Atezolizumab

The use of systemic corticosteroids or immunosuppressants before starting atezolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of atezolizumab. However, systemic corticosteroids or other immunosuppressants can be used to treat immune-mediated adverse reactions after starting atezolizumab.

Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Atezolizumab has not been studied in patients with severe hepatic impairment.

There are no data from the use of atezolizumab in pregnant women. No developmental and reproductive studies were conducted with atezolizumab. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway in murine pregnancy models can lead to immune-mediated rejection of the developing foetus resulting in foetal death. These results indicate a potential risk, based on its mechanism of action, that administration of atezolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.

Human immunoglobulins G1 (IgG1) are known to cross the placental barrier and atezolizumab is an IgG1; therefore, atezolizumab has the potential to be transmitted from the mother to the developing foetus.

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

It is unknown whether atezolizumab is excreted in human milk. Atezolizumab is a monoclonal antibody and is expected to be present in the first milk and at low levels afterwards. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue atezolizumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during and for 5 months after treatment with atezolizumab.

Fertility

No clinical data are available on the possible effects of atezolizumab on fertility. No reproductive and development toxicity studies have been conducted with atezolizumab; however, based on the 26-week repeat dose toxicity study, atezolizumab had an effect on menstrual cycles at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose and was reversible. There were no effects on the male reproductive organs.

Atezolizumab has minor influence on the ability to drive and use machines. Patients experiencing fatigue should be advised not to drive and use machines until symptoms abate.

Summary of the safety profile

The safety of atezolizumab as monotherapy is based on pooled data in 5 039 patients across multiple tumour types. The most common adverse reactions (>10%) were fatigue (29.3%), decreased appetite (20.1%), rash (19.7%), nausea (18.8%), cough (18.2%), diarrhoea (18.1%), pyrexia (17.9%), dyspnoea (16.6%), arthralgia (16.2%), pruritus (13.3%), asthenia (13%), back pain (12.2%), vomiting (11.7%), urinary tract infection (11%) and headache (10.2%).

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-mediated adverse reactions of atezolizumab in IMpower010 was 51.7% compared to 38.4% in the pooled monotherapy population with advanced disease. No new immune-mediated 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.

Tabulated list of adverse reactions

The adverse reactions (ARs) are listed by MedDRA system organ class (SOC) and categories of frequency in the table below 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.

Summary of adverse reactions occurring in patients treated with atezolizumab:

