IMJUDO 20mg / ml concentrate for solution for infusion medication leaflet

IMJUDO 20 mg/ml concentrate for solution for infusion.

Each mL of concentrate for solution for infusion contains 20 mg of tremelimumab.

One vial of 1.25 ml of concentrate contains 25 mg of tremelimumab.

One vial of 15 ml of concentrate contains 300 mg of tremelimumab.

Tremelimumab is a human anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) immunoglobulin

G2 IgG2a monoclonal antibody produced in murine myeloma cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to slightly yellow solution, free from or practically free fromvisible particles. The solution has a pH of approximately 5.5 and an osmolality of approximately285 mOsm/kg.

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

IMJUDO in combination with durvalumab and platinum-based chemotherapy is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) with no sensitising EGFRmutations or ALK positive mutations.

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

The recommended dose of IMJUDO is presented in Table 1. IMJUDO is administered as anintravenous infusion over 1 hour.

When IMJUDO 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 IMJUDO

Indication Recommended IMJUDO Duration of Therapydosage

Advanced or unresectable HCC IMJUDO 300 mga as a single Until disease progression ordose administered in combination unacceptable toxicity.

with durvalumab 1500 mga at

Cycle 1/Day 1,followed by durvalumabmonotherapy every 4 weeks.

Metastatic NSCLC During platinum chemotherapy: Up to a maximum of 5 doses.

75 mgb in combination with Patients may receive less thandurvalumab 1500 mg and five doses of IMJUDO inplatinum-based chemotherapy combination with durvalumabevery 3 weeks (21 days) for 4 1500 mg and platinum-basedcycles (12 weeks). chemotherapy if there is diseaseprogression or unacceptable

Post-platinum chemotherapy: toxicity.

Durvalumab 1500 mg every 4weeks and histology-basedpemetrexed maintenance ctherapy every 4 weeks.

A fifth dose of IMJUDO 75 mgd,eshould be given at week 16alongside durvalumab dose 6.

a For IMJUDO, HCC patients with a body weight of 40 kg or less must receive weight-based dosing, equivalentto IMJUDO 4 mg/kg until weight is greater than 40 kg. For durvalumab, patients with a body weight of 30 kgor less must receive weight-based dosing, equivalent to durvalumab 20 mg/kg until weight is greater than30 kg.b For IMJUDO, metastatic NSCLC patients with a body weight of 34 kg or less must receive weight-baseddosing, equivalent to 1 mg/kg of IMJUDO until the weight improves to greater than 34 kg. For durvalumab,patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to durvalumab20 mg/kg until the weight improves to greater than 30 kg.c Consider maintenance administration of pemetrexed for patients with non-squamous tumours who receivedtreatment with pemetrexed and carboplatin/cisplatin during the platinum-based chemotherapy stage.d In the case of dose delay(s), a fifth dose of IMJUDO can be given after Week 16, alongside durvalumab.e If patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of IMJUDO (upto a total of 5) alongside durvalumab should be given during the post-platinum chemotherapy phase.

Dose escalation or reduction is not recommended during treatment with IMJUDO in combination withdurvalumab. Treatment withholding or discontinuation may be required based on individual safety andtolerability.

Guidelines for management of immune-mediated adverse reactions are described in Table 2 (refer tosection 4.4 for further management recommendations, monitoring, and evaluation information). Referalso to the SmPC for durvalumab.

Table 2. Treatment modifications for IMJUDO in combination with durvalumab

Adverse reactions Severitya Treatment modification

Grade 2 Withhold doseb

Immune-mediatedpneumonitis/interstitial lung disease

Grade 3 or 4 Permanently discontinue

ALT or AST> 3 - ≤ 5 x ULN or total

Withhold dosebbilirubin> 1.5 - ≤ 3 x ULN

Withhold durvalumab and

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

Immune-mediated hepatitis

Concurrent ALT or AST> 3 x ULN and totalbilirubin > 2 x ULNc

Permanently discontinue

ALT or AST> 10 x ULN or totalbilirubin > 3 x ULN

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

ALT or AST > 5 - 7 x

BLV and ≤ 20 x ULN

Immune-mediated hepatitis in HCC (or or Withhold durvalumab andsecondary tumour involvement of the concurrent ALT or AST permanently discontinueliver with abnormal baseline values)d 2.5 - 5 x BLV and IMJUDO (where≤ 20 x ULN and total appropriate)bilirubin> 1.5 - < 2 x ULNc

ALT or AST > 7 x BLVor > 20 x ULN

Permanently discontinuewhichever occurs firstor bilirubin > 3 x ULN

Grade 2 Withhold doseb

Immune-mediated colitis or diarrhoea

Grade 3 or 4 Permanently discontinuee

Intestinal perforation ANY grade Permanently discontinue

Adverse reactions Severitya Treatment modification

Immune-mediated hyperthyroidism, Withhold dose until

Grade 2-4thyroiditis clinically stable

Immune-mediated hypothyroidism Grade 2-4 No changes

Immune-mediated adrenal

Withhold dose untilinsufficiency, Grade 2-4clinically stablehypophysitis/hypopituitarism

Immune-mediated Type 1 diabetes

Grade 2-4 No changesmellitus

Grade 2 with serumcreatinine > 1.5- Withhold doseb3 x (ULN or baseline)

Grade 3 with serum

Immune-mediated nephritiscreatinine > 3 x baselineor > 3-6 x ULN; Grade Permanently discontinue4 with serum creatinine> 6 x ULN

