This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Tecentriq 1,200 mg concentrate for solution for infusion.

2. Qualitative and quantitative composition

Each 20 mL vial of concentrate contains 1,200 mg atezolizumab*.

After dilution (see section 6.6), one mL of solution contains approximately 4.4 mg of atezolizumab.

*Atezolizumab is an Fc-engineered, humanised IgG1 anti-programmed death-ligand 1 (PD-L1) monoclonal antibody produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion.

Clear, colourless to slightly yellowish liquid.

4. Clinical particulars
4.1 Therapeutic indications

Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC):

• after prior platinum-containing chemotherapy, or

• who are considered cisplatin ineligible, and whose tumours have a PD-L1 expression ≥ 5% (see section 5.1).

Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. Patients with EGFR activating mutations or ALK-positive tumour mutations should also have received targeted therapy before receiving Tecentriq (see section 5.1).

4.2 Posology and method of administration

Tecentriq must be initiated and supervised by physicians experienced in the treatment of cancer.

PD-L1 testing for patients with UC

Patients with previously untreated UC should be selected for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).

Posology

The recommended dose of Tecentriq is 1,200 mg administered intravenously every three weeks.

Duration of treatment

It is recommended that patients are treated with Tecentriq until loss of clinical benefit (see section 5.1) or unmanageable toxicity.

Delayed or missed doses

If a planned dose of Tecentriq is missed, it should be administered as soon as possible; it is recommended not to wait until the next planned dose. The schedule of administration must be adjusted to maintain a 3-week interval between doses.

Dose modifications during treatment

Dose reductions of Tecentriq are not recommended.

Dose delay or discontinuation (see also sections 4.4 and 4.8)

Table 1: Dose modification advice for Tecentriq

Immune related adverse reaction

Severity

Treatment modification

Pneumonitis

Grade 2

Withhold Tecentriq

Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 3 or 4

Permanently discontinue Tecentriq

Hepatitis

Grade 2:

(ALT or AST > 3 to 5 x upper limit of normal [ULN]

or

blood bilirubin > 1.5 to 3 x ULN)

Withhold Tecentriq

Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 3 or 4:

(ALT or AST > 5 x ULN

or

blood bilirubin > 3 x ULN)

Permanently discontinue Tecentriq

Colitis

Grade 2 or 3 Diarrhoea (increase of ≥ 4 stools/day over baseline)

or

Symptomatic Colitis

Withhold Tecentriq

Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 4 Diarrhoea or Colitis (life threatening; urgent intervention indicated)

Permanently discontinue Tecentriq

Hypothyroidism or hyperthyroidism

Symptomatic

Withhold Tecentriq

Hypothyroidism:

Treatment may be resumed when symptoms are controlled by thyroid replacement therapy and TSH levels are decreasing

Hyperthyroidism:

Treatment may be resumed when symptoms are controlled by antithyroid medicinal product and thyroid function is improving

Adrenal insufficiency

Symptomatic

Withhold Tecentriq

Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy

Hypophysitis

Grade 2 or 3

Withhold Tecentriq

Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and patient is stable on replacement therapy

Grade 4

Permanently discontinue Tecentriq

Type 1 diabetes mellitus

Grade 3 or 4 hyperglycaemia (fasting glucose > 250 mg/dL or 13.9 mmol/L)

Withhold Tecentriq

Treatment may be resumed when metabolic control is achieved on insulin replacement therapy

Infusion-related reactions

Grade 1 or 2

Reduce infusion rate or interrupt. Treatment may be resumed when the event is resolved

Grade 3 or 4

Permanently discontinue Tecentriq

Rash

Grade 3

Withhold Tecentriq

Treatment may be resumed when rash is resolved and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 4

Permanently discontinue Tecentriq

Myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome and Meningoencephalitis

All Grades

Permanently discontinue Tecentriq

Pancreatitis

Grade 3 or 4 serum amylase or lipase levels increased (> 2 x ULN)

or Grade 2 or 3 pancreatitis

Withhold Tecentriq

Treatment may be resumed when serum amylase and lipase levels improve to Grade 0 or Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 4 or any grade of recurrent pancreatitis

Permanently discontinue Tecentriq

Myocarditis

Grade 2

Withhold Tecentriq

Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day

Grade 3 and 4

Permanently discontinue Tecentriq

Other immune-related adverse reactions

Grade 2 or Grade 3

Withhold until adverse reactions recovers to Grade 0-1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day.

Grade 4 or recurrent Grade 3

Permanently discontinue Tecentriq (except endocrinopathies controlled with replacement hormones)

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Event Version 4.0 (NCI-CTCAE v.4.).

Patients treated with Tecentriq must be given the Patient Alert Card and be informed about the risks of Tecentriq (see also package leaflet).

Special populations

Paediatric population

The safety and efficacy of Tecentriq in children and adolescents aged below 18 years have not been established. No data are available.

Elderly

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is required in patients ≥ 65 years of age.

Renal impairment

Based on a population pharmacokinetic analysis, no dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment

Based on a population pharmacokinetic analysis, no dose adjustment is required for patients with mild hepatic impairment. Tecentriq has not been studied in patients with moderate or severe hepatic impairment (see section 5.2).

Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2

Patients with ECOG performance status ≥ 2 were excluded from the clinical trials in NSCLC and 2nd line UC (see sections 4.4 and 5.1).

Method of administration

Tecentriq is for intravenous use. The infusions must not be administered as an intravenous push or bolus.

The initial dose of Tecentriq must be administered over 60 minutes. If the first infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

For instructions on dilution and handling of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to atezolizumab or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Most immune-related adverse reactions occurring during treatment with atezolizumab were reversible with interruptions of atezolizumab and initiation of corticosteroids and/or supportive care. Immune-related adverse reactions affecting more than one body system have been observed. Immune-related adverse reactions with atezolizumab may occur after the last dose of atezolizumab.

