Imjudo in combination with durvalumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC) who have not received prior treatment with a PD-1/PD-L1 inhibitor.

 

This indication is approved with commitment to provide verification and description of clinical benefit in a confirmatory trial

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

Indication	Recommended IMJUDO dosage	Duration of Therapy
Advanced or unresectable HCC	IMJUDO 300 mga as a single dose administered in combination with durvalumab 1500 mga at Cycle 1/Day 1, followed by durvalumab monotherapy every 4 weeks	Until disease progression or unacceptable toxicity

^a For IMJUDO, 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. For durvalumab, 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

Adverse reactions	Severitya	Treatment modification	Corticosteroid treatment unless otherwise specifiedb
Immune-mediated pneumonitis/interstitial lung disease	Grade 2	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 or 4	Permanently discontinue
Immune-mediated hepatitis	ALT or AST > 3 - ≤ 5 x ULN or total bilirubin > 1.5 - ≤ 3 x ULN	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	ALT or AST > 5 - ≤ 10 x ULN	Withhold durvalumab and permanently discontinue IMJUDO (where appropriate)
	Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULNd	Permanently discontinue
	ALT or AST > 10 x ULN or total bilirubin > 3 x ULN
Immune-mediated hepatitis in HCC (or secondary tumour involvement of the liver with abnormal baseline values)e	ALT or AST > 2.5 - ≤ 5 x BLV and ≤ 20 x ULN	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	ALT or AST > 5 - 7 x BLV and ≤ 20 x ULN or concurrent ALT or AST 2.5 - 5 x BLV and ≤ 20 x ULN and total bilirubin > 1.5 - < 2 x ULNd	Withhold durvalumab and permanently discontinue IMJUDO (where appropriate)
	ALT or AST > 7 x BLV or > 20 x ULN whichever occurs first or bilirubin > 3 x ULN	Permanently discontinue
Immune-mediated colitis or diarrhoea	Grade 2	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 or 4	Permanently discontinue
	Intestinal perforation of ANY grade	Permanently discontinue	Consult a surgeon immediately if an intestinal perforation is suspected
Immune-mediated hyperthyroidism, thyroiditis	Grade 2-4	Withhold dose until clinically stable	Symptomatic management
Immune-mediated hypothyroidism	Grade 2-4	No changes	Initiate thyroid hormone replacement as clinically indicated
Immune-mediated adrenal insufficiency, hypophysitis/hypopituitarism	Grade 2-4	Withhold dose until clinically stable	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated
Immune-mediated Type 1 diabetes mellitus	Grade 2-4	No changes	Initiate treatment with insulin as clinically indicated
Immune-mediated nephritis	Grade 2 with serum creatinine > 1.5-3 x (ULN or baseline)	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 with serum creatinine > 3 x baseline or > 3-6 x ULN; Grade 4 with serum creatinine > 6 x ULN	Permanently discontinue
Immune-mediated rash or dermatitis (including pemphigoid)	Grade 2 for > 1 week or Grade 3	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 4	Permanently discontinue
Immune-mediated myocarditis	Grade 2-4	Permanently discontinue	Initiate 2 to 4 mg/kg/day prednisone or equivalent followed by a taperf
Immune-mediated myositis/polymyositis	Grade 2 or 3	Withhold dosec,g	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 4	Permanently discontinue
Infusion-related reactions	Grade 1 or 2	Interrupt or slow the rate of infusion	May consider pre-medications for prophylaxis of subsequent infusion reactions
	Grade 3 or 4	Permanently discontinue	Manage severe infusion-related reactions per institutional standard, appropriate clinical practice guidelines and/or society guidelines
Immune-mediated myasthenia gravis	Grade 2-4	Permanently discontinue	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
Immune-mediated encephalitis	Grade 2-4	Permanently discontinue	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
Other immune-mediated adverse reactionsh	Grade 2 or 3	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 4	Permanently discontinue
Non-immune-mediated adverse reactions	Grade 2 and 3	Withhold dose until ≤ Grade 1 or return to baseline
	Grade 4	Permanently discontinue i

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

^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 aetiology or exclude alternate aetiologies.

