stainingat 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. Atreatment-free interval of at least 6 months was required if the patient had received priorneoadjuvant/adjuvant therapy with platinum-based chemotherapy.

The study excluded patients who had evidence of fistula or complete oesophageal obstruction notamenable to treatment.

Randomisation was stratified by geographical region (Asia [excluding Japan] versus Japan versus restof 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 incombination with investigator’s choice of chemotherapy (ICC) on a 21-day cycle. The chemotherapydoublet regimen consisted of:

* platinum (cisplatin [60 to 80 mg/m2 IV on day 1] or oxaliplatin [130 mg/m2 IV on day 1]) and afluoropyrimidine (5-FU [750 to 800 mg/m2 IV on days 1 to 5] or capecitabine [1000 mg/m2orally 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 or2]) and paclitaxel (175 mg/m2 IV on day 1).

Patients were treated with tislelizumab in combination with chemotherapy or placebo in combinationwith chemotherapy until disease progression, as assessed by the investigator per RECIST version 1.1or unacceptable toxicity. After 24 months of treatment, study therapy could be continued beyond twoyears if the investigator considered this to be in the best interest of the patient based on an assessmentof clinical benefit and potential risks.

The tumour assessments were conducted every 6 weeks for the first 48 weeks, and every 9 weeksthereafter.

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) andduration of response (DoR) as assessed by the investigator per RECIST v1.1, OS in the PD-L1positive (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 patientshad 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 and78.2% Asian. 87.7% had metastatic disease at study entry and 12.3% had locally advanced disease. Allpatients had histological confirmation of squamous cell carcinoma. Baseline ECOG performancestatus 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 astatistically 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 thetislelizumab 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) showedconsistent 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 and43.8 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 10and Figure 10.

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

Endpoint Tislelizumab + Placebo +chemotherapy chemotherapy(n = 172) (n = 186)

OS

Deaths, n (%) 128 (74.4) 151 (81.2)

Median (months) (95% CI) 19.1 (16.1, 24.1) 10.0 (8.6, 11.9)

HR (95% CI)a 0.62 (0.49, 0.79)p-valueb < 0.0001

PFS

Events, n (%) 119 (69.2) 153 (82.3)

Median (months) (95% CI) 8.2 (7.0, 9.8) 5.5 (4.3, 6.4)

HR (95% CI)a 0.50 (0.39, 0.65)p-valueb < 0.0001

ORR % (95% CI)c 64.0 (56.3, 71.1) 36.0 (29.1, 43.4)

OS = overall survival; CI = confidence interval; HR = hazard ratio; PFS = progression-free survival;

ORR = objective response ratea Based on a stratified Cox regression model.b One-sided nominal p-value from a stratified log rank test.c Exact Clopper-Person-2-sided confidence interval.

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)1.0

Tislelizumab + Chemotherapy : n = 172 , Events = 128 Median : 19.1 , 95% CI 16.1 - 24.10.9 Placebo + Chemotherapy : n = 186 , Events = 151 Median : 10.0 , 95% CI 8.6 - 11.90.8 HR (95% CI) : 0.62 (0.49 - 0.79)0.70.60.50.40.30.20.10.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60

Time (Months)

Number of Patients at Risk:

Time: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60

Tislelizumab+Chemotherapy 172 167 159 146 140 127 116 107 98 86 80 76 70 60 55 50 48 46 40 37 29 25 21 15 12 6 4 3 2 1 0

Placebo+Chemotherapy 186 181 159 142 113 89 74 69 64 55 50 43 39 35 32 30 28 24 22 22 20 16 13 11 7 5 1 1 0 0 0

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 theefficacy of tislelizumab versus chemotherapy in patients with unresectable, recurrent, locally advancedor metastatic OSCC who progressed on or after prior systemic treatment. Patients were enrolledregardless of their tumour PD-L1 expression level. Where available, the archival/fresh tumour tissuespecimens taken were retrospectively tested for PD-L1 expression status. PD-L1 expression wasevaluated at a central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1staining on both tumour and tumour-associated immune cells.

The study excluded patients with prior anti-PD-1/PD-L1 inhibitor treatment and tumour invasion intoorgans 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 (paclitaxelversus docetaxel versus irinotecan). The choice of ICC was determined by the investigator beforerandomisation.

Patients were randomised (1:1) to receive tislelizumab 200 mg every 3 weeks or investigator’s choiceof 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 ona 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 theinvestigator per RECIST version 1.1 or unacceptable toxicity.

