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The safety of atezolizumab given in combination with other medicinal products, has been evaluated in 4 535 patients across multiple tumour types. The most common adverse reactions (≥ 20%) were anaemia (36.8%), neutropenia (36.6%), nausea (35.5%), fatigue (33.1%), alopecia (28.1%), rash (27.8%), diarrhoea (27.6%), thrombocytopenia (27.1%), constipation (25.8%), decreased appetite (24.7%) and peripheral neuropathy (24.4%).
Use of atezolizumab in the adjuvant NSCLC setting: The safety profile of atezolizumab in the adjuvant setting in the non-small cell lung cancer (NSCLC) patient population (IMpower010) was generally consistent with the overall pooled monotherapy safety profile in the advanced setting. Nevertheless, the incidence of immune related adverse reactions of atezolizumab in IMpower010 was 51.7% compared to 38.4% in the pooled monotherapy population with advanced disease. No new immune related adverse reactions were identified in the adjuvant setting.
Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin: In the first-line NSCLC study (IMpower150), an overall higher frequency of adverse events was observed in the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin compared to atezolizumab, paclitaxel and carboplatin, including Grade 3 and 4 events (63.6% compared to 57.5%), Grade 5 events (6.1% compared to 2.5%), adverse events of special interest to atezolizumab (52.4% compared to 48.0%), as well as adverse events leading to withdrawal of any study treatment (33.8% compared to 13.3%). Nausea, diarrhoea, stomatitis, fatigue, pyrexia, mucosal inflammation, decreased appetite, weight decreased, hypertension and proteinuria were reported higher (≥5% difference) in patients receiving atezolizumab in combination with bevacizumab, paclitaxel and carboplatin. Other clinically significant adverse events which were observed more frequently in the atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events.
Further details on serious adverse reactions are provided in Precautions.
Tabulated list of adverse reactions: The adverse reactions (ARs) are listed by MedDRA system organ class (SOC) and categories of frequency in Table 19 for atezolizumab given as monotherapy or as combination therapy. Adverse reactions known to occur with atezolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. The following categories of frequency have been used: 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 the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. (See Tables 19a and 19b.)
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Click on icon to see table/diagram/imageDescription of selected adverse reactions: The following data reflect information for significant adverse reactions for atezolizumab as monotherapy in clinical trials (see Pharmacology: Pharmacodynamics under Actions). Details for the significant adverse reactions for atezolizumab when given in combination are presented if clinically relevant differences were noted in comparison to atezolizumab monotherapy. The management guidelines for these adverse reactions are described in Dosage & Administration and Precautions.
Immune-related pneumonitis: Pneumonitis occurred in 3.0% (130/ 4,349) of patients who received atezolizumab monotherapy. Of the 130 patients, two experienced fatal events. The median time to onset was 4.0 months (range: 3 days to 29.8 months). The median duration was 1.6 months (range: 1 day to 27.8+ months; + denotes a censored value). Pneumonitis led to discontinuation of atezolizumab in 29 (0.7%) patients. Pneumonitis requiring the use of corticosteroids occurred in 1.7% (76/4,349) of patients receiving atezolizumab monotherapy.
Immune-related hepatitis: Hepatitis occurred in 1.7% (75/4,349) of patients who received atezolizumab monotherapy. Of the 75 patients, two experienced fatal events. The median time to onset was 1.6 months (range: 7 days to 18.8 months). The median duration was 2.1 months (range: 1 day to 22.0+ months; + denotes a censored value). Hepatitis led to discontinuation of atezolizumab in 13 (0.3%) patients. Hepatitis requiring the use of corticosteroids occurred in 0.5% (22/4,349) of patients receiving atezolizumab monotherapy.
Immune-related colitis: Colitis occurred in 1.1 % (50/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 5.1 months (range: 15 days to 17.2 months). The median duration was 1.2 months (range: 1 day to 35.9+ months; + denotes a censored value). Colitis led to discontinuation of atezolizumab in 17 (0.4%) patients. Colitis requiring the use of corticosteroids occurred in 0.6% (24/4,349) of patients receiving atezolizumab monotherapy.
Immune-related endocrinopathies: Thyroid disorders: Hypothyroidism occurred in 7.6% (331/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 4.3 months (range: 1 day to 34.5 months). Hypothyroidism occurred in 17.4% (86/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting. The median time to onset was 4.0 months (range: 22 days to 11.8 months).
Hyperthyroidism occurred in 2.1% (93/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 2.6 months (range: 1 day to 24.3 months). Hyperthyroidism occurred in 6.5% (32/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting. The median time to onset was 2.8 months (range: 1 day to 9.9 months).
Adrenal insufficiency: Adrenal insufficiency occurred in 0.5% (21/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 6.1 months (range: 2 days to 21.4 months). The median duration was 16.8 months (range: 2 days to 35.4+ months; + denotes a censored value). Adrenal insufficiency led to discontinuation of atezolizumab in 5 (0.1%) patients. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.4% (17/4,349) of patients receiving atezolizumab monotherapy.
Hypophysitis: Hypophysitis occurred in < 0.1% (4/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 6.1 months (range: 23 days to 13.7 months). Three (< 0.1%) patients required the use of corticosteroids and treatment with atezolizumab was discontinued in 1 (< 0.1%) patient.
Hypophysitis occurred in 0.8% (3/393) of patients who received atezolizumab with bevacizumab, paclitaxel, and carboplatin. The median time to onset was 7.7 months (range: 5.0 to 8.8 months). Two patients required the use of corticosteroids.
Hypophysitis occurred in 0.4% (2/473) of patients who received atezolizumab in combination with nab-paclitaxel and carboplatin. The median time to onset was 5.2 months (range: 5.1 to 5.3 months). Both patients required the use of corticosteroids.
