Consumer medicine information

Tecentriq

Atezolizumab

BRAND INFORMATION

Brand name

Tecentriq

Active ingredient

Atezolizumab

Schedule

SUMMARY CMI

Tecentriq^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Tecentriq?

Tecentriq contains the active ingredient atezolizumab. Tecentriq is used to treat different types of cancers.

For more information, see Section 1. Why am I using Tecentriq? in the full CMI.

2. What should I know before I use Tecentriq?

Do not use if you have ever had an allergic reaction to Tecentriq or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Tecentriq? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tecentriq and affect how it works.

For more information see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Tecentriq?

Tecentriq is given by a slow drip into a vein (intravenous (IV) infusion) by a doctor or nurse once every two, three or four weeks. The first infusion will be over 60 minutes. If the first infusion is well tolerated, your infusion time may be shortened to 30 minutes. More instructions can be found in Section 4. How do I use Tecentriq? in the full CMI.

5. What should I know while using Tecentriq?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Tecentriq. Tell your doctor if you are pregnant, think you might be pregnant or are planning to become pregnant.
Driving or using machines	Be careful driving or operating machinery until you know how Tecentriq affects you.

For more information, see Section 5. What should I know while using Tecentriq? in the full CMI.

6. Are there any side effects?

Like all medicines, Tecentriq can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of your treatment.

When you are using Tecentriq, you can have some serious side effects. Serious side effects associated with Tecentriq may include lung problems, liver problems, intestinal problems, heart problems, muscle problems, kidney problems, problems in hormone glands (for example thyroid, pituitary, adrenal problems or diabetes), the nervous system, the skin, the immune system and other organs. The most common side effects when Tecentriq is used on its own include diarrhoea, nausea, vomiting, urinary tract infection, decreased appetite, feeling tired or weak, fever, cough, shortness of breath, rash, itchy skin and headache. The most common side effects when Tecentriq was given in combination with other anti-cancer medicines include feeling tired or weak, constipation, swelling of legs or arms, lung infections, hair loss, high blood pressure and common cold.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

Tecentriq^® (Tee-sen-trik)

Active ingredient(s): atezolizumab

This medicine has provisional approval in Australia for the treatment of locally advanced or metastatic triple-negative breast cancer. The decision to approve this medicine has been made on the basis of promising results from preliminary studies. More evidence is required to be submitted when available to fully confirm the benefit and safety of the medicine for this use.

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tecentriq. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Tecentriq.

Where to find information in this leaflet:

1. Why am I using Tecentriq?
2. What should I know before I use Tecentriq?
3. What if I am taking other medicines?
4. How do I use Tecentriq?
5. What should I know while using Tecentriq?
6. Are there any side effects?
7. Product details

1. Why am I using Tecentriq?

Tecentriq contains the active ingredient atezolizumab. Tecentriq works by attaching to a specific protein in your body called ‘PD-L1’. This protein makes the immune system in the body work less well. By attaching to the protein, Tecentriq works by helping your immune system fight your cancer.

Tecentriq may be given in combination with other medicines. It is important you read the Consumer Medicine Information for those medicines. Please ask your doctor if you have any questions about Tecentriq or any other medicines used with Tecentriq.

Tecentriq is used to treat:

non-small cell lung cancer, when the lung cancer has not spread to other parts of the body. Treatment will be given after surgery takes place and after chemotherapy has been given.
non-small cell lung cancer, when the lung cancer has spread to other parts of the body. Tecentriq is used together with other medicines (bevacizumab, paclitaxel and carboplatin; or nab-paclitaxel and carboplatin). Tecentriq can also be used as a single treatment (monotherapy) if the cancer has come back after previous treatment.
a type of cancer that affects the bladder and the urinary system, called “urothelial carcinoma”.
a type of cancer that affects the lungs, called small cell lung cancer (SCLC). Tecentriq is used together with the chemotherapy medicines etoposide and carboplatin.
a type of cancer that affects the breasts called triple-negative breast cancer. It is used if you have not received prior chemotherapy for this type of cancer. Tecentriq will be given to you together with nab-paclitaxel.
a type of cancer that affects the liver called hepatocellular carcinoma. Tecentriq is used together with a medicine called bevacizumab when the liver cancer is unable to be removed by surgery or has spread to other parts of the body

2. What should I know before I use Tecentriq?

Warnings

Do not use Tecentriq if:

you are allergic to atezolizumab, or any of the ingredients listed at the end of this leaflet.

Check with your doctor if you:

have any immune system problems such as Crohn's disease, ulcerative colitis, or lupus
have inflammation of the lungs (called ‘pneumonitis’)
have human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome
have liver problems, such as hepatitis
have thyroid problems
have been given a live, attenuated vaccine recently
have been told your cancer has spread to your brain
take any medicines for any other condition
have any allergies to any other medicines, foods, preservatives or dyes

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant. Tecentriq can harm your unborn baby.

If you are a woman who is able to become pregnant, you should use an effective method of birth control during your treatment with Tecentriq and for at least 5 months after your last dose of Tecentriq. Talk to your healthcare provider about birth control methods that you can use during this time.

Tell your doctor right away if you become pregnant during treatment with Tecentriq.

Tell your doctor if you are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with Tecentriq.

It is not known if Tecentriq passes into your breastmilk. A risk to the breastfed infant cannot be excluded.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop. Tell your doctor or pharmacist if you are taking other medicines that make your immune system weak, such as immunosuppressants and/or steroids

Some medicines may interfere with Tecentriq and affect how it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Tecentriq.

4. How do I use Tecentriq?

How to use Tecentriq

Tecentriq is prepared by a prepared by a healthcare professional and given by a drip into a vein (called an "intravenous infusion" or "IV").

Your first infusion of Tecentriq will be given over 60 minutes. Your doctor will monitor you carefully during the first infusion. If you do not have an infusion reaction, the next infusion may be given over 30 minutes.

When to use Tecentriq

Tecentriq is given every two weeks, every three weeks or every four weeks.
Your doctor will decide how long you should receive Tecentriq, this will depend on your response to the medicine and the state of your disease. If you are receiving Tecentriq for lung cancer after surgery, you may receive Tecentriq for up to 1 year.

If you forget to use Tecentriq

As Tecentriq is given under the supervision of your doctor, you are unlikely to miss a dose. However, if you forget or miss your appointment to receive Tecentriq, make another appointment as soon as possible.

If you use too much Tecentriq

As Tecentriq is given under the supervision of your doctor, it is unlikely that you will be given too much. However, if you experience any side effects after being given Tecentriq, tell your doctor immediately.

5. What should I know while using Tecentriq?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are receiving Tecentriq.

Tell any other doctors, dentists, and pharmacists who treat you that you are receiving this medicine.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

If you are a woman who is able to become pregnant, you must use effective contraception while you are being treated with Tecentriq and for at least 5 months after the last dose.

If you become pregnant while you are being treated with Tecentriq tell your doctor.

Ask your doctor if you should stop breastfeeding or if you should stop treatment with Tecentriq.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Tecentriq affects you. It is not known whether Tecentriq may impair your ability to drive or operate machinery.

6. Are there any side effects?

Like all medicines, Tecentriq can cause side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tecentriq may cause side effects that appear weeks or months after your last dose. See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

These side effects can sometimes become life-threatening and can lead to death. These side effects may happen anytime during treatment or even after your treatment has ended. You may experience more than one side effect at the same time. Some side effects can only be found when your doctor does blood tests from time to time to check your progress.

If you have any of the following symptoms, call or see your doctor right away.

