Tislelizumab

Tislelizumab is an Fc-engineered, humanised immunoglobulin G4 (IgG4) variant monoclonal antibody against programmed cell death protein 1 (PD-1), produced in recombinant Chinese hamster ovary cells. PD-1 is an inhibitory receptor on T cells. Some tumours switch on its ligands, PD-L1 and PD-L2, to hold back the T-cell attack, and tislelizumab blocks this checkpoint.

Mechanism of Action

• PD-1 binding: tislelizumab binds the extracellular domain of human PD-1 and competitively blocks both PD-L1 and PD-L2.
• Restored T-cell activity: when PD-L1 or PD-L2 bind PD-1, T-cell proliferation and cytokine production are inhibited. By preventing this, tislelizumab removes PD-1-mediated negative signalling and, in cell-based assays, increased the functional activity of T cells.
• Preclinical activity: tumour growth was reduced in xenograft models and in a human PD-1 transgenic mouse model.
• Immunogenicity: treatment-emergent anti-drug antibodies were found in 21.1% of 3,614 evaluable patients, and neutralising antibodies in 0.9%. They had no clinically relevant effect on pharmacokinetics or efficacy.

Pharmacokinetics

• Population analysis: the data come from 2,596 patients with advanced cancer given 0.5–10 mg/kg every 2 weeks, 2.0 or 5.0 mg/kg every 3 weeks, or 200 mg every 3 weeks. Ninety per cent of steady state is reached about 84 days (12 weeks) after 200 mg every 3 weeks, with roughly 2-fold accumulation.
• Absorption: it is given intravenously, so it is immediately and completely bioavailable.
• Distribution: the steady-state volume of distribution is 6.42 L, typical of antibodies with limited distribution.
• Metabolism: it is expected to be broken down into small peptides and amino acids by catabolic pathways, not by cytochrome P450 enzymes.
• Elimination: clearance is 0.153 L/day (inter-individual variability 26.3%) and the geometric mean terminal half-life is about 23.8 days (coefficient of variation 31%).
• Linearity: pharmacokinetics are linear and dose-proportional from 0.5 to 10 mg/kg every 2 or 3 weeks, including 200 mg every 3 weeks and 400 mg every 6 weeks.
• Special populations: age (18–90 years), body weight (32–130 kg), sex, race, mild or moderate renal impairment (creatinine clearance of at least 30 mL/min), mild or moderate hepatic impairment (total bilirubin up to 3 times the upper limit of normal with any AST) and tumour burden had no clinically relevant effect on exposure. No dedicated renal impairment studies were done, but clearance did not differ between patients with mild (60–89 mL/min) or moderate (30–59 mL/min) impairment and those with normal kidney function.

Tislelizumab is used in adults, as follows.

• Resectable non-small cell lung cancer (NSCLC): in combination with platinum-containing chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment, in patients at high risk of recurrence (the selection criteria are in section 5.1 of the SmPC).
• First-line non-squamous NSCLC: in combination with pemetrexed and platinum-containing chemotherapy, in patients whose tumours have PD-L1 expression on at least 50% of tumour cells and no EGFR or ALK mutations, who have locally advanced disease and are not candidates for surgical resection or platinum-based chemoradiation, or who have metastatic disease.
• First-line squamous NSCLC: in combination with carboplatin and either paclitaxel or nab-paclitaxel, in patients with locally advanced disease who are not candidates for surgical resection or platinum-based chemoradiation, or with metastatic disease.
• Previously treated NSCLC: as monotherapy in locally advanced or metastatic NSCLC after prior platinum-based therapy. Patients with EGFR-mutant or ALK-positive tumours should also have received targeted therapies first.
• Small cell lung cancer (SCLC): first-line treatment of extensive-stage disease, in combination with etoposide and platinum chemotherapy.
• Gastric or gastro-oesophageal junction (G/GEJ) adenocarcinoma: first-line treatment of HER2-negative, locally advanced unresectable or metastatic disease, in combination with platinum and fluoropyrimidine-based chemotherapy, when the tumour expresses PD-L1 with a tumour area positivity (TAP) score of at least 5%.
• Oesophageal squamous cell carcinoma (OSCC): first-line treatment of unresectable, locally advanced or metastatic disease, in combination with platinum-based chemotherapy, when the tumour expresses PD-L1 with a TAP score of at least 5%. As monotherapy, it is also used in unresectable, locally advanced or metastatic OSCC after prior platinum-based chemotherapy.
• Nasopharyngeal carcinoma (NPC): first-line treatment of recurrent disease not amenable to curative surgery or radiotherapy, or of metastatic disease, in combination with gemcitabine and cisplatin.

