Consumer medicine information

Imfinzi

Durvalumab

BRAND INFORMATION

Brand name

Imfinzi

Active ingredient

Durvalumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Imfinzi.

What is in this leaflet

This leaflet answers some common questions people ask about IMFINZI. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking IMFINZI against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor.

Keep this leaflet, you may need to read it again.

What IMFINZI is used for

This medicine is used to treat a type of lung cancer called Non-Small Cell Lung Cancer. It will be prescribed to you if:

  • your cancer has spread within your lung and cannot be removed by surgery and;
  • you have tried radiation and chemotherapy that contains platinum, and your cancer has shrunk or has not worsened.

This medicine is also used to treat a type of lung cancer called Extensive-Stage Small Cell Lung Cancer. It will be prescribed to you if your cancer has spread within

  • your lungs (or to other parts of the body) and
  • you have not received previous treatment.

IMFINZI will be given in combination with chemotherapy for this indication. It is important that you also read the consumer leaflets for the specific chemotherapy you will be receiving. If you have any questions about these medicines, ask your doctor.

IMFINZI is a monoclonal antibody, a type of protein. It is a type of immunotherapy and belongs to a group of medicines called immune checkpoint inhibitors. It works with your immune system to destroy cancer cells.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

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

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you are given IMFINZI

When you must not be given this medicine

You should not be given this medicine if you have an allergy to:

  • durvalumab or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You should not be given this medicine if you are pregnant. It may affect your developing baby if you use it during pregnancy.

You should not be given this medicine if you are breast-feeding. It is not known if the active ingredient in IMFINZI passes into breast milk, but if it does, there is a possibility that your baby may be affected.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given this medicine

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you:

  • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus
  • have had an organ transplant
  • have lung or breathing problems
  • have liver problems.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding or plan to breast-feed. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you are given IMFINZI.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

How IMFINZI is given to you

IMFINZI will be given to you as a liquid infusion into your vein (IV). An infusion takes about 1 hour and will normally be given every 2, 3 or 4 weeks.

Your doctor will decide how many treatments you need.

If you miss an appointment to be given IMFINZI

Call your doctor right away to reschedule your appointment.

It is very important that you do not miss a dose of this medicine.

While you are being treated IMFINZI

Things you must do

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

If you become pregnant while using this medicine, tell your doctor immediately.

If you are a woman who could become pregnant, you must use adequate birth control while you are being treated with this medicine and for at least 3 months after your last dose.

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

Things you must not do

Do not breast-feed if you are being given this medicine and for at least 3 months after the last dose. It is not known if the active ingredient in IMFINZI passes into breast milk, but if it does, there is a possibility that your baby may be affected.

Side effects

This medicine may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

IMFINZI can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work and this can cause the side effects.

If you have any of the following symptoms, call or see your doctor right away. Your doctor may give you other medicines in order to prevent more severe complications and reduce your symptoms. Your doctor may withhold the next dose of IMFINZI or stop your treatment with IMFINZI.

  • new or worsening cough, shortness of breath, or chest pain which may indicate inflammation of your lungs
  • nausea or vomiting, feeling less hungry, pain on the right side of stomach, yellowing of skin or whites of eyes, drowsiness, dark urine, or bleeding or bruising more easily than normal which may indicate inflammation of your liver
  • diarrhoea or more bowel movements than usual, black, tarry, sticky stools or stools with blood or mucus, severe stomach pain or tenderness which may indicate inflammation of your intestines
  • headaches that will not go away or unusual headaches, extreme tiredness, weight gain or weight loss, dizziness or fainting, feeling more hungry or thirsty than usual, hair loss, feeling cold, constipation, changes in your voice, urinating more often than usual, nausea or vomiting, stomach area (abdomen) pain, changes in mood or behaviour, such as decreased sex drive, irritability, or forgetfulness, fast and deep breathing, confusion, or a sweet smell to your breath, a sweet or metallic taste in your mouth or a different odour to your urine or sweat. These may indicate inflammation of some of your hormone glands
  • changes in the amount or colour of your urine, swelling in your ankles, or loss of appetite may indicate inflammation of your kidneys
  • the need to urinate urgently and frequently, burning pain or sensation when urinating, bladder still feels full after urinating, pain above your pubic bone, blood in the urine, all of which may indicate a urinary tract infection
  • rash, itching, skin blistering, or ulcers in mouth or other mucous membranes which may indicate inflammation of the skin or mouth
  • chest pain, shortness of breath, or irregular heartbeat which may indicate inflammation of the heart
  • chills or shaking, itching or rash, flushing, shortness of breath or wheezing dizziness, fever, feeling like passing out, back or neck pain, or facial swelling which may indicate infusion related reactions
  • muscle weakness, tiredness and/or pain, and/or rapid fatigue of the muscles, in one or more areas of your body which may indicate inflammation or problems of the muscles
  • bleeding (nose or gum bleeding) and/or bruising may indicate low number of platelets
  • seizures, neck stiffness, headache, fever, chills, vomiting, eye sensitivity to light, confusion and sleepiness which may indicate encephalitis or meningitis
  • pain, weakness, and paralysis in the extremities which may indicate Guillain-Barré syndrome.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

The most frequent serious side-effects experienced when IMFINZI was given alone are:

  • muscle and bone pain
  • problems with your liver
  • general physical health deterioration
  • infections
  • pain in your stomach area
  • too much calcium in your blood
  • vomiting
  • serious lung infections (pneumonia)
  • inflammation of the lung (pneumonitis)
  • fever.

The most common side-effects experienced when IMFINZI was given alone are:

  • muscle and bone pain
  • problems with your liver
  • upper respiratory tract infection such as in the nose or throat e.g. sinusitis or tonsilitis
  • lung infections which may be serious such as pneumonia or influenza
  • thrush in the mouth
  • infusion related reactions
  • feeling tired
  • constipation
  • decreased appetite
  • nausea
  • not enough red blood cells (anaemia)
  • diarrhoea and colitis (bowel inflammation)
  • rash or itchiness
  • swellings, especially on your legs or hands
  • shortness of breath
  • cough
  • fever
  • not enough sodium in your blood
  • insomnia
  • underactive thyroid gland that can cause tiredness or weight gain
  • overactive thyroid gland that can cause rapid heartbeat, weight loss, increased appetite and anxiety
  • pain in your stomach area.

The most frequent serious side-effects experienced when IMFINZI was given in combination with chemotherapy are:

  • not enough white blood cells with fever (febrile neutropenia)
  • serious lung infections (pneumonia)
  • not enough red blood cells (anaemia)
  • not enough red blood cells, white blood cells, and platelets (pancytopenia)
  • inflammation of the lung (pneumonitis)
  • Chronic Obstructive Pulmonary Disorder (COPD) which causes the narrowing of airways and makes it difficult to breathe.

The most common side-effects experienced when IMFINZI was given in combination with chemotherapy are:

  • not enough white blood cells (neutropenia and leukopenia)
  • not enough red blood cells (anaemia)
  • nausea
  • hair loss
  • decreased appetite
  • feeling tired or weak
  • constipation
  • not enough platelets (thrombocytopenia)
  • vomiting
  • cough.

Ask your doctor to answer any questions you may have about side effects.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some side effects can only be found when your doctor does blood tests from time to time to check your progress (for example, low white blood cell count, low red blood cell count and low platelet count).

After being given IMFINZI

Do not breast feed for at least 3 months after the last dose.

If you are a woman who could become pregnant, you must use adequate birth control for at least 3 months after your last dose.

Product description

What it looks like

IMFINZI concentrated solution for infusion is a clear to opalescent, colourless to slightly yellow liquid in a glass vial.

Ingredients

IMFINZI contains durvalumab as the active ingredient.

Other ingredients include:

  • histidine
  • histidine hydrochloride monohydrate
  • trehalose dihydrate
  • polysorbate 80
  • water for injection.

How to store IMFINZI

Store unopened vials under refrigeration at 2°C to 8°C in the original carton to protect from light. Do not freeze. Do not shake.

Supplier

IMFINZI is sponsored and supplied in Australia by:

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

This leaflet was prepared on
September 2021

Australian Registration Number(s):

IMFINZI, 500 mg (500 mg/10mL) in 10 mL vial for intravenous infusion - AUST R 283216

IMFINZI, 120 mg (120 mg/2.4mL) in 10 mL vial for intravenous infusion - AUST R 283215

© AstraZeneca 2021

Doc ID-003924994 v12

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Imfinzi

Active ingredient

Durvalumab

Schedule

S4

 

1 Name of Medicine

Durvalumab.

2 Qualitative and Quantitative Composition

Each vial of Imfinzi concentrated solution for infusion contains either 120 mg or 500 mg of durvalumab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sterile, preservative free, clear to opalescent and free from visible particles, colourless to slightly yellow, concentrated solution for infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Non-small cell lung cancer (NSCLC).

Imfinzi in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by Imfinzi as monotherapy after surgery, is indicated for the treatment of adults with resectable (tumours ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.
Imfinzi is indicated for the treatment of patients with locally advanced, unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy (CRT).

Small cell lung cancer (SCLC).

Imfinzi as monotherapy is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following platinum-based chemoradiation therapy (CRT).
Imfinzi in combination with etoposide and either carboplatin or cisplatin is indicated for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Biliary tract cancer (BTC).

Imfinzi in combination with gemcitabine and cisplatin is indicated for the treatment of patients with locally advanced or metastatic biliary tract cancer (BTC).

Hepatocellular carcinoma (HCC).

Imfinzi in combination with tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC) who have not received prior treatment with a PD1/PD-L1 inhibitor.

Endometrial cancer.

Imfinzi in combination with carboplatin and paclitaxel, followed by Imfinzi monotherapy, is indicated for the first-line treatment of patients with primary advanced or recurrent endometrial cancer.

4.2 Dose and Method of Administration

The recommended dose of Imfinzi depends on the indication as presented in Table 1. Imfinzi is administered as an intravenous infusion over 1 hour.
When Imfinzi is used in combination with other medicines, refer to the product information for the other medicines for their recommended dosing information. The studied medicines and doses are described in Section 5.1 Pharmacodynamic Properties, Clinical trials.
The proposed combination should be administered and monitored under the supervision of physicians experienced with the use of immunotherapy.
It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.
No dose reduction or escalation for Imfinzi is recommended. In general, withhold Imfinzi for severe (Grade 3) immune-mediated adverse drug reactions (ADR). Permanently discontinue Imfinzi for life-threatening (Grade 4) immune-mediated ADR, recurrent severe (Grade 3) immune-mediated ADR that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.
Immune-mediated ADR requiring specific management are summarised in Table 2. See Section 4.4 Special Warnings and Precautions for Use for further management recommendations, monitoring and evaluation information.
After withhold, Imfinzi can be resumed within 12 weeks if the ADR improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day. Imfinzi should be permanently discontinued for recurrent Grade 3 ADR, as applicable.
For nonimmune-mediated ADR, withhold Imfinzi for Grade 2 and 3 ADR until ≤ Grade 1 or baseline. Imfinzi should be discontinued for Grade 4 ADR (with the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue should be based on accompanying clinical signs/ symptoms and clinical judgment).

Special patient populations.

Renal impairment.

No dose adjustment is recommended for patients with mild or moderate renal impairment (see Section 5.2 Pharmacokinetic Properties). Durvalumab has not been studied in subjects with severe renal impairment.

Hepatic impairment.

Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild or moderate hepatic impairment. Imfinzi has not been studied in patients with severe hepatic impairment. However, due to minor involvement of hepatic processes in the clearance of durvalumab, no difference in exposure is expected for these patients (see Section 5.2 Pharmacokinetic Properties).

Use in paediatric patients.

The safety and efficacy of durvalumab have not been established in patients younger than 18 years of age. Currently available data of Imfinzi in combination with tremelimumab are described in Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties but no dosing recommendations can be made.

Use in the elderly.

No dose adjustment is required for elderly patients (≥ 65 years of age) (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Method of administration.

Preparation of Imfinzi solution and infusion.

Preparation of solution.

Imfinzi is for single use in one patient only. Discard any residue.
Imfinzi is supplied as single-dose vials and does not contain any preservatives. Aseptic technique must be observed.
Visually inspect drug product for particulate matter and discolouration. Imfinzi is a clear to opalescent, colourless to slightly yellow solution. Discard the vial if the solution is cloudy, discoloured or visible particles are observed. Do not shake the vial.
Withdraw the required volume from the vial(s) of Imfinzi and transfer into an intravenous (IV) bag containing 0.9% sodium chloride injection, or 5% dextrose injection. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. Do not freeze or shake the solution.
Care must be taken to ensure the sterility of prepared solutions.
Do not re-enter the vial after withdrawal of drug; only withdraw one dose per vial.
Discard any unused portion left in the vial.
No incompatibilities between Imfinzi and 9 g/L (0.9%) sodium chloride or 50 g/L (5%) dextrose in polyvinylchloride or polyolefin IV bags have been observed.

After preparation of infusion solution.

Imfinzi does not contain a preservative. Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the time from preparation should not exceed:
30 days at 2°C to 8°C and for up to;
12 hours at room temperature (up to 25°C) from the time of preparation.
Administration of Imfinzi infusion solution. Administer infusion solution intravenously over 1 hour through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
Do not coadminister other drugs through the same infusion line.

Imfinzi in combination with chemotherapy.

For resectable NSCLC, ES-SCLC, BTC and endometrial cancer when Imfinzi is administered in combination with chemotherapy, administer Imfinzi prior to chemotherapy on the same day.

Imfinzi in combination with tremelimumab.

For uHCC, when Imfinzi is administered in combination with tremelimumab, administer tremelimumab prior to Imfinzi on the same day. Imfinzi and tremelimumab are administered as separate intravenous infusions.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

See Section 4.2 Dose and Method of Administration, Table 2 for recommended treatment modifications and management of adverse reactions.

Immune-mediated adverse drug reactions (ADR).

Immune checkpoint inhibitors, including durvalumab, can cause severe and fatal immune-mediated ADR, which may involve any organ system. While immune-mediated ADR usually manifest during treatment, they can also manifest after discontinuation. Early identification of such reactions and timely intervention are an important part of the safe use of durvalumab. In clinical trials, most immune-mediated ADR were reversible and managed with interruptions of durvalumab, administration of corticosteroids and/or supportive care. Patients should be monitored for signs and symptoms and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration) and further below.
For suspected immune-mediated ADR, adequate evaluation should be performed to confirm aetiology or exclude alternate aetiologies. Based on the severity of the ADR, Imfinzi or Imfinzi in combination with tremelimumab should be withheld or permanently discontinued. Treatment with corticosteroids or endocrine therapy should be initiated. For events requiring corticosteroid therapy, and upon improvement to ≤ Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement.

Note.

Use of * in the below sections indicates that the relevant term is defined as requiring use of systemic corticosteroids with no clear alternate aetiology.
Immune-mediated pneumonitis. Immune-mediated pneumonitis/ interstitial lung disease*, including fatal cases, occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related aetiologies excluded, and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). For Grade 2 events, an initial dose of 1-2 mg/kg/day prednisone or equivalent should be initiated followed by a taper. For Grade 3 or 4 events, an initial dose of 2-4 mg/kg/day methylprednisolone or equivalent (or in accordance with local immune-related adverse events management guidelines where these differ) should be initiated followed by a taper.

Pneumonitis and radiation pneumonitis.

Radiation pneumonitis is frequently observed in patients receiving radiation therapy (RT) to the lung and the clinical presentation of pneumonitis and radiation pneumonitis is very similar.
In the PACIFIC study, in patients who had completed treatment with at least 2 cycles of concurrent CRT within 1 to 42 days prior to initiation of study treatment, pneumonitis or radiation pneumonitis occurred in 161 (33.9%) patients in the Imfinzi-treated group and 58 (24.8%) in the placebo group, including Grade 3 in 16 (3.4%) patients on Imfinzi vs 7 (3.0%) patients on placebo and Grade 5 in 5 (1.1%) patients on Imfinzi vs 4 (1.7%) patients on placebo. The median time to onset in the Imfinzi-treated group was 55 days (range: 1-406 days) vs. 55 days (range: 1-255 days) in the placebo group. Also see Section 4.8 Adverse Effects (Undesirable Effects).
In the ADRIATIC study, in patients who had completed treatment with CRT within 1 to 42 days prior to initiation of study treatment, pneumonitis or radiation pneumonitis occurred in 100 (38.2%) patients in the Imfinzi-treated group and 80 (30.2%) in the placebo group; including Grade 3 in 8 (3.1%) patients on Imfinzi vs 6 (2.3%) patients on placebo, and Grade 5 in 1 (0.4%) patient on Imfinzi vs 0 patients on placebo.
Immune-mediated hepatitis. Immune-mediated hepatitis*, including a fatal case, occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for abnormal liver tests prior to each infusion, and as indicated based on clinical evaluation during and after discontinuation of treatment with durvalumab. Immune-mediated hepatitis should be managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for all grades.
Immune-mediated colitis. Immune-mediated colitis* occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of colitis (including diarrhoea) and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered at an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for Grades 2-4. Consult a surgeon immediately if an intestinal perforation of any grade is suspected.
Immune-mediated endocrinopathies.

Immune-mediated hypothyroidism/ hyperthyroidism/ thyroiditis.

Immune-mediated hypothyroidism, hyperthyroidism or thyroiditis have occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). For immune-mediated hypothyroidism, initiate thyroid hormone replacement as clinically indicated for Grades 2-4. For immune-mediated hyperthyroidism/thyroiditis, symptomatic management can be implemented for Grades 2-4.

Immune-mediated adrenal insufficiency.

Immune-mediated adrenal insufficiency occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated for Grades 2-4.

Immune-mediated type 1 diabetes mellitus.

Immune-mediated type 1 diabetes mellitus, which can present with diabetic ketoacidosis, occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus, patients should be managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Treatment with insulin can be initiated as clinically indicated for Grades 2-4.

Immune-mediated hypophysitis/ hypopituitarism.

Immune-mediated hypophysitis/ hypopituitarism occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated for Grades 2-4.
Immune-mediated nephritis. Immune-mediated nephritis* occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for abnormal renal function tests prior to and periodically during treatment with durvalumab and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for Grades 2-4.
Immune-mediated dermatological adverse reactions. Immune-mediated dermatitis (including pemphigoid)* occurred in patients receiving durvalumab in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Bullous dermatitis and Stevens-Johnson syndrome (SJS)/ toxic epidermal necrolysis (TEN) have occurred with other products in this class. Patients should be monitored for signs and symptoms dermatitis (including rash) and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for Grade 2 > 1 week or Grade 3 and 4.
Immune-mediated myocarditis. Immune-mediated myocarditis, which can be fatal, occurred in patients receiving Imfinzi or Imfinzi in combination with tremelimumab (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managed as recommended in Section 4.2. Corticosteroids should be administered with an initial dose of 2-4 mg/kg/day prednisone or equivalent followed by a taper for Grades 2-4. If no improvement within 2 to 3 days despite corticosteroids, promptly start additional immunosuppressive therapy. Upon resolution (Grade 0), corticosteroid taper should be initiated and continued over at least 1 month.
Other immune mediated ADR. Given the mechanism of action of durvalumab, other immune-mediated ADR may occur. Other immune mediated ADR are: aseptic meningitis, haemolytic anaemia, immune thrombocytopenia, pancreatitis, encephalitis, myasthenia gravis, myelitis transverse, myositis, polymyositis, rhabdomyolysis, Guillain-Barré syndrome, immune-mediated arthritis and ocular inflammatory toxicity, including uveitis and keratitis. Patients should be monitored for signs and symptoms of immune-mediated ADR and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.
Also see Section 4.8 Adverse Effects (Undesirable Effects), Immune-mediated neurological adverse events in ongoing and completed trials.

Infusion-related reactions.

Patients should be monitored for signs and symptoms of infusion-related reactions and managed as recommended in Table 2 (see Section 4.2 Dose and Method of Administration). Severe infusion related reactions have been reported in patients receiving durvalumab (see Section 4.8 Adverse Effects (Undesirable Effects)). For Grade 1 or 2 severity, may consider pre-medications for prophylaxis of subsequent infusion reactions. For Grade 3 or 4, manage severe infusion-related reactions per institutional standard, appropriate clinical practice guidelines and/or society guidelines.

Efficacy in patients with PD-L1 expression < 1%.

Post hoc analyses for locally advanced NSCLC suggest efficacy may be different for patients with PD-L1 < 1%. Before initiating treatment, physicians are advised to carefully evaluate the individual patient and tumour characteristics, taking into consideration the observed benefits and the side effects of durvalumab (see Section 5.1 Pharmacodynamic Properties, PACIFIC study (locally advanced NSCLC)).

Use in the elderly.

No overall differences in safety were observed between patients treated with Imfinzi who were ≥ 65 years of age compared to younger patients in the PACIFIC study (NSCLC). Data from NSCLC patients 75 years of age or older are limited.
Of the 401 patients with resectable NSCLC treated with Imfinzi in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or effectiveness between patients ≥ 65 years of age and younger patients.
Of the 262 patients with LS-SCLC treated with Imfinzi, 103 (39.3%) patients were 65 years or older. There were no overall clinically meaningful differences in safety or effectiveness between patients ≥ 65 years of age and younger patients.
Of the 265 patients with ES-SCLC treated with Imfinzi in combination with chemotherapy, 101 (38%) patients were 65 years or older. There were no overall clinically meaningful differences in safety or effectiveness between patients ≥ 65 years of age and younger patients.
Of the 338 patients with BTC treated with Imfinzi in combination with chemotherapy, 158 (46.7%) patients were 65 years or older. No overall differences in safety or effectiveness were observed between patients ≥ 65 years of age and younger patients.
Of the 462 patients with uHCC treated with STRIDE, 173 (37.4%) patients were 65 years or older and 63 (13.6%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.
Of the 238 patients with endometrial cancer randomised to receive platinum-based chemotherapy + Imfinzi, 116 (48.7%) patients were 65 years or older and 29 (12.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.

Paediatric use.