For suspected immune-related adverse reactions, thorough evaluation to confirm aetiology or exclude other causes should be performed. Based on the severity of the adverse reaction, atezolizumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid should be tapered over ≥ 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with systemic corticosteroid use, administration of other systemic immunosuppressants may be considered.

Atezolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reactions, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).

Immune-related pneumonitis

Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis.

Treatment with atezolizumab should be withheld for Grade 2 pneumonitis, and 1 to 2 mg/kg/day prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 pneumonitis.

Immune-related hepatitis

Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin should be monitored prior to initiation of treatment, periodically during treatment with atezolizumab and as indicated based on clinical evaluation.

Treatment with atezolizumab should be withheld if Grade 2 event (ALT or AST > 3 to 5 x ULN or blood bilirubin > 1.5 to 3 x ULN) persists for more than 5 to 7 days, and 1 to 2 mg/kg/day of prednisone or equivalent should be started. If the event improves to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month.

Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or Grade 4 events (ALT or AST > 5.0 x ULN or blood bilirubin > 3 x ULN).

Immune-related colitis

Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of colitis.

Treatment with atezolizumab should be withheld for Grade 2 or 3 diarrhoea (increase of ≥ 4 stools/day over baseline) or colitis (symptomatic). For Grade 2 diarrhoea or colitis, if symptoms persist > 5 days or recur, treatment with 1 to 2 mg/kg/day prednisone or equivalent should be started. For Grade 3 diarrhoea or colitis, treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis.

Immune-related endocrinopathies

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab (see section 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies. Thyroid function should be monitored prior to and periodically during treatment with atezolizumab. Appropriate management of patients with abnormal thyroid function tests at baseline should be considered.

Asymptomatic patients with abnormal thyroid function tests can receive atezolizumab. For symptomatic hypothyroidism, atezolizumab should be withheld and thyroid hormone replacement should be initiated as needed. Isolated hypothyroidism may be managed with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, atezolizumab should be withheld and an antithyroid medicinal product should be initiated as needed. Treatment with atezolizumab may be resumed when symptoms are controlled and thyroid function is improving.

For symptomatic adrenal insufficiency, atezolizumab should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required).

For Grade 2 or Grade 3 hypophysitis, atezolizumab should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started, and hormone replacement should be initiated as needed. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required). Treatment with atezolizumab should be permanently discontinued for Grade 4 hypophysitis.

Treatment with insulin should be initiated for type 1 diabetes mellitus. For ≥ Grade 3 hyperglycaemia (fasting glucose > 250 mg/dL or 13.9 mmol/L), atezolizumab should be withheld. Treatment with atezolizumab may be resumed if metabolic control is achieved on insulin replacement therapy.

Immune-related meningoencephalitis

Meningoencephalitis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of meningitis or encephalitis.

Treatment with atezolizumab must be permanently discontinued for any grade of meningitis or encephalitis. Treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow.

Immune-related neuropathies

Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life threatening, were observed in patients receiving atezolizumab. Patients should be monitored for symptoms of motor and sensory neuropathy.

Treatment with atezolizumab must be permanently discontinued for any grade of myasthenic syndrome / myasthenia gravis or Guillain-Barré syndrome. Initiation of systemic corticosteroids (at a dose of 1 to 2 mg/kg/day of prednisone or equivalent) should be considered.

Immune-related pancreatitis

Pancreatitis, including increases in serum amylase and lipase levels, have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be closely monitored for signs and symptoms that are suggestive of acute pancreatitis.

Treatment with atezolizumab should be withheld for ≥ Grade 3 serum amylase or lipase levels increased (> 2 x ULN), or Grade 2 or 3 pancreatitis, and treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow. Treatment with atezolizumab may be resumed when serum amylase and lipase levels improve to ≤ Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4, or any grade of recurrent pancreatitis.

Immune-related myocarditis

Myocarditis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of myocarditis.

Treatment with atezolizumab should be withheld for Grade 2 myocarditis, and treatment with systemic corticosteroids at a dose of 1 to 2mg/kg/day of prednisone or equivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 myocarditis.

Infusion-related reactions

Infusion related reactions have been observed in clinical trials with atezolizumab (see section 4.8).

The rate of infusion should be reduced or treatment should be interrupted in patients with Grade 1 or 2 infusion related reactions. Atezolizumab should be permanently discontinued in patients with Grade 3 or 4 infusion related reactions. Patients with Grade 1 or 2 infusion-related reactions may continue to receive atezolizumab with close monitoring; premedication with antipyretic and antihistamines may be considered.

Patients excluded from clinical trials

Patients with the following conditions were excluded from clinical trials: a history of autoimmune disease, history of pneumonitis, active brain metastasis, HIV, hepatitis B or hepatitis C infection. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment; systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to study entry were excluded from clinical trials.

Patients with a baseline performance status ≥ 2 were excluded (apart from Study GO29293 [IMvigor210] Cohort 1 that enrolled patients with cisplatin ineligible urothelial carcinoma and allowed a baseline performance status ≥ 2) (see section 5.1).

In the absence of data, atezolizumab should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.

Use of atezolizumab in urothelial carcinoma for previously untreated patients who are considered cisplatin ineligible

The baseline and prognostic disease characteristics of the IMvigor210 Cohort 1 study population were overall comparable to patients in the clinic who would be considered cisplatin ineligible but would be eligible for a carboplatin-based combination chemotherapy. There are insufficient data for the subgroup of patients that would be unfit for any chemotherapy; therefore atezolizumab should be used with caution in these patients, after careful consideration of the potential balance of risks and benefits on an individual basis.

Patient Alert Card

All prescribers of Tecentriq must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of Tecentriq therapy with the patient. The patient will be provided with the Patient Alert Card and instructed to carry the card at all times.

4.5 Interaction with other medicinal products and other forms of interaction

No formal pharmacokinetic drug interaction studies have been conducted with atezolizumab. Since atezolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.

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-related adverse reactions after starting atezolizumab (see section 4.4).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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-related rejection of the developing foetus resulting in foetal death (see section 5.3). 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.