Grade 2 for > 1 week or

Withhold doseb

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

Grade 4 Permanently discontinue

Immune-mediated myocarditis Grade 2-4 Permanently discontinue

Grade 2 or 3 Withhold doseb,f

Immune-mediatedmyositis/polymyositis/rhabdomyolysis

Grade 4 Permanently discontinue

Interrupt or slow the rate

Grade 1 or 2of infusion

Grade 3 or 4 Permanently discontinue

Immune-mediated myasthenia gravis Grade 2-4 Permanently discontinue

Immune-mediated myelitis transverse Any grade Permanentely discontinue

Immune-mediated meningitis Grade 2 Withhold doseb

Adverse reactions Severitya Treatment modification

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 doseb

Other immune-mediated adversereactionsg

Grade 4 Permanently discontinue

Withhold dose until

Grade 2 and 3 ≤ Grade 1 or return to

Non-immune-mediated adverse baselinereactions

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

aspartate aminotransferase; ULN: upper limit of normal; BLV: baseline value.b After withholding, IMJUDO and/or durvalumab can be resumed within 12 weeks if the adverse reactionsimproved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent perday. IMJUDO and durvalumab should be permanently discontinued for recurrent Grade 3 adverse reactions,as applicable.c For patients with alternative cause follow the recommendations for AST or ALT increases without concurrentbilirubin elevations.d 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.e Permanently discontinue IMJUDO for Grade 3; however, treatment with durvalumab can be resumed onceevent has resolved.f Permanently discontinue IMJUDO and durvalumab if the adverse reaction does not resolve to ≤ Grade 1 within30 days or if there are signs of respiratory insufficiency.g Includes immune thrombocytopenia, pancreatitis, cystitis noninfective, immune-mediated arthritis, and uveitis.h With the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue treatmentshould be based on accompanying clinical signs/symptoms and clinical judgment.

No dose adjustment is required for elderly patients (≥ 65 years of age) (see section 5.2). Data onpatients aged 75 years or older with metastatic NSCLC are limited (see section 4.4).

No dose adjustment of IMJUDO 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 IMJUDO is recommended for patients with mild or moderate hepaticimpairment. IMJUDO has not been studied in patients with severe hepatic impairment (seesection 5.2).

The safety and efficacy of IMJUDO in children and adolescents below 18 years of age has not beenestablished with regard to HCC and NSCLC. No data are available. Outside its authorised indications,

IMJUDO in combination with durvalumab has been studied in children aged 1 to 17 years withneuroblastoma, solid tumour and sarcoma, however the results of the study did not allow to concludethat the benefits of such use outweigh the risks. Currently available data are described in sections 5.1and 5.2.

IMJUDO is for intravenous use, it is administered as an intravenous infusion after dilution, over 1 hour(see section 6.6).

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

IMJUDO in combination with durvalumab

For advanced or uHCC, when IMJUDO is given in combination with durvalumab, administer

IMJUDO as a separate intravenous infusion prior to durvalumab on the same day. Refer to the SmPCfor durvalumab administration information.

IMJUDO in combination with durvalumab and platinum-based chemotherapy

For NSCLC, when IMJUDO is given in combination with durvalumab and platinum-basedchemotherapy, IMJUDO is given first, followed by durvalumab and then platinum-basedchemotherapy on the day of dosing.

When IMJUDO is given as a fifth dose in combination with durvalumab and pemetrexed maintenancetherapy at week 16, IMJUDO is given first, followed by durvalumab and then pemetrexedmaintenance therapy on the day of dosing.

IMJUDO, durvalumab, and platinum-based chemotherapy are administered as separate intravenousinfusions. IMJUDO and durvalumab 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, IMJUDO is to be followed by durvalumab starting approximately 1 hour (maximum 2hours) after the end of the IMJUDO infusion. Platinum-based chemotherapy infusion should startapproximately 1 hour (maximum 2 hours) after the end of the durvalumab infusion. If there are noclinically significant concerns during cycle 1, then at the physician’s discretion, subsequent cycles ofdurvalumab can be given immediately after IMJUDO and the time period between the end of thedurvalumab infusion and the start of chemotherapy can be reduced to 30 minutes.

Hypersensitivity to the active substance 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 to confirm aetiology or excludealternate aetiologies. Based on the severity of the adverse reaction, IMJUDO incombination with durvalumab should be withheld and corticosteroids administered. Uponimprovement to ≤ Grade 1, corticosteroid taper should be initiated and continued over at least 1 month.

Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants ifthere 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 tremelimumab incombination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patientsshould be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should beconfirmed with radiographic imaging and other infectious and disease-related aetiologies excluded,and managed as recommended in section 4.2. For Grade 2 events, an initial dose of 1-2 mg/kg/dayprednisone or equivalent should be initiated followed by a taper. For Grade 3 or 4 events, an initialdose of 2-4 mg/kg/day methylprednisolone or equivalent should be initiated followed by a taper.

Immune-mediated hepatitis

Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clearalternate aetiology, occurred in patients receiving tremelimumab in combination with durvalumab, orwith durvalumab and chemotherapy (see section 4.8). Monitor alanine aminotransferase, aspartateaminotransferase, total bilirubin, and alkaline phosphatase levels prior to initiation of treatment andprior to each subsequent infusion. Additional monitoring is to be considered based on clinicalevaluation. Immune-mediated hepatitis should be managed as recommended in section 4.2.

Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalentfollowed 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 tremelimumab in combination withdurvalumab, or with durvalumab and chemotherapy (see section 4.8). Intestinal perforation and largeintestine perforation were reported in patients receiving tremelimumab in combination withdurvalumab. Patients should be monitored for signs and symptoms of colitis/diarrhoea and intestinalperforation and managed as recommended in section 4.2. Corticosteroids should be administered at aninitial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for Grades 2-4. Consult asurgeon immediately if intestinal perforation of ANY grade is suspected.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receivingtremelimumab in combination with durvalumab, or with durvalumab and 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 tremelimumab in combinationwith durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should bemonitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenalinsufficiency, patients should be managed as recommended in section 4.2. Corticosteroids should beadministered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and ahormone 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 tremelimumab in combination withdurvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored forclinical 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 tremelimumab incombination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patientsshould be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. Forsymptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in section4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone orequivalent followed by 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 tremelimumab in combination with durvalumab, orwith durvalumab and chemotherapy (see section 4.8). Patients should be monitored for abnormal renalfunction tests prior to and periodically during treatment and managed as recommended in section 4.2.

Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalentfollowed by taper 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 tremelimumab incombination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Events of

Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported in patients treated with

PD-1 and CTLA-4 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 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 tremelimumab incombination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patientsshould be monitored for signs and symptoms of immune-mediated myocarditis and managed asrecommended in section 4.2. Corticosteroids should be administered with an initial dose of 2-4mg/kg/day prednisone or equivalent followed by taper for Grades 2-4. If no improvement within 2 to 3days 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 tremelimumab in combination withdurvalumab and chemotherapy (see section 4.8). Patients should be monitored for signs and symptomsof immune-mediated pancreatitis and managed as recommended in section 4.2.

Other immune-mediated adverse reactions

Given the mechanism of action of tremelimumab in combination with durvalumab, other potentialimmune-mediated adverse reactions may occur. The following immune-related adverse reactions havebeen observed in patients treated with tremelimumab in combination with durvalumab, or withdurvalumab and chemotherapy: myasthenia gravis, myelitis transverse, myositis, polymyositis,rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia,cystitis noninfective, immune-mediated arthritis and uveitis (see section 4.8). Patients should bemonitored for signs and symptoms 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 bytaper for Grades 2-4.

Patients should be monitored for signs and symptoms of infusion-related reactions. Severeinfusion-related reactions have been reported in patients receiving tremelimumab in combination withdurvalumab (see section 4.8). Infusion-related reactions should be managed as recommended insection 4.2. For Grade 1 or 2 severity, may consider pre-medications for prophylaxis of subsequentinfusion reactions. For Grade 3 or 4, manage severe infusion-related reactions per insititutionalstandard, appropriate clinical practice guidelines and/or society guidelines.

Disease-specific precaution

Metastatic NSCLC

Limited data are available in elderly patients (≥ 75 years) treated with tremelimumab in combinationwith durvalumab and platinum-based chemotherapy (see sections 4.8 and 5.1). Careful considerationof the potential benefit/risk of this regimen on an individual basis is recommended.

Advanced or unresectable HCC

Patients with the following were excluded from clinical studies: Child-Pugh Score B or C, main portalvein thrombosis, liver transplant, uncontrolled hypertension, history of, or current brain metastases,spinal cord compression, co-infection of viral hepatitis B and hepatitis C, active or prior documentedgastrointestinal (GI) bleeding within 12 months, ascites requiring non-pharmacologic interventionwithin 6 months, hepatic encephalopathy within 12 months before the start of treatment, active or priordocumented autoimmune or inflammatory disorders. In the absence of data, tremelimumab should beused with caution in these populations after careful consideration of the potential benefit/risk on anindividual basis.

Metastatic NSCLC

Patients with the following were excluded from clinical studies: active or prior documentedautoimmune disease; active and/or untreated brain metastases; a history of immunodeficiency;administration of systemic immunosuppression within 14 days before the start of tremelimumab ordurvalumab, except physiological dose of systemic corticosteroids (< 10 mg/day prednisone orequivalent); uncontrolled intercurrent illness; active tuberculosis or hepatitis B or C or HIV infectionor patients receiving live attenuated vaccine within 30 days before or after the start of tremelimumabor durvalumab. In the absence of data, tremelimumab should be used with caution in these populationsafter careful consideration of the potential benefit/risk on an individual basis.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

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

No formal pharmacokinetic (PK) drug-drug interaction studies have been conducted withtremelimumab. Since the primary elimination pathways of tremelimumab are protein catabolism viareticuloendothelial system or target-mediated disposition, no metabolic drug-drug interactions areexpected. PK drug-drug interactions between tremelimumab in combination with durvalumab andplatinum-based chemotherapy were assessed in the POSEIDON study and showed no clinicallymeaningful PK interactions between tremelimumab, durvalumab, nab-paclitaxel, gemcitabine,pemetrexed, carboplatin or cisplatin in the concomitant treatment.

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

There are no data on the use of tremelimumab in pregnant women. Based on its mechanism of action,and placental transfer of human IgG2, tremelimumab has the potential to impact maintenance ofpregnancy and may cause foetal harm when administered to a pregnant woman. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

IMJUDO is not recommended during pregnancy and in women of childbearing potential not usingeffective contraception during treatment and for at least 3 months after the last dose.

There is no information regarding the presence of tremelimumab in human milk, the absorption andeffects on the breast-fed infant, or the effects on milk production. Human IgG2 is known to beexcreted in human milk. A risk to the breastfed child cannot be excluded. Breast-feeding should bediscontinued during treatment with IMJUDO and for at least 3 months after the last dose.

There are no data on the potential effects of tremelimumab on fertility in humans or animals. However,mononuclear cell infiltration in prostate and uterus was observed in repeat-dose toxicity studies (see

Section 5.3). The clinical relevance of these findings for fertility is unknown.

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

IMJUDO in combination with durvalumab

The safety of tremelimumab 300 mg as a single dose in combination with durvalumab, is based onpooled data in 462 HCC patients (HCC pool) 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%) and oedema peripheral (10.4%) (see Table 3).

The most common (> 3%) severe adverse reactions (NCI CTCAE Grade ≥ 3) were aspartateaminotransferase increased/alanine aminotransferase increased (8.9%), lipase increased (7.1%),amylase increased (4.3%) and diarrhoea (3.9%).

The most common (> 2%) serious adverse reactions were colitis (2.6%), diarrhoea (2.4%) andpneumonia (2.2%).

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

IMJUDO in combination with durvalumab and chemotherapy

The safety of tremelimumab given in combination with durvalumab and chemotherapy is based ondata in 330 patients with metastatic NSCLC. The most common (> 10%) adverse reactions wereanaemia (49.7%), nausea (41.5%), neutropenia (41.2%), fatigue (36.1%), decreased appetite (28.2%),rash (25.8%), thrombocytopenia (24.5%), diarrhoea (21.5%), leukopenia (19.4%), constipation(19.1%), vomiting (18.2%), aspartate aminotransferase increased/alanine aminotransferase increased(17.6%), pyrexia (16.1%), upper respiratory tract infections (15.5%), pneumonia (14.8%),hypothyroidism (13.3%), arthralgia (12.4%), cough/productive cough (12.1%) and pruritus (10.9%).

The most common (> 3%) severe adverse reactions (NCI CTCAE Grade ≥ 3) were neutropenia(23.9%), anaemia (20.6%), pneumonia (9.4%), thrombocytopenia (8.2%), leukopenia (5.5%), fatigue(5.2%), lipase increased (3.9%) and amylase increased (3.6%).