 

Special populations

 

Paediatric population

The safety and efficacy of IMJUDO in children and adolescents 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

Method of administration in HCC:

 

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 aetiology, occurred in patients receiving  tremelimumab 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 aetiology, occurred in patients receiving tremelimumab 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 aetiology, occurred in patients receiving tremelimumab in combination with durvalumab (see section 4.8). Intestinal perforation and large intestine perforation were reported in patients receiving tremelimumab 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 tremelimumab 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 tremelimumab 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 tremelimumab 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, occurred in patients receiving tremelimumab in combination with durvalumab (section 4.2.)

 

Immune-mediated hypophysitis/hypopituitarism

 

Immune‑mediated hypophysitis or hypopituitarism occurred in patients receiving tremelimumab 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 aetiology, occurred in patients receiving tremelimumab 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 aetiology, occurred in patients receiving tremelimumab 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 tremelimumab 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 tremelimumab 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 tremelimumab 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 tremelimumab 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, tremelimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

 

Patients with the following were excluded from clinical studies: active or prior documented autoimmune disease; active and/or untreated brain metastases; a history of immunodeficiency; administration of systemic immunosuppression within 14 days before the start of tremelimumab or durvalumab, except physiological dose of systemic corticosteroids (< 10 mg/day prednisone or equivalent); uncontrolled intercurrent illness; active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of tremelimumab or durvalumab. In the absence of data, tremelimumab 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 tremelimumab 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%), aspartate aminotransferase increased/alanine aminotransferase 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 4).

 

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

 

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

 

The frequency of treatment discontinuation due to adverse reactions is 6.5%. The most common adverse reactions leading to treatment discontinuation are 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 4, unless otherwise stated, lists the incidence of adverse reactions (ADRs) in patients treated with tremelimumab 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 4. Adverse reactions in patients with HCC treated with tremelimumab 300 mg in combination with durvalumab