Breast-feeding

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 Tecentriq therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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 (see section 5.3). There were no effects on the male reproductive organs.

4.7 Effects on ability to drive and use machines

Tecentriq 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 (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The safety of Tecentriq is based on pooled data in 2,619 patients with metastatic UC and NSCLC. The most common adverse reactions were fatigue (34.3%), decreased appetite (26.2%), nausea (22.9%), dyspnoea (20.6%), diarrhoea (19.3%), rash (18.7%), pyrexia (19.4%), vomiting (14.6%), arthralgia (13.6%), asthenia (15.0%) and pruritus (11.8%).

Tabulated list of adverse reactions

The Adverse Drug Reactions (ADRs) are listed below by MedDRA system organ class (SOC) and categories of frequency. 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Summary of adverse reactions occurring in patients treated with Tecentriq in clinical trials

Blood and lymphatic system disorders

Common

thrombocytopenia

Immune system disorders

Common

hypersensitivity

Endocrine disorders

Common

hypothyroidisma, hyperthyroidismb

Uncommon

diabetes mellitusc, adrenal insufficiencyd

Rare

hypophysitis

Metabolism and nutrition disorders

Very common

decreased appetite

Common

hypokalaemia, hyponatremia

Nervous system disorders

Uncommon

Guillain-Barré syndromee, noninfective meningitisf

Rare

noninfective encephalitisg, myasthenic syndromeh

Cardiac disorders

Rare

myocarditish

Vascular disorders

Common

hypotension

Respiratory, thoracic, and mediastinal disorders

Very common

cough, dyspnoea

Common

pneumonitisi, hypoxia, nasal congestion,

Gastrointestinal disorders

Very common

nausea, vomiting, diarrhoea

Common

abdominal pain, colitisj, dysphagia,

Uncommon

pancreatitisk, lipase increased, amylase increased

Infections and infestations

Very common

urinary tract infectionsl

Hepatobiliary disorders

Common

AST increased, ALT increased, hepatitism

Skin and subcutaneous tissue disorders

Very Common

rashn, pruritus

Musculoskeletal and connective tissue disorders

Very common

Arthralgia, back pain

Common

musculoskeletal pain

General disorders and administration site conditions

Very Common

pyrexia, fatigue, asthenia

Common

infusion related reactiono, influenza like illness, chills

a Includes reports of hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, blood thyroid stimulating hormone decreased, myxoedema, thyroid function test abnormal, thyroiditis acute, thyroxine decreased.

b Includes reports of hyperthyroidism, endocrine ophthalmopathy, exophthalmused.

c Includes reports of diabetes mellitus, type 1 diabetes mellitus and diabetic ketoacidosis.

d Includes reports of adrenal insufficiency, primary adrenal insufficiency, and Addison's disease.

e Includes reports of Guillain-Barré syndrome and demyelinating polyneuropathy.

f Includes reports of meningitis.

g Includes reports of encephalitis.

h Reported in studies other than those in metastatic UC and NSCLC patients. The frequency is based on the exposure in 8,000 patients across all atezolizumab clinical trials.

i Includes reports of pneumonitis, lung infiltration, bronchiolitis, interstitial lung disease, radiation pneumonitis.

j Includes reports of colitis, autoimmune colitis, colitis ischaemic, colitis microscopic, colitis ulcerative.

k Includes reports of pancreatitis and pancreatitis acute.

l Includes reports of urinary tract infection, cystitis, pyelonephritis, escherichia urinary tract infection, urinary tract infection bacterial, kidney infection, pyelonephritis acute, urinary tract infection fungal, urinary tract infection pseudomonal.mIncludes reports of ascites, autoimmune hepatitis, hepatocellular injury, hepatitis, hepatitis acute, hepatotoxicity, liver disorder, drug-induced liver injury, hepatic failure, hepatic steatosis, hepatic lesion, esophageal varices hemorrhage, varices hemorrhage.

n Includes reports of acne, eczema, erythema, erythema of eyelid, erythema multiforme, exfoliative rash, eyelid rash, folliculitis, furuncle, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative, drug eruption, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash papulosquamous, rash pruritic, rash pustular, seborrhoeic dermatitis, skin exfoliation, skin toxicity, skin ulcer, toxic epidermal necrolysis, toxic skin eruption.

o Includes infusion related reaction and cytokine release syndrome.

Description of selected adverse reactions

The data below reflect exposure to atezolizumab for clinically significant adverse reactions in clinical studies (see section 5.1). The management guidelines for these adverse reactions are described in sections 4.2 and 4.4.

Immune-related pneumonitis

Pneumonitis occurred in 2.9% (75/2,619) of patients who received atezolizumab. Of the 75 patients, one experienced a fatal event. The median time to onset was 3.5 months (range 3 days to 20.5 months). The median duration was 1.5 months (range 1+ days to 15.1+ months; + denotes a censored value). Pneumonitis led to discontinuation of atezolizumab in 10 (0.4%) patients. Pneumonitis requiring the use of corticosteroids occurred in 1.5% (39/2,619) of patients receiving atezolizumab.

Immune-related hepatitis

Hepatitis occurred in 1.8% (47/2,619) of patients who received atezolizumab. Of the 47 patients, one experienced a fatal event The median time to onset was 1.4 months (range 8 days to 18.8 months). The median duration was 1.3 months (range 1+ day to 19.7+ months; + denotes a censored value). Hepatitis led to discontinuation of atezolizumab in 5 (0.2%) patients. Hepatitis requiring the use of corticosteroids occurred in 0.4% (10/2,619) of patients receiving atezolizumab.

Immune-related colitis

Colitis occurred in 1.2% (31/2,619) of patients who received atezolizumab. The median time to onset was 4.2 months (range 15 days to 17.2 months). The median duration was 1.2 months (range 1+ day to 17.8+ months; + denotes a censored value). Colitis led to discontinuation of atezolizumab in 7 (0.3%)patients. Colitis requiring the use of corticosteroids occurred in 0.6% (16/2,619) of patients receiving atezolizumab.