The most common (> 2%) serious adverse reactions were pneumonia (11.5%), anaemia (5.5%),thrombocytopenia (3%), colitis (2.4%), diarrhoea (2.4%), pyrexia (2.4%) and febrile neutropenia(2.1%).

Tremelimumab was discontinued due to adverse reactions in 4.5% of patients. The most commonadverse reactions leading to treatment discontinuation were pneumonia (1.2%) and colitis (0.9%).

Tremelimumab was interrupted due to adverse reactions in 40.6% of patients. The most commonadverse reactions leading to dose interruption were neutropenia (13.6%), thrombocytopenia (5.8%),leukopenia (4.5%), diarrhoea (3.0%), pneumonia (2.7%), aspartate aminotransferase increased/alanineaminotransferase increased (2.4%), fatigue (2.4%), lipase increased (2.4%), colitis (2.1%), hepatitis(2.1%) and rash (2.1%).

Table 3, unless otherwise stated, lists the incidence of adverse reactions (ADRs) in patients treatedwith tremelimumab 300 mg in combination with durvalumab in the HCC pool of 462 patients, and

IMJUDO in combination with durvalumab and platinum-based chemotherapy in the POSEIDON

Study, in which 330 patients received tremelimumab. In the POSEIDON study, patients were exposedto tremelimumab during a median of 20 weeks.

Adverse reactions are listed according to system organ class in MedDRA. Within each system organclass, the ADRs are presented in decreasing frequency. The corresponding frequency category for each

ADR is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to< 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated fromavailable data). Within each frequency grouping, ADRs are presented in order of decreasingseriousness.

Table 3. Adverse reactions in patients treated with tremelimumab in combination withdurvalumab

Tremelimumab 75 mg in Tremelimumab 300 mg incombination with durvalumab combination with durvalumaband platinum-basedchemotherapy

Any Grade (%) Grade Any Grade (%) Grade3-4 (%) 3-4 (%)

Upper respiratory Very common 15.5 0.6 Common 8.4 0tract infectionsa

Pneumoniab Very common 14.8 7.3 Common 4.3 1.3

Influenza Common 3.3 0 Common 2.2 0

Oral candidiasis Common 2.4 0.3 Uncommon 0.6 0

Dental and oral soft Uncommon 0.6 0.3 Common 1.3 0tissue infectionsc

Anaemiad Very common 49.7 20.6

Neutropeniad,e Very common 41.2 23.9

Thrombocytopeniad,f Very common 24.5 8.2

Leukopeniad,g Very common 19.4 5.5

Febrile neutropeniad Common 3.0 2.1

Pancytopeniad Common 1.8 0.6

Immune Uncommon 0.3 0 Uncommonh 0.3 0thrombocytopenia

Hypothyroidismi Very common 13.3 0 Very common 13.0 0

Hyperthyroidismj Common 6.7 0 Common 9.5 0.2

Adrenal insufficiency Common 2.1 0.6 Common 1.3 0.2

Hypopituitarism/ Common 1.5 0.3 Uncommon 0.9 0

Hypophysitis

Thyroiditisk Common 1.2 0 Common 1.7 0

Diabetes insipidus Uncommon 0.3 0.3 Rarel <0.1 0

Type 1 diabetes Uncommon 0.3 0.3 Uncommonl 0.3 <0.1mellitus

Uveitis Uncommon 0.3 0 Rarel <0.1 0

Decreased appetited Very common 28.2 1.5

Neuropathy Common 6.4 0peripherald,m

Encephalitisn Uncommon 0.6 0.6 Rarel <0.1 0

Myasthenia gravis Rareo <0.1 <0.1 Uncommon 0.4 0

Guillain-Barré Rarep <0.1 0 Rarep <0.1 0syndrome

Meningitis Rareo 0.1 0 Uncommon 0.2 0.2

Myelitis transverseq Not known - - Not known - -

Myocarditisr Uncommon 0.3 0 Uncommon 0.4 0

Respiratory, thoracic, and mediastinal disorders

Cough/Productive Very common 12.1 0 Very common 10.8 0.2cough

Pneumonitiss Common 4.2 1.2 Common 2.4 0.2

Tremelimumab 75 mg in Tremelimumab 300 mg incombination with durvalumab combination with durvalumaband platinum-basedchemotherapy

Any Grade (%) Grade Any Grade (%) Grade3-4 (%) 3-4 (%)

Dysphonia Common 2.4 0 Uncommon 0.9 0

Interstitial lung Uncommon 0.6 0 Uncommon 0.2 0disease

Nausead Very common 41.5 1.8

Diarrhoea Very common 21.5 1.5 Very common 25.3 3.9

Constipationd Very common 19.1 0

Vomitingd Very common 18.2 1.2

Stomatitisd,t Common 9.7 0

Amylase increased Commono 8.5 3.6 Common 8.9 4.3

Abdominal painu Common 7.3 0 Very common 19.7 2.2

Lipase increased Commono 6.4 3.9 Common 10.0 7.1

Colitisv Common 5.5 2.1 Common 3.5 2.6

Pancreatitisw Common 2.1 0.3 Common 1.3 0.6

Intestinal perforation Rarep <0.1 <0.1 Rarep <0.1 <0.1

Large intestine Uncommonp 0.1 <0.1 Uncommonp 0.1 <0.1perforation

Coeliac disease Rarep 0.03 0.03 Rarep 0.03 0.03

Aspartate Very common 17.6 2.1 Very common 18.0 8.9aminotransferaseincreased/Alanineaminotransferaseincreasedx

