IMFINZI 50mg / ml perfusive solution concentrate medication leaflet

IMFINZI 50 mg/ml concentrate for solution for infusion.

Each ml of concentrate for solution for infusion contains 50 mg of durvalumab.

One vial of 2.4 ml of concentrate contains 120 mg of durvalumab.

One vial of 10 ml of concentrate contains 500 mg of durvalumab.

Durvalumab is produced in mammalian (Chinese hamster ovary) cells by recombinant DNAtechnology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to slightly yellow solution, free from visible particles. The solution hasa pH of approximately 6.0 and an osmolality of approximately 400 mOsm/kg.

Non-Small Cell Lung Cancer (NSCLC)

IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by

IMFINZI as monotherapy as adjuvant treatment, is indicated for the treatment of adults with resectable

NSCLC at high risk of recurrence and no EGFR mutations or ALK rearrangements (for selectioncriteria, see section 5.1).

IMFINZI as monotherapy is indicated for the treatment of locally advanced, unresectable non-smallcell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥ 1% of tumour cells and whosedisease has not progressed following platinum-based chemoradiation therapy (see section 5.1).

IMFINZI in combination with tremelimumab and platinum-based chemotherapy is indicated for thefirst-line treatment of adults with metastatic NSCLC with no sensitising EGFR mutations or ALKpositive mutations.

Small Cell Lung Cancer (SCLC)

IMFINZI as monotherapy is indicated for the treatment of adults with limited-stage small cell lungcancer (LS-SCLC) whose disease has not progressed following platinum-based chemoradiationtherapy.

IMFINZI in combination with etoposide and either carboplatin or cisplatin is indicated for the first-linetreatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Biliary Tract Cancer (BTC)

IMFINZI in combination with gemcitabine and cisplatin is indicated for the first-line treatment ofadults with unresectable or metastatic biliary tract cancer (BTC).

Hepatocellular Carcinoma (HCC)

IMFINZI as monotherapy is indicated for the first line treatment of adults with advanced orunresectable hepatocellular carcinoma (HCC).

IMFINZI in combination with tremelimumab is indicated for the first line treatment of adults withadvanced or unresectable hepatocellular carcinoma (HCC).

Endometrial Cancer

IMFINZI in combination with carboplatin and paclitaxel is indicated for the first-line treatment ofadults with primary advanced or recurrent endometrial cancer who are candidates for systemic therapy,followed by maintenance treatment with:

* IMFINZI as monotherapy in endometrial cancer that is mismatch repair deficient (dMMR)

* IMFINZI in combination with olaparib in endometrial cancer that is mismatch repairproficient (pMMR).

Treatment must be initiated and supervised by a physician experienced in the treatment of cancer.

PD-L1 testing for patients with locally advanced NSCLC

Patients with locally advanced NSCLC should be evaluated for treatment based on the tumourexpression of PD-L1 confirmed by a validated test (see section 5.1).

MMR testing for patients with endometrial cancer

Patients with endometrial cancer should be evaluated for treatment based on tumour MMR statusconfirmed by a validated test (see section 5.1).

The recommended dose for IMFINZI monotherapy and IMFINZI combination therapy is presented in

Table 1. IMFINZI is administered as an intravenous infusion over 1 hour.

When IMFINZI is administered in combination with other therapeutic agents, refer to the summary ofproduct characteristics (SmPC) of the therapeutic agents for further information.

Table 1. Recommended dose of IMFINZI monotherapy and combination therapy

Indication Recommended IMFINZI dose Duration of therapy

Locally Advanced NSCLC 10 mg/kg every 2 weeks or Until disease progression,1 500 mg every 4 weeksa unacceptable toxicity, or amaximum of 12 monthsb

LS-SCLC 1 500 mg every 4 weeksa Until disease progression,unacceptable toxicity, or amaximum of 24 months

HCC 1 500 mg every 4 weeksa Until disease progression oruntil unacceptable toxicity

Resectable NSCLC 1 500 mgc in combination with Neoadjuvant phase: untilplatinum-based chemotherapy disease progression thatevery 3 weeks for up to 4 precludes definitive surgery orcycles prior to surgery, unacceptable toxicity.

followed by 1 500 mg Adjuvant phase: untilmonotherapy every 4 weeks for recurrence, unacceptableup to 12 cycles after surgery. toxicity, or a maximum of 12cycles after surgery.

Indication Recommended IMFINZI dose Duration of therapy

Metastatic NSCLC During platinum chemotherapy: Until disease progression or1 500 mgd in combination with unacceptable toxicitytremelimumab 75 mgd andplatinum-based chemotherapyevery 3 weeks (21 days) for4 cycles (12 weeks)

Post-platinum chemotherapy:

1 500 mg every 4 weeks asmonotherapy and histology-based pemetrexed maintenanceetherapy every 4 weeks

A fifth dose of tremelimumab75 mgf,g should be given atweek 16 alongside IMFINZI

ES-SCLC 1 500 mgh in combination with Until disease progression orchemotherapy every 3 weeks unacceptable toxicity(21 days) for 4 cycles,followed by 1 500 mg every4 weeks as monotherapy

BTC 1 500 mgi in combination with Until disease progression orchemotherapy every 3 weeks until unacceptable toxicity(21 days) up to 8 cycles,followed by 1 500 mg every4 weeks as monotherapy

HCC IMFINZI 1 500 mgj Until disease progression oradministered in combination unacceptable toxicitywith 300 mgj tremelimumab asa single dose at Cycle 1/Day 1,followed by IMFINZI asmonotherapy every 4 weeks

Endometrial Cancer 1 120 mg in combination with Until disease progression orcarboplatin and paclitaxel every unacceptable toxicity3 weeks (21 days) for aminimum of 4 and up to6 cycles,followed by IMFINZI1 500 mgk every 4 weeks asmonotherapy (dMMR patients)or in combination with olaparib300 mg twice daily (pMMRpatients)a Patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than30 kg.b It is recommended to continue treatment for clinically stable patients with initial evidence of diseaseprogression until disease progression is confirmed.c Resectable NSCLC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZIat 20 mg/kg. In combination with platinum-based chemotherapy dose at 20 mg/kg every 3 weeks (21 days)prior to surgery, followed by monotherapy at 20 mg/kg every 4 weeks after surgery until weight increases togreater than 30 kg.

d Metastatic NSCLC patients with a body weight of 30 kg or less must receive weight-based dosing, equivalentto IMFINZI 20 mg/kg until weight increases to greater than 30 kg. Patients with a body weight of 34 kg orless must receive weight-based dosing equivalent to tremelimumab 1 mg/kg until weight increases to greaterthan 34 kg.e Consider maintenance administration of pemetrexed for patients with non-squamous tumours who receivedtreatment with pemetrexed and carboplatin/cisplatin during the platinum-based chemotherapy stage.f In the case of dose delay(s), a fifth dose of tremelimumab can be given after Week 16, alongside IMFINZI.g If patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of tremelimumab(up to a total of 5) alongside IMFINZI should be given during the post-platinum chemotherapy phase.h ES-SCLC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at20 mg/kg. In combination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every4 weeks as monotherapy until weight increases to greater than 30 kg.i BTC patients with a body weight of 36 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. Incombination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every 4 weeks asmonotherapy until weight increases to greater than 36 kg.j HCC patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI20 mg/kg until weight increases to greater than 30 kg. Patients with a body weight of 40 kg or less mustreceive weight-based dosing, equivalent to tremelimumab 4 mg/kg until weight increases to greater than40 kg.k Endometrial cancer patients with a body weight of 30 kg or less during maintenance phase must receiveweight-based dosing equivalent to IMFINZI at 20 mg/kg, until weight increases to greater than 30 kg.

Dose escalation or reduction is not recommended. Treatment withholding or discontinuation may berequired based on individual safety and tolerability, see Table 2.

Guidelines for management of immune-mediated and non-immune-mediated adverse reactions aredescribed in Table 2 (refer to section 4.4 for further management recommendations, monitoring andevaluation information).

Table 2. Treatment modifications for IMFINZI or IMFINZI in combination with other products

Adverse reactions Severitya Treatment modification

Immune-mediated adverse reactions

Grade 2 Withhold dose

Immune-mediatedpneumonitis/interstitial lung disease

Grade 3 or 4 Permanently discontinue

ALT or AST> 3 - ≤ 5 x ULNor Withhold dosetotal bilirubin

Immune-mediated hepatitis > 1.5 - ≤ 3 x ULN

Withhold IMFINZI and

ALT or AST permanently discontinue> 5 - ≤ 10 x ULN tremelimumab (whereappropriate)

Adverse reactions Severitya Treatment modification

Concurrent ALT or

AST > 3 x ULN andtotal bilirubin> 2 x ULNb

Permanently discontinue

ALT or AST> 10 x ULNortotal bilirubin> 3 x ULN

ALT or AST> 2.5 - ≤ 5 x BLV and Withhold dose≤ 20 x ULN

ALT or AST> 5 - 7 x BLV and≤ 20 x ULN

Withhold IMFINZI and

Immune-mediated hepatitis in HCC orpermanently discontinue(or secondary tumour involvement of concurrent ALT ortremelimumab (wherethe liver with abnormal baseline AST 2.5 - 5 x BLVappropriate).

values)c and ≤ 20 x ULN andtotal bilirubin> 1.5 - < 2 x ULNb

ALT or AST> 7 x BLV or> 20 ULN whichever

Permanently discontinueoccurs firstor bilirubin> 3 X ULN

Grade 2 Withhold dose

Grade 3 for IMFINZI

Withhold dosemonotherapy

Immune-mediated colitis or diarrhoea

Grade 3 for IMFINZI Permanently discontinue+ tremelimumab tremelimumabd

Grade 4 Permanently discontinue

Intestinal perforatione Any grade Permanently discontinue

Adverse reactions Severitya Treatment modification

Immune-mediated hyperthyroidism, Withhold dose until

Grade 2-4thyroiditis clinically stable

Immune-mediated

Grade 2-4 No changeshypothyroidism

Immune-mediated

Withhold dose untiladrenal insufficiency or Grade 2-4clinically stablehypophysitis/hypopituitarism

Immune-mediated

Grade 2-4 No changestype 1 diabetes mellitus

Grade 2 with serumcreatinine

Withhold dose> 1.5 - 3 x (ULN orbaseline)

Grade 3 with serum

Immune-mediated nephritiscreatinine> 3 x baseline or

Permanently discontinue> 3-6 x ULN; Grade 4with serum creatinine> 6 x ULN

Grade 2 for > 1 week

Withhold dose

Immune-mediated rash or dermatitis(including pemphigoid) Grade 3

Grade 4 Permanently discontinue

Immune-mediated myocarditis Grade 2-4 Permanently discontinue

Grade 2 or 3 Withhold dosef

Immune-mediatedmyositis/polymyositis/rhabdomyolysis

Grade 4 Permanently discontinue

Grade 1 or 2 Interrupt or slow the rate ofinfusion

Grade 3 or 4 Permanently discontinue

Withhold dose until

Infection Grade 3 or 4clinically stable

Immune-mediated myasthenia gravis Grade 2-4 Permanently discontinue

Adverse reactions Severitya Treatment modification

Immune-mediated Myelitis transverse Any grade Permanently discontinue

Grade 2 Withhold dose

Immune-mediated meningitis

Grade 3 or 4 Permanently discontinue

Immune-mediated encephalitis Grade 2-4 Permanently discontinue

Immune-mediated Guillain-Barré

Grade 2-4 Permanently discontinuesyndrome

Grade 2 or 3 Withhold dose

Other immune-mediated adversereactionsg

Grade 4 Permanently discontinue

Non-immune-mediated adverse reactions

Pure red cell aplasia (PRCA)h Any Grade Permanently discontinue

Withhold dose until

Grade 2 and 3 ≤ Grade 1 or return to

Other non-immune-mediated adverse baselinereactions

Grade 4 Permanently discontinueia Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST:

aspartate aminotransferase; ULN: upper limit of normal; BLV: baseline value.b For patients with alternative cause follow the recommendations for AST or ALT increases without concurrentbilirubin elevations.c If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold orpermanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.d Permanently discontinue tremelimumab for Grade 3; however, treatment with durvalumab can be resumed onceevent has resolved.e Adverse drug reaction is only associated with IMFINZI in combination with tremelimumab.f Permanently discontinue IMFINZI if adverse reaction does not resolve to ≤ Grade 1 within 30 days or if thereare signs of respiratory insufficiency.g Includes immune thrombocytopenia, pancreatitis, immune-mediated arthritis, uveitis, cystitis noninfective andpolymyalgia rheumatica.h Adverse drug reaction is only associated when olaparib maintenance treatment is used in combination with

IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy.i With the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue should bebased on accompanying clinical signs/symptoms and clinical judgment.

Based on the severity of the adverse reaction, IMFINZI and/or tremelimumab should be withheld andcorticosteroids administered (refer to section 4.4). After withhold, IMFINZI and/or tremelimumab canbe resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dosehas been reduced to ≤ 10 mg prednisone or equivalent per day. IMFINZI and tremelimumab should bepermanently discontinued for recurrent Grade 3 (severe) immune-mediated adverse reactions and forany Grade 4 (life-threatening) immune-mediated adverse reactions, except for endocrinopathies thatare controlled with replacement hormones.

No dose adjustment is required for elderly patients (≥ 65 years of age) (see section 5.1).

No dose adjustment of IMFINZI is recommended in patients with mild or moderate renal impairment.

Data from patients with severe renal impairment are too limited to draw conclusions on this population(see section 5.2).

No dose adjustment of IMFINZI is recommended for patients with mild or moderate hepaticimpairment. Data from patients with severe hepatic impairment are too limited to draw conclusions onthis population (see section 5.2).

The safety and efficacy of IMFINZI in children and adolescents aged below 18 years of age has notbeen established with regard to NSCLC, SCLC, BTC and HCC. No data are available. Outside itsauthorised indications, IMFINZI in combination with tremelimumab has been studied in children aged1 to 17 years with neuroblastoma, solid tumour and sarcoma, however the results of the study did notallow to conclude that the benefits of such use outweigh the risks. Currently available data aredescribed in sections 5.1 and 5.2.

IMFINZI is for intravenous use. It is to be administered as an intravenous infusion solution over 1hour (see section 6.6).

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

IMFINZI in combination with chemotherapy

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

IMFINZI in combination with tremelimumab and platinum-based chemotherapy

When IMFINZI is administered in combination with tremelimumab and platinum-basedchemotherapy, tremelimumab is given first, followed by IMFINZI and then platinum-basedchemotherapy on the same day of dosing.

When IMFINZI is administered in combination with a fifth dose of tremelimumab and pemetrexedmaintenance therapy at week 16, tremelimumab is given first, followed by IMFINZI and thenpemetrexed maintenance therapy on the same day of dosing.

IMFINZI, tremelimumab, and platinum-based chemotherapy are administered as separate intravenousinfusions. IMFINZI and tremelimumab are each given over 1 hour. For platinum-based chemotherapy,refer to the SmPC for administration information. For pemetrexed maintenance therapy, refer to the

SmPC for administration information. Separate infusion bags and filters for each infusion should beused.

During cycle 1, tremelimumab is to be followed by IMFINZI starting approximately 1 hour (maximum2 hours) after the end of the tremelimumab infusion. Platinum-based chemotherapy infusion shouldstart approximately 1 hour (maximum 2 hours) after the end of the IMFINZI infusion. If there are noclinically significant concerns during cycle 1, then at the physician’s discretion, subsequent cycles of

IMFINZI can be given immediately after tremelimumab and the time period between the end of the

IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.

IMFINZI in combination with tremelimumab

For uHCC, when IMFINZI is administered in combination with tremelimumab, administertremelimumab prior to IMFINZI on the same day. IMFINZI and tremelimumab are administered asseparate intravenous infusions. Refer to the SmPC for tremelimumab dosing information.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Refer to section 4.2, Table 2 for recommended treatment modifications.

For suspected immune-mediated adverse reactions, adequate evaluation should be performed toconfirm etiology or exclude alternate etiologies. Based on the severity of the adverse reaction,

IMFINZI or IMFINZI in combination with tremelimumab should be withheld or permanentlydiscontinued. Treatment with corticosteroids or endocrine therapy should be initiated. For eventsrequiring corticosteroid therapy, and upon improvement to ≤ Grade 1, corticosteroid taper should beinitiated and continued over at least 1 month. Consider increasing dose of corticosteroids and/or usingadditional systemic immunosuppressants if there is worsening or no improvement.

In order to improve the traceability of biological medicinal products, the tradename and the batchnumber of the administered product should be clearly recorded.

Immune-mediated pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemiccorticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI,

IMFINZI in combination with tremelimumab, IMFINZI in combination with platinum-basedchemotherapy followed by IMFINZI in combination with olaparib, or in combination withchemotherapy (see section 4.8). For Grade 2 events, an initial dose of 1-2 mg/kg/day prednisone orequivalent 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 should be initiated followed by a taper.

Pneumonitis and radiation pneumonitis

Radiation pneumonitis is frequently observed in patients receiving radiation therapy to the lung andthe 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 chemoradiationwithin 1 to 42 days prior to initiation of study treatment, pneumonitis or radiation pneumonitisoccurred in 161 (33.9%) patients in the IMFINZI-treated group and 58 (24.8%) in the placebo group,including Grade 3 (3.4% vs. 3.0%) and Grade 5 (1.1% vs. 1.7%). In the AEGEAN study, in patientswho have received post-operative radiotherapy (PORT), pneumonitis and radiation pneumonitisoccurred in 10 (33.3%) patients in the IMFINZI-treated group and 3 (11.1%) patients in the placebogroup, including 2 patients with maximum Grade 3 (6.7%) in the IMFINZI-treated group.