Immune-related endocrinopathies

Hypothyroidism occurred in 4.7% (122/2,619) of patients who received. The median time to onset was 5.1 months (range: 1 day to 31.3 months). Hyperthyroidism occurred in 1.0% (25/2,619) of patients who received atezolizumab. The median time to onset was 2.6 months (range 24 days to 15.7 months).

Adrenal insufficiency occurred in 0.3% (8/2,619) of patients who received atezolizumab. The median time to onset was 5.5 months (range: 2 days to 19 months). The median duration was 16.8 months (range: 1 day to 16.8 months). Adrenal insufficiency requiring the use of corticosteroids occurred in 0.2% (6/2,619) of patients receiving atezolizumab.

Hypophysitis occurred in < 0.1% (1/2,619) of patients who received atezolizumab. The time to onset for this patient was 13.7 months.

Diabetes mellitus occurred in 0.3% (8/2,619) of patients who received atezolizumab. The median time to onset was 3.6 months (range 2 days to 9.9 months). Diabetes mellitus led to the discontinuation of atezolizumab in 3 (< 0.1%) patient.

Immune-related meningoencephalitis

Meningitis occurred in 0.1% (3/2,619) of patients who received atezolizumab. The time to onset ranged from 15 to 16 days. The duration ranged from 14 days to 3.4 months. All three patients required the use of corticosteroids and discontinued atezolizumab.

Encephalitis occurred in < 0.1% (2/2,619) of patients who received atezolizumab. The time to onset was 14 and 16 days. Encephalitis led to discontinuation of atezolizumab in 1 (< 0.1%) patient. Encephalitis requiring the use of corticosteroids occurred in < 0.1% (1/2,619) of patients receiving atezolizumab.

Immune-related neuropathies

Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.2% (5/2,619) of patients who received atezolizumab. The median time to onset was 7 months (range: 20 days to 8.1 months). The median duration was 4.6 months (1+ day to 8.3+ 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% (2/2,619) of patients receiving atezolizumab.

Myasthenic syndrome

Myasthenia gravis occurred in < 0.1% (4/6,000) of patients across all atezolizumab clinical trials in multiple tumour types. The time to onset ranged from 20 days to 4 months. All four patients discontinued atezolizumab. Myasthenic syndrome/myasthenia gravis requiring the use of corticosteroids occurred in < 0.1% (3/6,000) of patients receiving atezolizumab.

Immune-related pancreatitis

Pancreatitis, including amylase increased and lipase increased, occurred in 0.6% (15/2,619) of patients who received atezolizumab. The median time to onset was 5.5 months (range: 9 days to 16.9 months). The median duration was 27 days (range 1+ day to 11.2+ months; + denotes a censored value). Pancreatitis led to the discontinuation of atezolizumab in 1 (<0.1%) patient. Pancreatitis requiring the use of corticosteroids occurred in 0.1% (3/2,619) of patients receiving atezolizumab.

Immune-related myocarditis

Myocarditis occurred in < 0.1% (2/8,000) of patients across all atezolizumab clinical trials in multiple tumour types. The time to onset was 18 and 33 days. Both patients required corticosteroids and discontinued atezolizumab.

Immunogenicity

In pooled assessment of studies IMvigor211 and OAK, 31.7% of patients tested positive for anti-atezolizumab antibodies (ATAs) at one or more post-dose time points. Overall, ATA positivity appeared to have no clinically relevant impact on pharmacokinetics, efficacy or safety.

No data are available to allow conclusions to be drawn on any possible effect of neutralising antibodies.

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 (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

There is no information on overdose with atezolizumab.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC

Mechanism of action

Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating immune cells, and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.

Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.

Clinical efficacy and safety

Duration of treatment

For previously untreated patients, treatment with Tecentriq was permitted until disease progression.

For previously treated patients in the pivotal studies treatment with Tecentriq was permitted until loss of clinical benefit as defined by the following criteria:

• Absence of symptoms and signs (including worsening of laboratory values [e.g., new or worsening hypercalcaemia]) indicating unequivocal progression of disease

• No decline in ECOG performance status

• Absence of tumour progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be readily managed and stabilised by protocol-allowed medical interventions prior to repeat dosing

• Evidence of clinical benefit as assessed by the investigator

Urothelial carcinoma

IMvigor211 (GO29294): Randomised trial in locally advanced or metastatic UC patients previously treated with chemotherapy

A phase III, open-label, multi-center, international, randomised study, (IMvigor211), was conducted to evaluate the efficacy and safety of atezolizumab compared with chemotherapy (investigator's choice of vinflunine, docetaxel, or paclitaxel) in patients with locally advanced or metastatic UC who progressed during or following a platinum-containing regimen. This study excluded patients who had a history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of a live, attenuated vaccine within 28 days prior to enrolment; and administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments were conducted every 9 weeks for the first 54 weeks, and every 12 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expression on tumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analyses described below.

A total of 931 patients were enrolled. Patients were randomised (1:1) to receive either atezolizumab or chemotherapy. Randomisation was stratified by chemotherapy (vinflunine vs taxane), PD-L1 expression status on IC (< 5% vs ≥ 5%), number of prognostic risk factors (0 vs. 1-3), and liver metastases (yes vs. no). Prognostic risk factors included time from prior chemotherapy of < 3 months, ECOG performance status > 0 and hemoglobin < 10 g/dL.

Atezolizumab was administered as a fixed dose of 1,200 mg by intravenous infusion every 3 weeks. No dose reduction of atezolizumab was allowed. Patients were treated until loss of clinical benefit as assessed by the investigator or unacceptable toxicity. Vinflunine was administered 320 mg/m2 by intravenous infusion on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. Paclitaxel was administered 175 mg/m2 by intravenous infusion over 3 hours on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. Docetaxel was administered 75 mg/m2 by intravenous infusion on day 1 of each 3-week cycle until disease progression or unacceptable toxicity. For all treated patients, the median duration of treatment was 2.8 months for the atezolizumab arm, 2.1 months for the vinflunine and paclitaxel arms and 1.6 months for the docetaxel arm.