• Hypersensitivity to tislelizumab or to any of the excipients.

The frequencies below come from pooled data on 1,952 patients given tislelizumab alone (200 mg every 3 weeks) and 1,950 patients given it with chemotherapy. The most common reactions (20% or more) on monotherapy were anaemia (27.7%), raised aspartate aminotransferase (24.7%), fatigue (24.6%) and raised alanine aminotransferase (22.0%). With chemotherapy they were neutropenia (71.6%), anaemia (67.2%), thrombocytopenia (48.7%), nausea (43.3%), fatigue (40.8%), decreased appetite (40.1%), raised alanine aminotransferase (30.6%), raised aspartate aminotransferase (30.3%), rash (21.4%) and diarrhoea (20.3%).

Very common (≥1/10): anaemia, thrombocytopenia, hypothyroidism, cough, nausea, diarrhoea, rash, pruritus, fatigue, pyrexia, decreased appetite, raised aspartate aminotransferase, alanine aminotransferase and blood bilirubin. With chemotherapy also: pneumonia, neutropenia, lymphopenia, hyperglycaemia, hyponatraemia, hypokalaemia, arthralgia and raised blood creatinine.

Common (≥1/100 to <1/10): hyperthyroidism, hypertension, dyspnoea, pneumonitis, stomatitis, hepatitis, myalgia, raised blood alkaline phosphatase and infusion-related reaction; on monotherapy also pneumonia, neutropenia, lymphopenia, thyroiditis, hyperglycaemia, hyponatraemia, hypokalaemia, arthralgia and raised blood creatinine; with chemotherapy also diabetes mellitus, myocarditis, pancreatitis, colitis and arthritis.

Uncommon (≥1/1,000 to <1/100): adrenal insufficiency, hypophysitis, uveitis, vitiligo, nephritis and myositis; on monotherapy also diabetes mellitus, myocarditis, pericarditis, pancreatitis, colitis, erythema multiforme and arthritis; with chemotherapy also thyroiditis, Sjögren’s syndrome and the myocarditis-myositis-myasthenia gravis overlap syndrome.

Rare (≥1/10,000 to <1/1,000): Guillain-Barré syndrome; on monotherapy also coeliac disease, Stevens-Johnson syndrome and non-infective cystitis; with chemotherapy also haemophagocytic lymphohistiocytosis, encephalitis, myasthenia gravis, pericarditis and erythema multiforme.

Not known: toxic epidermal necrolysis (post-marketing reports, some fatal); on monotherapy also haemophagocytic lymphohistiocytosis.

Serious reactions of note: immune-related reactions are the main concern. On monotherapy, immune-related pneumonitis occurred in 5.1% of patients (more often in NSCLC, 8.3%, and after prior chest radiotherapy, 8.4% against 3.6%), hepatitis in 1.2%, skin reactions in 12.6%, colitis in 0.6%, myositis or rhabdomyolysis in 0.8%, myocarditis in 0.8% and nephritis in 0.2%. Hypothyroidism occurred in 13.8%, hyperthyroidism in 5.1%, thyroiditis in 1.1%, adrenal insufficiency in 0.5%, hypophysitis in 0.3% and type 1 diabetes mellitus in 0.6%. Infusion-related reactions occurred in 3.0%, and anaphylaxis has been reported after marketing. Reactions leading to death occurred in 1.0% of patients on monotherapy, mainly pneumonia (0.61%), and in 1.3% of those given chemotherapy, mainly pneumonia (0.50%), pneumonitis (0.30%), dyspnoea (0.20%) and myocarditis (0.20%). As with other checkpoint inhibitors, pancreatic exocrine insufficiency might also occur. In patients aged 65–74 safety was no different from younger patients; data at 75 and over are too limited.

No formal pharmacokinetic interaction studies have been done. Tislelizumab is a monoclonal antibody cleared by catabolism and is not metabolised by cytochrome P450 or other drug-metabolising enzymes, so inhibition or induction of these enzymes by other medicines is not expected to affect it.

• Systemic corticosteroids and other immunosuppressants before starting: these should be avoided at baseline, except low-dose corticosteroid (10 mg/day prednisone or equivalent), because they may interfere with the pharmacodynamic activity and efficacy of tislelizumab.
• Corticosteroids after starting: systemic corticosteroids and other immunosuppressants can be used to treat immune-related adverse reactions.
• Corticosteroids with chemotherapy: they can be used as pre-medication when tislelizumab is combined with chemotherapy, for anti-emetic prophylaxis or to ease chemotherapy-related reactions.