The safety and efficacy of durvalumab have not been established in patients younger than 18 years of age. Currently available data of Imfinzi in combination with tremelimumab are described in Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties but no dosing recommendations can be made.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Durvalumab is an immunoglobulin. The primary elimination pathways of durvalumab are protein catabolism via reticuloendothelial system or target mediated disposition, therefore no formal pharmacokinetic (PK) drug-drug interaction studies have been conducted since no metabolic drug-drug interactions are expected. PK drug-drug interaction between durvalumab and etoposide, and carboplatin or cisplatin was assessed in the CASPIAN study and no clinically meaningful PK drug-drug interaction between durvalumab and the chemotherapy was identified.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of durvalumab on fertility in humans. In repeat-dose toxicology studies of durvalumab up to 3 months duration in sexually mature cynomolgus monkeys, there were no notable effects on the male and female reproductive organs. These animals received weekly doses of durvalumab yielding 11 times the clinical exposure (based on AUC) at the clinical dose of 1500 mg every 3 weeks and 23 times at the clinical dose of 10 mg/kg every 2 weeks.
(Category D)
There are no data on the use of durvalumab in pregnant women. Based on its mechanism of action, durvalumab has the potential to impact maintenance of pregnancy and may cause foetal harm when administered to a pregnant woman. Human IgG1 is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing foetus. Durvalumab use is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose.

Animal data.

As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the foetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signalling was shown to result in an increase in foetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 3 to 11 times the clinical exposure (based on AUC) at the clinical dose of 1500 mg every 3 weeks and 6 to 20 times at the clinical dose of 10 mg/kg every 2 weeks. Administration of durvalumab resulted in premature delivery, foetal loss (abortion and stillbirth) and increase in neonatal deaths compared to concurrent controls. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, foetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.
 There is no information regarding the presence of durvalumab in human milk, the absorption and effects on the breastfed infant, or the effects on milk production. Human IgG is excreted in human milk. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys was associated with dose-related low-level excretion of durvalumab in breast milk and was associated with premature neonatal death compared to concurrent controls. Because of the potential for adverse reactions in breastfed infants from durvalumab, lactating women should be advised not to breastfeed during treatment and for at least 3 months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Based on its pharmacodynamic properties, durvalumab is unlikely to affect the ability to drive and use machines. However, if patients experience adverse reactions affecting their ability to concentrate and react, they should be advised to use caution when driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Overall summary of adverse drug reactions (ADR).

The safety of Imfinzi as monotherapy is based on pooled data in 3006 patients from 9 studies across multiple tumour types. Imfinzi was administered at a dose of 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks. The most frequent (> 10%) ADR were cough/productive cough (21.5%), diarrhoea (16.3%), rash (16.0%), pyrexia (13.8%), upper respiratory tract infections (13.5%), abdominal pain (12.7%), pruritus (10.8%) and hypothyroidism (10.1%).

Tabulated list of adverse drug reactions (ADR).

Table 3 lists the incidence of ADR in the monotherapy safety dataset. ADR are listed according to system organ class (SOC) in MedDRA. Within each SOC, the ADR are presented in decreasing frequency. Within each frequency grouping, ADR are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is based on the CIOMS III convention and is defined as: very common (≥ 10%); common (≥ 1 to < 10%); uncommon (≥ 0.1 to < 1%); rare (≥ 0.01 to < 0.1%); very rare (< 0.01%); not determined (cannot be estimated from available data).

Laboratory abnormalities.

In patients treated with durvalumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.4% for alanine aminotransferase increased, 3.6% for aspartate aminotransferase increased and 0.5% for blood creatinine increased. The proportion of patients who experienced a thyroid-stimulating hormone (TSH) shift from baseline that was ≤ upper limit of normal (ULN) to any grade > ULN was 18.8% and a TSH shift from baseline that was ≥ lower limit of normal (LLN) to any grade < LLN was 18.1%.

Tabulated list of adverse events in individual studies.

The data described below reflect exposure to Imfinzi as monotherapy, in patients with locally advanced, unresectable NSCLC (PACIFIC study) and LS-SCLC (ADRIATIC study), in combination with chemotherapy in patients with resectable NSCLC (AEGEAN study), ES-SCLC (CASPIAN study) and BTC (TOPAZ-1 study), in combination with tremelimumab (STRIDE) in patients with uHCC (HIMALAYA study and Study 22), and in combination with chemotherapy followed by Imfinzi monotherapy in patients with endometrial cancer (DUO-E study).
Adverse events are listed according to MedDRA SOC. Within each SOC, the adverse events are presented in decreasing frequency.

Non-small cell lung cancer (NSCLC).

PACIFIC study (locally advanced NSCLC). The safety of Imfinzi in patients with locally advanced NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicentre, randomised, double-blind, placebo-controlled study. A total of 475 patients received Imfinzi 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following CRT, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive RT as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to Imfinzi was 10 months (range: 0.2 to 12.6).
Imfinzi was discontinued due to adverse events in 15% of patients. The most common adverse events leading to Imfinzi discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse events occurred in 29% of patients receiving Imfinzi. The most frequent serious adverse events reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse events (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnoea and rash.
Table 4 summarises the adverse events that occurred in at least 10% of patients treated with Imfinzi.
Other adverse events occurring in less than 10% of patients treated with Imfinzi were dysphonia, dysuria, night sweats, peripheral oedema, and increased susceptibility to infections.
AEGEAN study (resectable NSCLC). The safety of Imfinzi in combination with chemotherapy as neoadjuvant treatment, is based on data in 401 patients from the AEGEAN (resectable NSCLC) study and was consistent with known Imfinzi monotherapy and known chemotherapy safety profiles.
See Section 5.1 Pharmacodynamic Properties, Clinical trials for AEGEAN study design and patient population.
SAE occurred in 38% of patients receiving Imfinzi in combination with platinum-based chemotherapy. Fatal AEs occurred in 6% of patients receiving Imfinzi in combination with platinum-based chemotherapy including (in at least 2 patients), COVID-19 pneumonia, pneumonia, interstitial lung disease, COVID-19, sepsis and septic shock. Permanent discontinuation of Imfinzi due to an AE occurred in 12% of patients. AEs which required permanent discontinuation of Imfinzi (≥ 0.5%) were pneumonitis, rash, peripheral neuropathy, diarrhoea, increased alanine aminotransferase and immune mediated hepatitis.
Table 5 and Table 6 summarise the very common ADR and laboratory abnormalities in AEGEAN, respectively.

Neoadjuvant phase of AEGEAN.

A total of 401 patients received at least 1 dose of Imfinzi in combination with platinum-based chemotherapy as neoadjuvant treatment and 398 patients received at least 1 dose of placebo in combination with platinum-based chemotherapy as neoadjuvant treatment.
SAE occurred in 21% of patients who received Imfinzi in combination with platinum-based chemotherapy as neoadjuvant treatment; the most frequent (≥ 1%) SAE were pneumonia, anaemia, myelosuppression, vomiting and neutropenia (1%). Fatal AE occurred in 2% of patients, including death due to COVID-19 pneumonia, sepsis, myocarditis, decreased appetite, haemoptysis and death not otherwise specified.
Permanent discontinuation of Imfinzi due to an AE occurred in 7% of patients who received Imfinzi in combination with platinum-based chemotherapy as neoadjuvant treatment; the most frequent (≥ 0.5%) AE that led to permanent discontinuation of Imfinzi were peripheral sensory neuropathy and pneumonitis.
Of the 401 Imfinzi-treated patients and 398 placebo-treated patients who received neoadjuvant treatment, 2% and 1%, respectively, did not receive surgery due to AEs. The most frequent AE that led to cancellation of surgery in the Imfinzi arm were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colon cancer, pruritus and colitis.
Of the 325 Imfinzi-treated patients who received surgery, 4% experienced delay of surgery (defined as on-study surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period) due to AEs. Of the 326 placebo-treated patients who received surgery, 4% experienced delay of surgery due to AEs.
Of the 325 Imfinzi-treated patients who received surgery, 7% did not receive adjuvant treatment due to AEs. Of the 326 placebo-treated patients who received surgery, 6% did not receive adjuvant treatment due to AEs.

Adjuvant phase of AEGEAN.

A total of 265 patients in the Imfinzi arm and 254 patients in the placebo arm received at least 1 dose of adjuvant treatment.
Of the patients who received Imfinzi alone as adjuvant treatment, 13% experienced SAE. The most frequent SAE reported in > 1% of patients were pneumonia and COVID-19. Four fatal AE occurred during the adjuvant phase of the study including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Permanent discontinuation of adjuvant Imfinzi due to an AE occurred in 8% of patients. The most frequent (≥ 0.5%) AE that led to permanent discontinuation of adjuvant Imfinzi was rash.

Small cell lung cancer (SCLC).

ADRIATIC study (LS-SCLC).

The safety of Imfinzi as monotherapy in patients with LS-SCLC was based on data in 262 patients from the ADRIATIC study, with a median duration of exposure to Imfinzi of 9.2 months (range: 0.92 to 25). The safety profile was consistent with Imfinzi monotherapy.
See Section 5.1 Pharmacodynamic Properties, Clinical trials for ADRIATIC study design and patient population.
Table 7 and Table 8 summarise the very common adverse events and laboratory abnormalities respectively that occurred in patients treated with Imfinzi in the ADRIATIC study.

CASPIAN study (ES-SCLC).

The safety of Imfinzi in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, a randomised, open-label, multicentre, active-controlled trial. A total of 265 patients received Imfinzi 1500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by Imfinzi 1500 mg every 4 weeks until disease progression or unacceptable toxicity. The trial excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Among 266 patients receiving chemotherapy alone, 57% of the patients received 6 cycles of chemotherapy and 8% of the patients received PCI after chemotherapy.
Imfinzi was discontinued due to adverse reactions in 7% of the patients receiving Imfinzi plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving Imfinzi plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anaemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving Imfinzi plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue/asthenia and alopecia.
Table 9 summarises the adverse reactions that occurred in patients treated with Imfinzi plus chemotherapy.
Table 10 summarises the laboratory abnormalities that occurred in at least 20% of patients treated with Imfinzi plus chemotherapy.
The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 17.7% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 31.3%.

Biliary tract cancer (BTC).

TOPAZ-1 study.

The safety of Imfinzi in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomised, double-blind, placebo-controlled, multicentre trial. Safety data are available for the 680 patients, of which 338 patients received Imfinzi 1500 mg in combination with chemotherapy every 3 weeks up to 8 cycles followed by Imfinzi 1500 mg every 4 weeks until disease progression or unacceptable toxicity.
The trial excluded patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or active infections, including tuberculosis or hepatitis C (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Imfinzi was discontinued due to adverse events in 6.2% of the patients receiving Imfinzi plus chemotherapy. The most frequently reported adverse events resulting in discontinuation were sepsis (3 patients) and ischaemic stroke (2 patients). The remaining adverse events were dispersed across system organ classes and reported in 1 patient each. Serious adverse events occurred in 47.3% of patients receiving Imfinzi plus chemotherapy. The most frequent serious adverse events reported in at least 2% of patients were cholangitis (7.4%), pyrexia (3.8%), anaemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse events occurred in 3.6% of patients receiving Imfinzi plus chemotherapy. These include sepsis, ischaemic stroke, upper gastrointestinal haemorrhage (reported in 2 patients each). The most common adverse events (occurring in ≥ 20% of patients) were nausea, constipation, abdominal pain, fatigue, pyrexia, decreased appetite, anaemia, neutropenia, neutrophil count decreased and platelet count decreased. Table 11 summarizes the adverse events that occurred in ≥ 10% of patients treated with Imfinzi plus chemotherapy.
Table 12 summarises the laboratory abnormalities that occurred in at least 20% of patients treated with Imfinzi plus chemotherapy.

Hepatocellular carcinoma (HCC).

HIMALAYA study and study 22.