The demographic and baseline disease characteristics of the primary analysis population were well balanced between the treatment arms. The median age was 67 years (range: 31 to 88), and 77.1% of patients were male. The majority of patients were white (72.1%), 53.9% of patients within the chemotherapy arm received vinflunine, 71.4% of patients had at least one poor prognostic risk factor and 28.8% had liver metastases at baseline. Baseline ECOG performance status was 0 (45.6%) or 1 (54.4%). Bladder was the primary tumour site for 71.1% of patients and 25.4% of patients had upper tract urothelial carcinoma. There were 24.2% of patients who received only prior platinum-containing adjuvant or neoadjuvant therapy and progressed within 12 months.

The primary efficacy endpoint for IMvigor211 is overall survival (OS). Secondary efficacy endpoints evaluated per investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 are objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Comparisons with respect to OS between the treatment arm and control arm within the IC2/3, IC1/2/3, and ITT (Intention-to-treat, i.e. all comers) populations were tested using a hierarchical fixed-sequence procedure based on a stratified log-rank test at two-sided level of 5% as follows: step 1) IC2/3 population; step 2) IC1/2/3 population; step 3) all comers population. OS results for each of steps 2 and 3 could be formally tested for statistical significance only if the result in the preceding step was statistically significant.

The median survival follow-up is 17 months. The primary analysis of study IMvigor211 did not meet its primary endpoint of OS. Atezolizumab did not demonstrate a statistically significant survival benefit compared to chemotherapy in patients with previously treated, locally advanced or metastatic urothelial carcinoma. Per the pre-specified hierarchical testing order, the IC2/3 population was tested first, with an OS HR of 0.87 (95% CI: 0.63, 1.21; median OS of 11.1 vs. 10.6 months for atezolizumab and chemotherapy respectively). The stratified log-rank p-value was 0.41 and therefore the results are considered not statistically significant in this population. As a consequence, no formal tests of statistical significance could be performed for OS in the IC1/2/3 or all comer populations, and results of those analyses would be considered exploratory. The key results in the all comer population are summarised in Table 3. The Kaplan-Meier curve for OS in the all comer population is presented in Figure 1.

Table 3: Summary of efficacy in all comers (IMvigor211)

Efficacy endpoint

Atezolizumab

(n = 467)

Chemotherapy

(n = 464)

Primary efficacy endpoint

OS*

No. of deaths (%)

324 (69.4%)

350 (75.4%)

Median time to events (months)

8.6

8.0

95% CI

7.8, 9.6

7.2, 8.6

Stratifiedǂ hazard ratio (95% CI)

0.85 (0.73, 0.99)

12-month OS (%)**

39.2%

32.4%

Secondary and exploratory endpoints

Investigator-assessed PFS (RECIST v1.1)

No. of events (%)

407 (87.2%)

410 (88.4%)

Median duration of PFS (months)

2.1

4.0

95% CI

2.1, 2.2

3.4, 4.2

Stratified hazard ratio (95% CI)

1.10 (0.95, 1.26)

Investigator-assessed ORR (RECIST v1.1)

n = 462

n = 461

No. of confirmed responders (%)

62 (13.4%)

62 (13.4%)

95% CI

10.45, 16.87

10.47, 16.91

No. of complete response (%)

16 (3.5%)

16 (3.5%)

No. of partial response (%)

46 (10.0%)

46 (10.0%)

No. of stable disease (%)

92 (19.9%)

162 (35.1%)

Investigator-assessed DOR (RECIST v1.1)

n = 62

n = 62

Median in months ***

21.7

7.4

95% CI

13.0, 21.7

6.1, 10.3

CI=confidence interval; DOR=duration of response; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.

* An analysis of OS in the all comer population was performed based on the stratified log-rank test and the result is provided for descriptive purposes only (p=0.0378); according to the pre-specified analysis hierarchy, the p-value for the OS analysis in the all comer population cannot be considered statistically significant.

ǂ Stratified by chemotherapy (vinflunine vs taxane), status on IC (<5% vs. ≥ 5%), number of prognostic risk factors (0 vs. 1-3), and liver metastases (yes vs. no).

** Based on Kaplan-Meier estimate

*** Responses were ongoing in 63% of responders in the atezolizumab arm and in 21% of responders in the chemotherapy arm.

Figure 1: Kaplan-Meier curve for overall survival (IMvigor211)

IMvigor210 (GO29293): Single-arm trial in previously untreated urothelial carcinoma patients who are ineligible for cisplatin therapy and in urothelial carcinoma patients previously treated with chemotherapy

A phase II, multi-centre, international, two-cohort, single-arm clinical trial, IMvigor210, was conducted in patients with locally advanced or metastatic UC (also known as urothelial bladder cancer).

The study enrolled a total of 438 patients and had two patient cohorts. Cohort 1 included previously untreated patients with locally advanced or metastatic UC who were ineligible or unfit for cisplatin-based chemotherapy or had disease progression at least 12 months after treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Cohort 2 included patients who received at least one platinum-based chemotherapy regimen for locally advanced or metastatic UC or had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen.

In Cohort 1, 119 patients were treated with atezolizumab 1,200 mg by intravenous infusion every 3 weeks until disease progression. The median age was 73 years. Most patients were male (81%), and the majority of patients were White (91%).

Cohort 1 included 45 patients (38%) with ECOG performance status of 0, 50 patients (42%) with ECOG performance status of 1 and 24 patients (20%) with ECOG performance status of 2, 35 patients (29%) with no Bajorin risk factors (ECOG performance status ≥ 2 and visceral metastasis), 66 patients (56%) with one Bajorin risk factor and 18 patients (15 %) with two Bajorin risk factors, 84 patients (71%) with impaired renal function (glomerular filtration rate [GFR] < 60 mL/min), and 25 patients (21%) with liver metastasis.