Serious side effects

Serious side effects

What to do

Signs and symptoms of lung problems:

new or worsening cough
chest pain

Signs and symptoms of liver problems:

yellowing of skin and/or eyes
nausea and/or vomiting
bleeding or bruising
dark urine
stomach pain

Signs and symptoms of intestinal problems:

diarrhoea (watery, loose or soft stools)
blood in stools
stomach pain

Signs and symptoms of thyroid problems:

tiredness
weight loss or weight gain
changes in mood or behaviour
visual disturbances
increased sensitivity to cold or heat
slow or rapid heart rate
hair loss
constipation
headache and/or dizziness

Signs and symptoms of blood sugar problems (type 1 diabetes mellitus) and acid in the blood caused by diabetes (diabetic ketoacidosis):

feeling more hungry or thirsty than usual
need to urinate more often
weight loss
feeling tired

Signs and symptom of problems with the brain and the membrane around the spinal cord and brain:

neck stiffness
headache
fever
chills
vomiting
eye sensitivity to light
confusion and sleepiness
muscle weakness in the legs and arms
problems with mobility, the bladder and bowel

Signs and symptoms of problems with the nerves:

muscle weakness, numbness or tingling in hands and feet
difficulty with facial movements
pins and needles sensation in your fingers and toes
inability to walk or climb stairs
paralysis of the facial muscles

Signs and symptoms of problems with the pancreas:

abdominal pain
nausea and/or vomiting

Signs and symptoms of problems with the heart:

shortness of breath
difficulty breathing and speaking
feeling tired
irregular heart beat and/or pounding/racing heart beat (palpitations)
chest pain
fainting and/or light-headedness
swelling of legs or abdomen
pale and/or clammy skin

Signs and symptoms of problems with the muscles:

muscle pain or stiffness
skin rash

Signs and symptoms of problems with the kidneys:

change in urine output and/or colour
pain in pelvis
swelling of the body (oedema)

Signs and symptoms of infusion reactions:

fever
chills
flushing
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Signs and symptoms of severe skin reactions:

rash
itching
skin blistering, peeling or sores
ulcers in the mouth or in lining of the nose, throat or genital area

Signs and symptoms of excessive activation of the immune system:

fever
swollen lymph nodes
skin rash
yellow colour of the skin and eyes (jaundice)
lung (coughing, difficulty breathing), stomach (vomiting, diarrhoea) and nervous system (headache, changes in vision, weakness) symptoms

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

The following side effects have also been reported, in addition to the serious side effects above:

Side effects

What to do

The following side effects were reported when Tecentriq was given alone (monotherapy)

Signs and symptoms of lung problems

feeling tired with no energy (fatigue)
cough

Signs and symptoms of problems with your heart

dizziness or light-headedness

Signs and symptoms of problems with your kidneys

strong and frequent urge to urinate
cloudy, bloody, or strong-smelling urine
pain or a burning sensation when urinating

Signs and symptom of problems with your blood pressure

dizziness or light headedness
fainting
lack of concentration

Signs and symptoms of low oxygen levels in your blood (hypoxia):

changes of the colour of your skin
sweating

Signs and symptoms of systemic inflammatory disorder (sarcoidosis):

shortness of breath
cough
chest discomfort and/or pain
tender, painful, reddish bumps or patches on the skin
swollen and painful joints
swollen lymph nodes
eye pain
blurry vision and/or light sensitivity

Signs and symptoms of problems in other organs:

bleeding, bruising or blood in the urine or stool
red, itchy scaly patches of skin, including dry and cracked skin
dry skin
sore throat
difficulty swallowing
common cold
flu-like symptoms
nasal congestion
back, muscle, bone, tendon, joint or nerve pain
generalised weakness, tiredness and droopy eyelids
loss of appetite
pain and redness of the eye, including light sensitivity, dark floating spots in vision and blurred vision

The following side effects were reported in clinical trials when Tecentriq was given in combination with other medicines (in addition to those above).

Signs and symptoms of low iron in your blood (anaemia)

tiredness
headaches
being short of breath when exercising
dizziness
looking pale

Signs and symptoms of problems with your lungs

bronchitis
infections such as pneumonia

Signs and symptom of problems with your kidneys (proteinuria)

foamy or bubbly urine
swelling in the face, feet or ankles
muscle cramps at night

Signs and symptom of problems with your blood pressure

severe headaches
nose bleeds
irregular heartbeat

Signs and symptoms of problems in other organs:

a change in the way things taste
low white blood cell count, which can increase the risk of infection
inflamed and sore mouth, mouth ulcers and/or cold sores
dry mouth
constipation
changes in your voice or hoarseness
hair loss
swelling to the arms and legs (peripheral oedema)

Speak to your doctor straight away if you have any of these side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Tecentriq contains

Active ingredient
(main ingredient)

atezolizumab

Other ingredients
(inactive ingredients)

glacial acetic acid

histidine

sucrose

polysorbate 20

water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Tecentriq looks like

Tecentriq is a colourless to slightly yellow solution. Tecentriq is supplied as a single use glass vial and is available in two presentations:

840 mg of atezolizumab in 14 mL solution (AUST R 310681) and
1200 mg of atezolizumab in 20 mL solution (AUST R 277120)

Who distributes Tecentriq

Tecentriq is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30 – 34 Hickson Road
Sydney NSW 2000
AUSTRALIA

Medical enquiries: 1800 233 950 or via www.medinfo.roche.com/australia

This leaflet was prepared in March 2023.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Tecentriq

Active ingredient

Atezolizumab

Schedule

1 Name of Medicine

Atezolizumab.

2 Qualitative and Quantitative Composition

Tecentriq 840 mg/14 mL concentrated injection.

Each vial of 14 mL contains 840 mg of atezolizumab at a concentration of 60 mg/mL.

Tecentriq 1200 mg/20 mL concentrated injection.

Each vial of 20 mL contains 1200 mg of atezolizumab at a concentration of 60 mg/mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrated injection for intravenous infusion. Tecentriq is supplied as a single-use vial containing either 14 mL or 20 mL preservative-free, colourless to slightly yellow solution, at a concentration of 60 mg/mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Early-stage non-small cell lung cancer.

Tecentriq as monotherapy is indicated as adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adult patients with stage II to IIIA (as per 7th edition of the UICC/AJCC staging system) NSCLC whose tumours have PD-L1 expression on ≥ 50% of tumour cells.

Metastatic non-small cell lung cancer.

Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous non-small cell lung cancer (NSCLC). In patients with EGFR mutant or ALK-positive NSCLC, Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated only after failure of appropriate targeted therapies.
Tecentriq, in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and carboplatin, is indicated for first-line treatment of patients with metastatic non-squamous NSCLC who do not have tumour EGFR or ALK genomic aberrations.
Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC after prior chemotherapy. Patients with EGFR mutant or ALK-positive NSCLC should also have received targeted therapies before receiving Tecentriq.

Small cell lung cancer.

Tecentriq, in combination with carboplatin and etoposide, is indicated for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Urothelial carcinoma.

Tecentriq is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
are considered cisplatin ineligible and whose tumours express PD-L1 (PD-L1 stained tumour-infiltrating immune cells [IC] covering ≥ 5% of the tumour area), as determined by a validated test; or
are considered ineligible for any other platinum-containing chemotherapy regardless of the level of tumour PD-L1 expression.
This indication is approved based on overall response rate and duration of response in a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established.

Hepatocellular carcinoma.

Tecentriq, in combination with bevacizumab, is indicated for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.

4.2 Dose and Method of Administration

General.

Tecentriq must be initiated and supervised by physicians experienced in the treatment of cancer.
Tecentriq must be administered as an intravenous (IV) infusion. Do not administer as an IV push or bolus.
The initial dose of Tecentriq must be administered over 60 minutes. If the first infusion is tolerated all subsequent infusions may be administered over 30 minutes.
Do not co-administer other medicinal products through the same infusion line.
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 in the patient medical record.
Atezolizumab was originally developed using an every-three-weeks monotherapy dosing regimen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Subsequent approval of the every-two-weeks and every-four-weeks dosing regimens were based on pharmacokinetic and exposure-response modelling and simulations. Data from randomised controlled trials of every-two-weeks or every-four-weeks versus every-three-weeks dosing of atezolizumab, with sufficient sample size to demonstrate non-inferiority using clinical endpoint data (such as PFS or OS), is not available.

Dose.

Tecentriq monotherapy.

Patient selection for urothelial carcinoma.

Select cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma for treatment with Tecentriq based on the PD-L1 expression on tumour infiltrating immune cells confirmed by a validated test (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
See Table 1.

Tecentriq in combination therapy. Please also refer to the Product Information for the combination products.
See Table 2.

Delayed or missed doses.

If a planned dose of Tecentriq is missed, it should be administered as soon as possible. The schedule of administration must be adjusted to maintain the appropriate interval between doses.

Dose modifications.

Dose reductions of Tecentriq are not recommended. See Table 3.

Dose delay or discontinuation.

Also see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).

Patients treated with Tecentriq must be given the Patient Alert Card and be informed about the risks of Tecentriq.

Special dosage instructions.

Paediatric use.

The safety and efficacy of Tecentriq in children and adolescents below 18 years of age have not been established. Available safety data are described in Section 4.4.

Use in the elderly.

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is required in patients ≥ 65 years of age (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Use in Asian patients.

Due to increased haematologic toxicities observed in Asian patients in study GO29436 (IMpower150), it is recommended that the starting dose of paclitaxel should be 175 mg/m² every three weeks.

Renal impairment.

Based on a population pharmacokinetic analysis, no dose adjustment is required in patients with mild or moderate renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). 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 or moderate hepatic impairment. Tecentriq has not been studied in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Eastern cooperative oncology group (ECOG) performance status ≥ 2.

Patients with ECOG performance status ≥ 2 were excluded from the clinical trials in NSCLC, ES-SCLC and HCC (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Instructions for dilution.