A total of 462 patients with uHCC received STRIDE in two studies: HIMALAYA (N = 388), a randomised, open-label, multicentre study and Study 22 (N = 74), an open-label, multi-part, multicentre study. The patients were treated as long as clinical benefit was observed or until unacceptable toxicity.
The studies excluded patients with co-infection of viral hepatitis B and hepatitis C; active or prior documented GI bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the two studies combined (HCC pool), the median duration of exposure to STRIDE was 20 weeks (range: 2 to 185). STRIDE was discontinued due to adverse events in 63 (13.6%) patients. The most common adverse events leading to treatment discontinuation were pneumonitis, colitis, diarrhoea and AST increased. Serious adverse events occurred in 40.9% of patients. The most frequent serious adverse events reported in at least ≥ 2% of patients were pneumonitis, colitis and diarrhoea. The most common adverse events (occurring in ≥ 20% of patients) were rash, pruritus and diarrhoea.
Table 13 summarises the adverse events that occurred in patients treated with STRIDE in the HIMALAYA study.
Table 14 summarises the laboratory abnormalities that occurred patients treated with STRIDE in the HIMALAYA study.
Table 15 summarises the adverse events that occurred in patients treated with STRIDE in Study 22.
Table 16 summarises the laboratory abnormalities that occurred patients treated with STRIDE in Study 22.

Endometrial cancer.

DUO-E study.

The safety of Imfinzi in combination with carboplatin and paclitaxel followed by Imfinzi as monotherapy (N=235) is based on data in patients from the DUO-E (endometrial cancer) study. The safety profile was consistent with IMFINZI monotherapy and chemotherapy safety profiles.
Table 17 and Table 18 summarise the very common adverse drug reactions (ADR) and laboratory abnormalities in DUO-E, respectively. Refer to the Product Information for carboplatin and paclitaxel for additional information about ADR.

Description of selected adverse reactions.

The data below reflect information for significant adverse reactions for Imfinzi as monotherapy in the pooled safety dataset across tumour types (n = 3006) and Imfinzi in combination with tremelimumab (75 mg every 4 weeks) in the pooled safety dataset across tumour types (n = 2280; pan-tumour pool) and STRIDE in the HCC pool (n = 462). Significant adverse reactions for Imfinzi when given in combination with etoposide and carboplatin or cisplatin in the CASPIAN study were consistent with Imfinzi monotherapy and did not present clinically relevant differences. No new adverse reactions were identified for Imfinzi when given in combination with gemcitabine and cisplatin in the TOPAZ-1 study.
The management guidelines for these adverse reactions are described in Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.
Immune-mediated pneumonitis. In patients receiving Imfinzi monotherapy, immune-mediated pneumonitis occurred in 92 (3.1%) patients, including Grade 3 in 25 (0.8%) patients, Grade 4 in 2 (< 0.1%) patients, and Grade 5 in 6 (0.2%) patients. The median time to onset was 55 days (range: 2-785 days). Sixty-nine of the 92 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), 2 patients also received infliximab and 1 patient also received cyclosporine. Imfinzi was discontinued in 38 patients. Resolution occurred in 53 patients.
Immune-mediated pneumonitis occurred more frequently in patients in the PACIFIC study who had completed treatment with concurrent CRT within 1 to 42 days prior to initiation of study treatment (9.9%), compared to the other patients in the combined safety database (1.8%). In the PACIFIC study, (n = 475 in the Imfinzi arm, and n = 234 in the placebo arm) immune-mediated pneumonitis occurred in 47 (9.9%) patients in the Imfinzi treated group and 14 (6.0%) patients in the placebo group, including Grade 3 in 9 (1.9%) patients on Imfinzi vs. 6 (2.6%) patients on placebo and Grade 5 (fatal) in 4 (0.8%) patients on Imfinzi vs. 3 (1.3%) patients on placebo. The median time to onset in the Imfinzi treated group was 46 days (range: 2-342 days) vs. 57 days (range: 26-253 days) in the placebo group. In the Imfinzi treated group, 30 patients received high dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), and 2 patients also received infliximab. In the placebo group, 12 patients received high dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the Imfinzi treated group vs. 6 in placebo.
In the ADRIATIC study in patients with LS-SCLC (n=262 in the Imfinzi arm and n=265 in the placebo arm), who had completed treatment with CRT within 1 to 42 days prior to initiation of study treatment, immune-mediated pneumonitis occurred in 31 (11.8%) patients in the Imfinzi-treated group and 8 (3.0%) patients in the placebo group, including Grade 3 in 5 (1.9%) patients on Imfinzi vs 1 (0.4%) patient on placebo, and Grade 5 in 1 (0.4%) patient on Imfinzi. The median time to onset in the Imfinzi-treated group was 55 days (range: 1-375 days) vs 65.5 days (range: 24-124 days) in the placebo group. In the Imfinzi-treated group, 25 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received infliximab. In the placebo group, 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 18 patients in the Imfinzi-treated group vs 3 in placebo.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated pneumonitis occurred in 86 (3.8%) patients, including Grade 3 in 30 (1.3%) patients, Grade 4 in 1 (< 0.1%) patient, and Grade 5 in 7 (0.3%) patients. The median time to onset was 57 days (range: 8-912 days). All patients received systemic corticosteroids, and 79 of the 86 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients also received other immunosuppressants. Treatment was discontinued in 39 patients. Resolution occurred in 51 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated pneumonitis occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient and Grade 5 (fatal) in 1 (0.2%) patient. The median time to onset was 29 days (range: 5-774 days). Six patients received systemic corticosteroids, and 5 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received other immunosuppressants. Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.
Immune-mediated hepatitis. In patients receiving Imfinzi monotherapy, immune-mediated hepatitis occurred in 67 (2.2%) patients, including Grade 3 in 35 (1.2%) patients, Grade 4 in 6 (0.2%) and Grade 5 in 4 (0.1%) patients. The median time to onset was 36 days (range: 3-333 days). Forty-four of the 67 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received mycophenolate treatment. Imfinzi was discontinued in 9 patients. Resolution occurred in 29 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated hepatitis occurred in 80 (3.5%) patients, including Grade 3 in 48 (2.1%) patients, Grade 4 in 8 (0.4%) patients, and Grade 5 in 2 (< 0.1%) patients. The median time to onset was 36 days (range: 1-533 days). All patients received systemic corticosteroids, and 68 of the 80 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients also received other immunosuppressants. Treatment was discontinued in 27 patients. Resolution occurred in 47 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated hepatitis occurred in 34 (7.4%) patients, including Grade 3 in 20 (4.3%) patients, Grade 4 in 1 (0.2%) patient and Grade 5 (fatal) in 3 (0.6%) patients. The median time to onset was 29 days (range: 13-313 days). All patients received systemic corticosteroids, and 32 of the 34 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants. Treatment was discontinued in 10 patients. Resolution occurred in 13 patients.
Immune-mediated colitis. In patients receiving Imfinzi monotherapy, immune-mediated colitis or diarrhoea occurred in 58 (1.9%) patients, including Grade 3 in 9 (0.3%) patients and Grade 4 in 2 (< 0.1%) patients. The median time to onset was 70 days (range: 1-394 days). Thirty-eight of the 58 patients received high dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received infliximab treatment and one patient also received mycophenolate treatment. Imfinzi was discontinued in 9 patients. Resolution occurred in 43 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated colitis or diarrhoea occurred in 167 (7.3%) patients, including Grade 3 in 76 (3.3%) patients and Grade 4 in 3 (0.1%) patients. The median time to onset was 57 days (range: 3-906 days). All patients received systemic corticosteroids, and 151 of the 167 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty-two patients also received other immunosuppressants. Treatment was discontinued in 54 patients. Resolution occurred in 141 patients.
Intestinal perforation was observed in patients receiving Imfinzi in combination with tremelimumab.

HCC pool.

In patients receiving STRIDE, immune-mediated colitis or diarrhoea occurred in 31 (6.7%) patients, including Grade 3 in 17 (3.7%) patients. The median time to onset was 23 days (range: 2-479 days). All patients received systemic corticosteroids, and 28 of the 31 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also received other immunosuppressants. Treatment was discontinued in 5 patients. Resolution occurred in 29 patients.
Intestinal perforation was not observed in patients receiving STRIDE.
Immune-mediated endocrinopathies. Immune-mediated hypothyroidism. In patients receiving Imfinzi monotherapy, immune-mediated hypothyroidism occurred in 245 (8.2%) patients, including Grade 3 in 4 (0.1%) patients. The median time to onset was 85 days (range: 1-562 days). Of the 245 patients, 240 patients received hormone replacement therapy, 6 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism followed by hormone replacement. No patients discontinued Imfinzi due to immune-mediated hypothyroidism. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 20 patients or immune-mediated thyroiditis in 3 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated hypothyroidism occurred in 209 (9.2%) patients, including Grade 3 in 6 (0.3%) patients. The median time to onset was 85 days (range: 1-624 days). Thirteen patients received systemic corticosteroids, and 8 of the 13 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two-hundred and five patients required endocrine therapy. Treatment was discontinued in 3 patients. Resolution occurred in 52 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 25 patients or immune-mediated thyroiditis in 2 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated hypothyroidism occurred in 46 (10.0%) patients. The median time to onset was 85 days (range: 26-763 days). One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). Resolution occurred in 6 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 4 patients.
Immune-mediated hyperthyroidism. In patients receiving Imfinzi monotherapy, immune-mediated hyperthyroidism occurred in 50 (1.7%) patients, there were no Grade 3 or 4 cases. The median time to onset was 43 days (range: 1-253 days). Forty six of the 50 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker), 11 patients received systemic corticosteroids and 4 of the 11 patients received high-dose systemic corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued Imfinzi due to immune-mediated hyperthyroidism. Resolution occurred in 39 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated hyperthyroidism occurred in 62 (2.7%) patients, including Grade 3 in 5 (0.2%) patients. The median time to onset was 33 days (range: 4-176 days). Eighteen patients received systemic corticosteroids, and 11 of the 18 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Fifty-three patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). Treatment was discontinued in 1 patient. Resolution occurred in 47 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated hyperthyroidism occurred in 21 (4.5%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 30 days (range: 13-60 days). Four patients received systemic corticosteroids, and all of the four patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 17 patients.
Immune-mediated thyroiditis. In patients receiving Imfinzi monotherapy, immune-mediated thyroiditis occurred in 12 (0.4%) patients, including Grade 3 in 2 (< 0.1%) patients. The median time to onset was 49 days (range: 14-106 days). Of the 12 patients, 10 patients received hormone replacement therapy, 1 patient received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued Imfinzi due to immune-mediated thyroiditis.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated thyroiditis occurred in 15 (0.7%) patients, including Grade 3 in 1 (< 0.1%) patient. The median time to onset was 57 days (range: 22-141 days). Thirteen patients received systemic corticosteroids, and 2 of the 5 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Thirteen patients required other therapy, including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. No patients discontinued treatment due to immune-mediated thyroiditis. Resolution occurred in 5 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated thyroiditis occurred in 6 (1.3%) patients. The median time to onset was 56 days (range: 7-84 days). Two patients received systemic corticosteroids, and 1 of the 2 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. Resolution occurred in 2 patients.
Immune-mediated adrenal insufficiency. In patients receiving Imfinzi monotherapy, immune-mediated adrenal insufficiency occurred in 14 (0.5%) patients, including Grade 3 in 3 (< 0.1%) patients. The median time to onset was 146 days (range: 20-547 days). All 14 patients received systemic corticosteroids; 4 of the 14 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). No patients discontinued Imfinzi due to immune-mediated adrenal insufficiency. Resolution occurred in 3 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in 16 (0.7%) patients and Grade 4 in 1 (< 0.1%) patient. The median time to onset was 105 days (range: 20-428 days). Thirty-two patients received systemic corticosteroids, and 10 of the 32 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients required endocrine therapy. Treatment was discontinued in 1 patient. Resolution occurred in 11 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated adrenal insufficiency occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 64 days (range: 43-504 days). All patients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.
Immune-mediated type 1 diabetes mellitus. In patients receiving Imfinzi monotherapy, Grade 3 immune-mediate type 1 diabetes mellitus occurred in 1 (< 0.1%) patient. The time to onset was 43 days. This patient required long-term insulin therapy and Imfinzi was permanently discontinued due to immune-mediated type 1 diabetes mellitus.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated type 1 diabetes mellitus occurred in 6 (0.3%) patients, including Grade 3 in 1 (< 0.1%) patient and Grade 4 in 2 (< 0.1%) patients. The median time to onset was 58 days (range: 7-220 days). All patients required insulin. Treatment was discontinued in 1 patient. Resolution occurred in 1 patient.