The primary efficacy endpoint for Cohort 1 was confirmed objective response rate (ORR) as assessed by an independent review facility (IRF) using RECIST v1.1.

The primary analysis was performed when all patients had at least 24 weeks of follow-up. Median duration of treatment was 15.0 weeks and median duration of survival follow-up was 8.5 months in all comers. Clinically relevant IRF-assessed ORRs per RECIST v1.1 were shown; however, when compared to a pre-specified historical control response rate of 10%, statistical significance was not reached for the primary endpoint. The confirmed ORRs per IRF-RECIST v1.1 were 21.9% (95% CI: 9.3, 40.0) in patients with PD-L1 expression ≥ 5%, 18.8% (95% CI: 10.9, 29.0) in patients with PD-L1 expression ≥ 1%, and 19.3% (95% CI: 12.7, 27.6) in all comers. The median duration of response (DOR) was not reached in any PD-L1 expression subgroup or in all comers. OS was not mature with an event patient ratio of approximately 40%. Median OS for all patient subgroups (PD-L1 expression ≥ 5 % and ≥ 1 %) and in all comers was 10.6 months.

An updated analysis was performed with a median duration of survival follow-up of 17.2 months for Cohort 1 and is summarised in Table 4. The median DOR was not reached in any PD-L1 expression subgroup or in all comers.

Table 4: Summary of updated efficacy (IMvigor210 Cohort 1)

Efficacy endpoint

PD-L1 expression of ≥ 5% in IC

PD-L1 expression of ≥ 1% in IC

All Comers

ORR (IRF-assessed; RECIST v1.1)

n = 32

n = 80

n = 119

No. of Responders (%)

9 (28.1%)

19 (23.8%)

27 (22.7%)

95% CI

13.8, 46.8

15.0, 34.6

15.5, 31.3

No. of complete response (%)

95% CI

4 (12.5%)

(3.5, 29.0)

8 (10.0%)

(4.4, 18.8)

11 (9.2%)

(4.7, 15.9)

No. of partial response (%)

95% CI

5 (15.6%)

(5.3, 32.8)

11 (13.8%)

(7.1, 23.3)

16 (13.4%)

(7.9, 20.9)

DOR (IRF-assessed; RECIST v1.1)

n = 9

n = 19

n = 27

Patients with event (%)

3 (33.3%)

5 (26.3%)

8 (29.6%)

Median (months) (95% CI)

NE (11.1, NE)

NE (NE)

NE (14.1, NE)

PFS (IRF-assessed; RECIST v1.1)

n = 32

n = 80

n = 119

Patients with event (%)

24 (75.0%)

59 (73.8%)

88 (73.9%)

Median (months) (95% CI)

4.1 (2.3, 11.8)

2.9 (2.1, 5.4)

2.7 (2.1, 4.2)

OS

n = 32

n = 80

n = 119

Patients with event (%)

18 (56.3%)

42 (52.5%)

59 (49.6%)

Median (months) (95% CI)

12.3 (6.0, NE)

14.1 (9.2, NE)

15.9 (10.4, NE)

1-year OS rate (%)

52.4%

54.8%

57.2%

CI=confidence interval; DOR=duration of response; IC= tumour-infiltrating immune cells; IRF= independent review facility; NE=not estimable; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.

In Cohort 2, the co-primary efficacy endpoints were confirmed ORR as assessed by an IRF using RECIST v1.1 and investigator-assessed ORR according to Modified RECIST (mRECIST) criteria. There were 310 patients treated with atezolizumab 1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit. The primary analysis of Cohort 2 was performed when all patients had at least 24 weeks of follow-up. The study met its co-primary endpoints in Cohort 2, demonstrating statistically significant ORRs per IRF-assessed RECIST v1.1 and investigator-assessed mRECIST compared to a pre-specified historical control response rate of 10%.

An analysis was also performed with a median duration of survival follow-up of 21.1 months for Cohort 2. The confirmed ORRs per IRF-RECIST v1.1 were 28.0% (95% CI: 19.5, 37.9) in patients with PD-L1 expression ≥ 5%, 19.3% (95% CI: 14.2, 25.4) in patients with PD-L1 expression ≥ 1%, and 15.8% (95% CI: 11.9, 20.4) in all comers. The confirmed ORR per investigator-assessed mRECIST was 29.0% (95% CI: 20.4, 38.9) in patients with PD-L1 expression ≥ 5%, 23.7% (95% CI: 18.1, 30.1) in patients with PD-L1 expression ≥ 1%, and 19.7% (95% CI: 15.4, 24.6) in all comers. The rate of complete response per IRF-RECIST v1.1 in the all comer population was 6.1% (95% CI: 3.7, 9.4). For Cohort 2, median DOR was not reached in any PD-L1 expression subgroup or in all comers, however was reached in patients with PD-L1 expression < 1% (13.3 months; 95% CI 4.2, NE). The OS rate at 12 month was 37% in all comers.

IMvigor130 (WO30070): Phase III multi-center, randomized, placebo-controlled study of atezolizumab as monotherapy and in combination with platinum-based chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma

Based on an independent Data Monitoring Committee (iDMC) recommendation following an early review of survival data, accrual of patients on the atezolizumab monotherapy treatment arm whose tumours have a low PD-L1 expression (less than 5% of immune cells staining positive for PD-L1 by immunohistochemistry) was stopped after observing decreased overall survival for this subgroup. The iDMC did not recommend any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm. No other changes were recommended.

Non-small cell lung cancer

OAK (GO28915): Randomised phase III trial in locally advanced or metastatic NSCLC patients previously treated with chemotherapy

A phase III, open-label, multi-center, international, randomised study, OAK, was conducted to evaluate the efficacy and safety of atezolizumab compared with docetaxel in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen. This study excluded patients who had a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrolment, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments were conducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expression on tumour cells (TC) and tumour-infiltrating immune cells (IC).

A total of 1225 patients were enrolled and per the analysis plan the first 850 randomised patients were included in the primary efficacy analysis. Randomisation was stratified by PD-L1 expression status on IC, by the number of prior chemotherapy regimens, and by histology. Patients were randomised (1:1) to receive either atezolizumab or docetaxel.

Atezolizumab was administered as a fixed dose of 1,200 mg by intravenous infusion every 3 weeks. No dose reduction was allowed. Patients were treated until loss of clinical benefit as assessed by the investigator. Docetaxel was administered 75 mg/m2 by intravenous infusion on day 1 of each 3-week cycle until disease progression. For all treated patients, the median duration of treatment was 2.1 months for the docetaxel arm and 3.4 months for the atezolizumab arm.

The demographic and baseline disease characteristics of the primary analysis population were well balanced between the treatment arms. The median age was 64 years (range: 33 to 85), and 61% of patients were male. The majority of patients were white (70%). Approximately three-quarters of patients had non-squamous histology (74%), 10% had known EGFR mutation, 0.2% had known ALK rearrangements, 10% had CNS metastases at baseline, and most patients were current or previous smokers (82%). Baseline ECOG performance status was 0 (37%) or 1 (63%). Seventy five percent of patients received only one prior platinum-based therapeutic regimen.

The primary efficacy endpoint was OS. The key results of this study with a median survival follow-up of 21 months are summarised in Table 5. Kaplan-Meier curves for OS in the ITT population are presented in Figure 2. Figure 3 summarises the results of OS in the ITT and PD-L1 subgroups, demonstrating OS benefit with atezolizumab in all subgroups, including those with PD-L1 expression < 1% in TC and IC.

Table 5: Summary of efficacy in the primary analysis population (all comers)* (OAK)

Efficacy endpoint

Atezolizumab

(n = 425)

Docetaxel

(n = 425)

Primary efficacy endpoint

OS

No. of deaths (%)

271 (64%)

298 (70%)

Median time to events (months)

13.8

9.6

95% CI

(11.8, 15.7)

(8.6, 11.2)

Stratifiedǂ hazard ratio (95% CI)

0.73 (0.62, 0.87)

p-value**

0.0003

12-month OS (%)***

218 (55%)

151 (41%)

18-month OS (%)***

157 (40%)

98 (27%)

Secondary endpoints

Investigator-assessed PFS (RECIST v1.1)

No. of events (%)

380 (89%)

375 (88%)

Median duration of PFS (months)

2.8

4.0

95% CI

(2.6, 3.0)

(3.3, 4.2)

Stratified hazard ratio (95% CI)

0.95 (0.82, 1.10)

Investigator-assessed ORR (RECIST v1.1)

No. of responders (%)

58 (14%)

57 (13%)

95% CI

(10.5, 17.3)

(10.3, 17.0)

Investigator-assessed DOR (RECIST v1.1)

n = 58

n = 57

Median in months

16.3

6.2

95% CI

(10.0, NE)

(4.9, 7.6)

CI=confidence interval; DOR=duration of response; NE=not estimable; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.

*The primary analysis population consists of the first 850 randomised patients

ǂStratified by PD-L1 expression in tumour infiltrating immune cells, the number of prior chemotherapy regimens, and histology

** Based on the stratified log-rank test

*** Based on Kaplan-Meier estimates

Figure 2: Kaplan-Meier curve for overall survival in the primary analysis population (all comers) (OAK)

Figure 3: Forest plot of overall survival by PD-L1 expression in the primary analysis population (OAK)

aStratified HR for ITT and TC or IC ≥ 1%. Unstratified HR for other exploratory subgroups.

An improvement in OS was observed with atezolizumab compared to docetaxel in both non-squamous NSCLC patients (hazard ratio [HR] of 0.73, 95% CI: 0.60, 0.89; median OS of 15.6 vs. 11.2 months for atezolizumab and docetaxel, respectively) and squamous NSCLC patients (HR of 0.73, 95% CI: 0.54, 0.98; median OS of 8.9 vs. 7.7 months for atezolizumab and docetaxel, respectively). The observed OS improvement was consistently demonstrated across subgroups of patients including those with brain metastases at baseline (HR of 0.54, 95% CI: 0.31, 0.94; median OS of 20.1 vs. 11.9 months for atezolizumab and docetaxel respectively) and patients who were never smokers (HR of 0.71, 95% CI: 0.47, 1.08; median OS of 16.3 vs. 12.6 months for atezolizumab and docetaxel, respectively). However, patients with EGFR mutations did not show improved OS with atezolizumab compared to docetaxel (HR of 1.24, 95% CI: 0.71, 2.18; median OS of 10.5 vs. 16.2 months for atezolizumab and docetaxel, respectively).

Prolonged time to deterioration of patient-reported pain in chest as measured by the EORTC QLQ-LC13 was observed with atezolizumab compared to docetaxel (HR of 0.71, 95% CI: 0.49, 1.05; median not reached in either arm). The time to deterioration in other lung cancer symptoms (i.e. cough, dyspnoea, and arm/shoulder pain) as measured by the EORTC QLQ-LC13 was similar between atezolizumab and docetaxel. These results should be interpreted with caution due to the open-label design of the study.