	Tremelimumab 300 mg in combination with durvalumab (n=462)
Adverse Reaction	Frequency of any Grade		Frequency of Grade 3-4
Infections and infestations
Upper respiratory tract infectionsa	Common	39 (8.4%)
Pneumoniab	Common	20 (4.3%)	Common	6 (1.3%)
Influenza	Common	10 (2.2%)
Dental and oral soft tissue infectionsc	Common	6 (1.3%)
Oral candidiasis	Uncommon	3 (0.6%)
Blood and lymphatic system disorders
Immune thrombocytopeniad	Not known
Endocrine disorders
Hypothyroidisme	Very common	60 (13.0%)
Hyperthyroidismf	Common	44 (9.5%)	Uncommon	1 (0.2%)
Thyroiditisg	Common	8 (1.7%)
Adrenal insufficiency	Common	6 (1.3%)	Uncommon	1 (0.2%)
Hypopituitarism/Hypophysitis	Uncommon	4 (0.9%)
Diabetes insipidusd	Not known
Type 1 diabetes mellitusd	Not known
Nervous system disorders
Myasthenia gravis	Uncommon	2 (0.4%)
Meningitis	Uncommon	1 (0.2%)	Uncommon	1 (0.2%)
Guillain-Barré syndromed	Not known
Encephalitisd	Not known
Cardiac disorders
Myocarditis	Uncommon	2 (0.4%)
Respiratory, thoracic and mediastinal disorders
Cough/Productive cough	Very common	50 (10.8%)	Uncommon	1 (0.2%)
Pneumonitish	Common	11 (2.4%)	Uncommon	1 (0.2%)
Dysphonia	Uncommon	4 (0.9%)
Interstitial lung disease	Uncommon	1 (0.2%)
Gastrointestinal disorders
Diarrhoea	Very common	117 (25.3%)	Common	18 (3.9%)
Abdominal paini	Very common	91 (19.7%)	Common	10 (2.2%)
Lipase increased	Common	46 (10.0%)	Common	33 (7.1%)
Amylase increased	Common	41 (8.9%)	Common	20 (4.3%)
Colitisj	Common	16 (3.5%)	Common	12 (2.6%)
Pancreatitisk	Common	6 (1.3%)	Uncommon	3 (0.6%)
Intestinal perforationd	Not known
Large intestine perforationd	Not known
Hepatobiliary disorders
Aspartate aminotransferase increased/Alanine aminotransferase increasedl	Very common	83 (18.0%)	Common	41 (8.9%)
Hepatitism	Common	23 (5.0%)	Common	8 (1.7%)
Skin and subcutaneous tissue disorders
Rashn	Very common	150 (32.5%)	Common	14 (3.0%)
Pruritus	Very common	118 (25.5%)
Dermatitiso	Common	6 (1.3%)
Night sweats	Common	6 (1.3%)
Pemphigoid	Uncommon	1 (0.2%)
Musculoskeletal and connective tissue disorders
Myalgia	Common	16 (3.5%)	Uncommon	1 (0.2%)
Myositis	Uncommon	3 (0.6%)	Uncommon	1 (0.2%)
Polymyositis	Uncommon	1 (0.2%)	Uncommon	1 (0.2%)
Renal and urinary disorders
Blood creatinine increased	Common	21 (4.5%)	Uncommon	2 (0.4%)
Dysuria	Common	7 (1.5%)
Nephritisp	Uncommon	3 (0.6%)	Uncommon	2 (0.4%)
Cystitis noninfectived	Not known
General disorders and administration site conditions
Pyrexia	Very common	64 (13.9%)	Uncommon	1 (0.2%)
Oedema peripheralq	Very common	48 (10.4%)	Uncommon	2 (0.4%)
Injury, poisoning and procedural complications
Infusion-related reactionr	Common	6 (1.3%)

^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 tremelimumab 300 mg in combination with durvalumab in the HCC pool (n=462).

 

Immune‑mediated pneumonitis

 

In the combined safety database with tremelimumab in combination with durvalumab, 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 to onset was 57 days (range: 8 - 912 days). All patients received systemic corticosteroids and 79 of the 86 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients also received other immunosuppressants. Treatment was discontinued in 39 patients. Resolution occurred in 51 patients.

 

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 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 combined safety database with tremelimumab in combination with durvalumab, 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 was 36 days (range: 1 - 533 days). All patients received systemic corticosteroids and 68 of the 80 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients also received other immunosuppressants. Treatment was discontinued in 27 patients. Resolution occurred in 47 patients.

 

In the HCC pool (n=462), immune‑mediated hepatitis occurred in 34 (7.4%) patients, including Grade 3 in 20 (4.3%) patients, Grade 4 in 1 (0.2%) patient and Grade 5 (fatal) in 3 (0.6%) patients. 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 combined safety database with tremelimumab in combination with durvalumab, immune‑mediated colitis or diarrhoea occurred in 167 (7.3%) patients, including Grade 3 in 76 (3.3%) patients and Grade 4 in 3 (0.1%) patients. The median time to onset was 57 days (range: 3 - 906 days). All patients received systemic corticosteroids and 151 of the 167 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty-two patients also received other immunosuppressants. Treatment was discontinued in 54 patients. Resolution occurred in 141 patients.

 

Intestinal perforation and large intestine perforation were uncommonly reported in patients receiving tremelimumab in combination with durvalumab.

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‑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 tremelimumab in combination with durvalumab (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, immune-mediated hypothyroidism occurred in 209 (9.2%) patients, including Grade 3 in 6 (0.3%) patients. The median time to onset was 85 days (range: 1 - 624 days). Thirteen patients received systemic corticosteroids and 8 of the 13 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment discontinued in 3 patients. Resolution occurred in 52 patients.