HCC pool.

In patients receiving STRIDE, immune-mediated type 1 diabetes mellitus was not observed.
Immune-mediated hypophysitis/hypopituitarism. In patients receiving Imfinzi monotherapy, immune-mediated hypophysitis/ hypopituitarism occurred in 2 (< 0.1%) patients both Grade 3. The time to onset for the events was 44 days and 50 days. Both patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and one patient discontinued Imfinzi due to immune-mediated hypophysitis/hypopituitarism.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated hypophysitis/hypopituitarism occurred in 16 (0.7%) patients, including Grade 3 in 8 (0.4%) patients. The median time to onset was 123 days (range: 63-388 days). All patients received systemic corticosteroids, and 8 of the 16 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy. Treatment was discontinued in 2 patients. Resolution occurred in 7 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated hypophysitis/hypopituitarism occurred in 5 (1.1%) patients. The median time to onset for the events was 149 days (range: 27-242 days). Four patients received systemic corticosteroids, and 1 of the 4 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also required endocrine therapy. Resolution occurred in 2 patients.
Immune-mediated nephritis. In patients receiving Imfinzi monotherapy, immune-mediated nephritis occurred in 14 (0.5%) patients, including Grade 3 in 2 (< 0.1%) patients. The median time to onset was 71 days (range: 4-393 days). Nine patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received mycophenolate. Imfinzi was discontinued in 5 patients. Resolution occurred in 8 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated nephritis occurred in 9 (0.4%) patients, including Grade 3 in 1 (< 0.1%) patient. The median time to onset was 79 days (range: 39-183 days). All patients received systemic corticosteroids, and 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 3 patients. Resolution occurred in 5 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated nephritis occurred in 4 (0.9%) patients, including Grade 3 in 2 (0.4%) patients. The median time to onset was 53 days (range: 26-242 days). All patients received systemic corticosteroids, and 3 of the 4 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.
Immune-mediated rash. In patients receiving Imfinzi monotherapy, immune-mediated rash or dermatitis (including pemphigoid) occurred in 50 (1.7%) patients, including Grade 3 in 12 (0.4%) patients. The median time to onset was 43 days (range: 4-333 days). Twenty-four of the 50 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Imfinzi was discontinued in 3 patients. Resolution occurred in 31 patients.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, immune-mediated rash or dermatitis (including pemphigoid), occurred in 112 (4.9%) patients, including Grade 3 in 17 (0.7%) patients. The median time to onset was 35 days (range: 1-778 days). All patients received systemic corticosteroids, and 57 of the 112 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 10 patients. Resolution occurred in 65 patients.

HCC pool.

In patients receiving STRIDE, immune-mediated rash or dermatitis (including pemphigoid) occurred in 26 (5.6%) patients, including Grade 3 in 9 (1.9%) patients and Grade 4 in 1 (0.2%) patient. The median time to onset was 25 days (range: 2-933 days). All patients received systemic corticosteroids and 14 of the 26 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants. Treatment was discontinued in 3 patients. Resolution occurred in 19 patients.
Immune-mediated neurological adverse events in ongoing and completed trials. Meningitis.
Infusion-related reactions. In patients receiving Imfinzi monotherapy, infusion related reactions occurred in 49 (1.6%) patients, including Grade 3 in 5 (0.2%) patients. There were no Grade 4 or 5 events.

Imfinzi + tremelimumab pan-tumour pool.

In patients receiving Imfinzi in combination with tremelimumab, infusion-related reactions occurred in 45 patients (2.0%), including Grade 3 in 2 (< 0.1%) patients. There were no Grade 4 or 5 events.

HCC pool.

In patients receiving STRIDE, infusion-related reactions occurred in 13 (2.8%) patients.

Paediatrics and adolescents.

The safety of Imfinzi in combination with tremelimumab in paediatric and adolescents aged less than 18 years has not been established. No new safety signals were observed in a clinical study evaluating 50 paediatric patients (< 18 years), relative to the known safety profiles of Imfinzi and tremelimumab in adults. Of the 50 patients enrolled in the study, 42 received Imfinzi in combination with tremelimumab and 8 received Imfinzi only (see Section 5.2 Pharmacokinetic Properties).

Post-marketing experience.

The following adverse events have been identified during post-approval use of Imfinzi. Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic disorders.

Autoimmune haemolytic anaemia.

General disorders and administration site conditions.

Systemic inflammatory response syndrome.

Musculoskeletal and connective tissue disorders.

Sjogren's syndrome, tenosynovitis, polymyalgia rheumatica.

Nervous system disorders.

Myelitis transverse.

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 specific treatment in the event of durvalumab overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.
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.

Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response that helps tumours evade detection and elimination by the immune system. PD-L1 expression can be induced by inflammatory signals (e.g. IFN-gamma) and can be expressed on both tumour cells and tumour-associated immune cells in tumour microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.
Durvalumab is a fully human, high affinity, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Durvalumab does not induce antibody dependent cell-mediated cytotoxicity (ADCC). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions enhances antitumour immune responses. These antitumour responses may result in tumour elimination.
In preclinical studies, PD-L1 blockade by durvalumab led to increased T-cell activation and decreased tumour size in xenograft mouse models of human melanoma and/or pancreatic cancer cells as well as mouse syngeneic colorectal cancer.
The combination of durvalumab, a PD-L1 inhibitor, and tremelimumab, a CTLA-4 inhibitor functions to enhance anti-tumour T-cell activation and function at multiple stages of the immune response, maximizing anti-tumour immunity.

Clinical trials.

Durvalumab doses of 10 mg/kg every 2 weeks, 1120 mg every 3 weeks or 1500 mg every 4 weeks were evaluated in NSCLC, ES-SCLC and endometrial cancer clinical studies. Based on the modelling and simulation of exposure, exposure-safety relationships and exposure-efficacy data comparisons, there are no anticipated clinically significant differences in efficacy and safety between durvalumab doses of 10 mg/kg every 2 weeks, 1120 mg every 3 weeks or 1500 mg every 4 weeks.
Non-small cell lung cancer (NSCLC).

AEGEAN study (resectable NSCLC).

AEGEAN was a randomised, double-blind, placebo-controlled, multicentre, Phase III study designed to evaluate the efficacy of Imfinzi in combination with platinum-based chemotherapy as neoadjuvant treatment, then continued as Imfinzi monotherapy after surgery, in patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). The study enrolled previously untreated patients with documented squamous or non-squamous NSCLC and no prior exposure to immune-mediated therapy, a WHO/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and at least one RECIST 1.1 target lesion. Prior to randomisation, patients had tumour PD-L1 expression status confirmed using the Ventana PD-L1 (SP263) Assay.
The study excluded patients with active or prior documented autoimmune disease, or use of immunosuppressive medication within 14 days of the first dose of durvalumab. The study population for efficacy analysis (modified intent-to-treat [mITT]) excluded patients with known EGFR mutations or ALK rearrangements.
Randomisation was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression on tumour cells (TC; TC < 1% vs TC ≥ 1%) status.
The AEGEAN study randomised 802 patients in a 1:1 ratio to receive perioperative Imfinzi (Arm 1) or placebo (Arm 2) in combination with neoadjuvant chemotherapy. Crossover between the study arms was not permitted. Efficacy analysis was conducted based on 740 patients in the mITT population.
Arm 1: Imfinzi 1500 mg + chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by Imfinzi 1500 mg every 4 weeks for up to 12 cycles after surgery.
Arm 2: Placebo + chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by Placebo every 4 weeks for up to 12 cycles after surgery.
Patients who had surgical resection with R0 or R1 margins, and a post-surgical scan, were eligible to continue to adjuvant treatment. Following surgery, eligible patients started durvalumab or placebo treatment as soon as clinically feasible.
A RECIST 1.1 tumour assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). The first post-surgical CT/MRI scan of the chest and abdomen (including the entire liver and both adrenals) was acquired 5 weeks ± 2 weeks after surgery and prior to, but as close as possible to the start of adjuvant therapy. Tumour assessments were then conducted every 12 weeks (relative to the date of surgery) until week 48, every 24 weeks (relative to the date of surgery) until week 192 (approximately 4 years), and then every 48 weeks (relative to the date of surgery) thereafter until RECIST 1.1 defined radiological progressive disease, consent withdrawal, or death.
Survival assessments were conducted at month 2, 3, and 4 following treatment discontinuation and then every 2 months until month 12 followed by every 3 months.
The primary endpoints of the study were pathological complete response (pCR) by blinded central pathology review, and event-free survival (EFS) by Blinded Independent Central Review (BICR) assessment. The key secondary endpoints were major pathological response (MPR) by blinded central pathology review, disease free survival (DFS) by BICR, and overall survival (OS). Other secondary efficacy objectives included were EFS (PD-L1-TC ≥ 1% analysis set), pCR (PD-L1-TC ≥ 1% analysis set) and Patient Reported Outcomes (PRO).
At the planned interim analysis of pCR, the study met its prespecified boundary for declaring statistical significance for pCR and MPR. Subsequently, at the first planned interim analysis of EFS, the study met its prespecified boundary for declaring statistical significance for EFS.
The demographics and baseline disease characteristics were well balanced between the two study arms. Baseline demographics and disease characteristics of the population for efficacy analysis (mITT) were as follows: male (71.6%), female (28.4%), age ≥ 65 years (51.6%), median age 65 years (range: 30 to 88), WHO/ECOG PS 0 (68.4%), WHO/ECOG PS 1 (31.6), White (53.6%), Asian (41.5%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%), Hispanic or Latino (16.1%), Not Hispanic or Latino (83.9%). current or past smokers (85.5%), never smoker (14.5%), squamous histology (48.6%) and non-squamous histology (50.7%), Stage II (28.4%), Stage III (71.6%), PD-L1 expression status TC ≥ 1% (66.6%), PD-L1 expression status TC < 1% (33.4%). The demographics and baseline characteristics for the mITT population were similar to the ITT population except for the absence of patients with known EGFR mutations or ALK rearrangements.
Table 19 provides the curative intent surgery details for the mITT population.
The study demonstrated a statistically significant and clinically meaningful improvement in EFS of the Imfinzi arm compared to the placebo arm. The study also demonstrated a statistically significant and meaningful improvement in pCR of the Imfinzi arm compared to the placebo arm. OS data were not mature at the time of EFS analysis. See Table 20 and Figure 1.