Hepatitisy Common 3.9 0.9 Common 5.0 1.7

Alopeciad Very common 10.0 0

Rashz Very common 25.8 1.5 Very common 32.5 3.0

Pruritus Very common 10.9 0 Very common 25.5 0

Dermatitisaa Uncommon 0.6 0 Common 1.3 0

Night sweats Uncommon 0.6 0 Common 1.3 0

Pemphigoid Uncommon 0.3 0.3 Uncommon 0.2 0

Arthralgia Very common 12.4 0.3

Myalgia Common 4.2 0 Common 3.5 0.2

Myositisbb Uncommon 0.3 0.3 Uncommon 0.6 0.2

Polymyositisbb Uncommon 0.3 0.3 Uncommon 0.2 0.2

Immune-mediated Uncommono 0.2 0 Uncommon 0.6 0arthritis

Blood creatinine Common 6.4 0.3 Common 4.5 0.4increased

Dysuria Common 1.5 0 Common 1.5 0

Nephritiscc Uncommon 0.6 0 Uncommon 0.6 0.4

Cystitis noninfective Uncommon 0.3 0 Rarel <0.1 0

Fatigued Very common 36.1 5.2

Pyrexia Very common 16.1 0 Very common 13.9 0.2

Oedema peripheraldd Common 8.5 0 Very common 10.4 0.4

Tremelimumab 75 mg in Tremelimumab 300 mg incombination with durvalumab combination with durvalumaband platinum-basedchemotherapy

Any Grade (%) Grade Any Grade (%) Grade3-4 (%) 3-4 (%)

Infusion-related Common 3.9 0.3 Common 1.3 0reactioneea 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 Reported in studies outside of the HCC pool. Frequency is based on the POSEIDON study.

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 Reported in studies outside of the HCC pool. Frequency is based on a pooled data set of patients treated withtremelimumab in combination with durvalumab.m Includes neuropathy peripheral, parasthesia and peripheral sensory neuropathy.n Includes encephalitis and encephalitis autoimmune.o Reported in studies outside of the POSEIDON study. Frequency is based on a pooled data set of patients treatedwith tremelimumab in combination with durvalumab.p Reported in studies outside of the POSEIDON study and HCC pool. Frequency is based on a pooled data set ofpatients treated with tremelimumab in combination with durvalumab.q Reported in studies outside of the POSEIDON study and HCC pool.r Includes autoimmune myocarditis.s Includes immune-mediated pneumonitis and pneumonitis.t Includes mucosal inflammation and stomatitis.u Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.v Includes colitis, enteritis and enterocolitis.w Includes autoimmune pancreatitis, pancreatitis and pancreatitis acute.x Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increasedand transaminases increased.y Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity, hepatitis acute and immune-mediated hepatitis.z Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular, rash pruritic and rashpustular.aa Includes dermatitis and immune-mediated dermatitis.bb Includes rhabdomyolysis, myositis, and polymyositis.

cc Includes autoimmune nephritis and immune-mediated nephritis.dd Includes oedema peripheral and peripheral swelling.ee Includes infusion-related reaction and urticaria.

Tremelimumab is associated with immune-mediated adverse reactions. Most of these, including severereactions, resolved following initiation of appropriate medical therapy or withdrawal of tremelimumab.

The data for the following immune-mediated adverse reactions are based on 2280 patients from ninestudies across multiple tumour types who received tremelimumab 75 mg every 4 weeks or 1 mg/kgevery 4 weeks in combination with durvalumab 1500 mg every 4 weeks, 20 mg/kg every 4 weeks or10 mg/kg every 2 weeks. This combined safety dataset excludes the POSEIDON Study (and patientstreated with tremelimumab in combination with durvalumab and platinum-based chemotherapy).

Details for the significant adverse reactions for tremelimumab when given in combination withdurvalumab and platinum-based chemotherapy are presented if clinically relevant differences werenoted in comparison to tremelimumab in combination with durvalumab.

The data below also reflects information for significant adverse reactions for tremelimumab 300 mg incombination with durvalumab in the HCC pool (n=462).

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

Immune-mediated pneumonitis

In the combined safety database with tremelimumab in combination with durvalumab (n=2280),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 the 86patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Seven patients also received other immunosuppressants. Treatment was discontinued in 39 patients.

Resolution occurred in 51 patients.

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 was 29days (range: 5-774 days). All 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.

Immune-mediated hepatitis

In the combined safety database with tremelimumab in combination with durvalumab (n=2280),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 Grade3 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 tremelimumab in combination with durvalumab (n=2280),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.

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 in 29patients.

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

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism

In the combined safety database with tremelimumab in combination with durvalumab (n=2280),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 in 52patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 25patients 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 tremelimumab in combination with durvalumab (n=2280),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 corticosteriods, 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 tremelimumab in combination with durvalumab (n=2280),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 tremelimumab in combination with durvalumab (n=2280),immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in 16(0.7%) patients and Grade 4 in 1 (< 0.1%) patient. The median time to onset was 105 days (range: 20-428 days). Thirty-two patients received systemic corticosteroids, and 10 of the 32 patients receivedhigh-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment wasdiscontinued 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 tremelimumab in combination with durvalumab (n=2280),immune-mediated type 1 diabetes mellitus occurred in 6 (0.3%) patients, including Grade 3 in 1(< 0.1%) patient and Grade 4 in 2 (< 0.1%) patients. The median time to onset was 58 days (range:

7 - 220 days). All patients required insulin. Treatment was discontinued for 1 patient. Resolutionoccurred in 1 patient.

Immune-mediated type 1 diabetes mellitus was observed in patients receiving tremelimumab incombination with durvalumab (uncommon) in studies outside of the HCC pool.

Immune-mediated hypophysitis/hypopituitarism

In the combined safety database with tremelimumab in combination with durvalumab (n=2280),immune-mediated hypophysitis/hypopituitarism occurred in 16 (0.7%) patients, including Grade 3 in 8(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 tremelimumab in combination with durvalumab (n=2280),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 patients received high-dose corticosteroid treatment (at least40 mg prednisone or equivalent per day). Treatment was discontinued in 2 patients. Resolutionoccurred in 3 patients.

Immune-mediated rash

In the combined safety database with tremelimumab in combination with durvalumab (n=2280),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 in 26(5.6%) patients, including Grade 3 in 9 (1.9%) patients and Grade 4 in 1 (0.2%) patient. The mediantime to onset was 25 days (range: 2-933 days). All patients received systemic corticosteroids and 14 ofthe 26 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent perday). One patient received other immunosuppressants. Treatment was discontinued in 3 patients.

Resolution occurred in 19 patients.

In the combined safety database with tremelimumab in combination with durvalumab (n=2280),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 patients treated with tremelimumab in combination with durvalumab and platinum-basedchemotherapy in the POSEIDON study (n=330), the proportion of patients who experienced a shiftfrom baseline to a Grade 3 or 4 laboratory abnormality was as follows: 6.2% for alanineaminotransferase increased, pct. 5.2% for aspartate aminotransferase increased, 4.0% for blood creatinineincreased, 9.4% for amylase increased and 13.6% for lipase increased. The proportion of patients whoexperienced a TSH shift from baseline that was ≤ ULN to > ULN was 24.8% and a TSH shift frombaseline that was ≥ LLN to < LLN was 32.9%.

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 tremelimumab: pancreaticexocrine insufficiency.

As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity oftremelimumab is based on pooled data in 2075 patients who were treated with tremelimumab 75 mg or1 mg/kg and evaluable for the presence of anti-drug antibodies (ADAs). Two-hundred fifty-twopatients (12.1%) tested positive for treatment-emergent ADAs. Neutralising antibodies againsttremelimumab were detected in 10.0% (208/2075) patients. The presence of ADAs did not impacttremelimumab pharmacokinetics, and there was no apparent effect on safety.

In the HIMALAYA study, of the 182 patients who were treated with tremelimumab 300 mg as a singledose in combination with durvalumab and evaluable for the presence of ADAs against tremelimumab,20 (11.0%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies againsttremelimumab were detected in 4.4% (8/182) patients. The presence of ADAs did not have an apparenteffect on pharmacokinetics or safety.

In the POSEIDON study, of the 278 patients who were treated with tremelimumab 75 mg incombination with durvalumab 1500 mg every 3 weeks and platinum-based chemotherapy andevaluable for the presence of ADAs, 38 (13.7%) patients tested positive for treatment-emergent ADAs.

Neutralising antibodies against tremelimumab were detected in 11.2% (31/278) of patients. Thepresence of ADAs did not have an apparent effect on pharmacokinetics or safety.

Data from HCC patients 75 years of age or older are limited.

In the POSEIDON study in patients treated with tremelimumab in combination with durvalumab andplatinum-based chemotherapy, some differences in safety were reported between elderly (≥ 65 years)and younger patients. The safety data from patients 75 years of age or older are limited to a total of 74patients. There was a higher frequency of serious adverse reactions and discontinuation of any studytreatment due to adverse reactions in 35 patients aged 75 years of age or older treated withtremelimumab in combination with durvalumab and platinum-based chemotherapy (45.7% and 28.6%,respectively) relative to 39 patients aged 75 years of age or older who received platinum-basedchemotherapy only (35.9% and 20.5%, 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 tremelimumab. In case of overdose, patients should beclosely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatmentinstituted immediately.

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates. ATC code:

L01FX20

Cytotoxic T lymphocyte-associated antigen (CTLA-4) is primarily expressed on the surface of Tlymphocytes. Interaction of CTLA-4 with its ligands, CD80 and CD86, limits effector T-cellactivation, through a number of potential mechanisms, but primarily by limiting co-stimulatorysignalling through CD28.

Tremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversityand enhanced anti-tumour activity.

The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor results inimproved anti-tumour responses in metastatic non-small cell lung cancer and hepatocellularcarcinoma.

HCC - HIMALAYA Study

The efficacy of IMJUDO 300 mg as a single dose in combination with durvalumab was evaluated inthe HIMALAYA Study, a randomised, open-label, multicentre study in patients with confirmed uHCCwho did not receive prior systemic treatment for HCC. The study included patients with Barcelona

Clinic Liver Cancer (BCLC) Stage C or B (not eligible 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 gastro-intestinal (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 esophageal 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 1171 patients 1:1:1 to receive:

* Durvalumab 1500 mg every 4 weeks

* IMJUDO 300 mg as a single dose + durvalumab 1500 mg; followed by durvalumab 1500 mgevery 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 Overall Survival (OS) for the comparison of IMJUDO 300 mg as a singledose in combination with durvalumab vs. sorafenib. Secondary endpoints included Progression-Free

Survival (PFS), Investigator-assessed Objective Response Rate (ORR) and Duration of Response(DoR) according to RECIST v1.1.

The demographics and baseline disease characteristics were well balanced between 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%),extrahepatic spread (53.4%), baseline AFP < 400 ng/ml (63.7%), baseline AFP ≥ 400 ng/ml (34.5%),viral aetiology; 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 4 and Figure 1.

Table 4. Efficacy results for the HIMALAYA study for IMJUDO 300 mg with durvalumab vs.

Sorafenib

IMJUDO 300 mg + Sorafenibdurvalumab (n= 389)(n= 393)

Follow-up duration

Median follow-up (months)a 33.2 32.2

OS

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

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

HR (95% CI) 0.78 (0.66, 0.92)p-valueb 0.0035

PFS

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

Median PFS (months) 3.78 4.07(95% CI) (3.68, 5.32) (3.75, 5.49)

IMJUDO 300 mg + Sorafenibdurvalumab (n= 389)(n= 393)

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

ORR

ORR n (%)c 79 (20.1) 20 (5.1)

Complete Response n (%) 12 (3.1) 0

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

DoR

Median DoR (months) 22.3 18.4a Calculated using the reverse Kaplan-Meier technique (with censor indicator reversed).b 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 IMJUDO 300 mg + durvalumab vs.

Sorafenib was 0.0398 (Lan◦and◦DeMets 1983).c Confirmed complete response.