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

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

Survival Probability≥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 and75% with ECOG PS of 1. Ninety-five percent of the study population had metastatic disease at studyentry. 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 significantimprovement in OS for patients randomised to the tislelizumab arm as compared to the ICC arm. Thestratified HR was 0.70 (95% CI: 0.57, 0.85; 1-sided p-value of 0.0001), with a median OS of 8.6months (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 thetislelizumab arm and 21.1 months in the ICC arm.

An updated analysis with additional 24 months follow-up after the prespecified final analysis showedconsistent 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 11 and Figure 11.

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

Endpoint Tevimbra Chemotherapy(N = 256) (N = 256)

OS

Deaths, n (%) 233 (91.0) 233 (91.0)

Median (months)a (95% CI) 8.6 (7.5, 10.4) 6.3 (5.3, 7.0)

Hazard ratio (95% CI)b 0.71 (0.59, 0.86)p-valuec p = 0.0002

PFS assessed by investigatord

Disease progression or death, n (%) 229 (89.5) 181 (70.7)

Median (months) (95% CI) 1.6 (1.4, 2.7) 2.1 (1.5, 2.7)

Hazard ratio (95% CI) 0.82 (0.67, 1.01)

ORR with confirmation by investigatord

ORR (%) (95% CI) 15.2 (11.1, 20.2) 6.6 (3.9, 10.4)

Median duration of response with 11.3 (6.5, 14.4) 6.3 (2.8, 8.5)confirmation by investigator (months)(95% CI)

OS = overall survival; CI = confidence interval; PFS = progression-free survival; ORR = objective responseratea Estimated using Kaplan-Meier method.b Based on Cox regression model including treatment as covariate, and stratified by baseline ECOG statusand investigator’s choice of chemotherapy.c Nominal one-sided p-value based on a log-rank test stratified by ECOG performance status andinvestigator’s choice of chemotherapy.d Based on ad hoc analysis.

Figure 11 Kaplan-Meier plot of OS in BGB-A317-302 (ITT analysis set) - updated analysis

Nominal one-sided p-value is based on a log-rank test stratified by ECOG performance status and investigator’s choice of chemotherapy.

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 HRfor OS was 0.54 (95% CI: 0.36 to 0.79. The median survival was 10.2 months (95% CI: 8.5 to14.5 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.

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 tocompare the efficacy and safety of tislelizumab in combination with gemcitabine and cisplatin versusplacebo in combination with gemcitabine and cisplatin as first-line treatment in patients with recurrentor metastatic NPC.

Patients were treatment-naive for recurrent or metastatic NPC. A treatment-free interval of at least 6months was required if the patient had received prior neoadjuvant chemotherapy, adjuvantchemotherapy, radiotherapy, or chemoradiotherapy with curative intent for nonmetastatic disease. Thestudy excluded patients with local recurrence suitable for curative surgery or radiotherapy, andpatients 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 incombination with cisplatin 80 mg/m2 on Day 1 plus gemcitabine 1 g/m2 on Day 1 and Day 8 of each21-day cycle for 4 to 6 cycles. Randomised patients were stratified by gender and liver metastasisstatus.

Tislelizumab or placebo was administered until disease progression or unacceptable toxicity. Patientsin 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 includedoverall survival (OS), PFS as assessed by the investigator, objective response rate (ORR) and durationof response (DoR) as assessed by the IRC.

A total of 263 patients were randomised to receive either tislelizumab in combination withgemcitabine 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 to74 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 currentor former smokers. 95.1% of the study population had metastatic disease at randomisation, withhistological 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-A317-309demonstrated a statistically significant improvement in PFS for patients randomised to tislelizumab incombination with gemcitabine and cisplatin arm compared with the placebo plus gemcitabine andcisplatin arm. The stratified HR was 0.52 (95% CI: 0.38, 0.73; 1 sided p-value of < 0.0001), with amedian PFS of 9.2 months in the tislelizumab plus chemotherapy arm compared to 7.4 months in theplacebo plus chemotherapy arm.

An updated analysis (data cut-off date of 08-Dec-2023) showed consistent efficacy results with theinterim analysis (Table 12 and Figure 12). At this time, 52.3% of patients in the control arm hadcrossed 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 theplacebo 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

Endpoint Tislelizumab + Placebo +

Chemotherapy Chemotherapy(N=131) (N=132)

PFS by IRC

Events, n (%) 95 (72.5) 106 (80.3)

Median PFS (months) (95% CI)a 9.6 (7.6, 11.6) 7.4 (5.6, 7.6)

Stratified Hazard Ratio (95% CI)b 0.53 (0.39, 0.71)

OS

Deaths, n (%) 55 (42.0) 64 (48.5)

Median (months) (95% CI)a 45.3 (33.4, NE) 31.8 (25.0, NE)

Stratified Hazard Ratio (95% CI)b 0.73 (0.51, 1.05)

Abbreviations: NE = not estimable; OS = overall survival; CI = confidence interval; PFS = progression-freesurvival.a Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of

Brookmeyer and Crowley.b Stratified by gender (male versus female) and liver metastases status (with versus without).