Subgroup analysis.

The improvement in EFS and pCR favouring patients in Arm 1 compared to patients in Arm 2 were consistently observed across prespecified subgroups based on demographic and baseline disease characteristics, histology and planned chemotherapy.

PACIFIC study (locally advanced NSCLC).

The efficacy of Imfinzi was evaluated in the PACIFIC study, a randomised, double-blind, placebo-controlled, multicentre study in 713 patients with histologically or cytologically confirmed locally advanced, unresectable NSCLC. Patients had completed at least 2 cycles of definitive platinum-based chemotherapy with RT within 1 to 42 days prior to initiation of study treatment and had an ECOG PS of 0 or 1. Ninety-two percent of patients had received a total dose of 54 to 66 Gy of radiation. The study excluded patients who had progressed following CRT, patients with prior exposure to any anti-PD-1 or anti-PD-L1 antibody, patients with active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions that required systemic immunosuppression (except physiological dose of systemic corticosteroids); active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of Imfinzi. Patients were randomised 2:1 to receive 10 mg/kg Imfinzi (n = 476) or 10 mg/kg placebo (n = 237) via intravenous infusion every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression. Randomisation was stratified by gender, age (< 65 years vs. ≥ 65 years) and smoking status (smoker vs. nonsmoker). Patients with disease control at 12 months were given the option to be re-treated upon disease progression. Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter.
Patients were enrolled regardless of their tumour PD-L1 expression level. Where available, archival tumour tissue specimens taken prior to CRT were retrospectively tested for PD-L1 expression on TC using the VENTANA PD-L1 (SP263) IHC assay. Of the 713 patients randomised, 63% of patients provided a tissue sample of sufficient quality and quantity to determine PD-L1 expression and 37% were unknown.
The demographics and baseline disease characteristics were well balanced between study arms. Baseline demographics of the overall study population were as follows: male (70%), age ≥ 65 years (45%), White (69%), Asian (27%), other (4%), current smoker (16%), past-smoker (75%), and never smoker (9%), WHO/ECOG PS 0 (49%), WHO/ECOG PS 1 (51%). Disease characteristics were as follows: Stage IIIA (53%), Stage IIIB (45%), histological sub-groups of squamous (46%), nonsquamous (54%). Of 451 patients with PD-L1 expression available, 67% were TC ≥ 1% [PD-L1 TC 1-24% (32%), PD-L1 TC ≥ 25% (35%)] and 33% were TC < 1%.
The two primary endpoints of the study were Progression-Free Survival (PFS) and OS of Imfinzi vs. placebo. Secondary efficacy endpoints included PFS at 12 months (PFS 12) and 18 months (PFS 18) from randomisation and Time from Randomisation to Second Progression (PFS2). PFS was assessed by BICR according to RECIST 1.1.
At the primary analysis, the study demonstrated a statistically significant improvement in PFS and OS in the Imfinzi-treated group compared with the placebo group. In the 5-year follow-up analysis, with median follow-up of 34.2 months, Imfinzi continued to demonstrate improved OS and PFS compared to placebo (see Table 21 and Figure 2 and Figure 3).
The improvements in PFS and OS in favour of patients receiving Imfinzi compared to those receiving placebo were consistently observed in all predefined subgroups analysed, including ethnicity, age, gender, smoking history, EGFR mutation status and histology. ALK mutation status was not analysed in this study.

Post hoc subgroup analysis by PD-L1 expression.

Additional subgroup analyses were conducted to evaluate the efficacy by tumour PD-L1 expression (≥ 25%, 1-24%, ≥ 1%, < 1%) and for patients whose PD-L1 status could not be established (PD-L1 unknown). PFS and OS results from the 5-year follow-up are summarised in Figure 4 and Figure 5. Overall the safety profile of durvalumab in PD-L1 TC ≥ 1% subgroup was consistent with the intent to treat population, as was the PD-L1 TC < 1% subgroup.

Patient reported outcomes.

Patient-reported symptoms, function and health-related quality of life (HRQoL) were collected using the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaire (QLQ) QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). The LC13 and C30 were assessed at baseline and every 4 weeks for the first 8 weeks, then every 8 weeks until completion of the treatment period or discontinuation of study drug due to toxicity or disease progression. Compliance was similar between the Imfinzi and placebo treatment groups (83% vs 85.1% overall of evaluable forms completed).
At baseline, no differences in patient reported symptoms, function or HRQoL were observed between Imfinzi and placebo groups. Throughout the duration of the study to week 48, there was no clinically meaningful difference between Imfinzi and placebo groups in symptoms, functioning and HRQoL (as assessed by a difference of greater than or equal to 10 points).
Small cell lung cancer (SCLC).

ADRIATIC study (LS-SCLC).

ADRIATIC was a study designed to evaluate the efficacy of Imfinzi with or without tremelimumab. ADRIATIC was a randomised, double-blind, placebo-controlled multicentre study in 730 patients with histologically or cytologically confirmed LS-SCLC (Stage I to III according to AJCC, 8th edition) who had not progressed following concurrent CRT. Patients who were Stage I or II had to be medically inoperable as determined by the investigator. Patients completed 4 cycles of definitive platinum-based CRT, 60-66 Gy once daily (QD) over 6 weeks or 45 Gy twice daily (BID) over 3 weeks, within 1 to 42 days prior to the first dose of study treatment. Prophylactic cranial irradiation (PCI) could be delivered at the discretion of the investigator after CRT and within 1 to 42 days prior to the first dose of study treatment.
The study excluded patients with active or prior documented autoimmune disease within 5 years of initiation of the study; a history of active primary immunodeficiency; a history of Grade ≥ 2 pneumonitis or active tuberculosis or hepatitis B or C or HIV infection and patients with active interstitial lung disease. Patients with mixed SCLC and NSCLC histology were also excluded.
Randomisation was stratified by stage (I/II versus III) and receipt of PCI (yes vs no). Patients were randomised 1:1:1 to receive:
Arm 1: Imfinzi 1500 mg + placebo every 4 weeks for 4 cycles, followed by Imfinzi 1500 mg every 4 weeks.
Arm 2: Placebo + a second placebo every 4 weeks for 4 cycles, followed by a single placebo every 4 weeks.
Arm 3: Imfinzi 1500 mg + tremelimumab 75 mg every 4 weeks for 4 cycles, followed by Imfinzi 1500 mg every 4 weeks (information not included in Product Information. Analysis of data pending).
Once 600 patients had been randomised across all 3 arms, subsequent patients were randomised 1:1 to either Arm 1 or 2, and received either Imfinzi 1500 mg every 4 weeks or placebo every 4 weeks.
Treatment continued until disease progression, until unacceptable toxicity, or for a maximum of 24 months. Tumour assessments were conducted every 8 weeks for the first 72 weeks, then every 12 weeks up to 96 weeks, and then every 24 weeks thereafter.
The demographics and baseline disease characteristics were well balanced between study arms. Baseline demographics and disease characteristics of the Imfinzi and placebo arms were as follows: male (69.1%), age ≥ 65 years (39.2%), White (50.4%), Black or African-American (0.8%), Asian (47.5%), Hispanic or Latino (4.2%), other (1.3%), current smoker (22.3%), past-smoker (68.5%), never smoker (9.2%), WHO/ECOG PS 0 (48.7%), WHO/ECOG PS 1 (51.3%), Stage I (3.6%), Stage II (9.1%), Stage III (87.4%).
Prior to randomisation, all patients received platinum-based chemotherapy (66.2% cisplatin-etoposide, 33.8% carboplatin-etoposide); 72.1% of patients received RT QD (of which 92.4% received ≥ 60 - ≤ 66 Gy QD); 27.9% received RT BID (of which 96.6% received 45 Gy BID) and 53.8% patients received PCI. Response to CRT was as follows: complete response (12.3%), partial response (73.8%), stable disease (14.0%).
The dual primary endpoints of the study were OS and PFS of Imfinzi vs placebo. Secondary efficacy endpoints included ORR of Imfinzi vs placebo. PFS and ORR were assessed by BICR according to RECIST v1.1.
At a planned interim analysis (Data cut-off (DCO): 15 January 2024), the study demonstrated a statistically significant and clinically meaningful improvement in OS and PFS for Imfinzi compared with placebo. See Table 22 and Figure 6 and Figure 7.
The improvements in OS and PFS in favour of patients receiving Imfinzi compared to those receiving placebo were generally consistent across predefined subgroups analysed.

CASPIAN study (ES-SCLC).

The efficacy of Imfinzi in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC patients was investigated in CASPIAN, a randomised, open-label, multicentre study in treatment naïve ES-SCLC patients with WHO/ECOG performance status of 0 or 1. Patients in the trial were eligible to receive a platinum-based chemotherapy regimen as firstline treatment for SCLC, with life expectancy ≥ 12 weeks, at least one target lesion by RECIST 1.1 and adequate organ and bone marrow function. Patients with asymptomatic or treated brain metastases were permitted. The study excluded patients with a history of chest RT; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome (PNS); active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection; or patients receiving live attenuated vaccine within 30 days before or after the start of Imfinzi.
Randomisation was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin).
The evaluation of efficacy for ES-SCLC relied on comparison between:
Arm 1: Imfinzi 1500 mg + etoposide (80-100 mg/m2) and either carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m2);
Arm 2: Either carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m2) on Day 1 and etoposide (80-100 mg/m2) intravenously on Days 1, 2, and 3 of each 21-day cycle for between 4 and 6 cycles.
For patients randomised to Arm 1, etoposide and either carboplatin or cisplatin was limited to 4 cycles every 3 weeks subsequent to randomisation. Imfinzi monotherapy continued until disease progression or unacceptable toxicity. Administration of Imfinzi monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
Patients randomised to Arm 2, were permitted to receive a total of up to 6 cycles of etoposide and either carboplatin or cisplatin. After completion of chemotherapy, prophylactic cranial irradiation (PCI) was permitted only in Arm 2 per investigator discretion.
Tumour assessments were conducted at Week 6 and Week 12 from the date of randomisation, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.
The primary endpoints of the study were OS of Imfinzi + chemotherapy (Arm 1) vs. chemotherapy alone (Arm 2). The key secondary endpoint was PFS. Other secondary endpoints were ORR, OS and PFS landmarks and Patient Reported Outcomes (PRO). PFS and ORR were assessed using Investigator assessments according to RECIST v1.1.
At a planned interim (primary) analysis, Imfinzi + chemotherapy (Arm 1) vs. chemotherapy (Arm 2) met the efficacy boundary of the primary endpoint of OS and at a planned follow-up OS analysis Imfinzi + chemotherapy (Arm 1) vs. chemotherapy (Arm 2) continued to demonstrate improved OS. The results are summarised below.
The demographics and baseline disease characteristics were well balanced between the study arms (268 patients in Arm 1 and 269 patients in Arm 2). Baseline demographics of the overall study population were as follows: male (69.6%), age ≥ 65 years (39.6%), median age 63 years (range: 28 to 82 years), White (83.8%), Asian (14.5%), Black or African American (0.9%), other (0.6%), non-Hispanic or Latino (96.1%), current or past-smoker (93.1%), never smoker (6.9%), WHO/ECOG PS 0 (35.2%), WHO/ECOG PS 1 (64.8%), Stage IV 90.3%, 24.6% of the patients received cisplatin and 74.1% of the patients received carboplatin. In Arm 1, 1.1% of the patients received ≥ 5 cycles of chemotherapy and 0.4% of the patients received ≥ 6 cycles of chemotherapy based on etoposide exposure. In Arm 2, 62.8% of the patients received ≥ 5 treatment cycles, 56.8% of the patients received the maximum of 6 treatment cycles based on etoposide exposure and 7.8% of the patients received PCI after chemotherapy.
At the planned interim (primary) analysis (DCO 11 March 2019) the study demonstrated a statistically significant and clinically meaningful improvement in OS at the planned interim analysis with Imfinzi + chemotherapy (Arm 1) vs. chemotherapy alone (Arm 2) [HR = 0.73 (95% CI: 0.591, 0.909), p = 0.0047]. Imfinzi + chemotherapy demonstrated an improvement in PFS vs. chemotherapy alone [HR = 0.78 (95% CI: 0.645, 0.936)].
In the planned final OS analysis (median: 25.1 months; DCO 27 January 2020), the median OS for Arm 1 and Arm 2 was consistent with the OS primary analysis.
In the long-term follow-up analysis, with a median follow-up of 39.3 months (DCO 22 March2021), Imfinzi + etoposide + platinum (Arm 1) vs. etoposide + platinum (Arm 2) continued to demonstrate sustained improvement in OS.
Results for the final analysis and follow-up analysis are presented in Table 23. Kaplan-Meier curves for the long-term follow-up OS and the final analysis PFS are presented in Figure 8 and Figure 9.

