Tevimbra Adverse Reactions

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

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