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

Analysis

* Chemotherapy = Gemcitabine + Cisplatin.

The European Medicines Agency has waived the obligation to submit the results of studies withtislelizumab in all subsets of the paediatric population in the treatment of malignant neoplasms (exceptcentral nervous system, haematopoietic and lymphoid tissue) (see section 4.2 for information onpaediatric use).

The pharmacokinetics (PK) of tislelizumab were assessed for Tevimbra both as monotherapy and incombination with chemotherapy.

The PK of tislelizumab were characterised using population PK analysis with concentration data from2596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every2 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 onceevery 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately2-fold.

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

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

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

Based on population PK analysis, the clearance of tislelizumab was 0.153 l/day with an inter-individual variability of 26.3% and the geometrical mean terminal half-life was approximately23.8 days with a coefficient variation (CV) of 31%.

At the dosing regimens of 0.5 mg/kg to 10 mg/kg once every 2 or 3 weeks (including 200 mg onceevery 3 weeks and at 400 mg once every 6 weeks), the PK of tislelizumab were observed to be linearand the exposure was dose proportional.

The effects of various covariates on tislelizumab PK were assessed in population PK analyses. Thefollowing factors had no clinically relevant effect on the exposure of tislelizumab: age (range 18 to90 years), weight (range 32 to 130 kg), gender, race (White, Asian and other), mild to moderate renalimpairment (creatinine clearance [CLCr] ≥30 ml/min), mild to moderate hepatic impairment (totalbilirubin ≤3 times ULN and any AST), and tumour burden.

No dedicated studies of tislelizumab have been conducted in patients with renal impairment. In thepopulation PK analyses of tislelizumab, no clinically relevant differences in the clearance oftislelizumab were found between patients with mild renal impairment (CLCr 60 to 89 ml/min,

N = 1 046) or moderate renal impairment (CLCr 30 to 59 ml/min, n = 320) and patients with normalrenal function (CLCr ≥90 ml/min, n = 1 223). Mild and moderate renal impairment had no effect on theexposure of tislelizumab (see section 4.2). Based on the limited number of patients with severe renalimpairment (n = 5), the effect of severe renal impairment on the pharmacokinetics of tislelizumab isnot conclusive.

No dedicated studies of tislelizumab have been conducted in patients with hepatic impairment. In thepopulation PK analyses of tislelizumab, no clinically relevant differences in the clearance oftislelizumab 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 ofpatients with severe hepatic impairment (bilirubin >3 x ULN and any AST, n = 2), the effect of severehepatic impairment on the pharmacokinetics of tislelizumab is unknown.

In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration atdoses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations), no apparenttreatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every2 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 conductedwith tislelizumab.

No studies have been performed to assess the potential of tislelizumab for carcinogenicity orgenotoxicity.

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 medicinalproducts except those mentioned in section 6.6.

Unopened vial3 years.

Once opened, the medicinal product should be diluted and infused immediately (see section 6.6 forinstructions 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 beendemonstrated for 10 days (240 hours) at 2 °C to 8 °C. The 10 days (240 hours) include storage of thediluted 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. Thediluted 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 stopperwith 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 aseptictechnique.

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. Theconcentrate is a clear to slightly opalescent, colourless to slightly yellowish solution. Do not usea 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 asyringe 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 rangingfrom 2 to 5 mg/ml. Mix diluted solution by gentle inversion to avoid foaming or excessiveshearing of the solution.

* Administer the diluted Tevimbra solution by infusion through an intravenous administration linewith a sterile, non-pyrogenic, low-protein-binding 0.2 micron or 0.22 micron in-line or add-onfilter 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 welltolerated, subsequent infusions may be administered over 30 minutes.

The infusion of an initial dose of Tevimbra 400 mg should be delivered over 120 minutes (over90 minutes if it is used as subsequent treatment after the dose of 200 mg once every 3 weeks). Ifwell tolerated, the second infusion may be administered over 60 minutes. If the second infusionis 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.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

BeOne Medicines Ireland Limited10 Earlsfort Terrace

Dublin 2

D02 T380

Ireland

Tel. +353 1 566 7660

E-mail: beone.ireland@beonemed.com

EU/1/23/1758/001-002

Date of first authorisation: 15 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.