Subgroup analysis.

The improvements in OS in favour of patients receiving Imfinzi + chemotherapy compared to those receiving chemotherapy alone, were consistently observed across the prespecified subgroups based on demographics, geographical region, carboplatin or cisplatin use and disease characteristics.

Change from baseline in lung cancer symptoms over 12 months (mixed model for repeated measures).

Imfinzi + chemotherapy improved appetite loss by demonstrating a statistically significant difference in mean change from baseline versus chemotherapy alone during the overall time period from randomisation until 12 months (Estimated mean difference -4.5; 99% CI -9.04, -0.04; p = 0.009). Both treatment arms demonstrated numerical symptom reduction in cough, chest pain, dyspnoea and fatigue over the same time period.
Patient-reported outcome results should be interpreted in the context of the open-label study design.
In the exploratory subgroup analyses of OS based on the planned platinum chemotherapy received at cycle 1, the HR was 0.70 (95% CI 0.55, 0.89) in patients who received carboplatin, and the HR was 0.88 (95% CI 0.55, 1.41) in patients who received cisplatin.
Biliary tract carcinoma (BTC).

TOPAZ-1 study.

TOPAZ-1 was a study designed to evaluate the efficacy of Imfinzi in combination with gemcitabine and cisplatin. TOPAZ-1 was a randomised, double-blind, placebo-controlled, multicentre study in 685 patients with histologically confirmed locally advanced or metastatic BTC and ECOG PS of 0 or 1. Patients who developed recurrent disease more than 6 months after surgery and/or completion of adjuvant therapy were included. Patients must have had at least one target lesion by RECIST v1.1 and adequate organ and bone marrow function.
The study excluded patients with ampullary carcinoma, active or prior documented autoimmune or inflammatory disorders, HIV infection or active infections, including tuberculosis or hepatitis C or patients with current or prior use of immunosuppressive medication within 14 days before the first dose of Imfinzi.
Randomisation was stratified by disease status and primary tumour location.
Patients were randomised 1:1 to receive:
Arm 1: Imfinzi 1500 mg administered intravenously on Day 1+ gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles, followed by Imfinzi 1500 mg every 4 weeks as long as clinical benefit is observed or until unacceptable toxicity, or;
Arm 2: Placebo administered intravenously on Day 1+ gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles, followed by placebo every 4 weeks as long as clinical benefit is observed or until unacceptable toxicity.
Tumour assessments were conducted every 6 weeks for the first 24 weeks after the date of randomisation, and then every 8 weeks until confirmed objective disease progression.
The primary endpoint of the study was OS and the key secondary endpoint was PFS. Other secondary endpoints were ORR, DoR and PRO. PFS, ORR and DoR were Investigator assessed according to RECIST v1.1.
The demographics and baseline disease characteristics were well balanced between the two study arms (341 patients in Arm 1 and 344 patients in Arm 2). Baseline demographics of the overall study population were as follows: male (50.4%), age < 65 years (53.3%), White (37.2%), Asian (56.4%), Black or African American (2.0%), other (4.2%), non-Hispanic or Latino (93.1%), ECOG PS 0 (49.1%), vs. PS 1 (50.9%), primary tumour location (intrahepatic cholangiocarcinoma (55.9%), extrahepatic cholangiocarcinoma (19.1%) and gallbladder cancer (25.0%), disease status recurrent (19.1%) vs. initially unresectable (80.7%), metastatic (86.0%) vs. locally advanced (13.9%).
The study demonstrated a statistically significant and clinically meaningful improvement in OS and PFS at a pre-planned interim (primary) analysis. The results in OS were [HR = 0.80, (95% CI: 0.66, 0.97), p = 0.021] and in PFS [HR = 0.75, (95% CI: 0.63, 0.89), p = 0.001]. The maturity for OS was 61.9% and the maturity for PFS was 83.64%. Results from this analysis are presented in Table 24 and Figure 11.
An additional OS analysis was performed 6.5 months after the interim analysis with an OS maturity of 76.9%. The observed treatment effect was consistent with the interim analysis. The OS HR was 0.76 (95% CI: 0.64, 0.91) and median survival was 12.9 months (95% CI: 11.6, 14.1) for the Imfinzi + gemcitabine and cisplatin arm. Results from this analysis are presented in the Table 24 and Figure 10.
Hepatocellular carcinoma (HCC). HIMALAYA study (uHCC). The efficacy of STRIDE was evaluated in the HIMALAYA study, a randomised, open-label, multicentre study in patients with confirmed uHCC who did not receive prior systemic treatment for HCC. The study included patients with BCLC Stage C or B (not eligible for locoregional therapy) and Child-Pugh Score Class A.
The study excluded patients with co-infection of viral hepatitis B and hepatitis C; active or prior documented GI bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders.
Patients with oesophageal varices were included except those with active or prior documented GI bleeding within 12 months prior to study entry.
Randomisation was stratified by macrovascular invasion (MVI) (yes vs. no), aetiology of liver disease (confirmed hepatitis B virus vs. confirmed hepatitis C virus vs. others) and ECOG PS (0 vs.1).
The HIMALAYA study randomised 1171 patients 1:1:1 to receive:
Imfinzi: durvalumab 1500 mg every 4 weeks;
STRIDE: tremelimumab 300 mg as a single priming dose + Imfinzi 1500 mg; followed by Imfinzi 1500 mg every 4 weeks;
Sorafenib (S) 400 mg twice daily.
Treatment continued as long as clinical benefit was observed or until unacceptable toxicity. Patients in all arms could continue to receive treatment after evidence of disease progression if, in the Investigator's opinion, they were benefiting from study drug and met all inclusion and exclusion criteria for treatment beyond progression. In addition, patients in the STRIDE arm who continued treatment beyond progression were allowed to be rechallenged once with an additional single dose of tremelimumab 300 mg after cycle five of Imfinzi. Of the 182 patients enrolled to the STRIDE arm who received Imfinzi beyond progression, the median OS was 19.5 months (95% CI: 15.4, 23.4). Of the 30 patients who were enrolled to the STRIDE arm who were rechallenged with tremelimumab, the median OS was 30.4 months (95% CI: 23.4, NR).
Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter. Survival assessments were conducted every month for the first 3 months following treatment discontinuation and then every 2 months.
The primary endpoint was OS for STRIDE vs. sorafenib. The key secondary objective was OS for non-inferiority based on the comparison of Imfinzi vs. sorafenib. Key secondary endpoints were Investigator assessed PFS, ORR and DoR according to RECIST v1.1. PROs were also assessed.
The demographics and baseline disease characteristics were generally representative for patients with uHCC. The baseline demographics of the overall study population were as follows: male (83.7%), age < 65 years (50.4%), White (44.6%), Asian (50.7%), Black or African American (1.7%), other (2.3%), ECOG PS 0 (62.6%); Child-Pugh Class score A (99.5%), macrovascular invasion (25.2%), extrahepatic spread (53.4%), viral aetiology; hepatitis B (30.6%), hepatitis C (27.2%), uninfected (42.2%).
The study demonstrated a statistically significant and clinically meaningful improvement in OS with STRIDE vs. sorafenib [HR = 0.78 [95% CI 0.66, 0.92]; p = 0.0035]. The study also met the key secondary objective of OS non-inferiority of Imfinzi to sorafenib with the upper limit of the 95.67% CI being below the pre-specified non-inferiority margin of 1.08. See Table 25 and Figure 12.

Patient reported outcomes.

Patient-reported symptoms, function and HRQoL were collected using the EORTC QLQ-C30 and its HCC module (EORTC QLQ-HCC18). At baseline, patient-reported symptoms, functioning or HRQoL scores were comparable between the study arms.

Delay in time to deterioration of symptoms, functioning and global health status/QoL.

STRIDE vs. sorafenib demonstrated a clinically meaningful improvement by delaying time to deterioration in a broad range of patient-reported symptoms, function, and global health status/QoL compared to sorafenib. Longer time to deterioration (median in months) was observed in the STRIDE arm compared to S for the following symptoms: Global Health Status (7.5 vs. 5.7 months, HR 0.76, p = 0.0306); physical functioning (12.9 vs. 7.4 months, HR 0.68; p = 0.0020), fatigue (7.4 vs. 5.4 months, HR 0.71; p = 0.0026), nausea (25.0 vs. 11.0 months, HR 0.65; p = 0.0033), appetite loss (12.6 vs. 6.9 months, HR 0.59; p < 0.0001), abdominal pain (16.8 vs. 8.9 months, HR 0.61; p = 0.0008) and abdominal swelling (20.9 vs. 11.1 months, HR 0.74; p = 0.0431.

Change from baseline in patient-reported symptoms (mixed model for repeated measures).