In the ADRIATIC Study, in patients who had completed chemoradiation within 1 to 42 days prior toinitiation of study treatment, pneumonitis or radiation pneumonitis occurred in 100 (38.2%) patients inthe IMFINZI-treated group and 80 (30.2%) in the placebo group, including Grade 3 (3.1% vs. 2.3%),and Grade 5 (0.4% vs. 0.0).

Patients should be monitored for signs and symptoms of pneumonitis or radiation pneumonitis.

Suspected pneumonitis should be confirmed with radiographic imaging and other infectious anddisease-related aetiologies excluded, and managed as recommended in section 4.2.

Immune-mediated hepatitis

Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clearalternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination withtremelimumab, or in combination with chemotherapy (see section 4.8). Monitor alanineaminotransferase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase levels prior toinitiation of treatment and prior to each subsequent infusion. Additional monitoring is to be consideredbased on clinical evaluation. Immune-mediated hepatitis should be managed as recommended insection 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone orequivalent followed by taper for all grades.

Immune-mediated colitis

Immune-mediated colitis or diarrhoea, defined as requiring use of systemic corticosteroids and with noclear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination withtremelimumab, or in combination with chemotherapy (see section 4.8). Adverse drug reactions ofintestinal perforation and large intestine perforation were reported in patients receiving IMFINZI incombination with tremelimumab. Patients should be monitored for signs and symptoms ofcolitis/diarrhoea and intestinal perforation and managed as recommended in section 4.2.

Corticosteroids should be administered at an initial dose of 1-2 mg/kg/day prednisone or equivalentfollowed by a taper for Grades 2-4. Consult a surgeon immediately if intestinal perforation of ANYgrade is suspected.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receiving

IMFINZI or IMFINZI in combination with tremelimumab, or in combination with chemotherapy andhypothyroidism may follow hyperthyroidism (see section 4.8). Patients should be monitored forabnormal thyroid function tests prior to and periodically during treatment and as indicated based onclinical evaluation. Immune-mediated hypothyroidism, hyperthyroidism, and thyroiditis should bemanaged as recommended in section 4.2. For immune-mediated hypothyroidism, initiate thyroidhormone replacement as clinically indicated for Grades 2-4. For immune-mediatedhyperthyroidism/thyroiditis, symptomatic management can be implemented for Grades 2-4.

Immune-mediated adrenal insufficiency

Immune-mediated adrenal insufficiency occurred in patients receiving IMFINZI or IMFINZI incombination with tremelimumab, or in combination with chemotherapy (see section 4.8). Patientsshould be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomaticadrenal insufficiency, patients should be managed as recommended in section 4.2. Corticosteroidsshould be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by ataper and a hormone replacement as clinically indicated for Grades 2-4.

Immune-mediated type 1 diabetes mellitus

Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can befatal if not detected early, occurred in patients receiving IMFINZI or IMFINZI in combination withtremelimumab, or in combination with chemotherapy (see section 4.8). Patients should be monitoredfor clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus,patients should be managed as recommended in section 4.2. Treatment with insulin can be initiated asclinically indicated for Grades 2-4.

Immune-mediated hypophysitis/hypopituitarism

Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMFINZI or

IMFINZI in combination with tremelimumab, or in combination with chemotherapy (see section 4.8).

Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. Forsymptomatic hypophysitis or hypopituitarism, patients should be managed as recommended insection 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone orequivalent followed by a taper and a hormone replacement as clinically indicated for Grades 2-4.

Immune-mediated nephritis

Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clearalternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination withtremelimumab, or in combination with chemotherapy (see section 4.8). Patients should be monitoredfor abnormal renal function tests prior to and periodically during treatment with IMFINZI or IMFINZIin combination with tremelimumab and managed as recommended in section 4.2. Corticosteroidsshould be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by ataper for Grades 2-4.

Immune-mediated rash

Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemiccorticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or

IMFINZI in combination with tremelimumab, or in combination with chemotherapy (see section 4.8).

Events of Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported in patientstreated with PD-1 inhibitors. Patients should be monitored for signs and symptoms of rash ordermatitis and managed as recommended in section 4.2. Corticosteroids should be administered withan 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, or in combination with chemotherapy (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managedas recommended in section 4.2. Corticosteroids should be administered with an initial dose of 2-4 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4. If no improvement within 2 to3 days despite corticosteroids, promptly start additional immunosuppressive therapy. Upon resolution(Grade 0), corticosteroid taper should be initiated and continued over at least 1 month.

Immune-mediated pancreatitis

Immune-mediated pancreatitis occurred in patients receiving IMFINZI in combination withtremelimumab and chemotherapy, or in combination with chemotherapy (see section 4.8). Patientsshould be monitored for signs and symptoms of immune-mediated pancreatitis and managed asrecommended in section 4.2.

Other immune-mediated adverse reactions

Given the mechanism of action of IMFINZI or IMFINZI in combination with tremelimumab, otherpotential immune-mediated adverse reactions may occur. The following immune-related adversereactions have been observed in patients treated with IMFINZI monotherapy or IMFINZI incombination with tremelimumab, or in combination with chemotherapy: myasthenia gravis, myelitistransverse, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome,immune thrombocytopenia, immune-mediated arthritis, uveitis, cystitis noninfective and polymyalgiarheumatica (see section 4.8). Patients should be monitored for signs and symptoms and managed asrecommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.

Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusion-related reactions have been reported in patients receiving IMFINZI or IMFINZI in combination withtremelimumab, or in combination with chemotherapy (see section 4.8). Infusion-related reactionsshould be managed as recommended in section 4.2. For Grade 1 or 2 severity, may consider pre-medications for prophylaxis of subsequent infusion reactions. For Grade 3 or 4, manage severeinfusion-related reactions per institutional standard, appropriate clinical practice guidelines and/orsociety guidelines.

Patients with pre-existing autoimmune disease

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest anincreased risk of immune-related adverse reactions following immune-checkpoint inhibitor therapy ascompared with patients without pre-existing AID. In addition, flares of the underlying AID werefrequent, but the majority were mild and manageable.

Disease-specific precaution (BTC)

Cholangitis and biliary tract infections

Cholangitis and biliary tract infections are not uncommon in patients with advanced BTC. Cholangitisevents were reported in TOPAZ-1 in both treatment groups (14.5% [IMFINZI + chemotherapy] vs.

8.2% [placebo + chemotherapy]); these were mostly in association with biliary stents and were notimmune-mediated in aetiology. Patients with BTC (especially those with biliary stents) should beclosely monitored for development of cholangitis or biliary tract infections before initiation oftreatment and, regularly, thereafter.

Treatment-specific precaution (IMFINZI in combination with olaparib in endometrial cancer)

Pure red cell aplasia (PRCA) (see section 4.8) was reported when olaparib maintenance treatment wasused in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy. If PRCA is confirmed, treatment with IMFINZI and olaparib should bediscontinued.

Autoimmune haemolytic anemia (AIHA) was reported when olaparib maintenance treatment was usedin combination with IMFINZI, following treatment with IMFINZI in combination with platinum-basedchemotherapy. If AIHA is confirmed, treatment with IMFINZI and olaparib should be discontinued.

Metastatic NSCLC

Limited data are available in elderly patients (≥ 75 years) treated with IMFINZI in combination withtremelimumab and platinum-based chemotherapy (see sections 4.8 and 5.1). Careful consideration ofthe potential benefit/risk of this regimen on an individual basis is recommended.

Patients with the following were excluded from clinical studies: a baseline ECOG performance score≥ 2; active or prior documented autoimmune disease within 2 years of initiation of the study; a historyof immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions thatrequired systemic immunosuppression, except physiological dose of systemic corticosteroids(≤ 10 mg/day prednisone or equivalent); uncontrolled intercurrent illnesses; active tuberculosis orhepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before orafter the start of IMFINZI. In the absence of data, durvalumab should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.

The safety of concurrent prophylactic cranial irradiation (PCI) with IMFINZI in patients with

ES-SCLC is unknown.

For more information on exclusion criteria for each specific study see section 5.1.

The use of systemic corticosteroids or immunosuppressants before starting durvalumab, exceptphysiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent), is notrecommended because of their potential interference with the pharmacodynamic activity and efficacyof durvalumab. However, systemic corticosteroids or other immunosuppressants can be used afterstarting durvalumab to treat immune-related adverse reactions (see section 4.4).

No formal pharmacokinetic (PK) drug-drug interaction studies have been conducted with durvalumab.

Since the primary elimination pathways of durvalumab are protein catabolism via reticuloendothelialsystem or target-mediated disposition, no metabolic drug-drug interactions are expected. PK drug-druginteraction between durvalumab and chemotherapy was assessed in the CASPIAN study and showedconcomitant treatment with durvalumab did not impact the PK of etoposide, carboplatin or cisplatin.

Additionally, based on population PK analysis, concomitant chemotherapy treatment did notmeaningfully impact the PK of durvalumab. PK drug-drug interactions between durvalumab incombination with tremelimumab and platinum-based chemotherapy were assessed in the POSEIDONstudy and showed no clinically meaningful PK interactions between tremelimumab, durvalumab, nab-paclitaxel, gemcitabine, pemetrexed, carboplatin or cisplatin in the concomitant treatment.

Furthermore, in the DUO-E study, the exposure to durvalumab was similar in both treatment armswhich indicates that there were no clinically meaningful PK drug-drug interactions betweendurvalumab and olaparib, although exposure to olaparib was not measured throughout the study.

Women of childbearing potential should use effective contraception during treatment withdurvalumab and for at least 3 months after the last dose of durvalumab.

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 in a mouse allogeneicpregnancy model, disruption of PD-L1 signaling was shown to result in an increase in foetal loss.

Animal studies with durvalumab are not indicative of reproductive toxicity (see section 5.3). Human

IgG1 is known to cross the placental barrier and placental transfer of durvalumab was confirmed inanimal studies. Durvalumab may cause foetal harm when administered to a pregnant woman and is notrecommended during pregnancy and in women of childbearing potential not using effectivecontraception during treatment and for at least 3 months after the last dose.

It is unknown whether durvalumab is secreted in human breast milk. Available toxicological data incynomolgus monkeys have shown low levels of durvalumab in breast milk on day 28 after birth (seesection 5.3). In humans, antibodies may be transferred to breast milk, but the potential for absorptionand harm to the newborn is unknown. However, a potential risk to the breast-fed child cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue or abstainfrom durvalumab therapy taking into account the benefit of breast-feeding for the child and the benefitof therapy for the woman.

There are no data on the potential effects of durvalumab on fertility in humans or animals.

Durvalumab has no or negligible influence on the ability to drive and use machines.

IMFINZI as monotherapy

The safety of IMFINZI as monotherapy is based on pooled data in 4 642 patients across multipletumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every4 weeks or 1 500 mg every 4 weeks. The most common (> 10%) adverse reactions werecough/productive cough (18.1%), diarrhoea (15.1%), rash (15.0%), arthralgia (12.4%), pyrexia(12.5%), abdominal pain (11.8%), upper respiratory tract infections (11.8%), pruritus (11.1%), andhypothyroidism (11.6%). The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions werepneumonia (3.4%) and aspartate aminotransferase increased/alanine aminotransferase increased(2.5%).

IMFINZI was discontinued due to adverse reactions in 3.9% of patients. The most common adversereactions leading to treatment discontinuation were pneumonitis (1.1%) and pneumonia (0.8%).

IMFINZI was delayed or interrupted due to adverse reactions in 13.1% of patients. The most commonadverse reactions leading to dose delay or interruption were pneumonia (2.3%) and aspartateaminotransferase increased/alanine aminotransferase increased (2.0%).

The safety of IMFINZI as monotherapy in patients treated for HCC is based on data in 492 patientsand was consistent with the overall safety profile in the IMFINZI monotherapy pool (N=4 642). Themost common (> 10%) adverse reactions were AST increased/ALT increased (20.3%), abdominal pain(17.9%), diarrhoea (15.9%), pruritus (15.4%), and rash (15.2%). The most common (> 2%) Grade ≥ 3adverse reactions were AST increased/ALT increased (8.1%) and abdominal pain (2.2%).

IMFINZI was discontinued due to adverse reactions in 3.7% of patients. The most common adversereactions leading to treatment discontinuation were AST increased/ALT increased (0.8%) and hepatitis(0.6%).

IMFINZI was delayed or interrupted due to adverse reactions in 11.6% of patients. The most commonadverse reaction leading to dose delay or interruption was AST increased/ALT increased (5.9%).

IMFINZI in combination with chemotherapy

The safety of IMFINZI in combination with chemotherapy is based on pooled data in 1 239 patientsfrom 4 studies (TOPAZ-1, CASPIAN, DUO-E, and AEGEAN). The most common (> 10%) adversereactions were neutropenia (42.3%), anaemia (41.6%), fatigue (34.5%), nausea (34.4%), constipation(25.9%), alopecia (24.1%), thrombocytopenia (23.4%), decreased appetite (20.3%), rash (19.2%),neuropathy peripheral (18%), diarrhoea (17.2%), leukopenia (16.5%), vomiting (15.8%), abdominalpain (15.2%), cough/productive cough (12.2%), pruritus (12.1%), arthralgia (12%), hypothyroidism(11.5%), pyrexia (11.1%) and aspartate aminotransferase increased/alanine aminotransferase increased(10.9%). The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were neutropenia(26.9%), anaemia (13.6%), thrombocytopenia (7.8%), leukopenia (5.5%), fatigue (3.1%), pneumonia(2.3%) and febrile neutropenia (2.2%).

IMFINZI was discontinued due to adverse reactions in 5% of patients. The most common adversereactions leading to treatment discontinuation were pneumonitis (0.8%) and rash (0.7%).

IMFINZI was delayed or interrupted due to adverse reactions in 30.8% of patients. The most commonadverse reactions leading to dose delay or interruption were neutropenia (14.0%), thrombocytopenia(5.4%), anaemia (4.7%), leukopenia (2.4%), aspartate aminotransferase increased/alanineaminotransferase increased (2.0%), fatigue (1.6%), rash (1.5%) and pneumonitis (1.3%).

IMFINZI in combination with tremelimumab 75 mg and platinum-based chemotherapy

The safety of IMFINZI given in combination with tremelimumab 75 mg and chemotherapy is based ondata in 330 patients with metastatic NSCLC. The most common (> 20%) adverse reactions wereanaemia (49.7%), nausea (41.5%), neutropenia (41.2%), fatigue (36.1%), rash (25.8%),thrombocytopenia (24.5%) and diarrhoea (21.5%). The most common (> 2%) NCI CTCAE Grade ≥ 3adverse reactions were neutropenia (23.9%), anaemia (20.6%), pneumonia (9.4%), thrombocytopenia(8.2%), leukopenia (5.5%), fatigue (5.2%), lipase increased (3.9%), amylase increased (3.6%), febrileneutropenia (2.4%), colitis (2.1%) and aspartate aminotransferase increased/alanine aminotransferaseincreased (2.1%).

IMFINZI was discontinued due to adverse reactions in 8.5% of patients. The most common adversereactions leading to treatment discontinuation were pneumonia (2.1%) and colitis (1.2%).

IMFINZI was interrupted due to adverse reactions in 49.4% of patients. The most common adversereactions leading to dose interruption were neutropenia (16.1%), anaemia (10.3%), thrombocytopenia(7.3%), leukopenia (5.8%), pneumonia (5.2%), aspartate aminotransferase increased/alanineaminotransferase increased (4.8%), colitis (3.3%) and pneumonitis (3.3%).

IMFINZI in combination with tremelimumab 300 mg

The safety of IMFINZI given in combination with a single dose of tremelimumab 300 mg is based onpooled data (HCC pool) in 462 HCC patients from the HIMALAYA Study and another study in HCCpatients, Study 22. The most common (> 10%) adverse reactions were rash (32.5%), pruritus (25.5%),diarrhoea (25.3%), abdominal pain (19.7%), aspartate aminotransferase increased/alanineaminotransferase increased (18.0%), pyrexia (13.9%), hypothyroidism (13.0%), cough/productivecough (10.8%), oedema peripheral (10.4%) and lipase increased (10.0%) (see Table 4). The mostcommon severe adverse reactions (NCI CTCAE Grade ≥ 3) were aspartate aminotransferaseincreased/alanine aminotransferase increased (8.9%), lipase increased (7.1%), amylase increased(4.3%) and diarrhoea (3.9%).

The most common serious adverse reactions were colitis (2.6%), diarrhoea (2.4%), pneumonia (2.2%),and hepatitis (1.7%).

The frequency of treatment discontinuation due to adverse reactions was 6.5%. The most commonadverse reactions leading to treatment discontinuation were hepatitis (1.5%) and aspartateaminotransferase increased/alanine aminotransferase increased (1.3%).

The severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1=mild,grade 2=moderate, grade 3=severe, grade 4=life threatening and grade 5=death.

IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combinationwith olaparib 300 mg twice daily

The safety of IMFINZI given in combination with platinum-based chemotherapy followed by

IMFINZI in combination with olaparib 300 mg twice daily is based on data in 238 patients withendometrial cancer. The most common (> 20%) adverse reactions were anaemia (61.8%), nausea(54.6%), fatigue (54.2%), neuropathy peripheral (51.7%), alopecia (50.8%), neutropenia (39.5%),constipation (32.8%), thrombocytopenia (29.8%), diarrhoea (28.2%), vomiting (25.6%), arthralgia(24.4%), rash (23.5%), abdominal pain (23.5%), decreased appetite (23.1%) and leukopenia (20.2%).