CI=Confidence Interval

Figure 1. Kaplan-Meier curve of OS

Median OS (95% CI)

IMJUDO 300 mg 16.4 (14.2-19.6)+ durvalumab

Sorafenib 13.8 (12.3-16.1)

IMJUDO 300 mg + d

Hazard Ratio (95% CI) 0.78 (0.66, Sorafenib0.92) C ensored

S

IMJUDO 300 mg + d

Sorafenib

Time from randomization (months)

NSCLC - POSEIDON study

POSEIDON was a study designed to evaluate the efficacy of durvalumab with or without IMJUDO incombination with platinum-based chemotherapy. POSEIDON was a randomised, open-label,multicentre 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 IMJUDO or durvalumab, except physiologicaldose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection; or patients

Probability of Overall Survivalreceiving live attenuated vaccine within 30 days before or after the start of IMJUDO and/ordurvalumab (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: IMJUDO 75 mg with durvalumab 1500 mg and platinum-based chemotherapy every 3weeks for 4 cycles, followed by durvalumab 1500 mg every 4 weeks as monotherapy. A fifth doseof IMJUDO 75 mg was given at Week 16 alongside durvalumab dose 6.

* Arm 2: Durvalumab 1500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles,followed by durvalumab 1500 mg every 4 weeks as monotherapy.

* Arm 3: Platinum-based chemotherapy every 3 weeks for 4 cycles. Patients could receive 2additional cycles (a total of 6 cycles post-randomisation), as clinically indicated, at investigator’sdiscretion.

Patients received one of the following platinum-based chemotherapy regimens:

* Non-squamous NSCLC

* Pemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every 3weeks. Unless contraindicated by the investigator, pemetrexed maintenance could begiven.

* Squamous NSCLC

* Gemcitabine 1000 or 1250 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.

IMJUDO was given up to a maximum of 5 doses unless there was disease progression or unacceptabletoxicity. Durvalumab and histology-based pemetrexed maintenance therapy (when applicable) wascontinued 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 progression-free survival (PFS) and overall survival(OS) for durvalumab + platinum-based chemotherapy (Arm 2) vs. platinum-based chemotherapy alone(Arm 3). The key secondary endpoints of the study were PFS and OS for IMJUDO + durvalumab +platinum-based chemotherapy (Arm 1) and platinum-based chemotherapy alone (Arm 3). Thesecondary endpoints included objective response rate (ORR) and duration of response (DoR). PFS,

ORR, and DoR were assessed using Blinded Independent Central Review (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%) and 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%) and PD-L1 expression TC < 50% (71.1%).

The study showed a statistically significant improvement in OS with IMJUDO + durvalumab +platinum-based chemotherapy (Arm 1) vs. platinum-based chemotherapy alone (Arm 3). IMJUDO +durvalumab + platinum-based chemotherapy showed a statistically significant improvement in PFS vs.

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

Table 5. Efficacy results for the POSEIDON study

Arm 1: IMJUDO+durvalumab+ Arm 3: Platinum-basedplatinum-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: PFS0.00735, OS 0.00797; 2-sided) were determined by a Lan-DeMets alpha spending function that approximates 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.c2-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 2. Kaplan-Meier curve of OS

Median OS (95% CI

IMJUDO + durvalumab + platinum-based 14.0 (11.7, 16.1)chemotherapy

Platinum-based chemotherapy 11.7 (10.5, 13.1)

Hazard Ratio (95% CI)

IMJUDO + durvalumab + platinum-based 0.77 (0.650, 0.916)chemotherapy

IMJUDO + durvalumab + 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

IMJUDO + durvalumab + 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 3. Kaplan-Meier curve of PFS

Median PFS 95% CI

IMJUDO + durvalumab + platinum-based 6.2 (5.0, 6.5)chemotherapy

Platinum-based chemotherapy 4.8 (4.6, 5.8)

Hazard Ratio (95% CI)

IMJUDO + durvalumab + platinum-based 0.72 (0.600,chemotherapy 0.860)

IMJUDO + durvalumab + platinum-based chemotherapy

Platinum-based chemotherapy

Time from randomisation (months)

Number of patients at risk

Month0 3 6 9 12 15 18 21 24

IMJUDO + durvalumab + platinum-based chemotherapy338 243 161 94 56 32 13 5 0

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

Figure 4 summarises efficacy results of OS by tumour PD-L1 expression in prespecified subgroupanalyses.

Probability of PFS

Figure 4. Forest plot of OS by PD-L1 expression for IMJUDO + durvalumab + platinum-basedchemotherapy vs. platinum-based chemotherapy

No of events/patients (%)

IMJUDO + durvalumab Platinum-based HR (95% CI)+ platinum-based chemotherapychemotherapy251/338 (74.3%) 285/337 (84.6%) 0.77 (0.65, 0.92)

All Patients69/101 (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 < 50%151/213 (70.9%) 170/207 (82.1%) 0.76 (0.61, 0.95)

PD-L1 ≥ 1%

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 IMJUDO in combination with durvalumaband platinum-based 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 IMJUDOin combination with durvalumab and platinum-based chemotherapy vs. platinum-based chemotherapywithin this study subgroup. Due to the exploratory nature of this subgroup analysis no definitiveconclusions can be drawn, but caution is suggested when considering this regimen for elderly patients.

The safety and efficacy of IMJUDO in combination with durvalumab in children and adolescents agedless than 18 years has not been established. Study D419EC00001 was a multi centre, open-label dosefinding and dose expansion study to evaluate the safety, preliminary efficacy and pharmacokinetics of

IMJUDO in combination with durvalumab followed by durvalumab monotherapy in paediatricpatients with advanced malignant solid tumours (except primary central nervous system tumours) whohad disease progression and for whom no standard of care treatment exists. The study enrolled50 paediatric patients with an age range from 1 to 17 years with primary tumour categories:

neuroblastoma, solid tumour and sarcoma. Patients received IMJUDO 1 mg/kg either in combinationwith durvalumab 20 mg/kg or durvalumab 30 mg/kg every 4 weeks for 4 cycles, followed bydurvalumab as monotherapy every 4 weeks. In the dose finding phase, IMJUDO and durvalumabcombination therapy was preceded by a single cycle of durvalumab; 8 patients in this phase howeverdiscontinued treatment prior to receiving IMJUDO. Thus, of the 50 patients enrolled in the study, 42received IMJUDO in combination with durvalumab and 8 received durvalumab only. In the dose-expansion phase, an ORR of 5.0% (1/20 patients) was reported in the evaluable for response analysisset. No new safety signals were observed relative to the known safety profiles of IMJUDO anddurvalumab in adults. See section 4.2 for information on paediatric use.