STRIDE improved patient-reported HRQoL functioning and diarrhoea by demonstrating a nominal difference and clinically meaningful mean change from baseline vs. sorafenib from randomisation until 8 months (Estimated mean difference at 8 months: -18.5 (95% CI: -23.24, -13.84) and p-value: < 0.0001).
Patient-reported outcome results should be interpreted in the context of the open-label study design.
Study 22 (uHCC). The safety and efficacy of STRIDE was evaluated in Study 22, an open-label, uncontrolled, multipart Phase I/II study involving 433 immunotherapy-naïve patients with uHCC. Of the 75 patients who received the STRIDE treatment regimen (tremelimumab 300 mg as a single priming dose + Imfinzi 1500 mg; followed by Imfinzi 1500 mg every 4 weeks), more than a quarter received STRIDE as first line of systemic therapy (73.3% had received prior systemic therapy with sorafenib/other VEGFR TKI). The higher percentage of patients alive and in survival follow-up (including those still receiving study treatment) in the STRIDE treatment arm (30.7%) compared to the other treatment arms (Imfinzi monotherapy and two additional tremelimumab arms; ranging from 17.4% to 19.2%) at DCO was more likely indicative of the data in the STRIDE treatment arm being less mature than that in the other 3 treatment arms as enrolment in the STRIDE safety run-in treatment arm (Part 2B) began approximately 8 months after the start of the other 3 treatment arms (in Part 2A).
The study included patients with BCLC Stage C or B (not eligible for locoregional therapy), ECOG PS of 0 or 1 and Child-Pugh Score Class A.
The study excluded patients with co-infection of viral hepatitis B and hepatitis C; active or prior documented GI bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders.
Treatment continued as long as clinical benefit was observed or until unacceptable toxicity.
Patients who completed the assigned dosing cycles and were benefiting from study drug in the Investigator's opinion and subsequently had evidence of disease progression during the Imfinzi monotherapy phase could be rechallenged with tremelimumab 300 mg.
Tumour assessments were conducted every 8 weeks.
The primary objective was safety and tolerability. Key secondary endpoints included OS, ORR and DoR. ORR, DoR and PFS were based on Investigator assessments and BICR according to RECIST 1.1.
The baseline demographics of the study population (STRIDE) were as follows: male (86.7%); age < 65 years (45.3%), White (36.0%); Asian (58.7%); Black or African American (5.3%); other (0%), ECOG PS 0 (61.3%), Child-Pugh Class/Score A/5 (68.0%), Child-Pugh Class/Score A/6 (30.7%), macrovascular invasion (21.3%); extrahepatic spread (70.7%), viral aetiology; hepatitis B (36.0%), hepatitis C (28.0%), uninfected (36.0%); prior systemic therapy (73.3%).
Efficacy results for the STRIDE and Imfinzi monotherapy treatment arms only are shown in Table 26. Results from the other two tremelimumab arms have not been provided.
Endometrial cancer.

DUO-E study.

DUO-E was a randomised, multicentre, double-blind, placebo-controlled, Phase III study of first-line platinum-based chemotherapy (carboplatin plus paclitaxel) in combination with Imfinzi, followed by maintenance Imfinzi in patients with advanced or recurrent endometrial cancer. For patients with recurrent disease, prior chemotherapy was allowed only if it was administered in the adjuvant setting and there was at least 12 months from the date of last dose of chemotherapy administered to the date of subsequent relapse. The study included patients with epithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients with endometrial sarcoma were excluded.
Randomisation was stratified by tumour tissue's mismatch repair (MMR) status (proficient (pMMR) versus deficient (dMMR)), disease status (recurrent versus newly diagnosed) and geographic region (Asia versus rest of the world). Patients were randomised 1:1:1 across three treatment arms, including the following two:
Arm 1 (Platinum-based chemotherapy): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with durvalumab placebo every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received durvalumab placebo every 4 weeks and olaparib placebo tablets twice daily as maintenance treatment until disease progression.
Arm 2 (Platinum-based chemotherapy + Imfinzi): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1120 mg Imfinzi every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1500 mg durvalumab every 4 weeks with olaparib placebo tablets twice daily as maintenance treatment until disease progression.
Treatment was continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Assessment of tumour status was performed every 9 weeks for the first 18 weeks relative to randomisation and every 12 weeks thereafter.
The demographics and baseline disease characteristics were generally well balanced between the three study arms (241 patients in Arm 1, 238 patients in Arm 2 and 239 patients in Arm 3). Baseline demographics were as follows: age ≥ 65 years (47%), median age of 64 years (range: 22 to 86 years), white (57%), Asian (30%), Black (5%) and other (4%). Disease characteristics were as follows: WHO/ECOG PS 0 (67%) vs. PS 1 (33%), 47% newly diagnosed and 53% recurrent disease. The histologic subtypes were endometrioid (60%), serous (21%), carcinosarcoma (7%), mixed epithelial (4%), clear cell (3%), undifferentiated (2%), mucinous (< 1%) and other (3%).
MMR status was determined centrally using an MMR immunohistochemistry panel assay. Of a total of 479 patients randomised to Arm 1 and Arm 2, 384 (~80%) patients had pMMR tumour status and 95 (~20%) patients had dMMR tumour status. Demographics and baseline characteristics in the MMR-based subgroups were similar to the overall study population.
The primary endpoint was PFS, determined by investigator assessment using RECIST 1.1. Secondary efficacy endpoints included OS, ORR and DoR.
Key results for DUO-E are summarised in Table 27, Figure 13, Figure 14 and Figure 15. The study demonstrated a statistically significant improvement in PFS in the ITT population for patients treated with platinum-based chemotherapy + Imfinzi compared to platinum-based chemotherapy alone, however, the benefit is clearer for patients with dMMR tumours. Results by BICR assessment were not meaningfully different from those by investigator assessment. For the ITT, the median follow-up time in censored patients was 15.4 months in the platinum-based chemotherapy + Imfinzi arm and 12.6 months in the platinum-based chemotherapy arm. At the time of PFS analysis, interim OS data were 31% mature and a significant difference between arms had not been demonstrated in the ITT (see Table 27).

5.2 Pharmacokinetic Properties

The PK of durvalumab was assessed for Imfinzi as monotherapy in combination with chemotherapy (etoposide and carboplatin or cisplatin), in combination with tremelimumab and platinum-based chemotherapy, and in combination with platinum-based chemotherapy followed by Imfinzi. There was no clinically meaningful difference between the PK of durvalumab as monotherapy, or in any of the assessed combinations.
The PK of Imfinzi was studied in patients with solid tumours with doses ranging from 0.1 to 20 mg/kg administered once every two, three or four weeks.

Distribution.

PK exposure increased more than dose-proportionally (nonlinear PK) at doses < 3 mg/kg and dose proportionally (linear PK) at doses ≥ 3 mg/kg. Steady-state was achieved at approximately 16 weeks. Based on population PK analysis that included patients in the dose range of 10 mg/kg every 2 weeks (Q2W), 15 mg/kg every 3 weeks (Q3W) and 20 mg/kg every 4 weeks (Q4W), the steady-state volume of distribution (Vss) was 5.64 L.

Excretion.

Durvalumab clearance (CL) decreased over time resulting in a geometric mean steady-state clearance (CLss) of 8.16 mL/h at Day 365; the decrease in CLss was not considered clinically relevant. The terminal half-life (t1/2), based on baseline CL, was approximately 18 days.

Special populations.

Age (19-96 years), bodyweight (34-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, soluble PD-L1, tumour type, race, mild renal impairment (creatinine clearance (CrCl): 60 to 89 mL/min), moderate renal impairment (CrCl: 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 to 1.5 x ULN and any AST) moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) or ECOG/WHO status had no clinically significant effect on the pharmacokinetics of durvalumab.
The effect of severe renal impairment (CrCl 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3.0 x ULN and any AST) on the pharmacokinetics of durvalumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence durvalumab exposure.

Paediatric and adolescents.

The PK of durvalumab in combination with tremelimumab was evaluated in a study of 50 paediatric patients with an age range from 1 to 17 years, in Study D419EC00001. Patients received either durvalumab 20 mg/kg in combination with tremelimumab 1 mg/kg or durvalumab 30 mg/kg in combination with tremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by durvalumab as monotherapy every 4 weeks. Based on population PK analysis, durvalumab systemic exposure in paediatric patients ≥ 35 kg receiving durvalumab 20 mg/kg every 4 weeks was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks, whereas in paediatric patients (≥ 35 kg) receiving durvalumab 30 mg/kg every 4 weeks, exposure was approximately 1.5-fold higher compared to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks. In paediatric patients < 35 kg receiving durvalumab 30 mg/kg every 4 weeks, the systemic exposure was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity of Imfinzi as monotherapy is based on pooled data in 2280 patients who were treated with Imfinzi 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as monotherapy and evaluable for the presence of anti-drug antibodies (ADAs). Sixty nine patients (3.0%) tested positive for treatment-emergent ADAs. Neutralising antibodies against durvalumab were detected in 0.5% (12/2280) patients. The presence of ADAs did not have a clinically relevant effect on pharmacokinetics, pharmacodynamics or safety.
In the AEGEAN study, of the 375 patients who were treated with Imfinzi 1500 mg in combination with chemotherapy every 3 weeks prior to surgery, followed by Imfinzi 1500 mg every 4 weeks following surgery, and were evaluable for the presence of ADAs, 25 (6.7%) patients tested positive for treatment emergent ADAs. Neutralising antibodies against durvalumab were detected in 2 patients (0.5%). The presence of ADAs did not have an apparent effect on the pharmacokinetics or safety of Imfinzi.
In the ADRIATIC study, of the 206 patients who were treated with Imfinzi monotherapy and evaluable for the presence of ADAs, 7 (3.4%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against durvalumab were detected in 1% (2/206) patients. The presence of ADAs did not have an apparent effect on the pharmacokinetics or safety.
In the CASPIAN study, of the 201 patients who were treated with Imfinzi 1500 mg every 3 weeks in combination with etoposide, and carboplatin or cisplatin and evaluable for the presence of ADAs, 0 (0%) patients tested positive for treatment-emergent ADAs.
In the TOPAZ-1 study, of the 240 patients who were treated with Imfinzi 1500 mg every 3 weeks in combination with chemotherapy, followed by Imfinzi 1500 mg every 4 weeks and evaluable for the presence of ADAs, 2 (0.8%) patients tested positive for treatment-emergent ADAs. There were insufficient numbers of patients with treatment emergent ADAs or neutralising antibodies (2 patients each) to determine whether ADAs have an impact on pharmacokinetics and clinical safety of durvalumab.
In the HIMALAYA study, of the 294 patients who were treated with STRIDE and evaluable for the presence of ADAs, 9 (3.1%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against durvalumab were detected in 1.7% (5/294) patients. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.
In the DUO-E study, the number of the patients who were treated with platinum-based chemotherapy + Imfinzi (n=198) and evaluable for the presence of ADAs, 2 (1.0%) patients tested positive for treatment-emergent ADAs in the platinum-based chemotherapy + Imfinzi arm. Neutralising antibodies against durvalumab were detected in 1 (0.5%) patient in the platinum-based chemotherapy + Imfinzi arm. There were insufficient number of patients with treatment-emergent ADAs or neutralising antibodies to determine whether ADAs have an impact on pharmacokinetics or safety of durvalumab.
Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease.
For these reasons, comparison of incidence of antibodies to Imfinzi with the incidence of antibodies to other products may be misleading.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of durvalumab has not been evaluated. As a large protein molecule, durvalumab is not expected to interact directly with DNA or other chromosomal material.

Carcinogenicity.

The carcinogenic potential of durvalumab has not been evaluated.

6 Pharmaceutical Particulars

6.1 List of Excipients

Imfinzi concentrated solution for infusion contains the following excipients: histidine, histidine hydrochloride monohydrate, trehalose dihydrate, polysorbate 80 and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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.

6.4 Special Precautions for Storage

Store unopened vials under refrigeration at 2°C to 8°C in the original carton to protect from light. Do not freeze. Do not shake.

6.5 Nature and Contents of Container

10 mL of concentrated solution for infusion in a 10 mL Type 1 glass vial with an elastomeric stopper and a white flip-off aluminium seal containing 500 mg durvalumab. Pack size of 1 vial.
2.4 mL of concentrated solution for infusion in a 10 mL Type 1 glass vial with an elastomeric stopper and a grey flip-off aluminium seal containing 120 mg durvalumab. Pack size of 1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Durvalumab is a human immunoglobulin (IgG1κ) monoclonal antibody.

CAS number.

1428935-60-7.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes