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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-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 from visible particles. The solution has a pH of approximately 5.5 and an osmolality of approximately 285 mOsm/kg.

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

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

Posology

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

Table 1: Recommended dose of IMJUDO

^a HCC patients with a body weight of 40 kg or less must receive weight-based dosing, equivalent to IMJUDO 4 mg/kg until weight is greater than 40 kg. Patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to durvalumab 20 mg/kg until weight is greater than 30 kg.

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

Guidelines for management of immune-mediated adverse reactions are described in Table 2 (see section 4.4). Refer also to the summary of product characteristics (SmPC) for durvalumab.

Table 2.

Treatment modifications and management recommendations for IMJUDO in combination with durvalumab

^a Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal.

^b Upon improvement to ≤ Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement.

^c After withholding, IMJUDO and/or durvalumab can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day. IMJUDO and durvalumab should be permanently discontinued for recurrent Grade 3 adverse reactions, as applicable.

^d For patients with alternative cause follow the recommendations for AST or ALT increases without concurrent bilirubin elevations.

^e If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.

^f If no improvement within 2 to 3 days despite corticosteroids, promptly start additional immunosuppressive therapy. Upon resolution (Grade 0), corticosteroid taper should be initiated and continued over at least 1 month.

^g Permanently discontinue IMJUDO and durvalumab if the adverse reaction does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency.

^h Includes immune thrombocytopenia and pancreatitis.

ⁱ With the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue treatment should be based on accompanying clinical signs/symptoms and clinical judgment.

For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm etiology or exclude alternate etiologies.

Special populations

Paediatric population

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

Elderly

No dose adjustment is required for elderly patients (≥ 65 years of age) (see section 5.2).

Renal impairment

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).

Hepatic impairment

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

Method of administration

IMJUDO is for intravenous use.

Administer IMJUDO prior to durvalumab on the same day.

IMJUDO and durvalumab are administered as separate intravenous infusions. Refer to the SmPC for durvalumab administration information.

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

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

Traceability

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

Immune-mediated pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related aetiologies excluded, and managed as recommended in section 4.2.

Immune-mediated hepatitis

Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Monitor alanine aminotransferase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase levels prior to initiation of treatment and prior to each subsequent infusion. Additional monitoring is to be considered based on clinical evaluation . Immune-mediated hepatitis should be managed as recommended in section 4.2.

Immune-mediated colitis

Immune-mediated colitis or diarrhoea, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Intestinal perforation and large intestine perforation were reported in patients receiving IMJUDO in combination with durvalumab. Patients should be monitored for signs and symptoms of colitis/diarrhoea and intestinal perforation and managed as recommended in section 4.2.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receiving IMJUDO in combination with durvalumab, and hypothyroidism may follow hyperthyroidism (see section 4.8). Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and as indicated based on clinical evaluation. Immune-mediated hypothyroidism, hyperthyroidism, and thyroiditis should be managed as recommended in section 4.2.

Immune-mediated adrenal insufficiency

Immune-mediated adrenal insufficiency occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in section 4.2.

Immune-mediated type 1 diabetes mellitus

Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can be fatal if not detected early, occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus, patients should be managed as recommended in section 4.2.

Immune-mediated hypophysitis/hypopituitarism

Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in section 4.2.

Immune-mediated nephritis

Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Patients should be monitored for abnormal renal function tests prior to and periodically during treatment and managed as recommended in section 4.2.

Immune-mediated rash

Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMJUDO in combination with durvalumab (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 or dermatitis and managed as recommended in section 4.2.

Immune-mediated myocarditis

Immune-mediated myocarditis, which can be fatal, occurred in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managed as recommended in section 4.2.

Other immune-mediated adverse reactions

Given the mechanism of action of IMJUDO in combination with durvalumab, other potential immune-mediated adverse reactions may occur. The following immune-related adverse reactions have been observed in patients treated with IMJUDO in combination with durvalumab: myasthenia gravis, myositis, polymyositis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, cystitis noninfective and pancreatitis (see section 4.8). Patients should be monitored for signs and symptoms and managed as recommended in section 4.2.

Infusion-related reactions

Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusion-related reactions have been reported in patients receiving IMJUDO in combination with durvalumab (see section 4.8). Infusion-related reactions should be managed as recommended in section 4.2.

Patients excluded from clinical studies

Patients with the following were excluded from clinical studies: Child-Pugh Score B or C, main portal vein 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 documented gastrointestinal (GI) bleeding within 12 months, ascites requiring non-pharmacologic intervention within 6 months, hepatic encephalopathy within 12 months before the start of treatment, active or prior documented autoimmune or inflammatory disorders. In the absence of data, IMJUDO should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Sodium content

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, except physiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent), is not recommended because of their potential interference with the pharmacodynamic activity and efficacy of tremelimumab. However, systemic corticosteroids or other immunosuppressants can be used after starting tremelimumab to treat immune-related adverse reactions (see section 4.4).

No formal pharmacokinetic (PK) drug-drug interaction studies have been conducted with tremelimumab. Since the primary elimination pathways of tremelimumab are protein catabolism via reticuloendothelial system or target-mediated disposition, no metabolic drug-drug interactions are expected.

Women of childbearing potential/Contraception

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

Pregnancy

There are no data on the use of tremelimumab in pregnant women. Based on its mechanism of action, tremelimumab has the potential to impact maintenance of pregnancy and may cause foetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tremelimumab to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or any effects on maintenance of pregnancy or embryofoetal development (see section 5.3). Human IgG2 is known to cross the placental barrier. Tremelimumab is not recommended during pregnancy and in women of childbearing potential not using effective contraception during treatment and for at least 3 months after the last dose.

Breast-feeding

There is no information regarding the presence of tremelimumab in human milk, the absorption and effects on the breast-fed infant, or the effects on milk production. Human IgG2 is excreted in human milk. Because of the potential for adverse reactions from tremelimumab in breast-fed infants, breast-feeding women are advised not to breast-feed during treatment and for at least 3 months after the last dose.

Fertility

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.

Summary of the safety profile

The safety of IMJUDO 300 mg as a single dose in combination with durvalumab, is based on pooled data in 462 HCC patients (HCC pool) from the HIMALAYA Study and another study in HCC patients, Study 22. The most common (> 10%) adverse reactions were rash (32.5%), pruritus (25.5%), diarrhoea (25.3%), abdominal pain (19.7%), AST increased (18.0%), pyrexia (13.9%), hypothyroidism (13.0%), cough/productive cough (10.8%), oedema peripheral (10.4%) and lipase increased (10.0%) (see Table 3).

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

Study treatment was discontinued due to adverse reactions in 6.5% of patients. The most common adverse reactions leading to treatment discontinuation were hepatitis (1.5%) and aspartate aminotransferase 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

Tabulated list of adverse reactions

Table 3 lists the incidence of adverse reactions (ADRs) in patients treated with IMJUDO 300 mg in combination with durvalumab in the HCC pool of 462 patients. Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, 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 from available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Table 3. Adverse reactions in patients with HCC treated with IMJUDO 300 mg in combination with durvalumab

^a Includes nasopharyngitis, pharyngitis, rhinitis, tracheobronchitis and upper respiratory tract infection.

^b Includes pneumocystis jirovecii pneumonia and pneumonia.

^c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.

^d Adverse reaction was not observed in the HCC pool, but was reported in patients treated with durvalumab or durvalumab + tremelimumab in AstraZeneca-sponsored clinical studies.

^e Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.

^f Includes blood thyroid stimulating hormone decreased and hyperthyroidism.

^g Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.

^h Includes immune-mediated pneumonitis and pneumonitis.

ⁱ Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.

^j Includes colitis, enteritis and enterocolitis.

^k Includes pancreatitis and pancreatitis acute.

^l Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.

^m Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity and immune-mediated hepatitis.

ⁿ Includes eczema, erythema, rash, rash macular, rash maculo-papular, rash papular and rash pruritic.

^o Includes dermatitis and immune-mediated dermatitis.

^p Includes autoimmune nephritis and immune-mediated nephritis.

^q Includes oedema peripheral and peripheral swelling.

^r Includes infusion-related reaction and urticaria.

Description of selected adverse reactions

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

Immune-mediated pneumonitis

In the HCC pool, immune-mediated pneumonitis occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient and Grade 5 (fatal) in 1 (0.2%) patient. The median time to onset was 29 days (range: 5-774 days). Six patients received systemic corticosteroids, and 5 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received other immunosuppressants. Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.

Immune-mediated hepatitis

In the HCC pool, immune-mediated hepatitis occurred in 34 (7.4%) patients, including Grade 3 in 20 (4.3%) patients, Grade 4 in 1 (0.2%) patient and Grade 5 (fatal) in 3 (0.6%) patients. The median time to onset was 29 days (range: 13-313 days). All patients received systemic corticosteroids, and 32 of the 34 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants. Treatment was discontinued in 10 patients. Resolution occurred in 13 patients.

Immune-mediated colitis

In the HCC pool, immune-mediated colitis or diarrhoea occurred in 31 (6.7%) patients, including Grade 3 in 17 (3.7%) patients. The median time to onset was 23 days (range: 2-479 days). All patients received systemic corticosteroids, and 28 of the 31 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also received other immunosuppressants. Treatment was discontinued in 5 patients. Resolution occurred in 29 patients.

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

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism

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

Immune-mediated hyperthyroidism

In the HCC pool, immune-mediated hyperthyroidism occurred in 21 (4.5%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 30 days (range: 13-60 days). Four patients received systemic corticosteriods, and all of the four patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 17 patients.

Immune-mediated thyroiditis

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

Immune-mediated adrenal insufficiency

In the HCC pool, immune-mediated adrenal insufficiency occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 64 days (range: 43-504 days). All patients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.

Immune-mediated type 1 diabetes mellitus

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

Immune-mediated hypophysitis/hypopituitarism

In the HCC pool, immune-mediated hypophysitis/hypopituitarism occurred in 5 (1.1%) patients. The median time to onset for the events was 149 days (range: 27-242 days). Four patients received systemic corticosteroids, and 1 of the 4 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also required endocrine therapy. Resolution occurred in 2 patients.

Immune-mediated nephritis

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

Immune-mediated rash

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

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity of tremelimumab is based on pooled data in 2075 patients who were treated with tremelimumab 75 mg or 1 mg/kg and evaluable for the presence of anti-drug antibodies (ADAs). Two-hundred fifty-two patients (12.1%) tested positive for treatment-emergent ADAs. Neutralising antibodies against tremelimumab were detected in 10.0% (208/2075) patients. The presence of ADAs did not impact tremelimumab pharmacokinetics, and there was no apparent effect on efficacy and safety.

In the HIMALAYA study, of the 182 patients who were treated with IMJUDO 300 mg as a single dose 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 against tremelimumab were detected in 4.4% (8/182) patients. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.

Elderly

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

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

There is no information on overdose with tremelimumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates. ATC code: L01FX20

Mechanism of action

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

Tremelimumab is a selective, fully human IgG2 antibody that blocks CTLA-4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, resulting in increased T-cell diversity and enhanced antitumour activity.

The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor results in improved anti-tumour responses in metastatic non-small cell lung cancer In murine syngeneic tumour models, dual blockade of PD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.

Clinical efficacy

HCC - HIMALAYA Study

The efficacy of IMJUDO 300 mg as a single dose in combination with durvalumab 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 (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 viral hepatitis B and hepatitis C; active or prior documented gastro-intestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders.

Patients with esophageal varices were included except those with active or prior documented GI bleeding within 12 months prior to study entry.

Randomisation was stratified by macrovascular invasion (MVI) (yes vs. no), etiology of liver disease (confirmed hepatitis B virus vs. confirmed hepatitis C virus vs. others) and ECOG performance status (0 vs. 1). The HIMALAYA study randomized 1171 patients 1:1:1 to receive:

• D: durvalumab 1500 mg every 4 weeks

• IMJUDO 300 mg as a single dose + durvalumab 1500 mg; followed by durvalumab 1500 mg every 4 weeks

• S: Sorafenib 400 mg twice daily

Treatment continued as long as clinical benefit was observed or until unacceptable toxicity. Patients in all arms could continue to receive treatment after evidence of disease progression if, in the Investigator's opinion, they were benefiting from study drug.

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

The primary endpoint was Overall Survival (OS). 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. The baseline demographics of the overall study population were as follows: male (83.7%), age < 65 years (50.4%) White (44.6%), Asian (50.7%), Black or African American (1.7%), Other 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 etiology; 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. S

^a Calculated using reverse the 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 of events observed, the boundary for declaring statistical significance for IMJUDO 300 mg + durvalumab vs. S was 0.0398 (Lan◦and◦DeMets 1983).

^c Confirmed complete response.

NR=Not Reached, CI=Confidence Interval

Figure 1. Kaplan-Meier curve of OS

Paediatric population

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

The pharmacokinetics (PK) of tremelimumab was assessed for IMJUDO as monotherapy and in combination with durvalumab.

The PK of tremelimumab was studied in patients with doses ranging from 75 mg to 750 mg or 10 mg/kg administered intravenously once every 4 or 12 weeks as monotherapy, or at a single dose of 300 mg. PK exposure increased dose proportionally (linear PK) at doses ≥ 75 mg. Steady state was achieved at approximately 12 weeks. Based on population PK analysis that included patients who received tremelimumab monotherapy or in combination with other medicinal products in 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-life was approximately 14.2 days.

Special populations

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 no clinically significant effect on the PK of tremelimumab.

Patients with renal impairment

Mild (creatinine clearance (CrCL) 60 to 89 ml/min) and moderate renal impairment (creatinine clearance (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 is unknown.

Patients with hepatic impairment

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 clinically significant 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; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence tremelimumab exposure.

Animal toxicology

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

A dose-dependent increase in the incidence and severity of mononuclear cell infiltration with or without 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 was found in this study with animals treated with the lowest dose of 5 mg/kg/week, however the intermediate 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 to clinical relevant exposure.

Carcinogenicity and mutagenicity

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

Reproductive toxicology

Animal fertility studies have not been conducted with tremelimumab. Mononuclear cell infiltration in prostate and uterus was observed in repeat dose toxicity studies. Since animal fertility studies have not been conducted with tremelimumab, the clinical relevance of these findings for fertility is unknown. In reproduction studies, administration of tremelimumab to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or effects pregnancy losses, foetal weights, or external, visceral, skeletal abnormalities or weights of selected 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 medicinal products.

Unopened vial

4 years at 2 °C - 8 °C.

Diluted solution

Chemical and physical in-use stability has been demonstrated for up to 28 days at 2 °C to 8 °C and for up 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 the user 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 days at 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 elastomeric stopper 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 elastomeric stopper 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 technique must be observed.

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

• Withdraw the required volume from the vial(s) of IMJUDO and transfer into an intravenous 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 of the diluted solution should be between 0.1 mg/ ml and 10 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.

Administration

• Administer the infusion solution intravenously over 60 minutes through an intravenous line 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 local requirements.

AstraZeneca UK Limited,

1 Francis Crick Avenue,

Cambridge,

CB2 0AA,

UK.

PLGB 17907/0368

Date of first authorisation: 06 June 2023

06 June 2023