The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were neutropenia (25.2%),anaemia (23.5%), leukopenia (6.7%), thrombocytopenia (5.9%), fatigue (5.5%), febrile neutropenia(3.4%), nausea (2.9%), aspartate aminotransferase increased/alanine aminotransferase increased(2.9%) and neuropathy peripheral (2.5%).

IMFINZI was discontinued in 4.6% of patients. The most common adverse reaction leading totreatment discontinuation was pneumonitis (1.7%).

IMFINZI was interrupted in 38.2% of patients. The most common adverse reactions leading to doseinterruption were anaemia (13.4%), thrombocytopenia (11.8%), neutropenia (10.1%), leukopenia(2.9%), hypothyroidism (2.1%) and upper respiratory tract infection (2.1%).

Table 3 lists the incidence of adverse reactions in the IMFINZI monotherapy pooled safety dataset(N=4 642), in patients treated with IMFINZI in combination with chemotherapy (N=1 239) and inpatients treated with IMFINZI in combination with platinum-based chemotherapy followed by

IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib)(N=238). Unless otherwise stated, Table 4 lists the incidence of adverse reactions in patients treatedwith IMFINZI in combination with tremelimumab 75 mg and platinum-based chemotherapy in the

POSEIDON study (N=330) and in patients treated with IMFINZI in combination with a single dose oftremelimumab 300 mg in the HCC pool (N=462). Adverse reactions are listed according to systemorgan class in MedDRA. Within each system organ class, the adverse reactions are presented indecreasing frequency. The corresponding frequency category for each ADR is defined as: verycommon (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to< 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from available data). Within eachfrequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 3. Adverse drug reactions in patients treated with IMFINZI

IMFINZI as IMFINZI in Platinum-basedmonotherapy combination with chemotherapy +chemotherapy IMFINZI + olaparib*

Very Upper respiratory tract Upper respiratory tractcommon infectionsa infectiona

Common Pneumoniab,c, Influenza, Pneumoniab,c, Upper Pneumonia, Oral

Oral candidiasis, Dental respiratory tract candidiasis, Dental andand oral soft tissue infectionsa, Dental and oral soft tissue infectionsdinfectionsd oral soft tissue infectionsd

Uncommon Oral candidiasis, Influenza

Influenza

Very Anaemia, Leukopeniae, Anaemiah, Leukopeniah

Common Neutropeniaf, Neutropeniah,

Thrombocytopeniag Thrombocytopeniah

Common Febrile neutropenia Aplasia pure red cell,

Febrile neutropeniah,

Lymphopeniai

Uncommon Immune Pancytopeniac Pancytopeniahthrombocytopeniac

Rare Immunethrombocytopenia

Common Hypersensitivityi,j

Very Hypothyroidismk Hypothyroidismk Hypothyroidismcommon

Common Hyperthyroidisml Hyperthyroidisml Hyperthyroidism,

Uncommon Thyroiditism, Adrenal Adrenal insufficiency,insufficiency, Type 1 diabetes mellitus,

Hypophysitis/Hypopituita Hypophysitis/Hypopituitarism, Type 1 diabetes rism, Thyroiditismmellitus

Rare Diabetes insipidus

Uncommon Uveitis Uveitis

Rare Uveitis

Very Decreased appetite Decreased appetitehcommon

Nervous System Disorders

Very Neuropathy peripheraln Neuropathy peripheral,common Dizzinessi, Headachei,

Dysgeusiai,o

IMFINZI as IMFINZI in Platinum-basedmonotherapy combination with chemotherapy +chemotherapy IMFINZI + olaparib*

Uncommon Myasthenia gravis, Myasthenia gravis

Encephalitisc,p

Rare Meningitis Noninfective encephalitisp

Not known Guillain-Barré syndrome,

Myelitis transverseq

Common Venous thromboemboliceventsi,r

Uncommon Myocarditis

Rare Myocarditisc

Very Cough/Productive Cough Cough/Productive Cough Cough/Productive cough,common Dyspnoeai,s

Common Pneumonitisc,t, Dysphonia Pneumonitisc,t, Dysphonia Pneumonitis, Dysphonia

Uncommon Interstitial lung disease Interstitial lung diseasec Interstitial lung disease

Very Diarrhoea, Abdominal Diarrhoea, Abdominal Diarrhoea, Abdominalcommon painu painu, Constipation, painu, Constipationh,

Nausea, Vomiting Nauseah, Vomitingh,

Stomatitish

Common Stomatitisv, Colitisw Dyspepsiai, Colitisw

Uncommon Colitisc,w, Pancreatitisx Pancreatitisx

Rare Coeliac diseaseq Coeliac diseaseq

Very Aspartate Aspartatecommon aminotransferase aminotransferaseincreased or Alanine increased or Alanineaminotransferase aminotransferaseincreasedy increased

Common Hepatitisc,z, Aspartate Hepatitisc,zaminotransferaseincreased or Alanineaminotransferaseincreasedc,y

Uncommon Hepatitisz

Very Rashaa, Pruritus Rashaa, Alopecia, Pruritus Rashaa, Alopeciah,common Pruritus

Common Night sweats Dermatitis Dermatitisbb

Uncommon Dermatitis, Psoriasis, Pemphigoidcc, Night Night sweats

Pemphigoidcc sweats, Psoriasis

Very Arthralgia Arthralgia Arthralgiah, Myalgiacommon

Common Myalgia Myalgia

Uncommon Myositisdd, Immune- Immune-mediated Myositismediated arthritisee arthritisee, Myositis

Rare Polymyositisff, Polymyalgia rheumaticagg Polymyalgia rheumaticagg

Polymyalgia rheumatica

IMFINZI as IMFINZI in Platinum-basedmonotherapy combination with chemotherapy +chemotherapy IMFINZI + olaparib*

Very Blood creatininecommon increased

Common Blood creatinine Blood creatinine Dysuriaincreased, Dysuria increased, Dysuria

Uncommon Nephritishh, Cystitis Cystitis noninfective, Cystitis noninfectivehnoninfective Nephritishh

Very Pyrexia Pyrexia, Fatigueii Pyrexia, Fatigueh,common Peripheral oedemajj

Common Peripheral oedemajj Peripheral oedemajj

Common Infusion-related reactionkk Infusion-related reactionkk Infusion-related reaction

Adverse reaction frequencies may not be fully attributed to durvalumab alone but may contain contributionsfrom the underlying disease or from other medicinal products used in a combination.

* overall study of treatment with up to six 21-day cycles with platinum-based chemotherapy in combination with

IMFINZI, followed by IMFINZI in combination with olaparib.a includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis,tracheobronchitis and upper respiratory tract infection.b includes pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial,pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia pneumococcal, pneumonia streptococcal,candida pneumonia and pneumonia legionella.c including fatal outcome.d includes gingivitis, oral infection, periodontitis, pulpitis dental, tooth abscess and tooth infection.e includes leukopenia and white blood cell count decreased.f includes neutropenia and neutrophil count decreased.g includes thrombocytopenia and platelet count decreased.h adverse reaction only applies to chemotherapy ADRs in the DUO-E study.i adverse reaction only applies to olaparib ADRs in the DUO-E study.j includes drug hypersensitivity and hypersensitivity.k includes autoimmune hypothyroidism, hypothyroidism, immune-mediated hypothyroidism, blood thyroidstimulating hormone increased.l includes hyperthyroidism, Grave’s disease, immune-mediated hyperthyroidism and blood thyroid stimulatinghormone decreased.m includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis, and thyroiditis subacute.n includes neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.o includes dysgeusia and taste disorder.p includes encephalitis encephalitis autoimmune, immune-mediated encephalitis and noninfective encephalitis.

q events were reported from post-marketing data.r includes deep vein thrombosis, embolism, embolism venous, pelvic venous thrombosis, superficial veinthrombosis and thrombosis.s includes dyspnoea and dyspnoea exertional.t includes pneumonitis and immune-mediated lung disease.u includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.v includes stomatitis and mucosal inflammation.w includes colitis, enteritis, enterocolitis, immune-mediated enterocolitis and proctitis.x includes pancreatitis, pancreatitis acute, and immune-mediated pancreatitis.y includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increasedand transaminases increased.z includes hepatitis, autoimmune hepatitis, hepatitis toxic, hepatitis acute, hepatotoxicity, immune-mediatedhepatitis, and hepatic cytolysis.aa includes rash erythematous, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular,erythema, eczema and rash.

bb includes dermatitis and immune-mediated dermatitis.cc includes pemphigoid, dermatitis bullous and pemphigus. Reported frequency from completed and ongoingstudies is uncommon.dd includes myositis and rhabdomyolysis.ee includes autoimmune arthritis, immune-mediate arthritis, polyarthritis, and rheumatoid arthritis.ff polymyositis (fatal) was observed in a patient treated with IMFINZI from an ongoing sponsored clinical studyoutside of the pooled dataset.gg not observed in the IMFINZI+Chemotherapy pool or the platinum-based chemotherapy+IMFINZI+olaparibdataset, but observed in other AstraZeneca-sponsored clinical studies.hh includes autoimmune nephritis, tubulointerstitial nephritis, nephritis, glomerulonephritis, glomerulonephritismembranous, and immune-mediated nephritis.ii includes fatigue and asthenia.jj includes oedema peripheral and peripheral swelling.kk includes infusion-related reaction and urticaria with onset on the day of dosing or 1 day after dosing.

Table 4. Adverse drug reactions in patients treated with IMFINZI in combination withtremelimumab

IMFINZI in combination with IMFINZI in combination withtremelimumab 75 mg and tremelimumab 300 mgplatinum-based chemotherapy

Very common Upper respiratory tract infectionsa,

Pneumoniab

Common Influenza, Oral candidiasis Upper respiratory tract infectionsa,

Pneumoniab, Influenza, Dental and oralsoft tissue infectionsc

Uncommon Dental and oral soft tissue Oral candidiasisinfectionsc

Very Common Anaemiad, Neutropeniad,e,

Thrombocytopeniad,f, Leukopeniad,g

Common Febrile neutropeniad, Pancytopeniad

Uncommon Immune thrombocytopenia

Not known Immune thrombocytopeniah

Very common Hypothyroidismi Hypothyroidismi

Common Hyperthyroidismj, Adrenal Hyperthyroidismj, Thyroiditisk, Adrenalinsufficiency, Hypopituitarism/ insufficiency

Hypophysitis, Thyroiditisk

Uncommon Diabetes insipidus, Type 1 diabetes Hypopituitarism/Hypophysitismellitus

Not known Diabetes insipidush, Type 1 diabetesmellitush

Uncommon Uveitis

Rare Uveitish

Very common Decreased appetited

Common Neuropathy peripherald,l

Uncommon Encephalitism, Myasthenia gravis, Meningitis

IMFINZI in combination with IMFINZI in combination withtremelimumab 75 mg and tremelimumab 300 mgplatinum-based chemotherapy

Not known Myasthenia gravisn, Guillain-Barre Guillain-Barré syndromeh, Encephalitish,syndromen, Meningitisn, Transverse Transverse myelitisomyelitiso

Uncommon Myocarditisp Myocarditis

Respiratory, thoracic, and mediastinal disorders

Very common Cough/Productive Cough Cough/Productive cough

Common Pneumonitisq, Dysphonia Pneumonitisq

Uncommon Interstitial lung disease Dysphonia, Intersitial lung disease

Very common Nausead, Diarrhoea, Constipationd, Diarrhoea, Abdominal painr

Vomitingd

Common Stomatitisd,s, Amylase increased, Lipase increased, Amylase increased,

Abdominal painr, Lipase increased, Colitist, Pancreatitisu

Colitist, Pancreatitisu

Rare Coeliac diseasen Coeliac diseaseh

Not known Intestinal perforationn, Large Intestinal perforationh, Large intestinalintestine perforationn perforationh

Very common Aspartate aminotransferase Aspartate aminotransferaseincreased/Alanine aminotransferase increased/Alanine aminotransferaseincreasedv increasedv

Common Hepatitisw Hepatitisw

Very common Alopeciad, Rashx, Pruritus Rashx, Pruritus

Common Dermatitisy, Night sweats,

Uncommon Dermatitis, Night sweats, Pemphigoid

Pemphigoid

Very common Arthralgia

Common Myalgia Myalgia

Uncommon Myositisz, Polymyositisz, Immune- Myositisz, Polymyositisz, Immune-mediated arthritisn mediated arthritis, Polymyalgiarheumatica

Not known Polymyalgia rheumatican

Common Blood creatinine increased, Dysuria Blood creatinine increased, Dysuria

Uncommon Nephritis, Cystitis noninfective Nephritisaa

Not known Cystitis noninfectiveh

Very common Fatigued, Pyrexia Pyrexia, Oedema peripheralbb

Common Oedema peripheralbb

Common Infusion-related reactioncc Infusion-related reactioncca Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upperrespiratory tract infection.b Includes pneumocystis jirovecii pneumonia, pneumonia and pneumonia bacterial.c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.d Adverse reaction only applies to chemotherapy ADRs in the Poseidon study.e Includes neutropenia and neutrophil count decreased.f Includes platelet count decreased and thrombocytopenia.

g Includes leukopenia and white blood cell count decreased.h Adverse reaction was not observed in the HCC pool, but was reported in patients treated with IMFINZI or

IMFINZI+tremelimumab in AstraZeneca-sponsored clinical studies.i Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.j Includes blood thyroid stimulating hormone decreased and hyperthyroidism.k Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.l Includes neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.m Includes encephalitis and encephalitis autoimmune.n Adverse reaction was not observed in the POSEIDON study but was reported in patients treated with IMFINZIor IMFINZI+tremelimumab in clinical studies outside of the POSEIDON dataset.o Reported in studies outside of the POSEIDON study and HCC pool.p Includes autoimmune myocarditis.q Includes immune-mediated pneumonitis and pneumonitis.r Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.s Includes mucosal inflammation and stomatitis.t Includes colitis, enteritis and enterocolitis.u Includes autoimmune pancreatitis, pancreatitis and pancreatitis acute.v Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increasedand transaminases increased.w Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity, hepatitis acute and immune-mediated hepatitis.x Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular, rash pruritic and rashpustular.y Includes dermatitis and immune-mediated dermatitis.z Includes rhabdomyolysis, myositis, and polymyositis.aa Includes autoimmune nephritis and immune-mediated nephritis.bb Includes oedema peripheral and peripheral swelling.cc Includes infusion-related reaction and urticaria.

IMFINZI is associated with immune-mediated adverse reactions. Most of these, including severereactions, resolved following initiation of appropriate medical therapy and/or treatment modifications.

The data for the following immune-mediated adverse reactions reflect the IMFINZI monotherapycombined safety database of 4 642 patients which includes the PACIFIC, HIMALAYA and

ADRIATIC studies and additional studies in patients with various solid tumours, in indications forwhich durvalumab is not approved. Across all studies, IMFINZI was administered at a dose of10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks or 1 500 mg every 3 or 4 weeks. Details for thesignificant adverse reactions for IMFINZI when given in combination with chemotherapy arepresented if clinically relevant differences were noted in comparison to IMFINZI monotherapy.

The data for the following immune-mediated adverse reactions are also based on 2 280 patients whoreceived IMFINZI 20 mg/kg every 4 weeks in combination with tremelimumab 1 mg/kg or IMFINZI1 500 mg in combination with tremelimumab 75 mg every 4 weeks. Details for the significant adversereactions for IMFINZI when given in combination with tremelimumab and platinum-basedchemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI incombination with tremelimumab.

The data for the following immune-mediated adverse reactions also reflect the IMFINZI incombination with tremelimumab 300 mg combined safety database of 462 patients with HCC (the

HCC pool). In these two studies, IMFINZI was administered at a dose of 1 500 mg in combinationwith tremelimumab 300 mg every 4 weeks.

The management guidelines for these adverse reactions are described in section 4.2 and 4.4.

Immune-mediated pneumonitis

In the combined safety database with IMFINZI monotherapy, (n=4 642 multiple tumour types),immune-mediated pneumonitis occurred in 147 (3.2%) patients, including Grade 3 in 37 (0.8%)patients, Grade 4 in 2 (< 0.1%) patients and Grade 5 in 10 (0.2%) patients. The median time to onsetwas 56 days (range: 1-1 308 days). One hundred and fourteen of the 147 patients received high-dosecorticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 4 patients also receivedother immunosuppressants including infliximab and cyclosporine. IMFINZI was discontinued in 60patients. Resolution occurred in 85 patients.

Immune-mediated pneumonitis occurred more frequently in patients in the PACIFIC Study who hadcompleted treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of studytreatment (10.7%), than in the other patients in the combined safety database (1.0%).

In the PACIFIC Study, (n=475 in the IMFINZI arm, and n=234 in the placebo arm) immune-mediatedpneumonitis occurred in 47 (9.9%) patients in the IMFINZI-treated group and 14 (6.0%) patients in theplacebo group, including Grade 3 in 9 (1.9%) patients on IMFINZI vs. 6 (2.6%) patients on placeboand Grade 5 (fatal) in 4 (0.8%) patients on IMFINZI vs. 3 (1.3%) patients on placebo. The mediantime 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, all patients received systemiccorticosteroids, including 30 patients who received high-dose corticosteroid treatment (at least 40 mgprednisone or equivalent per day) and 2 patients also received infliximab. In the placebo group, allpatients received systemic corticosteroids, including 12 patients who received high-dose corticosteroidtreatment and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29patients 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 theplacebo arm), immune-mediated pneumonitis occurred in 31 (11.8%) patients in the IMFINZI-treatedgroup and 8 (3.0%) patients in the placebo group, including Grade 3 in 5 (1.9%) patients on IMFINZIvs. 1 (0.4%) patient on placebo and Grade 5 (fatal) in 1 (0.4%) patient on IMFINZI. The median timeto 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 all patients received systemiccorticosteroids, including 25 patients who received high-dose corticosteroid treatment (at least 40 mgprednisone or equivalent per day) and 1 patient also received infliximab. In the placebo group allpatients received systemic corticosteroids, including 7 patients who received high-dose corticosteroidtreatment. Resolution occurred for 18 patients in the IMFINZI treated group vs. 3 in placebo.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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 (fatal) in 7 (0.3%) patients. The median time toonset was 57 days (range: 8 - 912 days). All patients received systemic corticosteroids and 79 of the86 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent perday). Seven patients also received other immunosuppressants. Treatment was discontinued in39 patients. Resolution occurred in 51 patients.

In the HCC pool (n=462), 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 was29 days (range: 5-774 days). Six patients received systemic corticosteroids, and 5 of the 6 patientsreceived high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Onepatient also received other immunosuppressants. Treatment was discontinued in 2 patients. Resolutionoccurred in 3 patients.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combinationwith IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy +

IMFINZI + olaparib arm) immune-mediated pneumonitis occurred in 5 2.1%) patients, including

Grade 3 in 3 (1.3%) patients. The median time to onset was 85 days (range: 65-321 days). Fivepatients received systemic corticosteroids, including 4 patients who received high-dose corticosteroidtreatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 5 patients.

Immune-mediated hepatitis

In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in120 (2.6%) patients, including Grade 3 in 70 (1.5%) patients, Grade 4 in 9 (0.2%) patients and Grade 5(fatal) in 6 (0.1%) patients. The median time to onset was 36 days (range: 1-644 days). Ninety-four ofthe 120 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalentper day). Nine patients also received other immunosuppressants including mycophenolate treatment.

IMFINZI was discontinued in 30 patients. Resolution occurred in 56 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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 (fatal) in 2 (< 0.1%) patients. The median time to onset was36 days (range: 1 - 533 days). All patients received systemic corticosteroids and 68 of the 80 patientsreceived high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eightpatients also received other immunosuppressants. Treatment was discontinued in 27 patients.

Resolution occurred in 47 patients.

In the HCC pool (n=462), 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. Themedian 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 orequivalent per day). Nine patients also received other immunosuppressants. Treatment wasdiscontinued in 10 patients. Resolution occurred in 13 patients.

Immune-mediated colitis

In the combined safety database with IMFINZI monotherapy, immune-mediated colitis or diarrhoeaoccurred in 79 (1.7%) patients, including Grade 3 in 15 (0.3%) patients and Grade 4 in 2 (< 0.1%)patients. The median time to onset was 72 days (range: 1-920 days). Fifty-five of the 79 patientsreceived high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Fivepatients also received other immunosuppressants including infliximab treatment and mycophenolate.

IMFINZI was discontinued in 15 patients. Resolution occurred in 54 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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-dosecorticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty-two patients alsoreceived other immunosuppressants. Treatment was discontinued in 54 patients. Resolution occurredin 141 patients.

Intestinal perforation and large intestine perforation were uncommonly reported in patients receiving

IMFINZI in combination with tremelimumab.

In the HCC pool (n=462), 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-dosecorticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also receivedother immunosuppressants. Treatment was discontinued in 5 patients. Resolution occurred in29 patients.

Intestinal perforation was observed in patients receiving IMFINZI in combination with tremelimumab(rare) in studies outside of the HCC pool.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism

In the combined safety database with IMFINZI monotherapy, immune-mediated hypothyroidismoccurred in 384 (8.3%) patients, including Grade 3 in 7 (0.2%) patients. The median time to onset was90.5 days (range: 1-951 days). Of the 384 patients, 379 patients received hormone replacement therapyand 7 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) forimmune-mediated hypothyroidism. One patient discontinued IMFINZI due to immune-mediatedhypothyroidism. Resolution occurred in 79 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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 receivedsystemic corticosteroids and 8 of the 13 received high-dose corticosteroid treatment (at least 40 mgprednisone or equivalent per day). Treatment discontinued in 3 patients. Resolution occurred in52 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in25 patients or immune-mediated thyroiditis in 2 patients.

In the HCC pool (n=462), immune-mediated hypothyroidism occurred in 46 (10.0%) patients. Themedian time to onset was 85 days (range: 26-763 days). One patient received high-dose corticosteroidtreatment (at least 40 mg prednisone or equivalent per day). All patients required other therapyincluding hormone replacement therapy. Resolution occurred in 6 patients. Immune-mediatedhypothyroidism was preceded by immune-mediated hyperthyroidism in 4 patients.

Immune-mediated hyperthyroidism

In the combined safety database with IMFINZI monotherapy, immune-mediated hyperthyroidismoccurred in 76 (1.6%) patients. The median time to onset was 43 days (range: 1-253 days). Seventy-one of the 76 patients received medical therapy (thiamazole, carbimazole, propylthiouracil,perchlorate, calcium channel blocker or beta-blocker), 15 patients received systemic corticosteroidsand 8 of the 15 patients received high-dose systemic corticosteroid treatment (at least 40 mgprednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediatedhyperthyroidism. Resolution occurred in 62 patients. Thirty-one patients experienced hypothyroidismfollowing hyperthyroidism.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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 receivedsystemic corticosteroids, and 11 of the 18 patients received high-dose corticosteroid treatment (at least40 mg prednisone or equivalent per day). Fifty-three patients required other therapy (thiamazole,carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), One patientdiscontinued treatment due to hyperthyroidism. Resolution occurred in 47 patients.

In the HCC pool (n=462), 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). Fourpatients received systemic corticosteroids, and all of the four patients received high-dose corticosteroidtreatment (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 the combined safety database with IMFINZI monotherapy, immune-mediated thyroiditis occurredin 21 (0.5%) patients, including Grade 3 in 2 (< 0.1%) patients. The median time to onset was 57 days(range: 14-217 days). Of the 21 patients, 18 patients received hormone replacement therapy and3 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). Onepatient discontinued IMFINZI due to immune-mediated thyroiditis. Resolution occurred in 8 patients.

Five patients experienced hypothyroidism following thyroiditis.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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). Five patients received systemiccorticosteroids and 2 of the 5 patients received high-dose corticosteroid treatment (at least 40 mgprednisone or equivalent per day). Thirteen patients required other therapy including, hormonereplacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker,or beta-blocker. No patients discontinued treatment due to immune-mediated thyroiditis. Resolutionoccurred in 5 patients.

In the HCC pool (n=462), immune-mediated thyroiditis occurred in 6 (1.3%) patients. The mediantime to onset was 56 days (range: 7-84 days). Two patients received systemic corticosteroids, and 1 ofthe 2 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent perday). All patients required other therapy including hormone replacement therapy. Resolution occurredin 2 patients.

Immune-mediated adrenal insufficiency

In the combined safety database with IMFINZI monotherapy, immune-mediated adrenal insufficiencyoccurred in 24 (0.5%) patients, including Grade 3 in 8 (0.2%) patients. The median time to onset was157.5 days (range: 20-547 days). All 24 patients received systemic corticosteroids; 8 of the 24 patientsreceived high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Onepatient discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in6 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in16 (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 patientsreceived high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Treatment was discontinued in one patient. Resolution occurred in 11 patients.

In the HCC pool (n=462), 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). Allpatients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroidtreatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.

Immune-mediated type 1 diabetes mellitus

In the combined safety database with IMFINZI monotherapy, immune-mediated type 1 diabetesmellitus occurred in 5 (0.1%) patients, including Grade 3 in 3 (0.1%) patients and Grade 4 in1 (< 0.1%) patient. The time to onset was 43 days (range: 29-631 days). All five patients requiredinsulin therapy. IMFINZI was permanently discontinued in one patient. One patient recovered and onepatient recovered with sequelae.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),immune-mediated type 1 diabetes mellitus occurred in 6 (0.3%) patients, including Grade 3 in1 (< 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 for 1 patient. Resolutionoccurred in 1 patient.

Immune mediated hypophysitis/hypopituitarism

In the combined safety database with IMFINZI monotherapy, immune-mediatedhypophysitis/hypopituitarism occurred in 6 (0.1%) patients, including Grade 3 in 5 (0.1%) patients.

The time to onset for the events was 85 days (range: 44-225 days). Three patients received high-dosecorticosteroid treatment (at least 40 mg prednisone or equivalent per day), three patients discontinued

IMFINZI due to immune-mediated hypophysitis/hypopituitarism and resolution occurred in 1 patient.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),immune-mediated hypophysitis/hypopituitarism occurred in 16 (0.7%) patients, including Grade 3 in8 (0.4%) patients. The median time to onset for the events was 123 days (range: 63-388 days). Allpatients received systemic corticosteroids and 8 of the 16 patients received high-dose corticosteroidtreatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrinetherapy. Treatment was discontinued in 2 patients. Resolution occurred in 7 patients.

In the HCC pool (n=462), 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 patientsreceived 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 the combined safety database with IMFINZI monotherapy, immune-mediated nephritis occurred in17 (0.4%) patients, including Grade 3 in 4 (0.1%) patients and Grade 4 in 1 (< 0.1%) patient. Themedian time to onset was 84 days (range: 4-393 days). Twelve patients received high-dosecorticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also receivedmycophenolate. IMFINZI was discontinued in 7 patients. Resolution occurred in 8 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),immune-mediated nephritis occurred in 9 (0.4%) patients, including Grade 3 in 1 (< 0.1%) patient. Themedian time to onset was 79 days (range: 39-183 days). All patients received systemic corticosteroidsand 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent perday). Treatment was discontinued in 3 patients. Resolution occurred in 5 patients.

In the HCC pool (n=462), immune-mediated nephritis occurred in 4 (0.9%) patients, including Grade 3in 2 (0.4%) patients. The median time to onset was 53 days (range: 26-242 days). All patients receivedsystemic corticosteroids, and 3 of the 4 received high-dose corticosteroid treatment (at least 40 mgprednisone or equivalent per day). Treatment was discontinued in 2 patients. Resolution occurred in3 patients.

Immune-mediated rash

In the combined safety database with IMFINZI monotherapy, immune-mediated rash or dermatitis(including pemphigoid) occurred in 74 (1.6%) patients, including Grade 3 in 20 (0.4%) patients. Themedian time to onset was 56 days (range: 4-600 days). Thirty-seven of the 74 patients receivedhigh-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI wasdiscontinued in 5 patients. Resolution occurred in 46 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),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-dosecorticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinuedin 10 patients. Resolution occurred in 65 patients.

In the HCC pool (n=462), immune-mediated rash or dermatitis (including pemphigoid) occurred in26 (5.6%) patients, including Grade 3 in 9 (1.9%) patients and Grade 4 in 1 (0.2%) patient. Themedian time to onset was 25 days (range: 2-933 days). All patients received systemic corticosteroidsand 14 of the 26 patients received high-dose corticosteroid treatment (at least 40 mg prednisone orequivalent per day). One patient received other immunosuppressants. Treatment was discontinued in3 patients. Resolution occurred in 19 patients.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combinationwith IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy +

IMFINZI + olaparib arm) immune-mediated rash occurred in 8 (3.4%) patients, including Grade 3 in2 (0.8%) patients. The median time to onset was 155 days (range: 2-308 days). All patients receivedhigh-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolutionoccurred in all 8 patients.

In the combined safety database with IMFINZI monotherapy, infusion-related reactions occurred in70 (1.5%) patients, including Grade 3 in 6 (0.1%) patients. There were no Grade 4 or 5 events.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280),infusion-related reactions occurred in 45 (2.0%) patients, including Grade 3 in 2 (< 0.1%) patients.

There were no Grade 4 or 5 events.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combinationwith IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy +

IMFINZI + olaparib arm), infusion-related reactions occurred in 13 (5.5%) patients, including Grade 3in 1 (0.4%) patient. There were no Grade 4 or 5 events.

Pure Red Cell Aplasia

Pure Red Cell Aplasia (PRCA) has been reported when IMFINZI has been used in combination witholaparib. In a clinical study of patients with endometrial cancer treated with IMFINZI in combinationwith olaparib, the incidence of PRCA was 1.6%. All events were CTCAE Grade 3 or 4. Events weremanageable following discontinuation of both IMFINZI and olaparib. The majority of events weremanaged with blood transfusion and immunosuppression and recovered; there were no fatal events.

For management see section 4.4.

In patients treated with durvalumab monotherapy, the proportion of patients who experienced a shiftfrom baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.7% for alanineaminotransferase increased, 5.7% for aspartate aminotransferase increased, 0.9% for blood creatinineincreased, pct. 4.8% for amylase increased and 8.2% for lipase increased. The proportion of patients whoexperienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 20% and a TSH shiftfrom baseline that was ≥ LLN to any grade < LLN was 18.2%.

In patients treated with durvalumab in combination with chemotherapy, the proportion of patients whoexperienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 5.6% foralanine aminotransferase increased, 4.9% for aspartate aminotransferase increased, 2.5% for bloodcreatinine increased, 4.9% for amylase increased, and 8.5% for lipase increased. The proportion ofpatients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 23.9%and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 22.7%.

In patients treated with IMFINZI in combination with tremelimumab and platinum-basedchemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4laboratory abnormality was as follows: 6.2% for alanine aminotransferase increased, pct. 5.2% foraspartate aminotransferase increased, 4.0% for blood creatinine increased, 9.4% for amylase increasedand 13.6% for lipase increased. The proportion of patients who experienced a TSH shift from baselinethat was ≤ ULN to > ULN was 24.8% and a TSH shift from baseline that was ≥ LLN to < LLN was32.9%.

In patients treated with IMFINZI in combination with tremelimumab, the proportion of patients whoexperienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 5.1% foralanine aminotransferase increased, 5.8% for aspartate aminotransferase, 1.0% for blood creatinineincreased, 5.9% for amylase increased and 11.3% for lipase increased. The proportion of patients whoexperienced a TSH shift from baseline that was ≤ ULN to > ULN was 4.2% and a TSH shift frombaseline that was ≥ LLN to < LLN was 17.2%.

In patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by

IMFINZI either as monotherapy (platinum-based chemotherapy + IMFINZI arm) or in combinationwith olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), the proportion of patientswho experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows in theplatinum-based chemotherapy + IMFINZI arm: 3.5% for alanine aminotransferase increased, 3.0% foraspartate aminotransferase increased and 0.4% for blood creatinine increased, and as follows in theplatinum-based chemotherapy + IMFINZI + olaparib arm: 3.8% for alanine aminotransferaseincreased, 3.4% for aspartate aminotransferase increased and 1.7% for blood creatinine increased. Theproportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was27.2% and a TSH shift from baseline that was ≥ LLN to < LLN was 24.3% in the platinum-basedchemotherapy + IMFINZI arm and the proportion of patients who experienced a TSH shift frombaseline that was ≤ ULN to > ULN was 28.6% and a TSH shift from baseline that was ≥ LLN to< LLN was 20.1% in the platinum-based chemotherapy + IMFINZI + olaparib arm.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immunecheckpoint inhibitors which might also occur during treatment with durvalumab: pancreatic exocrineinsufficiency.

Immunogenicity of IMFINZI as monotherapy is based on pooled data in 3 069 patients who weretreated with IMFINZI 10 mg/kg every 2 weeks, or 20 mg/kg every 4 weeks as a single-agent andevaluable for the presence of anti-drug antibodies (ADAs). Eighty-four patients (2.7%) tested positivefor treatment emergent ADAs. Neutralising antibodies (nAb) against durvalumab were detected in0.5% (16/3 069) of patients. The presence of ADAs did not have a clinically relevant effect onpharmacokinetics or safety. There are insufficient number of patients to determine ADA impact onefficacy.

Across multiple phase III studies, in patients treated with IMFINZI in combination with othertherapeutic agents, 0% to 10.1% of patients developed treatment-emergent ADAs. Neutralizingantibodies against durvalumab were detected in 0% to 1.7% of patients treated with IMFINZI incombination with other therapeutic agents. The presence of ADAs did not have an apparent effect onpharmacokinetics or safety.

No overall differences in safety were reported between elderly (≥ 65 years) and younger patients.

In studies PACIFIC, ADRIATIC, CASPIAN, TOPAZ-1 and HIMALAYA data on safety for patients75 years and older are too limited to draw a conclusion on this population.

In first line metastatic NSCLC patients in the POSEIDON study, some differences in safety werereported between elderly (≥ 65 years) and younger patients. The safety data from patients 75 years ofage or older are limited to a total of 74 patients. There was a higher frequency of serious adversereactions and discontinuation rate of any study treatment due to adverse reactions in 35 patients aged75 years of age or older treated with IMFINZI in combination with tremelimumab and platinum-basedchemotherapy (45.7% and 28.6%, respectively) relative to 39 patients aged 75 years of age or olderwho received platinum-based chemotherapy only (35.9% and 20.5%, respectively).

In resectable NSCLC patients in the AEGEAN study, some differences in safety were reportedbetween elderly (≥ 65 years) and younger patients. The safety data from patients 75 years of age orolder are limited to 86 patients in both treatment arms. There was a higher frequency of seriousadverse reactions in patients aged 75 years or older who received IMFINZI in combination withchemotherapy relative to patients who received chemotherapy only (26.5% vs. 10.8%, respectively).

There was a higher frequency of discontinuation of any study treatment due to adverse reactions inpatients aged 75 years or older who received IMFINZI in combination with chemotherapy relative topatients who received chemotherapy only (16.3% vs. 8.1%, respectively).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no information on overdose with durvalumab. In case of overdose, patients should be closelymonitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatmentinstituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code:

L01FF03.

Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response thathelps tumours evade detection and elimination by the immune system. PD-L1 can be induced byinflammatory signals (e.g., IFN-gamma) and can be expressed on both tumour cells andtumour-associated immune cells in tumour microenvironment. PD-L1 blocks T-cell function andactivation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reducescytotoxic T-cell activity, proliferation and cytokine production.

Durvalumab is a fully human, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody thatselectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Durvalumab does not induceantibody dependent cell-mediated cytotoxicity (ADCC). Selective blockade of PD-L1/PD-1 and

PD-L1/CD80 interactions enhances antitumour immune responses and increases T-cell activation.

The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor functionsto enhance anti-tumour T-cell activation and function at multiple stages of the immune responseresulting in improved anti-tumour responses. In murine syngeneic tumour models, dual blockade of

PD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.

Durvalumab doses of 10 mg/kg every 2 weeks, 1 120 mg every 3 weeks or 1 500 mg every 4 weekswere evaluated in NSCLC, ES-SCLC and endometrial cancer clinical studies. Based on the modelingand simulation of exposure, exposure-safety relationships and exposure-efficacy data comparisons,there are no anticipated clinically significant differences in efficacy and safety between durvalumabdoses of 10 mg/kg every 2 weeks, 1 120 mg every 3 weeks or 1 500 mg every 4 weeks.

Resectable NSCLC - AEGEAN Study

AEGEAN was a randomised, double-blind, placebo-controlled, multicentre, Phase III study designedto evaluate the efficacy of IMFINZI in combination with platinum-based chemotherapy as neoadjuvanttreatment, then continued as IMFINZI monotherapy after surgery, in patients with resectable NSCLC.

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of a patient population with Stage IIA to select Stage IIIB asper the AJCC/UICC, 8th edition staging system:

* any patient with a tumour size ≥ 4 cm;

* any patient with N1 or N2 disease (regardless of primary tumour size), including multi-station

N2 disease;

* patients with multiple tumour nodules in the same lobe or tumours that involve the mainbronchus or tumours that invade visceral pleura, chest wall (including the parietal pleura andsuperior sulcus tumours), phrenic nerve or parietal pericardium; or tumours that are associatedwith atelectasis or obstructive pneumonitis that extends to the hilar region or involves part orall of the lung.

The study enrolled previously untreated patients with documented squamous or non-squamous

NSCLC and no prior exposure to immune-mediated therapy, a WHO/ECOG Performance status of 0or 1, and at least one RECIST 1.1 target lesion. Prior to randomisation, patients had tumour PD-L1expression status confirmed using the VENTANA PD-L1 (SP263) Assay.

The study excluded patients with active or prior documented autoimmune disease, or use ofimmunosuppressive medication within 14 days of the first dose of durvalumab. The study populationfor efficacy analysis (modified intent-to-treat [mITT]) excluded patients with known EGFR mutationsor ALK rearrangements. Following a protocol amendment, local ALK testing (unless squamoushistology) and central EGFR testing was mandated. There were 51 patients with EGFR mutations and11 patients with ALK rearrangements randomised into and treated within the study; however, thesepatients were not included in the mITT efficacy analysis and robust conclusions cannot be drawnregarding patients with EGFR mutations or ALK rearrangements.

Randomisation was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC< 1% vs. TC ≥ 1%) status.

Post-operative radiotherapy (PORT) was permitted for patients for whom it was indicated according tolocal guidance. PORT was to be started within 8 weeks of surgery and adjuvant durvalumab/placebomust then have been started within 3 weeks of the completion of PORT.

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 armswas not permitted.

* Arm 1: IMFINZI 1 500 mg + chemotherapy every 3 weeks for up to 4 cycles prior to surgery,followed by IMFINZI 1 500 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.

In the 2 treatment arms, patients received one of the following histology-based chemotherapyregimens:

* Squamous NSCLCo Carboplatin + paclitaxel: carboplatin AUC 6 and paclitaxel 200 mg/m2 via IV infusionon Day 1 of each 3-week cycle, for 4 cycles.

* Squamous NSCLCo Cisplatin + gemcitabine: cisplatin 75 mg/m2 via IV infusion on Day 1 of each 3-weekcycle, for 4 cycles, and gemcitabine 1250 mg/m2 via IV infusion on Day 1 and Day 8of each 3-week cycle, for 4 cycles.

* Non-squamous NSCLCo Pemetrexed + cisplatin: pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 via IVinfusion on Day 1 of each 3-week cycle, for 4 cycles.

* Non-squamous NSCLCo Pemetrexed + carboplatin: pemetrexed 500 mg/m2 and carboplatin AUC 5 via IVinfusion on Day 1 of each 3-week cycle, for 4 cycles.

In the event of unfavourable tolerability, patients could switch from cisplatin to carboplatin therapy atany point and in patients with comorbidities or unable to tolerate cisplatin per Investigators judgement,carboplatin AUC 5 could be administered from cycle 1.

A RECIST 1.1 tumour assessment was performed at baseline, and upon completion of the neoadjuvantperiod (prior to surgery). The first post-surgical CT/MRI scan of the chest and abdomen (including theentire liver and both adrenals) was acquired 5 weeks ± 2 weeks after surgery and prior to, but as closeas 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) untilweek 192 (approximately 4 years), and then every 48 weeks (relative to the date of surgery) thereafteruntil RECIST 1.1 defined radiological PD, consent withdrawal, or death. Survival assessments wereconducted at month 2, 3, and 4 following treatment discontinuation and then every 2 months untilmonth 12 followed by every 3 months.

The primary endpoints of the study were pathological complete response (pCR) by blinded centralpathology review, and event-free survival (EFS) by blinded independent central review (BICR)assessment. OS was a key secondary endpoint.

Efficacy analysis was conducted based on 740 patients in the mITT population: 366 patients in Arm 1and 374 patients in Arm 2. Baseline demographics and disease characteristics of the population wereas follows: male (71.6%), female (28.4%), age ≥ 65 years (51.6%), median age 65 years (range: 30 to88), 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%).

In the mITT population, there were 295 (80.6%) patients in Arm 1 who underwent curative intentsurgery compared to 302 (80.7%) patients in Arm 2. The number of patients who underwent PORTwere 26 (7.1%) in Arm 1 and 24 (6.4%) in Arm 2.

At the primary (pre-specified) EFS analysis (DCO: 10 November 2022), with a maturity of 31.9% anda median EFS follow-up in censored patients of 11.7 months, the study showed a statisticallysignificant improvement in the IMFINZI arm compared to the placebo arm [HR=0.68 (95% CI: 0.53,0.88), p=0.003902].

At the updated (pre-specified) EFS analysis (DCO: 10 May 2024), the median EFS follow-up incensored patients was 25.9 months. At this analysis, OS was not formally tested for statisticalsignificance; the HR for OS was 0.89 (95% CI: 0.70, 1.14) for IMFINZI arm compared to the placeboarm.

Table 5. Efficacy Results for the AEGEAN Study (mITT)

IMFINZI + chemotherapy Placebo + chemotherapy(N=366) (N=374)

EFSa,c

Number of events, n (%) 124 (33.9) 165 (44.1)

Median EFS (95% CI) (months) NR (42.3, NR) 30 (20.6, NR)

Hazard ratio (95% CI) 0.69 (0.55, 0.88)pCRa,b,c

Number of patients with response 63 16

Response rate, % (95% CI) 17.21 (13.49, 21.48) 4.28 (2.46, 6.85)

Difference in proportions, % (95% CI) 12.96 (8.67, 17.57)a Results are based on updated (pre-specified) EFS analysis (DCO: 10 May 2024) and pCR final analysis (DCO:

10 November 2022).b Based on a pre-specified pCR interim analysis (DCO: 14 January 2022) in n=402, the pCR rate was statisticallysignificant (p=0.000036) compared to significance level of 0.0082%.c The 2-sided p-value for pCR was calculated based on a stratified CMH test. The 2-sided p-value for EFS wascalculated based on a stratified log-rank test. Stratification factors included baseline PD-L1 and disease stage.

The boundary for declaring statistical significance for each of the efficacy endpoints were determined by a Lan-

DeMets alpha spending function that approximates an O’Brien Fleming approach (EFS=0.9899%,pCR=0.0082%, 2-sided).

Figure 1. Kaplan-Meier Curve of updated EFS analysis (DCO: 10 May 2024)

Median EFS in months (95% CI)

IMFINZI + SoC NR (42.3, NR)

Placebo + SoC 30 (20.6, NR)

HR (95% CI): 0.69 (0.55, 0.88)

IMFINZI + SoC

Placebo + SoC

Time from randomisation (months)

Number of patients at risk

IMFINZI + SoC 366 337 276 240 219 201 194 179 172 128 121 76 67 48 36 29 6 4 4 4 0 0 0

Placebo + SoC 374 338 261 225 201 176 172 151 142 93 83 57 53 36 32 25 8 3 2 2 0 0 0

NSCLC - PACIFIC Study

The efficacy of IMFINZI was evaluated in the PACIFIC Study, a randomised, double-blind,placebo-controlled, multicentre study in 713 patients with locally advanced, unresectable NSCLC.

Patients had completed at least 2 cycles of definitive platinum-based chemotherapy with radiationtherapy within 1 to 42 days prior to initiation of the study and had a ECOG performance status of 0 or1. Ninety-two percent of patients had received a total dose of 54 to 66 Gy of radiation. The studyexcluded patients who had progressed following chemoradiation therapy, patients with prior exposureto any anti-PD-1 or anti-PD-L1 antibody, patients with active or prior documented autoimmunedisease within 2 years of initiation of the study; a history of immunodeficiency; a history of severeimmune-mediated adverse reactions; medical conditions that required systemic immunosuppression,except physiological dose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIVinfection 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 orconfirmed disease progression. Randomisation was stratified by gender, age (< 65 years vs. ≥ 65years) and smoking status (smoker vs. non-smoker). Patients with disease control at 12 months weregiven the option to be re-treated upon disease progression. Tumour assessments were conducted every8 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, archivaltumour tissue specimens taken prior to chemoradiation therapy were retrospectively tested for PD-L1expression on tumour cells (TC) using the VENTANA PD-L1 (SP263) IHC assay. Of the 713 patients

Probability of event-free survivalrandomised, 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%), age ≥ 75 years (8%), White (69%), Asian (27%), other (4%), current smoker (16%),past-smoker (75%), never smoker (9%), ECOG Performance Status 0 (49%), ECOG Performance

Status 1 (51%). Disease characteristics were as follows: Stage IIIA (53%), Stage IIIB (45%),histological sub-groups of squamous (46%), non-squamous (54%). Of 451 patients with PD-L1expression available, 67% were TC ≥ 1% [PD-L1 TC 1-24% (32%), PD-L1 TC ≥ 25% (35%)] and33% were TC < 1%.

The two primary endpoints of the study were progression-free survival (PFS) and overall survival (OS)of IMFINZI vs. placebo. Secondary efficacy endpoints included PFS at 12 months (PFS 12) and18 months (PFS 18) from randomisation and Time from Randomisation to Second Progression (PFS2).

PFS was assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1.

The study demonstrated a statistically significant improvement in PFS in the IMFINZI-treated groupcompared with the placebo group [hazard ratio (HR)=0.52 (95% CI: 0.42, 0.65), p < 0.0001]. Thestudy demonstrated a statistically significant improvement in OS in the IMFINZI-treated groupcompared with the placebo group [HR=0.68 (95% CI: 0.53, 0.87), p=0.00251].

In the 5-year follow-up analysis, with a median follow-up of 34.2 months, IMFINZI continued todemonstrate improved OS and PFS compared to placebo. The OS and PFS results from the primaryanalysis and the follow-up analysis are summarized in Table 6.

Table 6. Efficacy results for the PACIFIC Study

Primary analysisa 5-year follow-up analysisb

IMFINZI Placebo IMFINZI Placebo(n=476) (n=237) (n=476) (n=237)

OS

Number of deaths (%) 183 (38.4%) 116 (48.9%) 264 (55.5%) 155 (65.4%)

Median (months) NR 28.7 47.5 29.1(95% CI) (34.7, NR) (22.9, NR) (38.1, 52.9) (22.1, 35.1)

HR (95% CI) 0.68 (0.53, 0.87) 0.72 (0.59, 0.89)2- sided p-value 0.00251

OS at 24 months (%) 66.3% 55.6% 66.3% 55.3%(95% CI) (61.7%, 70.4%) (48.9%, 61.3%) (61.8%, 70.4%) (48.6%, 61.4%)p-value 0.005

OS at 48 months (%) 49.7% 36.3%(95% CI) (45.0%, 54.2%) (30.1%, 42.6%)

OS at 60 months (%) 42.9% 33.4%(95% CI) (38.2%, 47.4%) (27.3%, 39.6%)

PFS

Number of events (%) 214 (45.0%) 157 (66.2%) 268 (56.3%) 175 (73.8%)

Median PFS (months) 16.8 5.6 16.9 5.6(95% CI) (13.0, 18.1) (4.6, 7.8) (13.0, 23.9) (4.8, 7.7)

HR (95% CI) 0.52 (0.42, 0.65) 0.55 (0.45, 0.68)p-value p < 0.0001

PFS at 12 months (%) 55.9% 35.3% 55.7% 34.5%(95% CI) (51.0%, 60.4%) (29.0%, 41.7%) (51.0%, 60.2%) (28.3%, 40.8%)

PFS at 18 months (%) 44.2% 27.0% 49.1% 27.5%(95% CI) (37.7%, 50.5%) (19.9%, 34.5%) (44.2%, 53.8%) (21.6%, 33.6%)

Primary analysisa 5-year follow-up analysisb

IMFINZI Placebo IMFINZI Placebo(n=476) (n=237) (n=476) (n=237)

PFS at 48 months (%) 35.0% 19.9%(95% CI) (29.9%, 40.1%) (14.4%, 26.1%)

PFS at 60 months (%) 33.1% 19.0%(95% CI) (28.0%, 38.2%) (13.6%, 25.2%)

PFS2c

Median PFS2 (months) 28.3 17.1(95% CI) (25.1, 34.7) (14.5, 20.7)

HR (95% CI) 0.58 (0.46, 0.73)p-value p < 0.0001a Primary analysis of PFS at data cut-off 13 February 2017. Primary analysis of OS and PFS2 at data cut-off 22

March 2018.b Follow-up OS and PFS analysis at data cut-off 11 January 2021.c PFS2 is defined as the time from the date of randomisation until the date of second progression (defined bylocal standard clinical practice) or death.

NR: Not Reached

Kaplan-Meier curves for OS and PFS from the 5-year follow-up analysis are presented in Figures 2and 3.

Figure 2. Kaplan-Meier curve of OS

Median OS (95% CI)

IMFINZI 47.5 (38.1, 52.9)

Placebo 29.1 (22.1, 35.1)

Hazard ratio (95% CI): 0.72 (0.59, 0.89)

IMFINZI

Placebo

Time from randomisation (months)

Number of patients at risk

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75

IMFINZI 476 464 431 414 385 364 343 319 298 289 273 264 252 241 236 227 218 207 196 183 134 91 40 18 2 0

Placebo 237 220 199 179 171 156 143 133 123 116 107 99 97 93 91 83 78 77 74 72 56 33 16 7 2 0

Probability of OS

Figure 3. Kaplan-Meier curve of PFS

Median PFS (95% CI)

IMFINZI 16.9 (13.0, 23.9)

Placebo 5.6 (4.8, 7.7)

Hazard ratio (95% CI): 0.55 (0.45, 0.68)

IMFINZI

Placebo

Time from randomisation (months)

Number of patients at risk

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

IMFINZI 476 377 301 267 215 190 165 147 137 128 119 110 103 97 92 85 81 78 67 57 34 22 11 5 0

Placebo 237 164 105 87 68 56 48 41 37 36 30 27 26 25 24 24 22 21 19 19 14 6 4 1 0

The improvements in PFS and OS in favour of patients receiving IMFINZI compared to thosereceiving placebo were consistently observed in all predefined subgroups analysed, includingethnicity, age, gender, smoking history, EGFR mutation status and histology.

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 cannot be established (PD-L1unknown). PFS and OS results from the 5-year follow-up analysis are summarised in Figures 4, 5, 6and 7.

Figure 4. Kaplan-Meier curve of OS for PD-L1 TC ≥ 1%

Median OS (95% CI)

IMFINZI 63.1 (43.7, NR)

Placebo 29.6 (17.7, 44.7)

Hazard ratio (95% CI): 0.61 (0.44, 0.85)

IMFINZI

Placebo

Time from randomisation (months)

Number of patients at risk

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75

IMFINZI 212 208 193 186 178 171 165 156 146 141 132 129 124 118 117 114 109 105 103 98 74 52 29 14 1 0

Probability of OS Probability of PFS

Placebo 91 81 75 67 64 58 52 47 45 44 41 38 38 37 36 33 31 31 30 29 24 14 8 5 2 0

Figure 5. Kaplan-Meier curve of PFS for PD-L1 TC ≥ 1%

Median PFS (95% CI)

IMFINZI 24.9 (16.9, 38.7)

Placebo 5.5 (3.6, 10.3)

Hazard ratio (95% CI): 0.47 (0.35, 0.64)

IMFINZI

Placebo

Time from randomisation (months)

Number of patients at risk

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

IMFINZI 212 175 142 127 107 95 82 70 67 63 57 55 50 47 45 42 39 38 34 31 22 15 8 4 0

Placebo 91 59 38 34 26 22 19 16 15 15 12 11 10 10 9 9 9 9 8 8 7 2 1 1 0

Figure 6. Forest plot of OS by PD-L1 expression

Events/N (%)

IMFINZI Placebo

All Patients 264/476 (55.5%) 155/237 (65.4%)

PD-L1 TC ≥ 1% 103/212 (48.6%) 56/91 (61.5%)

PD-L1 TC ≥ 25% 51/115 (44.3%) 27/44 (61.4%)

PD-L1 TC 1-24% 52/97 (53.6%) 29/47 (61.7%)

PD-L1 TC < 1% 59/90 (65.6%) 35/58 (60.3%)

PD-L1 Unknown 102/174 (58.6%) 64/88 (72.7%)

Probability of PFS

Figure 7. Forest plot of PFS by PD-L1 expression

Events/N (%)

IMFINZI Placebo

All Patients 268/476 (56.3%) 175/237 (73.8%)

PD-L1 TC ≥ 1% 111/212 (52.4%) 69/91 (75.8%)

PD-L1 TC ≥ 25% 61/115 (53.0%) 33/44 (75.0%)

PD-L1 TC 1-24% 50/97 (51.5%) 36/47 (76.6%)

PD-L1 TC < 1% 55/90 (61.1%) 41/58 (70.7%)

PD-L1 Unknown 102/174 (58.6%) 65/88 (73.9%)

Overall the safety profile of durvalumab in PD-L1 TC ≥ 1% subgroup was consistent with the intent totreat population, as was the PD-L1 TC < 1% subgroup.

Patient-reported outcomes (PRO)

Patient-reported symptoms, function and health-related quality of life (HRQoL) were collected usingthe EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). The LC13 and C30 wereassessed at baseline, every 4 weeks for the first 8 weeks, followed by every 8 weeks until completionof the treatment period or discontinuation of IMFINZI due to toxicity or disease progression.

Compliance was similar between the IMFINZI and placebo treatment groups (83% vs. 85.1% overallof evaluable forms completed).

At baseline, no differences in patient-reported symptoms, function and HRQoL were observedbetween IMFINZI and placebo groups. Throughout the duration of the study to Week 48, there was noclinically 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).

NSCLC - POSEIDON Study

POSEIDON was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumabin combination with platinum-based chemotherapy. POSEIDON was a randomised, open-label,multi-centre study in 1013 metastatic NSCLC patients with no sensitising epidermal growth factorreceptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumour aberrations.

Patients with histologically or cytologically documented metastatic NSCLC were eligible forenrolment. Patients had no prior chemotherapy or any other systemic therapy for metastatic NSCLC.

Prior to randomisation, patients had tumour PD-L1 status confirmed by using the Ventana PD-L1(SP263) assay. Patients had a World Health Organization (WHO)/Eastern Cooperative Oncology

Group (ECOG) performance status of 0 or 1 at enrolment.

The study excluded patients with active or prior documented autoimmune disease; active and/oruntreated brain metastases; a history of immunodeficiency; administration of systemicimmunosuppression within 14 days before the start of IMFINZI or tremelimumab, exceptphysiological 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 and/ortremelimumab (see section 4.4).

Randomisation was stratified by tumour cells (TC) PD-L1 expression (TC ≥ 50% vs. TC < 50%),disease stage (Stage IVA vs. Stage IVB, per the 8th edition of American Joint Committee on Cancer),and histology (non-squamous vs. squamous).

Patients were randomised 1:1:1 to receive:

* Arm 1: IMFINZI 1 500 mg with tremelimumab 75 mg and platinum-based chemotherapyevery 3 weeks for 4 cycles followed by, IMFINZI 1 500 mg every 4 weeks as monotherapy. Afifth dose of tremelimumab 75 mg was given at Week 16 alongside IMFINZI dose 6.

* Arm 2: IMFINZI 1 500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles,followed by IMFINZI 1 500 mg every 4 weeks as monotherapy.

* Arm 3: Platinum-based chemotherapy every 3 weeks for 4 cycles. Patients could receive2 additional cycles (a total of 6 cycles post-randomisation), as clinically indicated, at the

Investigator’s discretion.

In the 3 treatment arms, patients received one of the following histology-based chemotherapyregimens:

* Non-squamous NSCLC

* Pemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every3 weeks. Unless contraindicated by the investigator, pemetrexed maintenance could begiven.

* Squamous NSCLC

* Gemcitabine 1 000 or 1 250 mg/m2 on Days 1 and 8 with cisplatin 75 mg/m2 orcarboplatin AUC 5-6 on Day 1 every 3 weeks.

* Non-squamous or squamous NSCLC

* Nab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day 1every 3 weeks.

Tremelimumab was given up to a maximum of 5 doses unless there was disease progression orunacceptable toxicity. IMFINZI and histology-based pemetrexed maintenance therapy (whenapplicable) was continued until disease progression or unacceptable toxicity.

Tumour assessments were conducted at Week 6 and Week 12 from the date of randomisation, and thenevery 8 weeks until confirmed objective disease progression. Survival assessments were conductedevery 2 months following treatment discontinuation.

The dual primary endpoints of the study were PFS and OS for IMFINZI + platinum-basedchemotherapy vs. platinum-based chemotherapy alone. The key secondary endpoints of the study were

PFS and OS for IMFINZI + tremelimumab + platinum-based chemotherapy and platinum-basedchemotherapy alone. The secondary endpoints included objective response rate (ORR) and Duration of

Response (DoR). PFS, ORR, and DoR, were assessed using BICR according to RECIST v1.1.

The demographics and baseline disease characteristics were well-balanced between study arms.

Baseline demographics of the overall study population were as follows: male (76.0%), age ≥ 65 years(47.1%), age ≥ 75 years (11.3%) median age 64 years (range: 27 to 87 years), White (55.9%), Asian(34.6%), Black or African American (2.0%), Other (7.6%), non-Hispanic or Latino (84.2%), currentsmoker or past-smoker (78.0%), WHO/ECOG PS 0 (33.4%), WHO/ECOG PS 1 (66.5%). Diseasecharacteristics were as follows: Stage IVA (50.0%), Stage IVB (49.6%), histological sub-groups ofsquamous (36.9%), non-squamous (62.9%), brain metastases (10.5%), PD-L1 expression TC≥ 50%(28.8%), PD-L1 expression TC < 50% (71.1%).

The study showed a statistically significant improvement in OS with IMFINZI + tremelimumab +platinum-based chemotherapy vs. platinum-based chemotherapy. IMFINZI + tremelimumab +platinum-based chemotherapy showed a statistically significant improvement in PFS vs.

platinum-based chemotherapy alone. The results are summarised below.

T able 7. Efficacy results for the POSEIDON study

Arm 1: IMFINZI+tremelimumab Arm 3: Platinum-based+platinum-based chemotherapy chemotherapy(n=338) (n=337)

OSa

Number of deaths (%) 251 (74.3) 285 (84.6)

Median OS (months) 14.0 11.7(95% CI) (11.7, 16.1) (10.5, 13.1)

HR (95% CI) b 0.77 (0.650, 0.916)p-valuec 0.00304

PFSa

Number of events (%) 238 (70.4) 258 (76.6)

Median PFS (months) 6.2 4.8(95% CI) (5.0, 6.5) (4.6, 5.8)

HR (95% CI)b 0.72 (0.600, 0.860)p-valuec 0.00031

ORR n (%)d,e 130 (38.8) 81 (24.4)

Complete Response n (%) 2 (0.6) 0

Partial Response n (%) 128 (38.2) 81 (24.4)

Median DoR (months) 9.5 5.1(95% CI)d,e (7.2, NR) (4.4, 6.0)a Analysis of PFS at data cut off 24 July 2019 (median follow-up 10.15 months). Analysis of OS at data cut off12 March 2021 (median follow-up 34.86 months). The boundaries for declaring efficacy (Arm 1 vs. Arm 3:

PFS 0.00735, OS 0.00797; 2-sided) were determined by a Lan-DeMets alpha spending function thatapproximates an O’Brien Fleming approach. PFS was assessed by BICR according to RECIST v1.1.b HR are derived using a Cox pH model stratified by PD-L1, histology and disease stage.c 2-sided p-value based on a log-rank test stratified by PD-L1, histology and disease stage.d Confirmed Objective Response.e Post-hoc analysis.

NR=Not Reached, CI=Confidence Interval

Figure 8. Kaplan-Meier curve of OS

Median OS (95% CI)

IMFINZI + tremelimumab+platinum-based 14.0 (11.7, 16.1)chemotherapy

Platinum-based chemotherapy 11.7 (10.5, 13.1)

Hazard Ratio (95% CI)

IMFINZI + tremelimumab + platinum-based 0.77 (0.650, 0.916)chemotherapy

IMFINZI + tremelimumab + platinum-based chemotherapy

Platinum-based chemotherapy

Time from randomisation (months)

Number of patients at risk

Month0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Probability of OS

IMFINZI + tremelimumab + platinum-based chemotherapy338 298 256 217 183 159 137 120 109 95 88 64 41 20 9 0

Platinum-based chemotherapy337 284 236 204 160 132 111 91 72 62 52 38 21 13 6 0

Figure 9. Kaplan-Meier curve of PFS

Median PFS (95% CI

IMFINZI + tremelimumab+platinum-based chemotherapy 6.2 (5.0, 6.5)

Platinum-based chemotherapy 4.8 (4.6, 5.8)

Hazard Ratio (95% CI)

IMFINZI + tremelimumab+platinum-based chemotherapy 0.72 (0.600, 0.860)

IMFINZI + tremelimumab+platinum-based chemotherapy

Platinum-based chemotherapy

Time from randomisation (months)

Number of patients at risk

Month0 3 6 9 12 15 18 21 24

IMFINZI + tremelimumab + platinum-based chemotherapy338 243 161 94 56 32 13 5 0

Platinum-based chemotherapy337 219 121 43 23 12 3 2 0

Figure 10 summarises efficacy results of OS by tumour PD-L1 expression in prespecified subgroupanalyses.

Figure 10. Forest plot of OS by PD-L1 expression for IMFINZI+tremelimumab+platinum-basedchemotherapy vs. platinum-based chemotherapy

No of events/patients (%)

IMFINZI+tremelimum Platinum-based HR (95% CI)ab+platinum-based chemotherapychemotherapy

All Patients251 /338 (74.3%) 285 /337 (84.6%) 0.77 (0.65, 0.92)

PD-L1 ≥ 50% 69 /101 (68.3%) 80/97 (82.5%) 0.65 (0.47, 0.89)

PD-L1 < 50% 182 /237 (76.8%) 205 /240 (85.4%) 0.82 (0.67, 1.00)

PD-L1 ≥ 1%151 /213 (70.9%) 170 /207 (82.1%) 0.76 (0.61, 0.95)

PD-L1 < 1% 100 /125 (80.0%) 115 /130 (88.5%) 0.77 (0.58, 1.00)

Hazard Ratio (95% CI)

A total of 75 patients aged ≥ 75 years were enrolled in the IMFINZI in combination withtremelimumab and chemotherapy (n=35) and platinum-based chemotherapy only (n=40) arms of the

POSEIDON study. An exploratory HR of 1.05 (95% CI: 0.64, 1.71) for OS was observed for the

IMFINZI in combination with tremelimumab and platinum-based chemotherapy vs. platinum-based

Probability of PFSchemotherapy within this study subgroup. Due to the exploratory nature of this subgroup analysis nodefinitive conclusions can be drawn, but caution is suggested when considering this regimen forelderly patients.

SCLC - ADRIATIC Study

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 patientswith histologically or cytologically confirmed LS-SCLC (Stage I to III according to AJCC, 8th edition)who had not progressed following concurrent chemoradiation therapy. Patients who were Stage I or IIhad to be medically inoperable as determined by the investigator. Patients completed 4 cycles ofdefinitive platinum-based chemoradiation, 60-66 Gy once daily (QD) over 6 weeks or 45 Gy twicedaily (BID) over 3 weeks, within 1 to 42 days prior to the first dose of study treatment. Prophylacticcranial irradiation (PCI) could be delivered at the discretion of the investigator after chemoradiationtherapy and within 1 to 42 days prior to the first dose of study treatment. Patients had a WHO/ECOGperformance status of 0 or 1 at enrolment.

The study excluded patients with active or prior documented autoimmune disease within 5 years ofinitiation of the study; a history of active primary immunodeficiency; a history of Grade ≥ 2pneumonitis or active tuberculosis or hepatitis B or C or HIV infection and patients with activeinterstitial lung disease. Patients with mixed SCLC and NSCLC histology were also excluded.

Randomisation was stratified by stage (I/II vs. III) and receipt of PCI (yes vs. no). Patients wererandomised 1:1:1 to receive:

* Arm 1: IMFINZI 1 500 mg + placebo every 4 weeks for 4 cycles, followed by IMFINZI1 500 mg every 4 weeks.

* Arm 2: Placebo + a second placebo every 4 weeks for 4 cycles, followed by a single placeboevery 4 weeks.

* Arm 3: IMFINZI 1 500 mg + tremelimumab 75 mg every 4 weeks for 4 cycles, followed by

IMFINZI 1 500 mg every 4 weeks.

Once 600 patients had been randomised across all three arms, randomisation to arm 3 was completeand the subsequent 130 patients were randomised 1:1 to either arm 1 or 2, and received either

IMFINZI 1 500 mg every 4 weeks or placebo every 4 weeks.

Treatment continued until disease progression, until unacceptable toxicity, or for a maximum of24 months. Tumour assessments were conducted every 8 weeks for the first 72 weeks, then every12 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%), other (1.3%), Hispanic or Latino (4.2%), 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% ofpatients 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. Secondaryefficacy endpoints included ORR of IMFINZI vs. placebo. PFS and ORR were assessed by BICRaccording to RECIST v1.1.

At a planned interim analysis, the study demonstrated a statistically significant improvement in OSand PFS for IMFINZI compared with placebo. See Table 8 and Figures 11 and 12.

Table 8. Efficacy results for the ADRIATIC study

Arm 1: IMFINZI (n=264) Arm 2: Placebo (n=266)

OSa

Number of deaths (%) 115 (43.6) 146 (54.9)

Median OS (months) 55.9 (37.3, NR) 33.4 (25.5, 39.9)(95% CI)b

HR (95% CI)c 0.73 (0.569, 0.928)p-valued 0.01042

PFSe

Number of events (%) 139 (52.7) 169 (63.5)

Median PFS (months) 16.6 (10.2, 28.2) 9.2 (7.4, 12.9)(95% CI)b

HR (95% CI)f 0.76 (0.606, 0.950)p-valued 0.01608a Median duration of OS follow-up in censored patients was 37.19 months in the IMFINZI arm and 37.24 monthsin the placebo arm.b Calculated using the Kaplan Meier technique. CI for median derived based on Brookmeyer-Crowley method.c The analysis for HR was performed using a stratified Cox proportional hazards model and the 2-sided p-value isbased on a stratified log-rank test, both are adjusted for receipt of PCI.d p-value based on the results from the pre-planned interim analysis. Based on a Lan-DeMets alpha spendingfunction O'Brien Fleming type boundary and the actual number of events observed, the boundary for declaringstatistical significance for OS was 0.01679 for a 4.5% overall alpha and for PFS was 0.02805 for a 5% overallalpha (Lan◦and◦DeMets 1983).e Assessed by BICR according to RECIST v1.1.f The analysis for HR was performed using a stratified Cox proportional hazards model and the 2-sided p-value isbased on a stratified log-rank test, both are adjusted for TNM stage and receipt of PCI.

Figure 11: Kaplan-Meier Curve of OS

IMFINZI

Placebo

Time from randomisation (months)

Probability of OS

Number of patients at risk0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63

IMFINZI 264 261 248 236 223 207 189 183 172 162 141 110 90 68 51 39 27 19 11 5 1 0

Placebo 266 260 247 231 214 195 175 164 151 143 123 97 80 62 44 31 23 19 8 5 1 0

Figure 12: Kaplan-Meier Curve of PFS

IMFINZI

Placebo

Time from randomisation (months)

Number of patients at risk0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63

IMFINZI 264 212 161 135 113 105 101 98 84 78 51 51 33 21 19 10 10 4 4 0 0 0

Placebo 266 208 146 122 100 88 79 76 71 69 47 47 34 23 22 15 14 5 5 0 0 0

SCLC - CASPIAN Study

CASPIAN was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab incombination with etoposide and either carboplatin or cisplatin. CASPIAN was a randomised,open-label, multicentre study in 805 treatment naïve ES-SCLC patients with WHO/ECOG

Performance status of 0 or 1, body weight > 30 kg, suitable to receive a platinum-based chemotherapyregimen as first-line 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 treatedbrain metastases were eligible. The study excluded patients with a history of chest radiation therapy; ahistory of active primary immunodeficiency; autoimmune disorders including paraneoplasticsyndrome (PNS); active or prior documented autoimmune or inflammatory disorders; use of systemicimmunosuppressants within 14 days before the first dose of the treatment except physiological dose ofsystemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection; or patients receivinglive attenuated vaccine within 30 days before or after the start of IMFINZI.

Randomisation was stratified by the planned platinum-based (carboplatin or cisplatin) therapy incycle 1.

Patients were randomised 1:1:1 to receive:

* Arm 1: IMFINZI 1 500 mg + tremelimumab 75 mg + etoposide and either carboplatin orcisplatin.

* Arm 2: IMFINZI 1 500 mg + etoposide and either carboplatin or cisplatin.

Probability of PFS

* Arm 3: Either carboplatin (AUC 5 or 6 mg/ml/min) or cisplatin (75-80 mg/m2) on Day 1 andetoposide (80-100 mg/m2) intravenously on Days 1, 2, and 3 of each 21-day cycle for between4 - 6 cycles.