Diabetes mellitus: Diabetes mellitus occurred in 0.5% (20/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 5.5 months (range: 4 days to 29.0 months). Diabetes mellitus led to the discontinuation of atezolizumab in < 0.1% (3/4,349) patients.
Diabetes mellitus occurred in 2.0% (10/493) of HCC patients who received atezolizumab in combination with bevacizumab. The median time to onset was 4.4 months (range: 1.2 months - 8.3 months). No events of diabetes mellitus led to atezolizumab withdrawal.
Immune-related meningoencephalitis: Meningoencephalitis occurred in 0.4% (18/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 16 days (range: 1 day to 12.5 months). The median duration was 22 days (range: 6 days to 14.5+ months; + denotes a censored value). Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (10/4,349) of patients receiving atezolizumab and eight patients (0.2%) discontinued atezolizumab.
Immune-related neuropathies: Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.1% (6/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 4.1 months (range: 17 days to 8.1 months). The median duration was 8.0 months (range: 19 days to 24.5+ months; + denotes a censored value). Guillain-Barré syndrome led to discontinuation of atezolizumab in 1 patient (< 0.1%). Guillain-Barré syndrome requiring the use of corticosteroids occurred in < 0.1% (3/4,349) of patients receiving atezolizumab monotherapy.
Myasthenic syndrome: Myasthenia gravis occurred in < 0.1% (1/4,349) of patients who received atezolizumab monotherapy. The time to onset was 1.2 months.
Immune-related pancreatitis: Pancreatitis, including amylase increased and lipase increased, occurred in 0.7% (32/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 5.5 months (range: 1 day to 24.8 months). The median duration was 24 days (range: 3 days to 22.4+ months; + denotes a censored value). Pancreatitis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Pancreatitis requiring the use of corticosteroids occurred in 0.1% (5/4,349) of patients receiving atezolizumab monotherapy.
Immune-related myocarditis: Myocarditis occurred in < 0.1% (3/4,349) of patients who received atezolizumab monotherapy. Of the 3 patients, one experienced a fatal event in the adjuvant NSCLC setting. The median time to onset was 2.1 months (range: 1.5 to 4.9 months). The median duration was 14 days (range: 14 days to 2.8 months). Myocarditis led to the discontinuation of atezolizumab in 2 (< 0.1%) patients. Two (<0.1%) patients required the use of corticosteroids.
Immune-related nephritis: Nephritis occurred in 0.2% (10/4,349) of patients who received atezolizumab. The median time to onset was 5.0 months (range: 2 days to 17.5 months). Nephritis led to discontinuation of atezolizumab in 5 (0.1%) patients. Four (< 0.1%) patients required the use of corticosteroids.
Immune-related myositis: Myositis occurred in 0.5% (20/4,349) of patients who received atezolizumab monotherapy. The median time to onset was 3.3 months (range: 12 days to 11.0 months). The median duration was 5.7 months (range:2 days to 36.9+ months; + denotes a censored value). Myositis led to discontinuation of atezolizumab in 2 (< 0.1%) patients. Seven (0.2%) patients required the use of corticosteroids.
Immune-related severe cutaneous adverse reactions: Severe cutaneous adverse reactions (SCARs) occurred in 0.6% (28/4,349) of patients who received atezolizumab monotherapy. Of the 28 patients, one experienced a fatal event. The median time to onset was 5.2 months (range: 4 days to 15.5 months). The median duration was 2.4 months (range: 1 day to 37.5+ months; + denotes a censored value). SCARs led to discontinuation of atezolizumab in 3 (< 0.1%) patients. SCARs requiring the use of systemic corticosteroids occurred in 0.2% (9/4,349) of patients receiving atezolizumab monotherapy.
Immunogenicity: Across multiple phase II and III studies, 13.1% to 54.1% of patients developed treatment-emergent anti-drug antibodies (ADAs). Patients who developed treatment-emergent ADAs tended to have overall poorer health and disease characteristics at baseline. Those imbalances in health and disease characteristics at baseline can confound the interpretation of pharmacokinetic (PK), efficacy and safety analyses. Exploratory analyses adjusting for imbalances in baseline health and disease characteristics were conducted to assess the effect of ADA on efficacy. These analyses did not exclude possible attenuation of efficacy benefit in patients who developed ADA compared to patients who did not develop ADA. The median time to ADA onset ranged from 3 weeks to 5 weeks.
Across pooled datasets for patients treated with atezolizumab monotherapy (N=3,460) and with combination therapies (N= 2 285), the following rates of adverse events (AEs) have been observed for the ADA-positive population compared to the ADA-negative population, respectively: Grade 3-4 AEs 46.2% vs. 39.4%, Serious Adverse Events (SAEs) 39.6% vs. 33.3%, AEs leading to treatment withdrawal 8.5% vs 7.8% (for monotherapy); Grade 3-4 AEs 63.9% vs. 60.9%, SAEs 43.9% vs. 35.6%, AEs leading to treatment withdrawal 22.8% vs 18.4% (for combination therapy). However, available data do not allow firm conclusions to be drawn on possible patterns of adverse reactions.
Paediatric population: The safety of atezolizumab in children and adolescents has not been established. No new safety signals were observed in a clinical trial with 69 paediatric patients (< 18 years) and the safety profile was comparable to adults.
Elderly: No overall differences in safety were observed between patients ≥ 65 years of age and younger patients receiving atezolizumab monotherapy. In study IMpower150, age ≥ 65 was associated with an increased risk of developing adverse events in patients receiving atezolizumab in combination with bevacizumab, carboplatin and paclitaxel.
In studies IMpower150, IMpower133 and IMpower110, data for patients ≥ 75 years of age are too limited to draw conclusions on this population.
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