Tecentriq does not contain any antimicrobial preservative and should be prepared by a healthcare professional using aseptic technique. Use a sterile needle and syringe to prepare Tecentriq.
Withdraw the required volume of Tecentriq concentrate from the vial and dilute to the required administration volume in a polyvinyl chloride (PVC), polyethylene (PE), polyolefin or polypropylene (PP) infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection. After dilution, the final concentration of the diluted solution should be between 3.2 mg/mL and 16.8 mg/mL. The bag should be gently inverted to mix the solution in order to avoid foaming.
Tecentriq must not be mixed with other medicinal products.

Instructions for administration.

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.
The product is for single use in one patient only. Discard any residue.
Tecentriq must not be mixed with other medicinal products.
Do not co-administer other medicinal products through the same infusion line.

4.3 Contraindications

Tecentriq is contraindicated in patients with a known hypersensitivity to atezolizumab or any of the excipients.

4.4 Special Warnings and Precautions for Use

Assessment of PD-L1 status.

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations.

Immune-mediated adverse reactions.

Most immune-mediated adverse reactions occurring during treatment with Tecentriq were reversible with interruptions of Tecentriq and initiation of corticosteroids and/or supportive care. Immune-mediated adverse reactions affecting more than one body system have been observed. Immune-mediated adverse reactions with Tecentriq may occur after the last dose of Tecentriq. For suspected immune-mediated adverse reactions, a thorough evaluation to confirm aetiology or exclude other causes should be performed. Based on the severity of the adverse reaction, Tecentriq should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroids should be tapered over ≥ 1 month. Based on limited data from clinical studies in patients whose immune-mediated adverse reactions could not be controlled with systemic corticosteroid use, administration of other systemic immunosuppressants may be considered.
Tecentriq must be permanently discontinued for any Grade 3 immune-mediated adverse reaction that recurs; for any Grade 4 immune-mediated adverse reactions (except for endocrinopathies that are controlled with replacement hormones); and for some Grade 2 and 3 immune-mediated adverse reactions (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Immune-mediated pneumonitis.

Cases of pneumonitis, including fatal cases, have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of pneumonitis.
Treatment with Tecentriq should be withheld for Grade 2 pneumonitis, and 1 to 2 mg/kg prednisone or equivalent per day should be started. If symptoms improve to ≤ Grade 1, taper corticosteroids over ≥ 1 month. Treatment with Tecentriq 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 Tecentriq must be permanently discontinued for Grade 3 or 4 pneumonitis.

Immune-mediated hepatitis.

Cases of hepatitis, some leading to fatal outcomes, have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of hepatitis. Monitor aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin prior to and periodically during treatment with Tecentriq. Appropriate management of patients with abnormal liver function tests (LFTs) at baseline should be considered.
Treatment with Tecentriq should be withheld if Grade 2 (ALT or AST > 3 to 5 x ULN or blood bilirubin > 1.5 to 3.0 x ULN) persists for more than 5 to 7 days, and 1 to 2 mg/kg prednisone or equivalent per day should be started. If the event improves to ≤ Grade 1, taper corticosteroids over ≥ 1 month.
Treatment with Tecentriq may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg oral prednisone or equivalent per day. Treatment with Tecentriq 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-mediated colitis.

Cases of diarrhoea or colitis have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of colitis.
Treatment with Tecentriq 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, start 1 - 2 mg/kg prednisone or equivalent per day. Treat Grade 3 diarrhoea or colitis with IV corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent). Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1, taper corticosteroids over ≥ 1 month. Treatment with Tecentriq may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg oral prednisone or equivalent per day. Treatment with Tecentriq must be permanently discontinued for Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis.

Immune-mediated endocrinopathies.

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis, have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be monitored for clinical signs and symptoms of endocrinopathies and for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation). Patients may present with the following: fatigue, headache, mental status changes, heat or cold intolerance, tachycardia or bradycardia, unusual bowel habits, weight change, polyuria/polydipsia, blurred vision. Unless an alternative aetiology has been identified, signs and symptoms of endocrinopathies should be conservatively considered immune-mediated. Appropriate management of patients with abnormal thyroid function tests at baseline should be considered.
Asymptomatic patients with abnormal thyroid function tests can receive Tecentriq. For symptomatic hypothyroidism, Tecentriq 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, Tecentriq should be withheld and an anti-thyroid drug should be initiated as needed. Treatment with a beta blocker may also be considered. Treatment with Tecentriq may be resumed when symptoms are controlled and thyroid function is improving.
For symptomatic adrenal insufficiency, Tecentriq should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg per day of methylprednisolone or equivalent) should be started. Once symptoms improve, follow with 1 to 2 mg/kg per day of prednisone or equivalent. If symptoms improve to ≤ Grade 1, taper corticosteroids over ≥ 1 month. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required).
Treatment with Tecentriq should be withheld for Grade 2 or Grade 3 hypophysitis. Treatment with intravenous corticosteroids (1 to 2 mg/kg per day IV methylprednisolone or equivalent) should be started, and hormone replacement should be initiated as needed. Once symptoms improve, treatment with 1 to 2 mg/kg per 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 per day prednisone or equivalent and the patient is stable on replacement therapy (if required). Treatment with Tecentriq 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 greater than 13.9 mmol/L), Tecentriq should be withheld. Treatment with Tecentriq may be resumed if metabolic control is achieved on insulin replacement therapy.

Immune-mediated meningoencephalitis.

Meningoencephalitis has been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for clinical signs and symptoms of meningitis or encephalitis.
Treatment with Tecentriq must be permanently discontinued for any grade of meningitis or encephalitis. Treatment with intravenous corticosteroids (1 to 2 mg/kg IV methylprednisolone or equivalent per day) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg oral prednisone or equivalent per day should follow.

Immune-mediated neuropathies.

Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life-threatening, and facial paresis were observed in patients receiving Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for symptoms of motor and sensory neuropathy.
Treatment with Tecentriq must be permanently discontinued for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg oral prednisone or equivalent per day.
Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 facial paresis. Treatment with Tecentriq should be withheld for Grade 1 or 2 facial paresis, and treatment with systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) should be considered. Treatment may be resumed when symptoms improve to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day.

Immune-mediated myelitis.

Myelitis has been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be closely monitored for signs and symptoms that are suggestive of myelitis. Treatment with Tecentriq must be permanently discontinued for Grade 2, 3 or 4 myelitis.

Immune-mediated pancreatitis.

Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be closely monitored for signs and symptoms that are suggestive of acute pancreatitis.
Treatment with Tecentriq should be withheld for ≥ Grade 3 serum amylase or lipase levels increased (> 2.0 ULN), or Grade 2 or 3 pancreatitis, and treatment with intravenous corticosteroids (1 to 2 mg/kg methylprednisolone or equivalent per day), should be started. Once symptoms improve, follow with 1 to 2 mg/kg oral prednisone or equivalent per day. Treatment with Tecentriq 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 Tecentriq should be permanently discontinued for Grade 4, or any grade of recurrent pancreatitis.

Haemophagocytic lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, has been reported in patients receiving Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). HLH should be considered when the presentation of cytokine release syndrome is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH. Treatment with Tecentriq must be permanently discontinued for suspected haemophagocytic lymphohistiocytosis.

Immune-mediated myocarditis.

Myocarditis, including fatal cases, has been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of myocarditis. Myocarditis may also be a clinical manifestation of myositis and should be managed accordingly.
Treatment with Tecentriq should be withheld for suspected myocarditis and treatment with systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent should be started. Treatment with Tecentriq must be permanently discontinued for Grade 2 or above myocarditis.

Immune-mediated myositis.

Cases of myositis, including fatal cases, have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of myositis. Patients with possible myositis should be monitored for signs of myocarditis.
Treatment with Tecentriq should be withheld for Grade 2 or 3 myositis and corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) should be initiated. If symptoms improve to ≤ Grade 1, taper corticosteroids as clinically indicated. Treatment with Tecentriq 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 Tecentriq should be permanently discontinued for Grade 4 or Grade 3 recurrent myositis.

Immune-mediated pericardial disorders.

Pericardial disorders, including pericarditis, pericardial effusion and cardiac tamponade, some leading to fatal outcomes, have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). Patients should be monitored for clinical signs and symptoms of pericardial disorders.
For suspected Grade 1 pericarditis, treatment with Tecentriq should be withheld and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. For suspected Grade 2, 3 or 4 pericardial disorders, treatment with Tecentriq should be withheld, prompt treatment with systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent should be started and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of a pericardial disorder event is established, treatment with Tecentriq must be permanently discontinued for Grade 2, 3 or 4 pericardial disorders.

Immune-mediated nephritis.

Nephritis has been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for changes in renal function.
Treatment with Tecentriq should be withheld for Grade 2 nephritis. Treatment with systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) should be initiated. Treatment with Tecentriq may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg prednisone or equivalent per day. Tecentriq must be permanently discontinued for Grade 3 or 4 nephritis.