The pharmacokinetics (PK) of tremelimumab was assessed for tremelimumab as monotherapy,incombination with durvalumab and in combination with platinum-based chemotherapy.

The PK of tremelimumab was studied in patients with doses ranging from 75 mg to 750 mg or10 mg/kg administered intravenously once every 4 or 12 weeks as monotherapy, or at a single dose of300 mg. PK exposure increased dose proportionally (linear PK) at doses ≥ 75 mg. Steady state wasachieved at approximately 12 weeks. Based on population PK analysis that included patients(n = 1605) who received tremelimumab monotherapy or in combination with other medicinal productsin the dose range of ≥ 75 mg (or 1 mg/kg) every 3 or 4 weeks, the estimated tremelimumab clearance(CL) and volume of distribution (Vd) were 0.309 l/day and 6.33 l, respectively. The terminal half-lifewas approximately 14.2 days. The primary elimination pathways of tremelimumab are proteincatabolism via reticuloendothelial system or target mediated disposition.

Age (18-87 years), body weight (34-149 kg), gender, positive anti-drug antibody (ADA) status,albumin levels, LDH levels, creatinine levels, tumour type, race or ECOG/WHO status had noclinically significant effect on the PK of tremelimumab.

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 tremelimumab.

The effect of severe renal impairment (CrCL 15 to 29 ml/min) on the PK of tremelimumab isunknown; the potential need for dose adjustment cannot be determined. However, as IgG monoclonalantibodies are not primarily cleared via renal pathways, a change in renal function is not expected toinfluence tremelimumab exposure.

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

AST) and moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) had no clinicallysignificant effect on the PK of tremelimumab. The effect of severe hepatic impairment (bilirubin> 3.0 x ULN and any AST) on the PK of tremelimumab is unknown; the potential need for doseadjustment cannot be determined. However, as IgG monoclonal antibodies are not primarily clearedvia hepatic pathways, a change in hepatic function is not expected to influence tremelimumabexposure.

The PK of tremelimumab in combination with durvalumab was evaluated in a study of 50 paediatricpatients with an age range from 1 to 17 years in study D419EC00001. Patients received tremelimumab1 mg/kg either in combination with durvalumab 20 mg/kg or in combination with durvalumab30 mg/kg every 4 weeks for 4 cycles, followed by durvalumab as monotherapy every 4 weeks. Basedon population PK analysis, tremelimumab systemic exposure in paediatric patients ≥ 35kg receivingtremelimumab 1 mg/kg every 4 weeks was similar to exposure in adults receiving 1 mg/kg every4 weeks, whereas in paediatric patients < 35kg, exposure was lower relative to adults.

Animal toxicology

In the chronic 6-month study in cynomolgus monkeys, treatment with tremelimumab was associatedwith dose-related incidence in persistent diarrhoea and skin rash, scabs and open sores, which weredose-limiting. These clinical signs were also associated with decreased appetite and body weight andswollen peripheral lymph nodes. Histopathological findings correlating with the observed clinicalsigns included reversible chronic inflammation in the cecum and colon, mononuclear cell infiltrationin the skin and hyperplasia in lymphoid tissues.

A dose-dependent increase in the incidence and severity of mononuclear cell infiltration with orwithout mononuclear cell inflammation was observed in the salivary gland, pancreas (acinar), thyroid,parathyroid, adrenal, heart, esophagus, tongue, periportal liver area, skeletal muscle, prostate, uterus,pituitary, eye (conjunctiva, extra ocular muscles), and choroid plexus of the brain. No NOAEL wasfound in this study with animals treated with the lowest dose of 5 mg/kg/week, however theintermediate dose of 15 mg/kg week was considered the highest non-severely toxic dose (HNSTD).

This dose provided an exposure-based safety margin of 1.77-5.33 to clinical relevant exposure basedon the clinical dosing regimen of either a 300 mg single dose or 75 mg every three weeks.

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

Mononuclear cell infiltration in prostate and uterus was observed in repeat dose toxicity studies. Sinceanimal fertility studies have not been conducted with tremelimumab, the relevance of these findingsfor fertility is unknown. In reproduction studies, administration of tremelimumab to pregnantcynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity oreffects on pregnancy losses, foetal weights, or external, visceral, skeletal abnormalities or weights ofselected foetal organs.

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Disodium edetate dihydrate

Polysorbate 80

Water for injections

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

Unopened vial4 years at 2 °C - 8 °C.

Chemical and physical in-use stability has been demonstrated for up to 28 days at 2 °C to 8 °C and forup to 48 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.

Lack of microbial growth in the prepared solution for infusion has been demonstrated for up to 28 daysat 2 °C to 8 °C and for up to 48 hours at room temperature (up to 25 °C) from the time of preparation.

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 IMJUDO are available:

* 1.25 ml (a total of 25 mg tremelimumab) concentrate in a Type I glass vial with an elastomericstopper and a violet flip-off aluminum seal. Pack size of 1 single-dose vial.

* 15 ml (a total of 300 mg tremelimumab) concentrate in a Type I glass vial with an elastomericstopper and a dark blue flip-off aluminum seal. Pack size of 1 single-dose vial.

Not all pack sizes may be marketed.

Preparation of solution

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

* Visually inspect medicinal product for particulate matter and discolouration. IMJUDO isclear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if thesolution is cloudy, discoloured or visible particles are observed. Do not shake the vial.

* Withdraw the required volume from the vial(s) of IMJUDO and transfer into anintravenous bag containing sodium chloride 9 mg/ml (0.9%) solution for injection, orglucose 50 mg/ml (5%) solution for injection. Mix diluted solution by gentle inversion.

The final concentration of the diluted solution should be between 0.1 mg/ml and10 mg/ml. Do not freeze or shake the solution.

* Care must be taken to ensure the sterility of the prepared solution.

* Do not re-enter the vial after withdrawal of the medicinal product.

* Discard any unused portion left in the vial.

* Administer the infusion solution intravenously over 60 minutes through an intravenousline containing 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/1/22/1713/001 25 mg vial

EU/1/22/1713/002 300 mg vial

Date of first authorisation: 20 February 2023

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

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