For patients randomised to Arm 1 and 2, etoposide and either carboplatin or cisplatin was limited to 4cycles on an every 3-week schedule subsequent to randomisation. IMFINZI monotherapy continuedevery 4 weeks until disease progression or unacceptable toxicity. Administration of IMFINZImonotherapy was permitted beyond disease progression if the patient was clinically stable andderiving clinical benefit as determined by the investigator.

Patients randomised to Arm 3 were permitted to receive a total of up to 6 cycles of etoposide andeither carboplatin or cisplatin. After completion of etoposide + platinum, PCI was permitted only in

Arm 3 per investigator discretion.

Tumour assessments were conducted at Week 6 and Week 12 from the date of randomisation, and thenevery 8 weeks until confirmed objective disease progression. Survival assessments were conductedevery 2 months following treatment discontinuation.

The primary endpoints of the study were OS of IMFINZI + etoposide + platinum (Arm 2) vs.

etoposide + platinum alone (Arm 3) and IMFINZI + tremelimumab + etoposide + platinum (Arm 1)vs. etoposide + platinum alone (Arm 3). The key secondary endpoint was PFS. Other secondaryendpoints were ORR, OS and PFS landmarks and PRO. PFS and ORR were assessed using

Investigator assessments according to RECIST v1.1.

The demographics and baseline disease characteristics were well balanced between the two study arms(268 patients in Arm 2 and 269 patients in Arm 3). Baseline demographics of the overall studypopulation were as follows: male (69.6%), age ≥ 65 years (39.6%), median age 63 years (range: 28 to82 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 cisplatinand 74.1% of the patients received carboplatin. In Arm 3, 56.8% of the patients received 6 cycles ofetoposide + platinum and 7.8% of the patients received PCI.

At a planned interim (primary) analysis the study demonstrated a statistically significant improvementin OS with IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3)[HR=0.73 (95% CI: 0.591, 0.909), p=0.0047]. Although not formally tested for significance, IMFINZI+ etoposide + platinum demonstrated an improvement in PFS vs. etoposide + platinum alone[HR=0.78 (95% CI: 0.645, 0.936)].

The PFS, ORR and DoR results from the planned final analysis (DCO: 27 Jan 2020) are summarizedin Table 9. Kaplan-Meier curve for PFS is presented in Figure 14.

The OS results with the planned long-term OS follow-up analysis (DCO: 22 March 2021) (medianfollow-up: 39.3 months) are presented in Table 9. IMFINZI + etoposide + platinum (Arm 2) vs.

etoposide + platinum (Arm 3) continued to demonstrate sustained improvement in OS. Kaplan-Meiercurve for OS is presented in Figure 13.

Table 9. Efficacy Results for the CASPIAN Study

Final analysisa Long-term follow-up analysisb

Arm 2: Arm 3: Arm 2: Arm 3:

IMFINZI + etoposide + and IMFINZI + etoposide +etoposide and either etoposide and eithereither carboplatin or and either carboplatin orcarboplatin or cisplatin carboplatin cisplatincisplatin (n=269) or cisplatin (n=269)(n=268) (n=268)

OS

Number of deaths (%) 210 (78.4) 231 (85.9) 221 (82.5) 248 (92.2)

Median OS (months) 12.9 10.5 12.9 10.5(95% CI) (11.3, 14.7) (9.3, 11.2) (11.3, 14.7) (9.3, 11.2)

HR (95% CI)b,c 0.75 (0.625, 0.910) 0.71 (0.595, 0.858)p-valued 0.0032 0.0003

OS at 18 months (%) 32.0 24.8 32.0 24.8(95% CI) (26.5, 37.7) (19.7, 30.1) (26.5, 37.7) (19.7, 30.1)

OS at 36 months (%) 17.6 5.8(95% CI) (13.3, 22.4) (3.4, 9.1)

PFS

Number of events (%) 234 (87.3) 236 (87.7)

Median PFS 5.1 5.4(months) (4.7, 6.2) (4.8, 6.2)(95% CI)

HR (95% CI)c 0.80 (0.665, 0.959)

PFS at 6 months (%) 45.4 45.8(95% CI) (39.3, 51.3) (39.5, 51.9)

PFS at 12 months 17.9 5.3(%) (95% CI) (13.5, 22.8) (2.9, 8.8)

ORR n (%) 182 (67.9) 156 (58.0)(95% CI)e (62.0, 73.5) (51.8, 64.0)

Complete Response n 7 (2.6) 2 (0.7)(%)

Partial Response n 175 (65.3) 154 (57.2)(%)

Median DoR (months) 5.1 5.1(95% CI)e,f (4.9, 5.3) (4.8, 5.3)a Final PFS, ORR and DoR analysis at data cut-off 27 January 2020.b Long-term follow-up OS analysis at data cut-off 22 March 2021.c The analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1(carboplatin or cisplatin), and using the rank tests of association approach.

d At the interim analysis (data cut-off 11 March 2019) the OS p-value was 0.0047, which met the boundary fordeclaring statistical significance of 0.0178 for a 4% overall 2-sided alpha, based on a Lan-DeMets alphaspending function with O'Brien Fleming type boundary with the actual number of events observed.e Confirmed Objective Response.f Post-hoc analysis.

Figure 13. Kaplan-Meier curve of OS

IMFINZI+etoposide+platinumetoposide+platinumcensored

Median OS (95% CI)

IMFINZI + etoposide + platinum 12.9 (11.3, 14.7)etoposide + platinum 10.5 (9.3, 11.2)

Hazard Ratio (95% CI)

IMFINZI + etoposide + platinum vs. etoposide + platinum: 0.71 (0.595, 0.858)

Time from randomisation (months)

Number of patients at risk 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

IMFINZI + etoposide + 268 244 214 177 140 109 85 70 60 54 50 46 39 25 13 3 0 0platinumetoposide + platinum 269 243 212 156 104 82 64 51 36 24 19 17 13 10 3 0 0 0

Probability of OS

Figure 14. Kaplan-Meier curve of PFS

IMFINZI+etoposide+platinumetoposide+platinumcensored

Median PFS (95% CI)

IMFINZI + etoposide + platinum 5.1 (4.7, 6.2)etoposide + platinum 5.4 (4.8, 6.2)

H azard Rati o ( 95% CI)

IMFINZI + etoposide + platinum vs. etoposide + platinum: 0.80 (0.665, 0.959)

Time from randomisation (months)

Number of patients at risk 0 3 6 9 12 15 18 21 24 27 30 33

IMFINZI + etoposide + platinum 268 220 119 55 45 40 35 24 18 8 5 0etoposide + platinum 269 195 110 33 12 9 7 7 6 1 0 0

The improvements in OS in favour of patients receiving IMFINZI + etoposide + platinum compared tothose receiving etoposide + platinum alone, were consistently observed across the prespecifiedsubgroups based on demographics, geographical region, carboplatin or cisplatin use and diseasecharacteristics.

BTC - TOPAZ-1 Study

TOPAZ-1 was a study designed to evaluate the efficacy of IMFINZI in combination with gemcitabineand cisplatin. TOPAZ-1 was a randomised, double-blind, placebo-controlled, multicentre study in685 patients with unresectable or metastatic BTC (including intrahepatic and extrahepaticcholangiocarcinoma and gallbladder carcinoma) and ECOG Performance status of 0 or 1. Patients hadnot received previous therapy in the advanced/unresectable setting. Patients who developed recurrentdisease > 6 months after surgery and/or completion of adjuvant therapy were included. Patients musthave had an adequate organ and bone marrow function, and have had acceptable serum bilirubin levels(≤ 2.0 x the upper limit of normal (ULN)), and any clinically significant biliary obstruction had to beresolved before randomisation.

The study excluded patients with ampullary carcinoma, with brain metastases, active or priordocumented autoimmune or inflammatory disorders, HIV infection or active infections, includingtuberculosis or hepatitis C or patients with current or prior use of immunosuppressive medicationwithin 14 days before the first dose of IMFINZI. Patients with active HBV were allowed to participateif they were on antiviral therapy.

Randomisation was stratified by disease status (initially unresectable vs. recurrent) and primarytumour location (intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladdercarcinoma).

Patients were randomised 1:1 to receive:

Probability of PFS

* Arm 1: IMFINZI 1 500 mg administered on Day 1 + gemcitabine 1 000 mg/m2 and cisplatin25 mg/m2 (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles,followed by IMFINZI 1 500 mg every 4 weeks until disease progression or unacceptabletoxicity, or

* Arm 2: Placebo administered on Day 1 + gemcitabine 1 000 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 byplacebo every 4 weeks until disease progression or unacceptable toxicity.

Tumour assessments were conducted every 6 weeks for the first 24 weeks after the date ofrandomisation, and then every 8 weeks until confirmed objective disease progression.

The primary endpoint of the study was OS, the key secondary endpoint was PFS. Other secondaryendpoints 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 studypopulation 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 bile duct 55.9%, extrahepatic bileduct 19.1% and gallbladder 25.0%), disease status [recurrent (19.1%) vs. unresectable (80.7%),metastatic (86.0%) vs. locally advanced (13.9%)]. PD-L1 expression was evaluated on tumour andimmune cells using the Ventana PD-L1 (SP263) assay and the TAP (tumour area positivity) algorithm,58.7% patients had TAP ≥ 1% and 30.1% TAP < 1%.

OS and PFS were formally tested at a pre-planned interim analysis (data cut-off 11 Aug 2021) after amedian follow-up of 9.8 months. Efficacy results are shown in Table 10 and Figure 16. The maturityfor OS was 62% and the maturity for PFS was 84%. IMFINZI + chemotherapy (Arm 1) showedstatistically significant improvement vs. placebo + chemotherapy (Arm 2) in OS and in PFS.

Table 10. Efficacy Results for the TOPAZ-1 Studya

IMFINZI + gemcitabine Placebo + gemcitabine andand cisplatin cisplatin(n=341) (n=344)

OS

Number of deaths (%) 198 (58.1) 226 (65.7)

Median OS (months) 12.8 11.5(95% CI)b (11.1, 14.0) (10.1, 12.5)

HR (95% CI)c 0.80 (0.66, 0.97)p-valuec,d 0.021

Median follow-up in all patients10.2 9.5(months)

PFS

Number of events (%) 276 (80.9) 297 (86.3)

Median PFS (months) 7.2 5.7(95% CI)b (6.7, 7.4) (5.6, 6.7)

HR (95% CI)c 0.75 (0.63, 0.89)p-valuec,e 0.001

Median follow-up in all patients7.2 5.6(months)

ORRf 91 (26.7) 64 (18.7)

Complete Response n (%) 7 (2.1) 2 (0.6)

Partial Response n (%) 84 (24.6) 62 (18.1)

DoR

Median DoR (months)b 6.4 (5.9, 8.1) 6.2 (4.4, 7.3)(95% CI)a Analysis at data cut-off 11 August 2021.b Calculated using the Kaplan-Meier technique. CI for median derived based on Brookmeyer-Crowley method.c The analysis for HR was performed using a stratified Cox proportional hazards model and 2-sided p-value isbased on a stratified log-rank test, both are adjusted for disease status and primary tumour location.d At the interim analysis (data cut-off 11 August 2021) the OS p-value was 0.021, which met the boundary fordeclaring statistical significance of 0.03 for a 4.9% overall 2-sided alpha, based on a Lan-DeMets alpha spendingfunction with O'Brien Fleming type boundary with the actual number of events observed.e At the interim analysis (data cut-off 11 August 2021) the PFS p-value was 0.001, which met the boundary fordeclaring statistical significance of 0.0481 for a 4.9% overall 2-sided alpha, based on a Lan-DeMets alphaspending function with Pocock-type boundary with the actual number of events observed.f Confirmed objective response.

An additional planned follow-up analysis of OS (data cut-off 25 Feb 2022) was performed 6.5 monthsafter the interim analysis with an OS maturity of 77%. IMFINZI + chemotherapy continued todemonstrate improved OS vs. chemotherapy alone [HR=0.76, (95% CI: 0.64, 0.91)] and the medianfollow-up increased to 12 months.

Figure 15: Kaplan-Meier curve of OS, follow-up OS analysis at data cut-off 25 February 2022

Median OS in months (95% CI)

IMFINZI + Chemotherapy 12.9 (11.6, 14.1)

Placebo + Chemotherapy 11.3 (10.1, 12.5)

Hazard Ratio (95% CI)

IMFINZI + chemotherapy vs chemotherapy 0..76 (0.64, 0.91)

IMFINZI + Chemotherapy (N=341)

Chemotherapy (N=344)

Time from randomisation (months)

Number of subjects at risk

IMFINZI + Chemotherapy:

Chemotherapy:

Figure 16: Kaplan-Meier curve of PFS, inferential (primary) analysis at data cut-off 11 August

Median PFS in months (95% CI)

IMFINZI + Chemotherapy 7.2 (6.7, 7.4)

Placebo + Chemotherapy 5.7 (5.6, 6.7)

Hazard Ratio (95% CI):

IMFINZI + chemotherapy vs chemotherapy 0.75 (0.63, 0.89)

IMFINZI + Chemotherapy (N=341)

Chemotherapy (N=344)

Number of subjects at risk Time from randomisation in months

IMFINZI + Chemotherapy

Chemotherapy

Probability of Overall Survival

Probability of progression free survival

HCC - HIMALAYA Study

The efficacy of IMFINZI as monotherapy and given in combination with a single dose oftremelimumab 300 mg 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 Barcelona Clinic Liver Cancer (BCLC) Stage C or B (noteligible for locoregional therapy) and Child-Pugh Score Class A.

The study excluded patients with brain metastases or a history of brain metastases, co-infection of viralhepatitis B and hepatitis C; active or prior documented gastrointestinal (GI) bleeding within 12months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathywithin 12 months before the start of treatment; active or prior documented autoimmune orinflammatory disorders.

Patients with oesophageal varices were included except those with active or prior documented GIbleeding 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 performance status(0 vs. 1). The HIMALAYA study randomised 1 171 patients 1:1:1 to receive:

* IMFINZI: durvalumab 1 500 mg every 4 weeks.

* Tremelimumab 300 mg as a single dose + IMFINZI 1 500 mg; followed by IMFINZI1 500 mg every 4 weeks.

* Sorafenib 400 mg twice daily.

Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeksthereafter. Survival assessments were conducted every month for the first 3 months followingtreatment discontinuation and then every 2 months.

The primary endpoint was OS superiority for the comparison of IMFINZI given in combination with asingle dose of tremelimumab vs. Sorafenib. The key secondary objectives were OS non-inferiorityfollowed by superiority for the comparison of IMFINZI vs. Sorafenib. Other secondary endpointsincluded PFS, Investigator-assessed ORR and DoR according to RECIST v1.1.

The demographics and baseline disease characteristics were well balanced among study arms. Thebaseline 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 race (2.3%), ECOG

PS 0 (62.6%); Child-Pugh Class score A (99.5%), macrovascular invasion (25.2%), extrahepaticspread (53.4%), baseline AFP < 400 ng/ml (63.7%), baseline AFP ≥ 400 ng/ml (34.5%), viralaetiology; hepatitis B (30.6%), hepatitis C (27.2%), uninfected (42.2%), evaluable PD-L1 data(86.3%), PD-L1 Tumour area positivity (TAP) ≥ 1% (38.9%), PD-L1 TAP < 1% (48.3%) [Ventana

PD-L1 (SP263) assay].

Results are presented in Table 11, Figure 17 and Figure 18.

Table 11. Efficacy Results for the HIMALAYA Study for IMFINZI given in combination with asingle dose of tremelimumab 300 mg and IMFINZI as monotherapy vs. Sorafenib

IMFINZI + Sorafenib IMFINZItremelimumab (n=389) (n=389)300 mg(n=393)

Follow-up duration

Median follow up (months)a 33.2 32.2 32.6

OS

Number of deaths (%) 262 (66.7) 293 (75.3) 280 (72.0)

IMFINZI + Sorafenib IMFINZItremelimumab (n=389) (n=389)300 mg(n=393)

Median OS (months) 16.4 13.8 16.6(95% CI) (14.2, 19.6) (12.3, 16.1) (14.1, 19.1)

HR (95% CI)b,c 0.78 (0.66, 0.92) -p-valued 0.0035 -

HR (95% CI)b,c,e - 0.86 (0.73, 1.03)

PFS

Number of events (%) 335 (85.2) 327 (84.1) 345 (88.7)

Median PFS (months) 3.78 4.07 3.65(95% CI) (3.68-5.32) (3.75-5.49) (3.19-3.75)

HR (95% CI) 0.90 (0.77, 1.05) -

HR (95% CI) - 1.02 (0.88, 1.19)

ORR

ORR n (%)f 79 (20.1) 20 (5.1) 66 (17.0)

Complete Response n (%) 12 (3.1) 0 6 (1.5)

Partial Response n (%) 67 (17.0) 20 (5.1) 60 (15.4)

DoR

Median DoR (months) 22.3 18.4 16.8a Calculated using reverse the Kaplan-Meier technique (with censor indicator reversed).b Based on stratified Cox-model adjusting for treatment, etiology of liver disease (HBV vs. HCV vs. others),

ECOG (0 vs. 1).c Performed using stratified log-rank test adjusting for treatment, etiology of liver disease (HBV vs. HCV vs.

others), ECOG (0 vs. 1), and macro-vascular invasion (yes vs. no).d Based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary and the actual number ofevents observed, the boundary for declaring statistical significance for IMFINZI + tremelimumab 300 mg vs.