Immune-mediated severe cutaneous adverse reactions.

Immune-mediated severe cutaneous adverse reactions (SCARs), including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving Tecentriq. Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, Tecentriq should be withheld for Grade 3 skin reactions and treatment with systemic corticosteroids at a dose of 1-2 mg/kg/day of prednisone or equivalent should be initiated. 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 Tecentriq should be permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered at a dose of 1-2 mg/kg/day of prednisone or equivalent.
For suspected SCARs, patients should be referred to a specialist for further diagnosis and management. Tecentriq should be withheld for patients with suspected SJS or TEN. For confirmed SJS or TEN, Tecentriq should be permanently discontinued.
Caution should be used when considering the use of Tecentriq in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.

Autoimmune haemolytic anaemia.

Tecentriq can cause autoimmune haemolytic anaemia (AIHA). Patients should be monitored for signs and symptoms of drug-induced AIHA, and if this adverse reaction is observed, administration of Tecentriq should be permanently discontinued. Treatment for AIHA should be initiated, as deemed medically appropriate.

Infusion-related reactions.

Infusion related reactions (IRRs), including hypersensitivity and anaphylaxis, have been observed in clinical trials with Tecentriq (see Section 4.8 Adverse Effects (Undesirable Effects)).
The rate of infusion should be reduced or treatment should be interrupted in patients with Grade 1 or 2 infusion related reactions. Tecentriq 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 Tecentriq with close monitoring; premedication with an antipyretic and antihistamines may be considered.

Disease-specific precautions.

Patients excluded from clinical trials.

Patients with the following conditions were excluded from clinical trials: 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 Pharmacodynamic Properties).

Use of Tecentriq in combination with bevacizumab, paclitaxel and carboplatin in metastatic non-squamous NSCLC.

Physicians should carefully consider the combined risks of the four-drug regimen of Tecentriq, bevacizumab, paclitaxel, and carboplatin before initiating treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with NSCLC that had clear tumour infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions, as seen on imaging, were excluded from the pivotal clinical study IMpower150 after several cases of fatal pulmonary haemorrhage were observed, which is a known risk factor of treatment with bevacizumab. In the absence of data, Tecentriq should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.

Use of Tecentriq 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 Tecentriq should be used with caution in these patients, after careful consideration of the potential balance of risks and benefits on an individual basis.

Use of Tecentriq in combination with bevacizumab in hepatocellular carcinoma.

Bleeding (including fatal events) is a known adverse reaction with bevacizumab. Serious bleeding events, including fatalities, have occurred in hepatocellular cancer patients treated with the combination of Tecentriq and bevacizumab.
There is lack of clinical data to support the combination of Tecentriq and bevacizumab in hepatocellular cancer patients with bleeding varices (including recent bleeds), untreated varices or varices at high risk of bleeding because these patients were excluded from treatment with Tecentriq and bevacizumab in the IMbrave150 pivotal study (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Carefully consider the risks of Tecentriq plus bevacizumab in patients with HCC before initiating treatment. Patients with HCC should be evaluated for the presence of varices and have varices treated as indicated within 6 months prior to initiating therapy with the combination of Tecentriq and bevacizumab.
Refer to the bevacizumab Product Information for full prescribing information on the risks of bleeding events.

Use in hepatic impairment.

Based on a population pharmacokinetic analysis, no dose adjustment is required for patients with mild or moderate hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). There are no data in patients with moderate or severe hepatic impairment.

Use in renal impairment.

Based on a population pharmacokinetic analysis, no dose adjustment is required in patients with mild or moderate renal impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Use in the elderly.

No overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Tecentriq is not approved for use in patients under the age of 18 years. The safety and efficacy of Tecentriq in the population has not been established. An early phase study conducted in paediatric and young adult patients did not demonstrate clinical benefit of atezolizumab.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal pharmacokinetic drug-drug interaction studies have been conducted with Tecentriq. Since Tecentriq 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-mediated adverse reactions after starting atezolizumab.

4.6 Fertility, Pregnancy and Lactation

Effects on 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. Atezolizumab had an effect on menstrual cycles in all female monkeys in the 50 mg/kg/week dose group characterised by an irregular cycle pattern during the dosing phase and correlated with the lack of fresh corpora lutea in the ovaries at the terminal necropsy; this effect was reversible during the dose-free recovery period. The AUC at the no effect level (15 mg/kg/week) was approximately 3.5 times that anticipated in patients at the clinical dose yielding the highest exposure. There was no effect on the male reproductive organs.
(Category D)
Based on the mechanism of action, the use of Tecentriq may cause foetal harm. Administration of Tecentriq is expected to have an adverse effect on pregnancy and poses a risk to the human foetus, including embryofoetal lethality. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to an increased risk of immune-mediated rejection of the developing foetus resulting in foetal death.
No dedicated reproductive or teratogenicity studies in animals have been conducted with atezolizumab.
There are no clinical studies of Tecentriq in pregnant women. Tecentriq is not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. Pregnant women should be advised of the potential risk to the foetus.
Women of childbearing potential should use highly effective contraception during treatment with Tecentriq and for 5 months after the last dose.
The safety of Tecentriq during labor and delivery has not been established.
It is not known whether atezolizumab is excreted in human breast milk. No studies have been conducted to assess the impact of atezolizumab on milk production or its presence in breast milk. As the potential for harm to the nursing infant is unknown, a decision must be made to either discontinue breast-feeding or discontinue Tecentriq therapy.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and to use machines have been performed.
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.

4.8 Adverse Effects (Undesirable Effects)

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 < 1/1000), very rare (< 1/10,000).

Tecentriq monotherapy.

The safety of Tecentriq as a monotherapy is based on pooled data in 3178 patients across multiple tumour types with supporting data from the estimated cumulative exposure in > 13,000 patients across all clinical trials. The most common adverse reactions (> 10%) were fatigue (35.9%), decreased appetite (25.5%), nausea (23.5%), cough (20.8%), dyspnoea (20.5%), pyrexia (20.1%), diarrhoea (19.7%), rash (19.3%), musculoskeletal pain (15.4%), back pain (15.3%), vomiting (15.0%), asthenia (14.5%), arthralgia (13.9%), pruritus (12.6%), headache (11.1%) and urinary tract infection (11.6%).
Table 4 summarises the adverse drug reactions (ADRs) that have been reported in association with the use of Tecentriq monotherapy.

Tecentriq combination therapy.

The safety of Tecentriq given in combination with other medicinal products is based on pooled data in 4,371 patients in clinical trials across multiple tumour types. Additional ADRs associated with the use of Tecentriq in combination therapy (not reported in monotherapy trials) are summarised in Table 5. ADRs with a clinically relevant difference when compared to monotherapy (see Table 4) are also presented. The most common adverse reactions (≥ 10%) were anaemia (36.8%), neutropenia (35.8%), thrombocytopenia (27.7%), alopecia (26.4%), constipation (25.7%), peripheral neuropathy (23.0%), hypertension (14.0%), hypothyroidism (13.4%), leucopenia (13.1%), lung infection (12.9%), peripheral oedema (10.3%) and nasopharyngitis (10.1%).

One patient treated with Tecentriq in combination with carboplatin and etoposide in Study GO30081 (IMpower133) experienced Grade 3 anaphylaxis and discontinued treatment with Tecentriq.

Additional information for selected adverse reactions.

The data below reflect information for significant adverse reactions for Tecentriq monotherapy. Details for the significant adverse reactions for Tecentriq when given in combination are presented if clinically relevant differences were noted in comparison to Tecentriq monotherapy. See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use for management of the following:
Immune-mediated pneumonitis. Pneumonitis occurred in 2.7% (87/3178) of patients who received Tecentriq monotherapy. Of the 87 patients, one event was fatal. The median time to onset was 3.4 months (range: 0.1 to 24.8 months). The median duration was 1.4 months (range 0 to 21.2⁺ months; ⁺ denotes a censored value). Pneumonitis led to discontinuation of Tecentriq in 12 (0.4%) patients. Pneumonitis requiring the use of corticosteroids occurred in 1.6% (51/3178) of patients receiving Tecentriq.
Immune-mediated hepatitis. Hepatitis occurred in 2.0% (62/3178) of patients who received Tecentriq monotherapy. Of the 62 patients, two events were fatal. The median time to onset was 1.5 months (range 0.2 to 18.8 months). The median duration was 2.1 months (range 0 to 22.0⁺ months; ⁺ denotes a censored value). Hepatitis led to discontinuation of Tecentriq in 6 (0.2%) patients. Hepatitis requiring the use of corticosteroids occurred in 0.6% (18/3178) of patients receiving Tecentriq.
Immune-mediated colitis. Colitis occurred in 1.1% (34/3178) of patients who received Tecentriq. The median time to onset was 4.7 months (range 0.5 to 17.2 months). The median duration was 1.2 months (range 0.1 to 17.8⁺ months; ⁺ denotes a censored value). Colitis led to discontinuation of Tecentriq in 8 (0.3%) patients. Colitis requiring the use of corticosteroids occurred in 0.6% (19/3178) of patients receiving Tecentriq.
Immune-mediated endocrinopathies.

Thyroid disorders.

Hypothyroidism occurred in 5.2% (164/3178) of patients who received Tecentriq monotherapy. The median time to onset was 4.9 months (range 0 to 31.3 months).
Hyperthyroidism occurred in 0.9% (30/3178) of patients who received Tecentriq monotherapy. The median time to onset was 2.1 months (range 0.7 to 15.7 months). The median duration was 2.6 months (range: 0⁺ to 17.1⁺ months; ⁺ denotes a censored value).
Hyperthyroidism occurred in 4.9% (23/473) of patients who received Tecentriq in combination with carboplatin and nab-paclitaxel. Hyperthyroidism led to discontinuation in 1 (0.2%) patient.

Adrenal insufficiency.

Adrenal insufficiency occurred in 0.3% (11/3178) of patients who received Tecentriq monotherapy. The median time to onset was 5.5 months (range 0.1 to 19.0 months). The median duration was 16.8 months (range 0 to 16.8 months). Adrenal insufficiency led to discontinuation of Tecentriq in 1 (< 0.1%) patient. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.3% (9/3178) of patients receiving Tecentriq.
Adrenal insufficiency occurred in 1.5% (7/473) of patients who received Tecentriq in combination with carboplatin and nab-paclitaxel. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.8% (4/473) of patients receiving Tecentriq in combination with carboplatin and nab-paclitaxel.

Hypophysitis.

Hypophysitis occurred in < 0.1% (2/3178) of patients who received Tecentriq monotherapy. The median time to onset was 7.2 months (range: 0.8 to 13.7 months). One patient required the use of corticosteroids and treatment with Tecentriq was discontinued.
Hypophysitis occurred in 0.8% (3/393) of patients who received Tecentriq 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 led to the discontinuation of treatment in one patient.

Diabetes mellitus.

Diabetes mellitus occurred in 0.3% (10/3178) of patients who received Tecentriq monotherapy. The median time to onset was 4.2 months (range 0.1 to 9.9 months). The median duration was 1.6 months (range: 0.1 to 15.2⁺ months; ⁺ denotes a censored value). Diabetes mellitus led to the discontinuation of Tecentriq in 3 (< 0.1%) patients.
Immune-mediated meningoencephalitis. Meningoencephalitis occurred in 0.4% (14/3178) of patients who received Tecentriq monotherapy. The median time to onset was 0.5 months (range 0 to 12.5 months). The median duration was 0.7 months (range 0.2 to 14.5⁺ months; ⁺ denotes a censored value). Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (6/3178) of patients receiving Tecentriq and led to discontinuation of Tecentriq in 4 (0.1%) patients.
Immune-mediated neuropathies.

Guillain-Barré syndrome and demyelinating polyneuropathy.

Guillain-Barré syndrome and demyelinating polyneuropathy, occurred in 0.2% (5/3178) of patients who received Tecentriq monotherapy. The median time to onset was 7.0 months (range: 0.6 to 8.1 months). The median duration was 8.0 months (0.6 to 8.3⁺ months; ⁺ denotes a censored value). Guillain-Barré syndrome led to the discontinuation of Tecentriq in 1 (< 0.1%) patient. Guillain-Barré syndrome requiring the use of corticosteroids occurred in < 0.1% (2/3178) of patients receiving Tecentriq.

Facial paresis.

Facial paresis occurred in < 0.1% (1/3178) of patients who received Tecentriq monotherapy. The time to onset was 0.95 months. The duration was 1.1 months. The event did not require the use of corticosteroids and the event did not lead to the discontinuation of Tecentriq.
Immune-mediated myelitis. Myelitis occurred in < 0.1% (1/3178) of patients who received Tecentriq monotherapy. The time to onset was 0.76 months. The event required the use of corticosteroids but did not lead to the discontinuation of Tecentriq.
Immune-mediated pancreatitis. Pancreatitis, including amylase increased and lipase increased, occurred in 0.6% (18/3178) of patients who received Tecentriq monotherapy. The median time to onset was 5.0 months (range 0.3 to 16.9 months). The median duration was 0.8 months (range 0.1 to 12.0⁺ months; ⁺ denotes a censored value). Pancreatitis led to discontinuation of Tecentriq in 3 (< 0.1%) patients. Pancreatitis requiring the use of corticosteroids occurred in 0.1% (4/3178) of patients receiving Tecentriq.
Haemophagocytic lymphohistiocytosis. Haemophagocytic lymphohistiocytosis (HLH) occurred in < 0.1% (1/3178) of patients who received Tecentriq monotherapy. The time to onset was 1.6 months. The duration was 1.4 months. HLH led to discontinuation of Tecentriq in 1 (< 0.1%) patient. The patient did not require the use of corticosteroids.
Immune-mediated myocarditis. Myocarditis occurred in < 0.1% (2/8000) of patients across all Tecentriq clinical trials in multiple tumour types and treatment combinations. The time to onset was 18 and 33 days. Both patients required corticosteroids and discontinued Tecentriq.
Immune-mediated pericardial disorders. Pericardial disorders occurred in 1.4% (45/3178) of patients who received Tecentriq monotherapy. The median time to onset was 1.4 months (range 0.2 to 17.5 months). The median duration was 1.4 months (range 0 to 19.3 months). Pericardial disorders led to discontinuation of Tecentriq in 3 (< 0.1%) patients. Pericardial disorders requiring the use of corticosteroids occurred in 0.2% (7/3178) of patients.
Immune-mediated myositis. Myositis occurred in 0.4% (13/3178) of patients who received Tecentriq monotherapy. The median time to onset was 5.1 months (range 0.7 to 11.0 months). The median duration was 5.0 months (range 0.7 to 22.6⁺ months, ⁺ denotes a censored value). Myositis led to discontinuation of Tecentriq in 1 (< 0.1%) patient. Seven (0.2%) patients required the use of corticosteroids.
Immune-mediated nephritis. Nephritis occurred in < 0.1% (3/3178) of patients who received Tecentriq monotherapy. The median time to onset was 13.1 months (range 9.0 to 17.5 months). The median duration was 2.8 months (range 0.5 to 9.5⁺ months, ⁺ denotes a censored value). Nephritis led to discontinuation of Tecentriq in 2 (< 0.1%) of patients. One patient required the use of corticosteroids.
Immune-mediated severe cutaneous adverse reactions. Severe cutaneous adverse reactions (SCARs) occurred in 0.7% (22/3178) of patients who received Tecentriq monotherapy. The median time to onset was 5.9 months (range 0.1 to 15.5 months). The median duration of the first event was 1.6 months (range 0 to 22.1⁺ months; ⁺ denotes a censored value). SCARs led to discontinuation of Tecentriq in 3 (< 0.1%) patients. SCARs requiring the use of systemic corticosteroids occurred in 0.2% (6/3178) of patients receiving Tecentriq monotherapy.
Use of Tecentriq in combination with bevacizumab, paclitaxel and carboplatin. In Study GO29436 (IMpower150), an overall higher frequency of adverse events was observed in the four-drug regimen of Tecentriq, bevacizumab, paclitaxel, and carboplatin compared to Tecentriq, 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 Tecentriq (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 Tecentriq in combination with bevacizumab, paclitaxel and carboplatin. Other clinically significant adverse events which were observed more frequently in the Tecentriq, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to atezolizumab with the incidence of antibodies to other products may be misleading.
Across multiple phase II and III studies, 13.1% to 54.1% of patients developed treatment-emergent anti-drug antibodies (ADAs) and 4.3% to 27.5% of patients developed neutralising antibodies (NAbs). The median time to ADA onset ranged from 3 weeks to 5 weeks.
A decrease in exposure (9% increase in clearance) was observed in ADA-positive patients compared to ADA-negative patients; however, this effect on exposure is not expected to be clinically meaningful given the flat exposure-response relationship and adequate target exposure achieved regardless of ADA status.
Patients who developed treatment emergent ADAs tended to have overall poorer health and disease characteristics at baseline. 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 develop ADA compared to patients who did not develop ADA.
Across pooled datasets for patients treated with atezolizumab monotherapy and with combination therapies, the rates of adverse events (AEs) which have been observed for the ADA-positive population compared to the ADA-negative population is presented in Table 6. Available data do not allow conclusions to be drawn on possible patterns of adverse drug reactions or their causal relationship with ADAs.

Laboratory abnormalities.