^a Includes reports of urinary tract infection, cystitis, pyelonephritis, escherichia urinary tract infection, urinary tract infection bacterial, kidney infection, pyelonephritis acute, pyelonephritis chronic, pyelitis, renal abscess, streptococcal urinary tract infection, urethritis, urinary tract infection fungal, urinary tract infection pseudomonal.
^b Includes reports of pneumonia, bronchitis, lower respiratory tract infection, infectious pleural effusion, tracheobronchitis, atypical pneumonia, lung abscess, infective exacerbation of chronic obstructive airways disease, paracancerous pneumonia, pyopneumothorax, pleural infection, post procedural pneumonia.
^c Includes reports of blood creatinine increased, hypercreatininaemia.
^d Includes reports of thrombocytopenia, platelet count decreased.
^e Includes reports of neutropenia, neutrophil count decreased, febrile neutropenia, neutropenic sepsis, granulocytopenia.
^f Includes reports of white blood cell count decreased, leukopenia.
^g Includes reports of lymphopenia, lymphocyte count decreased.
^h Includes reports of infusion-related reaction, cytokine release syndrome, hypersensitivity, anaphylaxis.
ⁱ Includes reports of anti-thyroid antibody positive, autoimmune hypothyroidism, autoimmune thyroiditis, blood thyroid stimulating hormone decreased, blood thyroid stimulating hormone increased, euthyroid sick syndrome, goitre, hypothyroidism, immune-mediated hypothyroidism, immune-mediated thyroiditis, myxoedema, primary hypothyroidism, thyroid disorder, thyroid hormones decreased, thyroid function test abnormal, thyroiditis, thyroiditis acute, thyroxine decreased, thyroxine free decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine decreased, tri-iodothyronine increased, tri-iodothyronine free abnormal, tri-iodothyronine free decreased, tri-iodothyronine free increased, silent thyroiditis.
^j Includes reports of hyperthyroidism, Basedow’s disease, endocrine ophthalmopathy, exophthalmos.
^k Includes reports of diabetes mellitus, type 1 diabetes mellitus, diabetic ketoacidosis, ketoacidosis.
^l Includes reports of adrenal insufficiency, blood corticotropin decreased, glucocorticoid deficiency, primary adrenal insufficiency, secondary adrenocortical insufficiency.
^m Includes reports of hypophysitis, hypopituitarism, secondary adrenocortical insufficiency, temperature regulation disorder.
ⁿ Includes reports of hypomagnesaemia, blood magnesium decreased.
° Includes reports of neuropathy peripheral, autoimmune neuropathy, peripheral sensory neuropathy, polyneuropathy, herpes zoster, peripheral motor neuropathy, neuralgic amyotrophy, peripheral sensorimotor neuropathy, toxic neuropathy, axonal neuropathy, lumbosacral plexopathy, neuropathic arthropathy, peripheral nerve infection, neuritis, immune-mediated neuropathy.
^p Includes reports of Guillain-Barré syndrome, ascending flaccid paralysis, demyelinating polyneuropathy.
^q Includes reports of encephalitis, encephalitis autoimmune, meningitis, meningitis aseptic, photophobia.
^r Includes reports of myasthenia gravis.
^s Includes reports of myocarditis, autoimmune myocarditis, and immune-mediated myocarditis.
^t Includes reports of pneumonitis, lung infiltration, bronchiolitis, immune-mediated lung disease, immune-mediated pneumonitis, interstitial lung disease, alveolitis, lung opacity, pulmonary fibrosis, pulmonary toxicity, radiation pneumonitis.
^u Includes reports of diarrhoea, defaecation urgency, frequent bowel movements, gastrointestinal hypermotility.
^v Includes reports of colitis, autoimmune colitis, colitis ischaemic, colitis microscopic, colitis ulcerative, diversion colitis, eosinophilic colitis, immune-mediated enterocolitis.
^w Includes reports of oropharyngeal pain, oropharyngeal discomfort, throat irritation.
^x Includes reports of autoimmune pancreatitis, pancreatitis, pancreatitis acute, lipase increased, amylase increased.
^y Includes reports of ascites, autoimmune hepatitis, hepatic cytolysis, hepatitis, hepatitis acute, hepatitis toxic, hepatotoxicity, immune-mediated hepatitis, liver disorder, drug-induced liver injury, hepatic failure, hepatic steatosis, hepatic lesion, liver injury, oesophageal varices haemorrhage, varices oesophageal, spontaneous bacterial peritonitis.
^z Includes reports of acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, drug eruption, eczema, eczema infected, erythema, erythema of eyelid, eyelid rash, fixed eruption, folliculitis, furuncle, hand dermatitis, immune-mediated dermatitis, lip blister, oral blood blister, palmar-plantar erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash pustular, rash vesicular, scrotal dermatitis, seborrhoeic dermatitis, skin exfoliation, skin toxicity, skin ulcer, vascular access site rash.
^aa Includes reports of musculoskeletal pain, myalgia, bone pain.
^ab Includes reports of myositis, rhabdomyolysis, polymyalgia rheumatica, dermatomyositis, muscle abscess, myoglobin urine present, myopathy, polymyositis.
^ac Includes reports of proteinuria, protein urine present, haemoglobinurea, urine abnormality, nephrotic syndrome, albuminuria.
^ad Includes reports of nephritis, autoimmune nephritis, Henoch-Schonlein purpura nephritis, paraneoplastic glomerulonephritis, tubulointerstitial nephritis.
^ae Includes reports of hypokalaemia, blood potassium decreased.
^af Includes reports of hyponatraemia, blood sodium decreased.
^ag Includes reports of hypoxia, oxygen saturation decreased, pO₂ decreased.
^ah Includes reports of alopecia, madarosis, alopecia areata, alopecia totalis, hypotrichosis.
^ai Includes reports of hypertension, blood pressure increased, hypertensive crisis, blood pressure systolic increased, diastolic hypertension, blood pressure inadequately controlled, retinopathy hypertensive, hypertensive nephropathy, essential hypertension, orthostatic hypertension.
^aj Includes reports of sepsis, septic shock, urosepsis, neutropenic sepsis, pulmonary sepsis, bacterial sepsis, klebsiella sepsis, abdominal sepsis, candida sepsis, escherichia sepsis, pseudomonal sepsis, staphylococcal sepsis.
^ak Includes reports of dermatitis bullous, exfoliative rash, erythema multiforme, dermatitis exfoliative, dermatitis exfoliative generalised, toxic skin eruption, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, cutaneous vasculitis.
^al Includes reports of cystitis noninfective and immune-mediated cystitis.
^am Includes reports of nasopharyngitis, nasal congestion and rhinorrhoea.
^an Includes reports of psoriasis, dermatitis psoriasiform.
^ao Includes reports of pericarditis, pericardial effusion, cardiac tamponade and pericarditis constrictive.
^ap Includes reports of dry skin, xerosis.