Sorafenib was 0.0398 (Lan◦and◦DeMets 1983).e Non-inferiority margin for HR (IMFINZI vs. Sorafenib) is 1.08 using a 95.67% confidence interval based on a

Lan-DeMets alpha spending function with O'Brien Fleming type boundary and the actual number of eventsobserved (Lan◦and◦DeMets 1983). P-value based on superiority testing of IMFINZI vs. Sorafenib was 0.0674and did not reach statistical significance.f Confirmed complete response.

CI=Confidence Interval

Figure 17. Kaplan-Meier curve of OS of IMFINZI given in combination with a single dose oftremelimumab 300 mg

Median OS (95% CI)

IMFINZI + T300mg 16.4 (14.2-19.6)

IMFINZI + T300mg

Sorafenib 13.8 (12.3-16.1) Sorafenib

Censored

Hazard Ratio (95% CI) 0.78 (0.66, 0.92)

IMFINZI + T300mg

Sorafenib

Time from randomisation (months)

Figure 18. Kaplan-Meier curve of OS of IMFINZI given as monotherapy

Median OS (95% CI)

IMFINZI

IMFINZI 16.6 (14.1-19.1) Sorafenib

Censored

Sorafenib 13.8 (12.3-16.1)

Hazard Ratio (95% CI) 0.86 (0.73, 1.02)

S

IMFINZI

Sorafenib

Time from randomisation (months)

Endometrial Cancer - DUO-E Study

DUO-E was a randomised, multicentre, double-blind, placebo-controlled Phase III study of first-lineplatinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI with or withoutolaparib in patients with advanced or recurrent endometrial cancer. Patients had to have endometrialcancer in one of the following categories: newly diagnosed Stage III disease (measurable disease per

RECIST v1.1 following surgery or diagnostic biopsy), newly diagnosed Stage IV disease (with orwithout disease following surgery or diagnostic biopsy), or recurrence of disease (measurable ornon-measurable disease per RECIST v1.1) where the potential for cure by surgery alone or incombination is poor. For patients with recurrent disease, prior chemotherapy was allowed only if itwas administered in the adjuvant setting and there was at least 12 months from the date of last dose ofchemotherapy administered to the date of subsequent relapse. The study included patients withepithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients withendometrial sarcoma were excluded.

Probability of Overall Survival Probability of Overall Survival

Randomisation was stratified by tumour tissue’s mismatch repair (MMR) status (proficient versusdeficient), disease status (recurrent versus newly diagnosed), and geographic region (Asia versus restof the world). Patients were randomised 1:1:1 to one of the following arms:

* Arm 1 (Platinum-based chemotherapy): Platinum-based chemotherapy (paclitaxel andcarboplatin) every 3 weeks for a maximum of 6 cycles with durvalumab placebo every 3weeks. Following completion of chemotherapy treatment, patients without objective diseaseprogression received durvalumab placebo every 4 weeks and olaparib placebo tablets twicedaily as maintenance treatment until disease progression.

* Arm 2 (Platinum-based chemotherapy + IMFINZI): Platinum-based chemotherapy (paclitaxeland carboplatin) every 3 weeks for a maximum of 6 cycles with 1 120 mg durvalumab every 3weeks. Following completion of chemotherapy treatment, patients without objective diseaseprogression received 1 500 mg durvalumab every 4 weeks with olaparib placebo tablets twicedaily as maintenance treatment until disease progression.

* Arm 3 (Platinum-based chemotherapy + IMFINZI + olaparib): Platinum-based chemotherapy(paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1 120 mgdurvalumab every 3 weeks. Following completion of chemotherapy treatment, patients withoutobjective disease progression received 1 500 mg durvalumab every 4 weeks with 300 mgolaparib tablets twice daily as maintenance treatment until disease progression.

Patients who discontinued either product (IMFINZI/placebo or olaparib/placebo) for reasons otherthan disease progression could continue treatment with the other product if appropriate based ontoxicity considerations and investigator discretion.

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 torandomisation and every 12 weeks thereafter.

The primary endpoint was PFS, determined by investigator assessment using RECIST v1.1. Secondaryefficacy endpoints included OS, ORR and DoR.

The study demonstrated a statistically significant improvement in PFS in the ITT population, forpatients treated with platinum-based chemotherapy + IMFINZI + olaparib compared to platinum-basedchemotherapy [HR=0.55 (95% CI: 0.43, 0.69), p=<0.0001], and for patients treated withplatinum-based chemotherapy + IMFINZI compared to platinum-based chemotherapy [HR=0.71 (95%

CI: 0.57, 0.89), p=0.003]. At the time of PFS analysis, interim OS data were 28% mature with eventsin 199 of 718 patients.

Mismatch repair (MMR) status was determined centrally using an MMR immunohistochemistry panelassay. Of a total of 718 patients randomised in the study, 575 (80%) patients had MMR-proficient(pMMR) tumour status and 143 (20%) patients had MMR-deficient (dMMR) tumour status.

Patients with MMR-deficient (dMMR) endometrial cancer

Among patients with dMMR tumour status, demographic and baseline characteristics were generallywell balanced between the treatment arms. Baseline demographics across all three arms were asfollows: median age of 62 years (range: 34 to 85), 41% age 65 or older, 1.5% age 75 or older, 62%

White, 29% Asian, and 2% Black or African American. Disease characteristics were as follows:

ECOG PS of 0 (58%) or 1 (42%), 46% newly diagnosed and 54% recurrent disease. The histologicsubtypes were endometrioid (83%), mixed epithelial (5%), serous (3%), carcinosarcoma (3%),undifferentiated (2%), and other (3%).

In patients with dMMR tumour status, the results are summarised in Table 12 and Figure 19. Themedian follow-up time for PFS in censored patients with dMMR tumour status was 15.5 months in theplatinum-based chemotherapy + IMFINZI arm and 10.2 months in the platinum-based chemotherapyarm. At the time of PFS analysis, interim OS data were 26% mature with events in 25 of 95 patientstreated with platinum-based chemotherapy + IMFINZI and platinum-based chemotherapy.

Table 12. Efficacy results for the DUO-E Study (Patients with dMMR tumour status)

Platinum-based Platinum-basedchemotherapy + chemotherapy

IMFINZI

N=46 N=49

PFSa,b

Number of events (%) 15 (32.6) 25 (51.0)

Median PFS (months) (95% CI)c NR (NR, NR) 7.0 (6.7, 14.8)

HR (95% CI) 0.42 (0.22, 0.80) -

OSb

Number of events (%) 7 (15.2) 18 (36.7)

Median OS (months) (95% CI)c NR (NR, NR) 23.7 (16.9, NR)

HR (95% CI) 0.34 (0.13, 0.79) -

ORRb

ORRd n (%) 30 (71.4) 17 (40.5)

DoRb

Median DoR (months) (95% CI)c NR (NR, NR) 10.5 (4.3, NR)a Investigator assessed.

b Results are based on the first interim analysis (DCO: 12 April 2023).c Calculated using the Kaplan-Meier technique.d Response: Best objective response as confirmed complete response or partial response. Based on number ofpatients in treatment group with measurable disease at baseline (N=42 in platinum-based chemotherapy +

IMFINZI arm, N=42 in platinum-based chemotherapy arm).

CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached

Figure 19. Kaplan-Meier curve of PFS in DUO-E (Patients with dMMR tumour status)

Platinum-based chemotherapy + IMFINZI

Platinum-based chemotherapy

Median PFS (95% CI)

Chemotherapy + IMFINZI NR (NR-NR)

Chemotherapy 7.0 (6.7-14.8)

Hazard Ratio (95% CI)

Chemotherapy + IMFINZI vs. Chemotherapy 0.42 (0.22, 0.80)

Time from randomisation (months)

Number of patients at risk:

Platinum-based chemotherapy + IMFINZI

Platinum-based chemotherapy

Proportion of patients event free

Patients with MMR-proficient (pMMR) endometrial cancer

Among patients with pMMR tumour status, demographic and baseline characteristics were generallywell balanced between the treatment arms. Baseline demographics across all three arms were asfollows: median age of 64 years (range: 22 to 86), 48% age 65 or older, 8.1% age 75 or older, 56%

White, 30% Asian, and 6% Black or African American. Disease characteristics were as follows:

ECOG PS of 0 (69%) or 1 (31%), 47% newly diagnosed and 53% recurrent disease. The histologicsubtypes were endometrioid (54%), serous (26%), carcinosarcoma (8%), mixed epithelial (4%), clearcell (3%), undifferentiated (2%), mucinous (< 1%), and other (3%).

Results in patients with pMMR tumour status are summarised in Table 13 and Figure 20. The medianfollow-up time in censored patients with pMMR tumour status was 15.2 months in the platinum-basedchemotherapy + IMFINZI + olaparib arm, and 12.8 months in the platinum-based chemotherapy arm.

At the time of PFS analysis, interim OS data were 29% mature with events in 110 of 383 patientstreated with platinum-based chemotherapy + IMFINZI + olaparib and platinum-based chemotherapy.

Table 13. Efficacy results for the DUO-E Study (Patients with pMMR tumour status)

Platinum-based Platinum-basedchemotherapy + IMFINZI chemotherapy+ olaparib

N=191 N=192

PFSa,b

Number of events (%) 108 (56.5) 148 (77.1)

Median PFS (months) (95% CI)c 15.0 (12.4, 18.0) 9.7 (9.2, 10.1)

HR (95% CI) 0.57 (0.44, 0.73) -

OSb

Number of events (%) 46 (24.1) 64 (33.3)

Median OS (months) (95% CI)c NR (NR, NR) 25.9 (25.1, NR)

HR (95% CI) 0.69 (0.47, 1.00) -

ORRb

ORRd n (%) 90 (61.2) 92 (59.0)

DoRb

Median DoR (months) (95% CI)c 18.7 (10.5, NR) 7.6 (7.1, 10.2)a Investigator assessed.

b Results are based on the first interim analysis (DCO: 12 April 2023).c Calculated using the Kaplan-Meier technique.d Response: Best objective response as confirmed complete response or partial response. Based on number ofpatients in treatment group with measurable disease at baseline (N=147 in platinum-based chemotherapy +

IMFINZI + olaparib arm, N=156 in platinum-based chemotherapy arm).

CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached

Figure 20. Kaplan-Meier curve of PFS in DUO-E (Patients with pMMR tumour status)

Platinum-based chemotherapy + IMFINZI + olaparib

Platinum-based chemotherapy

Median PFS (95% CI)

Chemotherapy + IMFINZI + olaparib 15.0 (12.4-18.0)

Chemotherapy 9.7 (9.2-10.1)

Hazard Ratio (95% CI)

Chemotherapy + IMFINZI + olaparib vs. Chemotherapy 0.57 (0.44, 0.73)

Time from randomisation (months)

Number of patients at risk:

Platinum-based chemotherapy + IMFINZI + olaparib

Platinum-based chemotherapy

Among patients with pMMR tumour status, the PFS HRs were 0.44 (95% CI: 0.31, 0.61) in patientswith PD-L1 expression positive status (236/383; 62%) and 0.87 (95% CI: 0.59, 1.28) in patients with

PD-L1 expression negative status (140/383; 37%), for the platinum-based chemotherapy + IMFINZI +olaparib arm compared to the platinum-based chemotherapy arm. PD-L1 expression positive wasdefined as tumour area positive (TAP) ≥ 1%.

The safety and efficacy of IMFINZI in combination with tremelimumab in children and adolescentsaged less than 18 years has not been established. Study D419EC00001 was a multi-centre, open-labeldose finding and dose expansion study to evaluate the safety, preliminary efficacy andpharmacokinetics of IMFINZI in combination with tremelimumab followed by IMFINZImonotherapy, in paediatric patients with advanced malignant solid tumours (except primary centralnervous system tumours) who had disease progression and for whom no standard of care treatmentexists. The study enrolled 50 paediatric patients with an age range from 1 to 17 years with primarytumour categories: neuroblastoma, solid tumour and sarcoma. Patients received either IMFINZI20 mg/kg in combination with tremelimumab 1 mg/kg or IMFINZI 30 mg/kg in combination withtremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by IMFINZI asmonotherapy every 4 weeks. In the dose finding phase, IMFINZI and tremelimumab combinationtherapy was preceded by a single cycle of IMFINZI monotherapy; 8 patients in this phase howeverdiscontinued treatment prior to receiving tremelimumab. Thus, of the 50 patients enrolled in the study,42 received IMFINZI in combination with tremelimumab and 8 received IMFINZI only. In thedose-expansion phase, an ORR of 5.0% (1/20 patients) was reported in the evaluable for responseanalysis set. No new safety signals were observed relative to the known safety profiles of IMFINZIand tremelimumab in adults. See section 4.2 for information on paediatric use.

The pharmacokinetics (PK) of durvalumab was assessed for IMFINZI as a single agent, incombination with chemotherapy, in combination with tremelimumab and platinum-based

Proportion of patients event freechemotherapy, in combination with tremelimumab and in combination with platinum-basedchemotherapy followed by IMFINZI in combination with olaparib.

The PK of durvalumab was studied in 2903 patients with solid tumours with doses ranging from 0.1 to20 mg/kg administered intravenously once every two, three or four weeks as monotherapy. PKexposure increased more than dose-proportionally (non-linear PK) at doses < 3 mg/kg, and doseproportionally (linear PK) at doses ≥ 3 mg/kg. Steady state was achieved at approximately 16 weeks.

Based on population PK analysis that included 1878 patients who received durvalumab monotherapyin the dose range of ≥ 10 mg/kg every 2 weeks, the geometric mean steady state volume ofdistribution (Vss) was 5.64 L. Durvalumab clearance (CL) decreased over time resulting in a geometricmean steady state clearance (CLss) of 8.16 ml/h at Day 365; the decrease in CLss was not consideredclinically relevant. The terminal half-life (t1/2), based on baseline CL, was approximately 18 days.

There was no clinically meaningful difference between the PK of durvalumab as a single agent, incombination with chemotherapy, in combination with tremelimumab and platinum-basedchemotherapy, in combination with tremelimumab and in combination with platinum-basedchemotherapy followed by IMFINZI in combination with olaparib. The primary elimination pathwaysof durvalumab are protein catabolism via reticuloendothelial system or target mediated disposition.

Age (19-96 years), body weight (31-149 kg), gender, positive anti-drug antibody (ADA) status,albumin levels, LDH levels, creatinine levels, soluble PD-L1, tumour type, race or ECOG status hadno clinically significant effect on the PK of durvalumab.

Mild (creatinine clearance (CrCL) 60 to 89 ml/min) and moderate renal impairment (creatinineclearance (CrCL) 30 to 59 ml/min) had no clinically significant effect on the PK of durvalumab. Theeffect of severe renal impairment (CrCL 15 to 29 ml/min) on the PK of durvalumab is unknown;however, as IgG monoclonal antibodies are not primarily cleared via renal pathways, a change in renalfunction is not expected to influence durvalumab exposure.

Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 to 1.5 x ULN and any

AST) or moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) had no clinicallysignificant effect on the PK of durvalumab. The effect of severe hepatic impairment (bilirubin> 3.0 x ULN and any AST) on the pharmacokinetics of durvalumab is unknown; however, as IgGmonoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function isnot expected to influence durvalumab exposure.

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

The carcinogenic and genotoxic potential of durvalumab has not been evaluated.

As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy bymaintaining maternal immune tolerance to the foetus, and in mouse allogeneic pregnancy modelsdisruption of PD-L1 signalling was shown to result in an increase in foetal loss. In animal reproductionstudies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation ofpregnancy through delivery, at exposure levels approximately 18-times higher than those observed atthe clinical dose of 10 mg/kg of durvalumab (based on AUC), was associated with placental transferbut not with maternal toxicity or effects on embryofoetal development, pregnancy outcome orpostnatal development. Negligible levels of durvalumab was found in milk of cynomolgous monkeyon Day 28 after birth.

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial3 years.

Chemical and physical in-use stability has been demonstrated for up to 30 days at 2 °C to 8 °C and forup to 24 hours at room temperature (up to 25 °C) from the time of preparation.

From a microbiological point of view, the prepared solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and would normally not be longer than 24 hours at 2 °C to 8 °C or 12 hours at room temperature(up to 25 °C), unless dilution has taken place in controlled and validated aseptic conditions.

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

Do not freeze.

Store in the original package in order to protect from light.

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

Two pack sizes of IMFINZI are available:

2.4 ml (a total of 120 mg durvalumab) of concentrate in a Type 1 glass vial with an elastomericstopper and a gray flip-off aluminium seal. Pack size of 1 vial.

10 ml (a total of 500 mg durvalumab) of concentrate in a Type 1 glass vial with an elastomeric stopperand a white flip-off aluminium seal. Pack size of 1 vial.

Not all pack sizes may be marketed.

Preparation of solution

IMFINZI is supplied as a single-dose vial and does not contain any preservatives, aseptic techniquemust be observed.

* Visually inspect the medicinal product for particulate matter and discolouration. IMFINZI isclear to opalescent, colourless to slightly yellow solution. Discard the vial if the solution iscloudy, 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 sodium chloride 9 mg/ml (0.9%) solution for injection, or glucose 50 mg/ml(5%) solution for injection. Mix diluted solution by gentle inversion. The final concentration ofthe diluted solution should be between 1 mg/ml and 15 mg/ml. Do not freeze or shake thesolution.

* Discard any unused portion left in the vial.

* Administer the infusion solution intravenously over 1 hour through an intravenous linecontaining a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

* Do not co-administer other medicinal products through the same infusion line.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/18/1322/002 120 mg vial

EU/1/18/1322/001 500 mg vial

Date of first authorisation: 21 September 2018

Date of latest renewal: 24 April 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.