Tislelizumab

The use of systemic corticosteroids and other immunosuppressants at baseline, before starting tislelizumab, except for low doses of systemic corticosteroid (10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of tislelizumab. However, systemic corticosteroids and other immunosuppressants can be used after starting tislelizumab to treat immune-related adverse reactions. Corticosteroids can also be used as pre-medication when tislelizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

Data from patients with severe renal impairment are too limited to make dosing recommendations for this population.

Data from patients with severe hepatic impairment are too limited to make dosing recommendations for this population.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with tislelizumab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with tislelizumab versus the risk of possible organ rejection should be considered in these patients.

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

Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in increased foetal loss.

Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing foetus. Women should be advised of the potential risk to a foetus.

Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab.

It is unknown whether tislelizumab is excreted in human milk. Its effects on breast-fed newborns/infants and on milk production are also unknown.

Because of the potential for serious adverse drug reactions in breast-fed newborns/infants from tislelizumab, women should be advised not to breast-feed during treatment and for at least 4 months after the last dose of tislelizumab.

Women of childbearing potential/Contraception

Tislelizumab should not be used in women of childbearing potential not using effective contraception unless the clinical condition of the woman requires treatment with tislelizumab. Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) during treatment and for at least 4 months following the last dose of tislelizumab.

Fertility

No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10 or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations).

Tislelizumab has minor influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of tislelizumab.

Summary of the safety profile

The safety of tislelizumab as monotherapy is based on pooled data in 1 534 patients across multiple tumour types who received 200 mg tislelizumab every 3 weeks. The most common adverse reactions were anaemia (29.8%), fatigue (23.9%) and aspartate aminotransferase increased (21.3%). The most common Grade ¾ adverse reactions were anaemia (5.1%), pneumonia (4.4%), hyponatraemia (2.9%), aspartate aminotransferase increased (2.6%), hypertension (2.3%), blood bilirubin increased (2.1%), pneumonitis (2.0%) and fatigue (2.0%). 1.1% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.72%), hepatitis (0.07%), abnormal hepatic function (0.07%), pneumonitis (0.07%), dyspnoea (0.07%), decreased appetite (0.07%) and decreased platelet count (0.07%). Among the 1 534 patients, 40.8% were exposed to tislelizumab for 6 months or longer, and 24.0% were exposed for 12 months or longer.

The safety of tislelizumab given in combination with chemotherapy is based on data in 1 319 patients with G/GEJ adenocarcinoma, OSCC or NSCLC. The most common adverse reactions were neutropenia (65.6%), anaemia (63.6%), thrombocytopenia (48.8%), nausea (44.0%), fatigue (43.1%), decreased appetite (41.8%), aspartate aminotransferase increased (31.7%), alanine aminotransferase increased (30.4%), diarrhoea (22.7%), and rash (20.8%). The most common Grade ¾ adverse reactions were neutropenia (38.4%), thrombocytopenia (13.3%), anaemia (13.3%), fatigue (5.0%), hypokalaemia (4.4%), hyponatraemia (3.9%), pneumonia (3.8%), decreased appetite (3.3%), rash (2.6%), lymphopenia (2.5%), alanine aminotransferase increased (2.4%), aspartate aminotransferase increased (2.4%), diarrhoea (2.4%), pneumonitis (2.0%), and hepatitis (2.0%). 1.1% of patients experienced adverse reactions leading to death. The adverse reactions leading to death were pneumonia (0.5%), pneumonitis (0.2%), dyspnoea (0.2%), myocarditis (0.2%), colitis (0.1%), hypokalaemia (0.1%), and myositis (0.1%). Among the 1 319 patients, 57.1% were exposed to tislelizumab for 6 months or longer, and 29.7% were exposed for 12 months or longer.

Tabulated list of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with tislelizumab monotherapy (N=1 534) and in combination with chemotherapy (N=1 319) are presented in the table below. Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in decreasing frequency. The corresponding frequency category for each adverse reaction is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions with tislelizumab as monotherapy (N=1 534) and in combination with chemotherapy (N=1 319):

¹ Pneumonia includes preferred terms (PTs) of pneumonia, lower respiratory tract infection, lower respiratory tract infection bacterial, pneumonia bacterial, pneumonia fungal, pneumonia staphylococcal, pneumonia viral and pneumocystis jirovecii pneumonia.
² Anaemia includes PTs of anaemia and haemoglobin decreased.
³ Thrombocytopenia includes PTs of thrombocytopenia, immune thrombocytopenia and platelet count decreased.
⁴ Neutropenia includes PTs of neutropenia and neutrophil count decreased.
⁵ Lymphopenia includes PTs of lymphopenia, lymphocyte count decreased and lymphocyte percentage decreased.
⁶ Hypothyroidism includes PTs of hypothyroidism, thyroxine free decreased, tri-iodothyronine free decreased, tri-iodothyronine decreased, primary hypothyroidism, central hypothyroidism and thyroxine decreased.
⁷ Hyperthyroidism includes PTs of hyperthyroidism, blood thyroid stimulating hormone decreased, tri-iodothyronine free increased, thyroxine free increased, thyroxine increased and tri-iodothyronine increased.
⁸ Thyroiditis includes PTs of thyroiditis, autoimmune thyroiditis and thyroiditis subacute.
⁹ Adrenal insufficiency includes PTs of adrenal insufficiency, glucocorticoid deficiency, immune-mediated
adrenal insufficiency and secondary adrenocortical insufficiency.
¹⁰ Hypophysitis includes PT of 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, type 1 diabetes mellitus, diabetic ketoacidosis and latent autoimmune diabetes in adults.
¹⁵ Encephalitis includes the PT of immune-mediated encephalitis.
¹⁶ Uveitis includes PTs of uveitis, iritis, chorioretinitis and iridocyclitis.
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 and organising pneumonia.
²⁰ Diarrhoea includes PTs of diarrhoea and frequent bowel movements.
²¹ Stomatitis includes PTs of stomatitis, mouth ulceration, aphthous ulcer and oral mucosa erosion.
²² Pancreatitis includes PTs of pancreatitis, amylase increased, lipase increased, and pancreatitis acute.
²³ Colitis includes PTs of colitis and immune-mediated enterocolitis.
²⁴ Hepatitis includes PTs of hepatitis, hepatic function abnormal, immune-mediated hepatitis, liver injury, drug-induced liver injury, hepatotoxicity and autoimmune hepatitis.
²⁵ Rash includes PTs of rash, rash maculo-papular, eczema, rash erythematous, dermatitis, dermatitis allergic, rash papular, urticaria, erythema, skin exfoliation, drug eruption, rash macular, psoriasis, rash pustular, dermatitis acneiform, rash pruritic, lichenoid keratosis, hand dermatitis, immune-mediated dermatitis, rash follicular, acute febrile neutrophilic dermatosis, erythema nodosum and pemphigoid.
²⁶ Vitiligo includes PTs of vitiligo, skin hypopigmentation, skin depigmentation and leukoderma.
²⁷ Severe skin reaction includes PT of erythema multiforme.
²⁸ Post-marketing experience.
²⁹ Myositis includes PTs of myositis, rhabdomyolysis and immune-mediated myositis.
³⁰ Arthritis includes PTs of arthritis, immune-mediated arthritis and polyarthritis.
³¹ Nephritis includes PTs of nephritis, focal segmental glomerulosclerosis, immune-mediated nephritis and tubulointerstitial nephritis.
³² Fatigue includes PTs of fatigue, asthenia, malaise and lethargy.
³³ Pyrexia includes the PTs of pyrexia and body temperature increased.
³⁴ Blood bilirubin increased includes PTs of blood bilirubin increased, bilirubin conjugated increased, blood bilirubin unconjugated increased and hyperbilirubinaemia.
³⁵ Infusion-related reaction includes PTs of infusion-related reaction, rash, chills, rhinitis allergic, urticaria, drug hypersensitivity, type I hypersensitivity, laryngeal oedema, rash erythematous, rash pruritic, lip oedema, lip swelling, mouth swelling, swelling face, tongue oedema, anaphylactic reaction, corneal oedema, dermatitis allergic, drug eruption, face oedema, gingival swelling and pruritus allergic. Cases of anaphylaxis, including anaphylactic reaction and anaphylactic shock, have been reported in the post-marketing setting.
^* including fatal outcomes

Description of selected adverse reactions

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

Immune-related pneumonitis

In patients treated with tislelizumab as monotherapy, immune-related pneumonitis occurred in 5.4% of patients, including Grade 1 (1.3%), Grade 2 (2.2%), Grade 3 (1.6%), Grade 4 (0.3%) and Grade 5 (0.1%) events.

The median time from first dose to onset of the event was 3.3 months (range: 1.0 day to 26.2 months), and the median duration from onset to resolution was 6.1 months (range: 1.0+ day to 33.9+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 2.0% of patients and tislelizumab treatment was interrupted in 1.9% of patients. Pneumonitis resolved in 48.2% of patients.

In patients treated with tislelizumab as monotherapy, pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (7.8%) than in patients who did not receive prior thoracic radiation (3.8%).

Pneumonitis occurred in 9.1% of patients with NSCLC treated with tislelizumab in combination with chemotherapy. In patients with NSCLC treated with tislelizumab as monotherapy, pneumonitis occurred in 6.0% of patients.

Immune-related hepatitis

In patients treated with tislelizumab as monotherapy, immune-related hepatitis occurred in 1.1% of patients, including Grade 1 (0.1%), Grade 2 (0. 2%), Grade 3 (0.5%), Grade 4 (0.3%) and Grade 5 (0.1%) events.

The median time from first dose to onset of the event was 22.0 days (range: 4.0 days to 2.7 months), and the median duration from onset to resolution was 1.9 months (range: 6.0 days to 6.6 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.6% of patients for immune-related hepatitis. Hepatitis resolved in 64.7% of patients.

Immune-related skin adverse reactions

In patients treated with tislelizumab as monotherapy, immune-related skin adverse reactions occurred in 13.4% of patients, including Grade 1 (9.0%), Grade 2 (3.7%), Grade 3 (0.7%) and Grade 4 (0.1%) events.

The median time from first dose to onset of the event was 1.6 months (range: 1.0 day to 25.8 months). The median duration from onset to resolution was 1.7 months (range: 1.0 day to 35.4+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients, and tislelizumab treatment was interrupted in 0.8% of patients. Skin adverse reactions resolved in 68.9% of patients.

Cases of SJS and TEN have been reported from post-marketing experience, some with fatal outcome.

Immune-related colitis

In patients treated with tislelizumab as monotherapy, immune-related colitis occurred in 0.5% of patients, including Grade 1 (0.1%), Grade 2 (0.3%) and Grade 3 (0.1%) events.

The median time from first dose to onset of the event was 10.1 months (range: 12.0 days to 28.2 months), and the median duration from onset to resolution was 27.0 days (range: 2.0 days to 6.5 months). Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.2% of patients. Colitis resolved in 87.5% of patients.

Immune-related myositis/rhabdomyolysis

In patients treated with tislelizumab as monotherapy, immune-related myositis/rhabdomyolysis occurred in 0.9% of patients, including Grade 1 (0.3%), Grade 2 (0.3%) and Grade 3 (0.3%) events.

The median time from first dose to onset of the event was 1.5 months (range: 15.0 days to 11.7 months), and the median duration from onset to resolution was 1.2 months (range: 5.0 days to 5.2 months). Tislelizumab was permanently discontinued in 0.3% of patients and tislelizumab treatment was interrupted in 0.5% of patients. Myositis/rhabdomyolysis resolved in 71.4% of patients.

Immune-related endocrinopathies

Thyroid disorders

Hypothyroidism:

In patients treated with tislelizumab as monotherapy, hypothyroidism occurred in 14.3% of patients, including Grade 1 (6.6%), Grade 2 (7.6%) and Grade 4 (0.1%) events.

The median time from first dose to onset of the event was 3.5 months (range: 1.0 day to 29.0 months). The median duration from onset to resolution was 12.5 months (range: 1.0+ day to 37.3+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.5% of patients. Hypothyroidism resolved in 33.6% of patients.

Hyperthyroidism:

In patients treated with tislelizumab as monotherapy, hyperthyroidism occurred in 5.0% of patients, including Grade 1 (4.4%) and Grade 2 (0.6%) events.

The median time from first dose to onset of the event was 2.1 months (range: 6.0 days to 25.6 months). The median duration from onset to resolution was 1.4 months (range: 5.0 days to 29.0+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Hyperthyroidism resolved in 76.3% of patients.

Thyroiditis:

In patients treated with tislelizumab as monotherapy, thyroiditis occurred in 1.2% of patients, including Grade 1 (0.6%) and Grade 2 (0.6%) events.

The median time from first dose to onset of the event was 2.1 months (range: 20.0 days to 20.7 months). The median duration from onset to resolution was 4.9 months (range: 20.0 days to 26.1+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.1% of patients. Thyroiditis resolved in 50.0% of patients.

Adrenal insufficiency

In patients treated with tislelizumab as monotherapy, adrenal insufficiency occurred in 0.4% of patients, including Grade 2 (0.2%), Grade 3 (0.1%) and Grade 4 (0.1%) events.

The median time from first dose to onset of the event was 7.9 months (range: 1.3 months to 16.9 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 1.0 month to 18.2+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was not permanently discontinued in any patient and tislelizumab treatment was interrupted in 0.3% of patients. Adrenal insufficiency resolved in 33.3% of patients.

Hypophysitis

In patients treated with tislelizumab as monotherapy, hypophysitis (Grade 2) occurred in 0.2% of patients.

The median time from first dose to onset of the event was 8.3 months (range: 22.0 days to 9.0 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 13.0+ months to 23.3+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was neither interrupted nor permanently discontinued in any patient. Hypophysitis did not resolve in any patient.

Type 1 diabetes mellitus

In patients treated with tislelizumab as monotherapy, type 1 diabetes mellitus occurred in 0.9% of patients, including Grade 1 (0.1%), Grade 2 (0.5%) and Grade 3 (0.3%) events.

The median time from first dose to onset of the event was 5.3 months (range: 8.0 days to 33.2 months). The median duration from onset to resolution was 3.3 months (range: 5.0 days to 30.1+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Type 1 diabetes mellitus resolved in 28.6% of patients.

Immune-related nephritis and renal dysfunction

In patients treated with tislelizumab as monotherapy, immune-related nephritis and renal dysfunction occurred in 0.3% of patients, including Grade 1 (0.1%), Grade 2 (0.1%) and Grade 3 (0.1%) events.

The median time from first dose to onset of the event was 1.5 months (range: 15.0 days to 12.1 months). The median duration from onset to resolution was not evaluable based on currently available data (range: 9.0 days to 16.2+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.1% of patients and tislelizumab treatment was interrupted in 0.1% of patients. Immune-related nephritis and renal dysfunction resolved in 50.0% of patients.

Immune-related myocarditis

In patients treated with tislelizumab as monotherapy, immune-related myocarditis occurred in 0.8% of patients, including Grade 1 (0.3%), Grade 2 (0.3%), Grade 3 (0.2%) and Grade 4 (0.1%) events.

The median time from first dose to onset of the event was 1.6 months (range: 14.0 days to 6.1 months), and the median duration from onset to resolution was 5.1 months (range: 4.0 days to 26.4+ months). + denotes a censored observation, with ongoing events at the time of the analysis. Tislelizumab was permanently discontinued in 0.5% of patients and tislelizumab treatment was interrupted in 0.4% of patients. Myocarditis resolved in 53.8% of patients.

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

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with tislelizumab: pancreatic exocrine insufficiency.

Infusion-related reactions

In patients treated with tislelizumab as monotherapy, infusion-related reactions occurred in 2.9% of patients, including Grade 3 (0.13%) events. Tislelizumab was permanently discontinued in 0.07% of patients and tislelizumab treatment was interrupted in 0.07% of patients.

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

Laboratory abnormalities

In patients treated with tislelizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 0.1% for increased haemoglobin, 4.8% for decreased haemoglobin, 0.9% for decreased leukocytes, 9.7% for decreased lymphocytes, 0.07% for increased lymphocytes, 1.9% for decreased neutrophils, 1.2% for decreased platelets, 2.2% for increased alanine aminotransferase, 0.7% for decreased albumin, 2.5% for increased alkaline phosphatase, 3.4% for increased aspartate aminotransferase, 2.3% for increased bilirubin, 2.1% for increased creatine kinase, 0.9% for increased creatinine, 0.9% for increased potassium, 2.5% for decreased potassium, 0.1% for increased sodium, 6.0% for decreased sodium.

In patients treated with tislelizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 12.9% for decreased haemoglobin, 18.8% for decreased leukocytes, 14.8% for decreased lymphocytes, 0.1% for increased lymphocytes, 39.8% for decreased neutrophils, 13.2% for decreased platelets, 4.4% for increased alanine aminotransferase, 0.6% for decreased albumin, 0.9% for increased alkaline phosphatase, 4.0% for increased aspartate aminotransferase, 2.1% for increased bilirubin, 2.1% for increased creatine kinase, 2.4% for increased creatinine, 0.4% for decreased glucose, 1.8% for increased glucose, 1.8% for increased potassium, 8.6% for decreased potassium, 0.4% for increased sodium, 11.7% for decreased sodium.

Immunogenicity

Of 2 686 antidrug antibodies (ADA)-evaluable patients treated at the recommended dose of 200 mg once every 3 weeks with tislelizumab as monotherapy or in combination with chemotherapies, 19.5% of patients tested positive for treatment-emergent ADA, and neutralising antibodies (NAbs) were detected in 1.0% of patients. Population pharmacokinetic analysis showed that ADA status was a 17 statistically significant covariate on clearance; however, the presence of treatment-emergent ADA against tislelizumab appears to have no clinically relevant impact on pharmacokinetics or efficacy.

Among ADA-evaluable patients receiving 200 mg once every 3 weeks, the following rates of adverse events (AEs) have been observed for the ADA-positive population compared to the ADA-negative population, respectively: Grade ≥3 AEs 51.7% vs. 41.2%, serious adverse events (SAEs) 37.9% vs. 31.0%, AEs leading to tislelizumab treatment discontinuation 12.1% vs 10.7% (for monotherapy); Grade ≥3 AEs 78.5% vs. 74.5%, SAEs 44.7% vs. 41.5%, AEs leading to tislelizumab treatment discontinuation 14.4% vs 13.8% (for combination therapy). Patients who developed treatment-emergent ADAs tended to have overall poorer health and disease characteristics at baseline which can confound the interpretation of the safety analysis. Available data do not allow firm conclusions to be drawn on possible patterns of adverse drug reactions.

Elderly

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