All identified laboratory abnormalities were reported as ADRs. See Section 4.4 Special Warnings and Precautions for Use, Immune-mediated hepatitis, Immune-mediated endocrinopathies for management of the following: AST, ALT, bilirubin; thyroid function.

Postmarketing experience.

The following adverse reactions have been identified during post-approval use of Tecentriq (see Table 7). Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no information on overdose with Tecentriq.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells suppresses cytotoxic T-cell activity through the inhibition of T-cell proliferation and cytokine production. PD-L1 may be expressed on tumour cells and tumour-infiltrating immune cells, and can contribute to the inhibition of the anti-tumour immune response in the microenvironment.
Atezolizumab is an Fc-engineered humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and blocks interactions with the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 pathway-mediated inhibition of the immune response, including reactivating the anti-tumour immune response. Atezolizumab leaves the PD-L2/PD-1 interaction intact, allowing PD-L2/PD-1 mediated inhibitory signals to persist. In syngeneic mouse tumour models, blocking PD-L1 activity resulted in decreased tumour growth.

PD-L1 expression by immunohistochemistry.

The VENTANA PD-L1 (SP142) Assay has been validated to detect PD-L1 expression in tumour-infiltrating immune cells (IC) and tumour cells (TC). The VENTANA PD-L1 (SP263) Assay has been validated to detect PD-L1 expression in TC.
The test detects the presence of any discernible PD-L1 staining of any intensity.
Scoring for tumour cells was defined as TC0 (< 1%), TC1 (≥ 1% and < 5%), TC2 (≥ 5% and < 50%), and TC3 (≥ 50%). Scoring for tumour-infiltrating immune cells was defined as IC0 (< 1%), IC1 (≥ 1% and < 5%), IC2 (≥ 5% and < 10%) and IC3 (≥ 10%).

Clinical trials.

Non-small cell lung cancer. Early-stage NSCLC.

GO29527.

A phase III, open-label, multi-centre, randomised study, GO29527 (IMpower010), was conducted to evaluate the efficacy and safety of Tecentriq for the adjuvant treatment of patients with stage IB (tumours ≥ 4 cm) - IIIA NSCLC (per the Union for International Cancer Control/American Joint Committee on Cancer staging system, 7th edition). A total of 1280 enrolled patients had complete tumour resection and were eligible to receive up to 4 cycles of cisplatin-based chemotherapy. The cisplatin-based chemotherapy regimens are described in Table 8.

After completion of cisplatin-based chemotherapy (up to four cycles), a total of 1005 patients were randomised in a 1:1 ratio to receive Tecentriq (Arm A) or best supportive care (BSC) (Arm B). Tecentriq was administered as a fixed dose of 1200 mg by IV infusion every 3 weeks for 16 cycles unless there was disease recurrence or unacceptable toxicity. Randomisation was stratified by sex, stage of disease, histology, and PD L1 expression.
Patients were excluded if they had a history of autoimmune disease; administration of a live, attenuated vaccine within 28 days prior to randomisation; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomisation. Tumour assessments were conducted at baseline of the randomisation phase and every 4 months for the first year following Cycle 1, Day 1 and then every 6 months until year five, then annually thereafter.
The median age was 62 years (range: 26 to 84), and 67% of patients were male. The majority of patients were White (73%), and 24% were Asian. Most patients were current or previous smokers (78%) and baseline ECOG performance status in patients was 0 (55%) or 1 (44%). Overall, 12% of patients had stage IB, 47% had stage II and 41% had stage IIIA disease. As measured by the VENTANA PD-L1 (SP263) Assay, 55% of patients had tumors with PD-L1 expression ≥ 1% on TC and 26% of patients had tumours with PD-L1 expression ≥ 50% on TC.
The primary efficacy outcome measure was disease-free survival (DFS) as assessed by the investigator. DFS was defined as the time from the date of randomisation to the date of occurrence of any of the following: first documented recurrence of disease, new primary NSCLC, or death due to any cause, whichever occurred first. DFS was assessed hierarchically in the following patient populations: stage II-IIIA NSCLC with PD-L1 expression ≥ 1% TC, all randomised patients with stage II-IIIA NSCLC, and all randomised ITT patients. DFS in the PD-L1 ≥ 50% TC stage II-IIIA population and OS in the ITT population were pre-specified key secondary objectives.
At the time of the interim DFS analysis, the study met its primary endpoint and demonstrated a statistically significant improvement in DFS in the Tecentriq arm compared to the BSC arm in the PD-L1 ≥ 1% TC stage II - IIIA patient population. The median follow-up time was approximately 32 months.
In the secondary objective analysis of stage II-IIIA patients with PD-L1 TC ≥ 50%, a clinically meaningful improvement in DFS was shown in the Tecentriq arm compared to the BSC arm with an unstratified HR of 0.43 (95% CI: 0.27, 0.68). The OS data were immature at the time of the DFS interim analysis.
The key efficacy results are summarised in Table 9. The Kaplan-Meier curve for DFS for the PD-L1 ≥ 50% TC stage II-IIIA patient population is presented in Figure 1.

1L metastatic non-squamous NSCLC.

IMpower150 (GO29436).

A phase III, open-label, multicentre, international, randomised study, IMpower150 (GO29436), was conducted to evaluate the efficacy and safety of Tecentriq in combination with paclitaxel and carboplatin, with or without bevacizumab, in chemotherapy-naïve patients with metastatic non-squamous NSCLC.
Patients were excluded if they had history of autoimmune disease, administration of a live, attenuated vaccine within 28 days prior to randomisation, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomisation, active or untreated CNS metastases, clear tumour infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions, as seen on imaging. Tumour assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Tumour specimens were evaluated for PD-L1 expression on tumour cells (TC) and tumour-infiltrating immune cells (IC) using the VENTANA PD-L1 (SP142) Assay and the results were used to define the PD-L1 expression subgroups for the analyses described below.
A total of 1202 patients were enrolled and were randomised (1:1:1) to receive one of the treatment regimens described in Table 10. Randomisation was stratified by sex, presence of liver metastases and PD-L1 tumour expression on TC and IC.

The demographics and baseline disease characteristics of the study population were well balanced between the treatment arms. The median age was 63 years (range: 31 to 90), and 60% of patients were male. The majority of patients were White (82%). Approximately 10% of patients had known EGFR mutation, 4% had known ALK rearrangements, 14% had liver metastasis at baseline, and most patients were current or previous smokers (80%). Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (43%) or 1 (57%). 51% of patients' tumours had PD-L1 expression of ≥ 1% TC or ≥ 1% IC and 49% of patients' tumours had PD-L1 expression of < 1% TC and < 1% IC.
At the time of the final analysis for PFS, patients had a median follow up time of 15.3 months. The ITT population, including patients with EGFR mutations or ALK rearrangements who should have been previously treated with tyrosine kinase inhibitors, demonstrated clinically meaningful PFS improvement in Arm B as compared to Arm C (HR of 0.61, 95% CI: 0.52, 0.72; median PFS 8.3 vs. 6.8 months).
At the time of the interim OS analysis, patients had a median follow-up of 19.7 months. The key results from this analysis as well as from the updated PFS analysis in the ITT population are summarised in Tables 11 and 12. The Kaplan-Meier curve for OS in the ITT population is presented in Figure 2. Figure 3 summarises the results of OS in the ITT and PD-L1 subgroups. Updated PFS results are also presented in Figures 4 and 5.

In Arm B as compared to Arm C, pre-specified subgroup analyses from the interim OS analysis showed an OS improvement for patients with EGFR mutations or ALK rearrangements (hazard ratio [HR] of 0.54, 95% CI: 0.29, 1.03; median OS not reached vs. 17.5 months), and liver metastases (HR of 0.52, 95% CI: 0.33, 0.82; median OS 13.3 vs 9.4 months). PFS improvements were also shown in patients with EGFR mutations or ALK rearrangements (HR of 0.55, 95% CI: 0.35, 0.87; median PFS 10.0 vs. 6.1 months) and liver metastases (HR of 0.41, 95% CI: 0.26, 0.62; median PFS 8.2 vs. 5.4 months). OS results were similar for patients aged < 65 and ≥ 65 subgroups, respectively. Data for patients ≥ 75 years of age are too limited to draw conclusions on this population. For all subgroup analyses, formal statistical testing was not planned.

IMpower130 (GO29537).

A phase III, open-label, randomised study, IMpower130 (GO29537) was conducted to evaluate the efficacy and safety of Tecentriq in combination with nab-paclitaxel and carboplatin, in chemotherapy-naïve patients with metastatic non-squamous NSCLC. Patients including those with EGFR or ALK genomic tumour aberrations, were enrolled and were randomised in a 2:1 ratio to receive one of the treatment regimens described in Table 13. Randomisation was stratified by sex, presence of liver metastases and PD-L1 tumour expression on tumour cells (TC) and tumour infiltrating cells (IC). Patients in treatment regimen B were able to crossover and receive Tecentriq monotherapy following disease progression.