Description of selected adverse reactions

The data below reflect information for significant adverse reactions for atezolizumab as monotherapy in clinical trials. 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.

Immune-mediated pneumonitis

Pneumonitis occurred in 3.0% (151/5 039) of patients who received atezolizumab monotherapy. Of these patients, three experienced fatal events. The median time to onset was 3.7 months (range: 3 days to 29.8 months). The median duration was 1.7 months (range: 0 days to 27.8+ months; + denotes a censored value). Pneumonitis led to discontinuation of atezolizumab in 41 (0.8%) patients. Pneumonitis requiring the use of corticosteroids occurred in 1.8% (92/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated hepatitis

Hepatitis occurred in 1.7% (88/5 039) of patients who received atezolizumab monotherapy. Of the 88 patients, three experienced fatal events. The median time to onset was 1.4 months (range: 0 days to 26.3 months). The median duration was 1 month (range: 0 day to 52.1+ months; + denotes a censored value). Hepatitis led to discontinuation of atezolizumab in 46 (0.9%) patients. Hepatitis requiring the use of corticosteroids occurred in 2.6% (130/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated colitis

Colitis occurred in 1.2% (62/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.5 months (range: 15 days to 36.4 months). The median duration was 1.4 months (range: 3 days to 50.2+ months; + denotes a censored value). Colitis led to discontinuation of atezolizumab in 24 (0.5%) patients. Colitis requiring the use of corticosteroids occurred in 0.6% (30/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated endocrinopathies

Thyroid disorders

Hypothyroidism occurred in 8.5% (427/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.2 months (range: 0 days to 38.5 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 2.4% (121/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 2.7 months (range: 0 days 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% (25/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 6.2 months (range: 3 days to 21.4 months). Adrenal insufficiency led to discontinuation of atezolizumab in 5 (0.1%) patients. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.4% (20/5 039) of patients receiving atezolizumab monotherapy.

Hypophysitis

Hypophysitis occurred in 0.2% (9/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5.3 months (range: 21 days to 13.7 months). Six (0.1%) patients required the use of corticosteroids and treatment with atezolizumab was discontinued in 1 (<0.1%) patient.

Hypophysitis occurred in 1.4% (15/1 093) of patients who received atezolizumab in combination with paclitaxel followed by atezolizumab, dose-dense doxorubicin or epirubicin, and cyclophosphamide. The median time to onset was 3.8 months (range: 2.4 to 10.7 months). Eleven patients (1.0%) required the use of corticosteroids. Treatment with atezolizumab was discontinued in 7 (0.6%) patients.