POPLAR (GO28753): Randomised phase II trial in locally advanced or metastatic NSCLC patients previously treated with chemotherapy

A phase II, multi-centre, international, randomised, open-label, controlled study, POPLAR, was conducted in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The primary efficacy outcome was overall survival. A total of 287 patients were randomised 1:1 to receive either atezolizumab (1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit) or docetaxel (75 mg/m2 by intravenous infusion on day 1 of each 3-week cycle until disease progression). Randomisation was stratified by PD-L1 expression status on IC, by the number of prior chemotherapy regimens and by histology. An updated analysis with a total of 200 deaths observed and a median survival follow-up of 22 months showed a median OS of 12.6 months in patients treated with atezolizumab, vs. 9.7 months in patients treated with docetaxel (HR of 0.69, 95% CI: 0.52, 0.92). ORR was 15.3% vs. 14.7% and median DOR was 18.6 months vs. 7.2 months for atezolizumab vs. docetaxel, respectively.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Tecentriq in all subsets of the paediatric population in the treatment of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Exposure to atezolizumab increased dose proportionally over the dose range 1 mg/kg to 20 mg/kg including the fixed dose 1,200 mg administered every 3 weeks. A population analysis that included 472 patients described atezolizumab pharmacokinetics for the dose range: 1 to 20 mg/kg with a linear two-compartment disposition model with first-order elimination. A population pharmacokinetic analysis suggests that steady-state is obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the curve, maximum concentration and trough concentration was 1.91, 1.46 and 2.75-fold, respectively.

Absorption

Atezolizumab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.

Distribution

A population pharmacokinetic analysis indicates that central compartment volume of distribution is 3.28 L and volume at steady-state is 6.91 L in the typical patient.

Biotransformation

The metabolism of atezolizumab has not been directly studied. Antibodies are cleared principally by catabolism.

Elimination

A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day and the typical terminal elimination half-life is 27 days.

Special populations

Based on population PK and exposure-response analyses age (21-89 years), region, ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG performance status have no effect on atezolizumab pharmacokinetics. Body weight, gender, positive ATA status, albumin levels and tumour burden have a statistically significant, but not clinically relevant effect on atezolizumab pharmacokinetics. No dose adjustments are recommended.

Elderly

No dedicated studies of atezolizumab have been conducted in elderly patients. The effect of age on the pharmacokinetics of atezolizumab was assessed in a population pharmacokinetic analysis. Age was not identified as a significant covariate influencing atezolizumab pharmacokinetics based on patients of age range of 21-89 years (n=472), and median of 62 years of age. No clinically important difference was observed in the pharmacokinetics of atezolizumab among patients < 65 years (n=274), patients between 65-75 years (n=152) and patients > 75 years (n=46) (see section 4.2).

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of atezolizumab in children or adolescents.

Renal impairment

No dedicated studies of atezolizumab have been conducted in patients with renal impairment. In the population pharmacokinetic analysis, no clinically important differences in the clearance of atezolizumab were found in patients with mild (estimated glomerular filtration rate [eGFR] 60 to 89 mL/min/1.73 m2; n=208) or, moderate (eGFR 30 to 59 mL/min/1.73 m2; n=116) renal impairment compared to patients with normal (eGFR greater than or equal to 90 mL/min/1.73 m2; n=140) renal function. Only a few patients had severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2; n=8) (see section 4.2). The effect of severe renal impairment on the pharmacokinetics of atezolizumab is unknown.

Hepatic impairment

No dedicated studies of atezolizumab have been conducted in patients with hepatic impairment. In the population pharmacokinetic analysis, there were no clinically important differences in the clearance of atezolizumab between patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 × to 1.5 × ULN and any AST, n= 71) and normal hepatic function (bilirubin and AST ≤ ULN, n= 401). No data are available in patients with either moderate or severe hepatic impairment. Hepatic impairment was defined by the National Cancer Institute (NCI) criteria of hepatic dysfunction (see section 4.2). The effect of moderate or severe hepatic impairment (bilirubin > 1.5 × to 3 × ULN and any AST or bilirubin > 3 × ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.

5.3 Preclinical safety data

Carcinogenicity

Carcinogenicity studies have not been performed to establish the carcinogenic potential of atezolizumab.

Mutagenicity

Mutagenicity studies have not been performed to establish the mutagenic potential of atezolizumab. However, monoclonal antibodies are not expected to alter DNA or chromosomes.

Fertility

No fertility studies have been conducted with atezolizumab; however assessment of the cynomolgus monkey male and female reproductive organs was included in the chronic toxicity study. Weekly administration of atezolizumab to female monkeys at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries which were reversible. There was no effect on the male reproductive organs.

Teratogenicity

No reproductive or teratogenicity studies in animals have been conducted with atezolizumab. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to immune-related rejection of the developing foetus resulting in foetal death. Administration of atezolizumab could cause foetal harm, including embryo-foetal lethality.

6. Pharmaceutical particulars
6.1 List of excipients

L-histidine

Glacial acetic acid

Sucrose

Polysorbate 20

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

3 years.

Diluted solution

Chemical and physical in-use stability has been demonstrated for no more than 24 hours at 2 °C to 8 °C or 24 hours at ≤ 30 °C from the time of preparation.

From a microbiological point of view, the prepared solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C or 8 hours at ambient temperature (≤ 25 °C).

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vial with a butyl rubber stopper containing 20 mL of solution.

Pack of one vial.

6.6 Special precautions for disposal and other handling

Tecentriq does not contain any antimicrobial preservative and should be prepared by a healthcare professional using aseptic technique.

Do not shake.

Instructions for dilution

Twenty mL of Tecentriq concentrate should be withdrawn from the vial and diluted into a 250 mL PVC, polyethylene (PE) or polyolefin infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection. After dilution, one mL of solution should contain approximately 4.4 mg of Tecentriq (1,200 mg/270 mL). The bag should be gently inverted to mix the solution in order to avoid foaming. Once the infusion is prepared it should be administered immediately (see section 6.3).

Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. If particulates or discoloration are observed, the solution should not be used.

No incompatibilities have been observed between Tecentriq and intravenous bags with product-contacting surfaces of polyvinyl chloride (PVC), polyethylene (PE) or polyolefin (PO). In addition, no incompatibilities have been observed with in-line filter membranes composed of polyethersulfone or polysulfone, and infusion sets and other infusion aids composed of PVC, PE, polybutadiene, or polyetherurethane. The use of in-line filter membranes is optional.

Disposal

The release of Tecentriq in the environment should be minimised. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

8. Marketing authorisation number(s)

EU/1/17/1220/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 21 September 2017

10. Date of revision of the text

02 July 2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.