Patients were excluded if they had history of autoimmune disease, administration of live, attenuated vaccine within 28 days prior to randomisation, administration of immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomisation, and active or untreated CNS metastases. Tumour assessments were conducted every 6 weeks for the first 48 weeks following cycle 1, then every 9 weeks thereafter.
The demographics and baseline disease characteristics of the study population (n = 723) were well balanced between the treatment arms. The median age was 64 years (range 18 to 86). The majority of the patients were, male (57%), White (90%). 14.8% of patients had liver metastases at baseline, and most patients were current or previous smokers (88%). The majority of patients had ECOG performance status of 0 or 1, with the latter group representing 58.6% of the patients.
The primary analysis was conducted in all patients, excluding those with EGFR or ALK genomic tumour aberrations (n = 679). Patients had a median survival follow up time of 18.6 months. Improvements in OS and PFS were demonstrated with Tecentriq + nab-paclitaxel + carboplatin compared to the control. The key results are summarised in Table 14 and Kaplan-Meier curves for OS and PFS are presented in Figures 6 and 8, respectively.
All PD-L1 subgroups, regardless of expression, derived benefit in terms of OS and PFS; the results are summarised in Figures 7 and 9. Consistent OS and PFS benefit was demonstrated in all other pre-specified subgroups, with the exception of patients with liver metastases who did not show improved OS with Tecentriq, nab-paclitaxel and carboplatin, compared to nab-paclitaxel and carboplatin (HR of 1.04, 95% CI: 0.63, 1.72).
Approximately 66% of patients in the nab-paclitaxel and carboplatin arm received any anti-cancer therapy after disease progression compared to 39% in the Tecentriq, nab-paclitaxel and carboplatin arm. These included, approximately 59% of patients in the nab-paclitaxel and carboplatin arm received any cancer immunotherapy after disease progression, which includes Tecentriq as crossover (41% of all patients), compared to 7.3% in the Tecentriq, nab-paclitaxel and carboplatin arm.

The study also evaluated physical function and patient reported treatment-related symptoms using the EORTC QLQ-C30 and EORTC QLQ-LC13 measures. On average, patients who received Tecentriq with nab-paclitaxel and carboplatin reported high functioning and no clinically meaningful worsening in treatment-related symptoms. There was no difference in delay of lung-related symptoms (dyspnoea, cough and chest pain) however patients receiving Tecentriq, nab-paclitaxel and carboplatin reported less worsening of these symptoms over time.
2L NSCLC.

OAK (GO28915).

A phase III, open-label, multicentre, international, randomised study, OAK (GO28915), was conducted to evaluate the efficacy and safety of Tecentriq compared with docetaxel in patients with locally advanced or metastatic NSCLC who have progressed during or following a platinum-containing regimen. A total of 1225 patients were enrolled, with the primary analysis population consisting of the first 850 randomised patients. Eligible patients were stratified by PD-L1 expression status in tumour-infiltrating immune cells (IC), by the number of prior chemotherapy regimens, and by histology. Patients were randomised (1:1) to receive either Tecentriq or docetaxel. 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 medications within 2 weeks prior to enrolment. Tumour assessments were conducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter.
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 disease (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.
Tecentriq was administered as a fixed dose of 1200 mg by IV 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 at 75 mg/m² by IV infusion on day 1 of each 21 day 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 Tecentriq arm.
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 15. Kaplan-Meier curves for OS in the ITT population are presented in Figure 10. Figure 11 summarises the results of OS in the ITT and PD-L1 subgroups, demonstrating OS benefit with Tecentriq in all subgroups, including the TC0/IC0 subgroup (PD-L1 expression < 1% in TC and IC).

An improvement in OS was observed with Tecentriq 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 Tecentriq 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 Tecentriq 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 Tecentriq 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 Tecentriq and docetaxel, respectively). However, patients with EGFR mutations did not show improved OS with Tecentriq compared to docetaxel (HR of 1.24, 95% CI: 0.71, 2.18; median OS of 10.5 vs. 16.2 months for Tecentriq and docetaxel, respectively).
Prolonged time to deterioration of patient-reported pain in chest as measured by the EORTC QLQ-LC13 was observed with Tecentriq compared with docetaxel (HR 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 Tecentriq and docetaxel. The average global health status and functioning scores (i.e. physical, role, social, emotional, and cognitive) as measured by the EORTC QLQ-C30 did not show clinically meaningful deterioration over time for both treatment groups, suggesting maintained health-related quality of life and patient-reported functioning for patients remaining on treatment.

POPLAR (GO28753).

A phase II, multicentre, international, randomised, open-label, controlled study, POPLAR (GO28753) 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 Tecentriq (1200 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 Tecentriq, 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 Tecentriq vs. docetaxel, respectively.
Small cell lung cancer.

IMpower133 (GO30081).

A Phase I/III, randomised, multicentre, double-blind, placebo controlled study, IMpower133 (GO30081), was conducted to evaluate the efficacy and safety of Tecentriq in combination with carboplatin and etoposide in patients with chemotherapy-naïve ES-SCLC. A total of 403 patients were randomised (1:1) to receive one of the treatment regimens described in Table 16. Randomisation was stratified by sex, ECOG performance status, and presence of brain metastases.
This study excluded patients who had active or untreated CNS metastases; history of autoimmune disease; administration of live, attenuated vaccine within 4 weeks prior to randomisation; administration of systemic immunosuppressive medications within 1 week prior to randomisation. Tumour assessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeks thereafter. Patients treated beyond disease progression had tumour assessment conducted every 6 weeks until treatment discontinuation.

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: 26 to 90 years). The majority of patients were male (65%), White (80%), and 9% had brain metastases and most patients were current or previous smokers (97%). Baseline ECOG performance status was 0 (35%) or 1 (65%).
At the time of the primary analysis, patients had a median survival follow up time of 13.9 months. The key results are summarised in Table 17. Kaplan-Meier curves for OS and PFS are presented in Figures 12 and 13.

Urothelial carcinoma.

IMvigor210 (GO29293).

The efficacy of Tecentriq was investigated in IMvigor210 (Cohort 1) (GO29293), a multicentre, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. Patients were considered cisplatin-ineligible if they met any one of the following criteria at study entry: impaired renal function [creatinine clearance (CLcr) of 30 to 59 mL/min], ECOG performance status (PS) of 2, hearing loss of ≥ 25 decibels (dB) at two contiguous frequencies, or Grades 2 to 4 peripheral neuropathy. 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; or administration of systemic immunostimulatory agents within 6 weeks or systemic immunosuppressive medications within 2 weeks prior to enrolment.
Patients received Tecentriq 1200 mg as an intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Tumour response assessments were conducted every 9 weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed overall response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumours (RECIST v1.1), duration of response (DoR) and overall survival (OS).
In this study, the median age was 73 years, 81% were male, and 91% were White. Thirty-five percent of patients had non-bladder urothelial carcinoma and 66% had visceral metastases. Eighty percent of patients had an ECOG PS of 0 or 1. Reasons for ineligibility for cisplatin containing chemotherapy were: 70% had impaired renal function, 20% had an ECOG PS of 2, 14% had a hearing loss of ≥ 25 dB, and 6% had Grades 2 to 4 peripheral neuropathy at baseline. Twenty percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.
Tumour specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory, and the results were used to define subgroups for pre-specified analyses. Of the 119 patients, 27% were classified as having PD-L1 expression of ≥ 5% (defined as PD-L1 stained tumour-infiltrating immune cells [IC] covering ≥ 5% of the tumour area, IC2/3). The remaining 73% of patients were classified as having PD-L1 expression of < 5% (PD-L1 stained tumour infiltrating IC covering < 5% of the tumour area, IC0/1).
Among the 32 patients with PD-L1 expression of ≥ 5%, median age was 67 years, 81% were male, 19% female, and 88% were White. Twenty-eight percent of patients had non-bladder urothelial carcinoma and 56% had visceral metastases. Seventy-two percent of patients had an ECOG PS of 0 or 1. Reasons for ineligibility for cisplatin-containing chemotherapy were: 66% had impaired renal function, 28% had an ECOG PS of 2, 16% had a hearing loss ≥ 25 dB, and 9% had Grades 2 - 4 peripheral neuropathy at baseline. Thirty-one percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.
Confirmed ORR in all patients and the two PD-L1 subgroups are summarised in Table 18. The median follow-up time for this study was 14.4 months. In 24 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 33% (95% CI: 16%, 55%).

IMvigor130 (WO30070).