Treatment must be started and supervised by a physician experienced in cancer treatment. Tislelizumab is given by intravenous infusion only; it must never be given as an intravenous push or bolus. Where an indication depends on PD-L1 expression, the tumour is tested with a CE-marked in vitro diagnostic test for that purpose; if none is available, another validated test is used.

Recommended Dose

• Monotherapy: 200 mg once every 3 weeks, or 400 mg once every 6 weeks.
• With chemotherapy: 200 mg once every 3 weeks, or 400 mg once every 6 weeks. On days when both are given, tislelizumab goes first. Chemotherapy doses and corticosteroid pre-medication follow the chemotherapy SmPC.
• Resectable NSCLC: neoadjuvant tislelizumab 200 mg every 3 weeks with chemotherapy for 3 or 4 cycles (or until progression that rules out surgery, or unacceptable toxicity), then adjuvant tislelizumab 400 mg every 6 weeks as monotherapy for up to 8 cycles (or until recurrence, metastasis or unacceptable toxicity).
• Duration: otherwise until disease progression or unacceptable toxicity.
• Dosing interval: modelling shows no clinically significant difference in efficacy or safety between 200 mg every 3 weeks and 400 mg every 6 weeks.

Infusion

• 200 mg: the first infusion runs over 60 minutes; if it is well tolerated, later infusions run over 30 minutes.
• 400 mg: the first infusion runs over 120 minutes (90 minutes if it follows treatment with 200 mg every 3 weeks). If well tolerated, the second runs over 60 minutes, and if that is well tolerated, later infusions run over 30 minutes.
• Line and filter: the infusion is given through a line with a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on filter. No other medicine is mixed or given through the same line.
• Dilution: the concentrate is diluted before use (SmPC section 6.6) in sodium chloride 9 mg/mL (0.9%) solution for infusion.

Dose Adjustments for Side Effects

Dose reductions are not recommended, alone or in combination. Tislelizumab is instead withheld or permanently stopped according to safety and tolerability; Table 1 in section 4.2 of the SmPC gives the action for each type and grade of reaction. For a suspected immune-related reaction, the cause is confirmed and infection excluded, tislelizumab is withheld and corticosteroids are started according to severity. Other systemic immunosuppressants can be considered if corticosteroids do not control the reaction. Once the reaction improves to grade 1 or less, corticosteroids are tapered over at least 1 month.

Special Populations

• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.
• Elderly: no dose adjustment for patients aged 65 and over.
• Renal impairment: no adjustment in mild or moderate impairment; data in severe impairment are too limited for a dosing recommendation.
• Hepatic impairment: no adjustment in mild or moderate impairment; data in severe impairment are too limited for a dosing recommendation.

Patient Card and Immune-Related Reactions

Every patient must be given the Patient Card describing the risks of immune-related adverse reactions, and the prescriber must discuss these risks with them. Immune-related reactions, including fatal cases, can affect more than one organ system at once and can appear even after the last dose. Most improved with interruption, corticosteroids and/or supportive care. In patients with pre-existing autoimmune disease, observational data suggest a higher risk of immune-mediated reactions after checkpoint inhibitors; flares of the underlying disease were frequent but mostly mild and manageable.

Lung, Liver and Bowel

• Pneumonitis: including fatal cases. Patients are monitored for symptoms, suspected cases have imaging, and infection or disease-related causes are ruled out.
• Hepatitis: including fatal cases. Liver function tests are done at baseline and periodically during treatment.
• Colitis: frequently with diarrhoea. Infectious and disease-related causes are ruled out.

Skin Reactions

Immune-related rash and dermatitis occur. Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, some fatal, have been reported. Patients are monitored for a prodrome of fever, flu-like symptoms, mucosal lesions or a progressive rash. If a severe reaction is suspected, tislelizumab is withheld and the patient referred for specialist care; if it is confirmed, tislelizumab is stopped permanently.

Endocrine Disorders

Thyroid disorders, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus (including diabetic ketoacidosis) have occurred, and long-term hormone replacement may be needed.

• Thyroid: function is checked at the start and periodically. Hypothyroidism may be managed with hormone replacement without interrupting treatment and without corticosteroids; hyperthyroidism is managed symptomatically.
• Adrenal and pituitary: patients are monitored for signs of adrenal insufficiency and hypophysitis; adrenal or pituitary function and hormone levels should be considered. Corticosteroids and hormone replacement are given as clinically indicated.
• Type 1 diabetes: patients are monitored for hyperglycaemia and insulin is given. In severe hyperglycaemia or ketoacidosis (grade 3 or higher) tislelizumab is withheld, and it may be resumed once metabolic control is achieved.