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 0.6% (30/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5.5 months (range: 3 days to 29.0 months). Diabetes mellitus led to the discontinuation of atezolizumab in <0.1% (3/5 039) patients. Four (<0.1%) patients required the use of corticosteroids.

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-mediated meningoencephalitis

Meningoencephalitis occurred in 0.4% (22/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 15 days (range: 0 days to 12.5 months). The median duration was 24 days (range: 6 days to 14.5+ months; + denotes a censored value).

Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (12/5 039) of patients receiving atezolizumab and eight patients (0.2%) discontinued atezolizumab.

Immune-mediated neuropathies

Guillain-Barré syndrome and demyelinating polyneuropathy

Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.1% (6/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 4.1 months (range: 18 days to 8.1 months). The median duration was 8.0 months (range: 18 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% (3/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated facial paresis

Facial paresis occurred in <0.1% (1/5 039) of patients who received atezolizumab monotherapy. The time to onset was 29 days. The duration was 1.1 months. The event did not require the use of corticosteroids and the event did not lead to discontinuation of atezolizumab.

Immune-mediated myelitis

Myelitis occurred in <0.1% (1/5 039) of patients who received atezolizumab monotherapy. The time to onset was 3 days. The event required the use of corticosteroids but did not lead to discontinuation of atezolizumab.

Myasthenic syndrome

Myasthenia gravis occurred in <0.1% (2/5 039) of patients (including 1 fatal case) who received atezolizumab monotherapy. The median time to onset was 2.6 months (range: 1.2 months to 4 months).

Immune-mediated pancreatitis

Pancreatitis, including amylase increased and lipase increased, occurred in 0.8% (40/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 5 months (range: 0 days to 24.8 months). The median duration was 24 days (range: 3 days to 40.4+ 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 0.2% (8/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated myocarditis

Myocarditis occurred in <0.1% (5/5 039) of patients who received atezolizumab monotherapy. Of the 5 patients, one experienced a fatal event in the adjuvant NSCLC setting. The median time to onset was 3.7 months (range: 1.5 to 4.9 months). The median duration was 14 days (range: 12 days to 2.8 months). Myocarditis led to the discontinuation of atezolizumab in 3 (<0.1%) patients. Three (<0.1%) patients required the use of corticosteroids.

Immune-mediated nephritis

Nephritis occurred in 0.2% (11/5 039) of patients who received atezolizumab. The median time to onset was 5.1 months (range: 3 days to 17.5 months). Nephritis led to discontinuation of atezolizumab in 5 (≤0.1%) patients. Five (0.1%) patients required the use of corticosteroids.

Immune-mediated myositis

Myositis occurred in 0.6% (32/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 3.5 months (range: 12 days to 11.5 months). The median duration was 3.2 months (range: 9 days to 51.1+ months; + denotes a censored value). Myositis led to discontinuation of atezolizumab in 6 (0.1%) patients. Ten (0.2%) patients required the use of corticosteroids.

Immune-mediated severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) occurred in 0.6% (30/5 039) of patients who received atezolizumab monotherapy. Of the 30 patients, one experienced a fatal event. The median time to onset was 4.8 months (range: 3 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% (9/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated pericardial disorders

Pericardial disorders occurred in 1% (49/5 039) of patients who received atezolizumab monotherapy. The median time to onset was 1.4 months (range: 6 days to 17.5 months). The median duration was 2.5 months (range: 0 to 51.5+ months; + denotes a censored value). Pericardial disorders led to discontinuation of Tecentriq in 3 (<0.1%) patients. Pericardial disorders requiring the use of corticosteroids occurred in 0.2% (7/5 039) of patients.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reaction(s) reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with atezolizumab: pancreatic exocrine insufficiency.

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, 65-74, and 75-84 years of age receiving atezolizumab monotherapy. The data for patients ≥85 years of age are too limited to draw meaningful conclusions about this population.

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 were too limited to draw conclusions. In the IPSOS study in 1L platinum-ineligible NSCLC patients, there were no overall differences in the safety profile for 1L atezolizumab monotherapy between the patient age subgroups.