IMvigor130 (WO30070) is an ongoing multicentre, randomised study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study contains three arms: Tecentriq monotherapy, Tecentriq with platinum-based chemotherapy (i.e. cisplatin or carboplatin with gemcitabine), and platinum-based chemotherapy alone (comparator). Both cisplatin-eligible and cisplatin-ineligible patients are included in the study. Tumour specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory.
The independent Data Monitoring Committee (iDMC) for the study conducted a review of early data and found that patients classified as having PD-L1 expression of < 5% (IC0/1) when treated with Tecentriq monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended closure of the monotherapy arm to further accrual of patients with low PD-L1 expression, however, no other changes were recommended for the study, including any change of therapy for patients who had already been randomised to and were receiving treatment in the monotherapy arm.
Hepatocellular carcinoma.

IMbrave150 (YO40245).

A global phase III, randomised, multi-centre, open-label study, IMbrave150 (YO40245), was conducted to evaluate the efficacy and safety of Tecentriq in combination with bevacizumab, in patients with locally advanced or metastatic and/or unresectable HCC, who have not received prior systemic treatment. A total of 501 patients were randomised (2:1) to receive either Tecentriq 1200 mg and 15 mg/kg of bevacizumab every 3 weeks administered via IV infusion, or sorafenib 400 mg orally twice per day. Randomisation was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (< 400 vs. ≥ 400 nanogram/mL) and ECOG performance status (0 vs. 1). Patients in both arms received treatment until loss of clinical benefit, or unacceptable toxicity. Patients could discontinue either Tecentriq or bevacizumab (e.g. due to adverse events) and continue on single-agent therapy until loss of clinical benefit or unacceptable toxicity associated with the single-agent.
The study enrolled adults who were ECOG 0/1. Patients were required to be evaluated for the presence of varices within 6 months prior to treatment, and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding or high risk of bleeding. Patients were also excluded if they had Child-Pugh B or C cirrhosis; moderate or severe ascites; history of hepatic encephalopathy; a history of autoimmune disease; administration of a live, attenuated vaccine within 4 weeks prior to randomisation; administration of systemic immunostimulatory agents within 4 weeks, or systemic immunosuppressive medications within 2 weeks prior to randomisation; untreated or corticosteroid-dependent brain metastases. Tumour assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter.
The demographic and baseline disease characteristics of the study population were balanced between the treatment arms. The median age was 65 years (range: 26 to 88 years) and 83% were male. The majority of patients were Asian (57%) and White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥ 400 nanogram/mL. Baseline ECOG performance status was 0 (62%) or 1 (38%). HCC risk factors were Hepatitis B virus infection in 48% of patients, Hepatitis C virus infection in 22% of patients, and non-viral disease in 31% of patients. HCC was categorised as Barcelona Clinic Liver Cancer (BCLC) stage C in 82% of patients, stage B in 16% of patients, and stage A in 3% of patients.
The co-primary efficacy endpoints were overall survival (OS) and independent review facility (IRF)-assessed progression free survival (PFS) according to RECIST v1.1. Additional efficacy outcome measures were IRF-assessed objective response rate (ORR) per RECIST v1.1 and HCC modified RECIST (mRECIST). Efficacy results are summarised in Table 19. Kaplan-Meier curves for OS and PFS are presented in Figures 14 and 15.

The study also evaluated patient-reported outcomes using the EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires. Treatment with Tecentriq and bevacizumab delayed clinically meaningful deterioration of patient-reported physical functioning, role functioning, global health status/quality of life and key symptoms (i.e. appetite loss, diarrhoea, fatigue and pain) versus sorafenib.
Immunogenicity.

GO29436 (IMpower150).

Exploratory analyses adjusting for imbalances in baseline health and disease characteristics showed that the subset of patients in the four drug regimen arm who were ADA positive by week 4 (32%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (68%). The OS hazard ratio comparing the ADA-positive subgroup of the four drug regimen to the three drug regimen (control) was 0.77 (95% CI: 0.57, 1.02). The OS hazard ratio comparing the ADA-negative subgroup to control was 0.73 (95% CI: 0.58, 0.93).

GO28915 (OAK).

Exploratory analyses adjusting for imbalances in baseline health and disease characteristics showed that the subset of patients who were ADA positive by week 4 (22%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (78%). The OS hazard ratio comparing the ADA-positive subgroup of the Tecentriq arm to docetaxel was 0.75 (95% CI: 0.57, 0.98). The OS hazard ratio comparing the ADA-negative subgroup to docetaxel was 0.69 (95% CI: 0.56, 0.84).

YO40245 (IMbrave150).

Exploratory analyses adjusting for imbalances in baseline health and disease characteristics showed that the subset of patients (20%) who were ADA-positive by week 6 appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week 6. ADA-positive patients by week 6 appeared to have similar overall survival compared to sorafenib-treated patients. The OS hazard ratio comparing the ADA-positive subgroup of the Tecentriq and bevacizumab arm to sorafenib was 0.95 (95% CI: 0.57, 1.59). The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was 0.41 (95% CI: 0.27, 0.62).

5.2 Pharmacokinetic Properties

The pharmacokinetics of atezolizumab have been characterised in patients in multiple clinical trials at doses 0.01 mg/kg to 20 mg/kg every 3 weeks including the fixed dose of 1200 mg. Exposure to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg. A population analysis that included 472 patients described atezolizumab pharmacokinetics for the dose range 1 - 20 mg/kg with a linear two-compartment disposition model with first-order elimination. The pharmacokinetic properties of atezolizumab 840 mg administered every 2 weeks and 1200 mg administered every 3 weeks, are comparable. A population pharmacokinetic analysis suggests that steady-state is obtained after multiple doses. The maximum systemic accumulation in area under the curve (AUC), maximum concentration (C_max) and trough concentration (C_min) are 2.54, 1.84 and 3.05-fold, respectively.
Based on analyses of population pharmacokinetics and exposure-safety and efficacy relationships, the following factors have no clinically relevant effect: age (21 - 89 years), body weight, gender, albumin levels, tumour burden, region or ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or Eastern Cooperative Oncology Group (ECOG) status. No dose adjustments are recommended.

Absorption.

Tecentriq is administered as an intravenous (IV) infusion. There have been no studies performed with other routes of administration.

Distribution.

A population pharmacokinetic analysis indicates that central compartment volume of distribution (V₁) is 3.28 L and volume at steady-state (V_ss) is 6.91 L in the typical patient.

Metabolism.

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

Excretion.

A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day and the typical terminal elimination half-life (t_1/2) is 27 days.

Pharmacokinetics in special populations.

Hepatic impairment.

No dedicated studies of Tecentriq 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 x ULN and any AST) or moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST). No data are available in patients with severe (bilirubin > 3.0 x ULN and any AST) hepatic impairment. Hepatic impairment was defined by the National Cancer Institute (NCI) criteria of hepatic dysfunction (see Section 4.2 Dose and Method of Administration). The effect of moderate or severe hepatic impairment (bilirubin > 1.5 x to 3 x ULN and any AST or bilirubin > 3 x ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.

Renal impairment.

No dedicated studies of Tecentriq 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 (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 Dose and Method of Administration). The effect of severe renal impairment on the pharmacokinetics of atezolizumab is unknown.

Elderly.

No dedicated studies of Tecentriq 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 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with atezolizumab.

Carcinogenicity.

No carcinogenicity studies have been conducted with atezolizumab.

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. Atezolizumab had an effect on menstrual cycles in all female monkeys in the 50 mg/kg dose group characterised by an irregular cycle pattern during the dosing phase and correlated with the lack of fresh corpora lutea in the ovaries at the terminal necropsy; this effect was reversible during the dose-free recovery period. The AUC at the no effect level was approximately 5 times that anticipated in patients. There was no effect on the male reproductive organs.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine, glacial acetic acid, sucrose, polysorbate 20 and water for injections.

6.2 Incompatibilities

No incompatibilities have been observed between Tecentriq and IV bags with product-contacting surfaces of polyvinyl chloride (PVC), polyethylene (PE), polyolefin or polypropylene (PP). 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.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
The diluted solution for infusion should be used immediately. If the solution is not used immediately, it can be stored for up to 24 hours at 2°C to 8°C, or 8 hours at ambient temperature (≤ 25°C).

6.4 Special Precautions for Storage

Store the vials at 2°C to 8°C. Do not freeze.
Tecentriq should be protected from light. Do not shake.
This medicine should not be used after the expiry date (EXP) shown on the pack.

6.5 Nature and Contents of Container

Tecentriq is available in a single-use glass vial containing 14 mL or 20 mL solution in a pack size of 1 vial.

6.6 Special Precautions for Disposal

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.

Tecentriq is an engineered, humanised, monoclonal antibody that directly binds to PD-L1 and blocks interactions with the PD-1 and B7.1 receptors. Tecentriq is a non-glycosylated IgG1 immunoglobulin that has a calculated molecular mass of 145 kDa.

CAS number.

1380723-44-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

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