Kidney and Other Immune-Related Reactions

• Nephritis with renal dysfunction: serum creatinine is monitored and other causes of renal dysfunction excluded.
• Other reactions: myositis, myocarditis, arthritis, polymyalgia rheumatica, pericarditis, non-infective cystitis, immune thrombocytopenia, encephalitis, myasthenia gravis, Sjögren’s syndrome and Guillain-Barré syndrome have been reported.
• Overlap syndrome: myocarditis-myositis-myasthenia gravis overlap syndrome (two or all three conditions together), some fatal, has been seen. Early recognition and aggressive management are essential.

Haemophagocytic Lymphohistiocytosis

This life-threatening syndrome (fever, skin rash, enlarged lymph nodes, enlarged liver and/or spleen, and low blood counts) has been reported. Patients are monitored for its signs; if it is suspected, tislelizumab is interrupted for diagnosis and treatment, and if it is confirmed, tislelizumab is stopped.

Infusion-Related Reactions

Severe (grade 3 or higher) infusion-related reactions have been reported, and anaphylaxis has been seen after marketing. Patients are monitored during infusion, and reactions are managed as set out in Table 1 of the SmPC.

Solid Organ Transplant Recipients

Rejection of solid organ transplants has been reported with PD-1 inhibitors, and tislelizumab may increase the risk. The benefit of treatment must be weighed against the risk of rejection.

Patients Not Studied in Clinical Trials

The studies excluded patients with: performance status ECOG 2 or worse; active brain or leptomeningeal metastases; active autoimmune disease or a history of autoimmune disease that may relapse; a need for systemic corticosteroids above 10 mg/day prednisone (or equivalent) or other immunosuppressants within 14 days before treatment; active or untreated HIV; untreated hepatitis B or hepatitis C carriers; a history of interstitial lung disease; a live vaccine within 14 days before treatment; an infection needing systemic therapy within 14 days before treatment; or a history of severe hypersensitivity to another monoclonal antibody. In these groups tislelizumab is used with caution after weighing the benefit and risk for the individual.

PD-L1 Testing and Traceability

A well validated PD-L1 method should be chosen to limit false negative and false positive results. As tislelizumab is a biological medicine, the name and batch number of each administered product must be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of child-bearing potential who do not use effective contraception (methods with less than 1% pregnancy rate) should not be given tislelizumab unless their clinical condition requires treatment. They should use it during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women and no animal reproduction studies. On its mechanism, tislelizumab can cause foetal harm; in mouse models, PD-1/PD-L1 blockade disrupted tolerance to the foetus and increased foetal loss. Human IgG4 crosses the placenta. It should not be used in pregnancy unless the woman’s condition requires it, and women should be told of the potential risk to the foetus.
• Breastfeeding: it is not known whether tislelizumab passes into milk. Women should not breastfeed during treatment and for at least 4 months after the last dose.
• Fertility: no clinical data are available on its effects on fertility.

Sodium and Polysorbate 20

Each 10 mL vial contains 16 mg of sodium (1.6 mg/mL), equal to 0.8% of the WHO recommended maximum daily intake of 2 g for an adult. The concentrate is diluted in 0.9% sodium chloride, which should be taken into account in patients on a controlled sodium diet. It also contains 0.2 mg/mL of polysorbate 20 (4 mg in the two 10 mL vials of a single 200 mg infusion), which may cause allergic reactions; patients with known allergies should be taken into consideration.

Effect on Driving

Tislelizumab has a minor influence on the ability to drive and use machines. Fatigue has been reported after infusion in some patients.

Store the vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Keep the cold chain unbroken from dispatch to the hospital pharmacy. For storage after dilution, see Shelf Life. The medicine is supplied in 10 mL glass vials, in packs of 1 vial or multipacks of 2.

3 years for the unopened vial. Once opened, the medicine should be diluted and infused immediately. Tevimbra contains no preservative: after preparation of the infusion solution, chemical and physical in-use stability has been shown for 10 days (240 hours) at 2–8 °C. This includes storage of the diluted solution under refrigeration, the time to return to room temperature (25 °C or below) and the time to complete the infusion within 4 hours. From a microbiological point of view the diluted product should be used immediately; if it is not, in-use times and conditions are the responsibility of the user.

Prescription only (Rx). Treatment must be started and supervised by a physician experienced in cancer treatment. Tislelizumab is given as an intravenous infusion in a hospital or clinic, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C. Each treated patient is given the Patient Card.