 

In the HCC pool (n=462), 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 therapyincluding 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 combined safety database with tremelimumab in combination with durvalumab, immune-mediated hyperthyroidism occurred in 62 (2.7%) patients, including Grade 3 in 5 (0.2%) patients. The median time to onset was 33 days (range: 4 - 176 days). Eighteen patients received systemic coticosteroids, and 11 of the 18 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Fifty-three patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), One patient discontinued 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). 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 combined safety database with tremelimumab in combination with durvalumab, 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 systemic corticosteroids and 2 of the 5 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Thirteen patients required other therapy including, hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. No patients discontinued treatment due to immune-mediated thyroiditis. Resolution occurred in 5 patients.

 

In the HCC pool (n=462), 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 combined safety database with tremelimumab in combination with durvalumab, immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in 16 (0.7%) patients and Grade 4 in 1 (< 0.1%) patient. The median time to onset was 105 days (range: 20-428 days). Thirty-two patients received systemic corticosteroids, and 10 of the 32 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in one patient. Resolution occurred in 11 patients.

In the HCC pool (n=462), immune-mediated adrenal insufficiency occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 64 days (range: 43-504 days). All patients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.

 

Immune-mediated type 1 diabetes mellitus

In the combined safety database with tremelimumab in combination with durvalumab, 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. Resolution occurred in 1 patient.

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

 

Immune-mediated hypophysitis/hypopituitarism

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 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 combined safety database with tremelimumab in combination with durvalumab, 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). All patients received systemic corticosteroids and 8 of the 16 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy. Treatment was discontinued in 2 patients. Resolution occurred in 7 patients.

 

In the HCC pool (n=462), 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 combined safety database with tremelimumab in combination with durvalumab, immune-mediated rash or dermatitis (including pemphigoid) occurred in 112 (4.9%) patients, including Grade 3 in 17 (0.7%) patients. The median time to onset was 35 days (range: 1 - 778 days). All patients received systemic corticosteroids, and 57 of the 112 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 10 patients. Resolution occurred in 65 patients.

 

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 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.

 

 

Infusion-related reactions

In the combined safety database with tremelimumab in combination with durvalumab, 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.

 

Immunogenicity

 

In the HIMALAYA study, of the 182 patients who were treated with tremelimumab 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. The presence of ADAs did not impact tremelimumab pharmacokinetics, and there was no apparent effect on efficacy and safety .

 

 

Elderly

 

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

 

To report any side effect(s):

• Saudi Arabia:

 

- The National Pharmacovigilance Centre (NPC) o   Toll free phone: 19999 o   E-mail: npc.drug@sfda.gov.sa    o   Website: https://ade.sfda.gov.sa/

 

·   Other GCC States:

 

-    Please contact the relevant competent authority.

 

 

 

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.

 

 

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), 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 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

 

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 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 5 and Figure 1.

 

Table 5. Efficacy Results for the HIMALAYA Study for IMJUDO 300 mg with durvalumab vs. S

	IMJUDO 300 mg + durvalumab (n= 393)	S (n= 389)
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) (95% CI)	16.4 (14.2, 19.6)	13.8 (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) (95% CI)	3.78 (3.68, 5.32)	4.07 (3.75, 5.49)
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	18.4

^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 tremelimumab 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. The primary elimination pathways of tremelimumab are protein catabolism via reticuloendothelial system or target mediated disposition.

Special populations

 

For HIMALAYA:

 

Age (22 - 97 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. the potential need for dose adjustment cannot be determined. However, as IgG monoclonal antibodies are not primarily cleared via renal pathways, a change in renal function is not expected to influence tremelimumab exposure.

 

Patients with hepatic impairment

 

Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 to 1.5 × ULN and any AST) had no clinically significant effect on the PK of tremelimumab. The effect of moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) or severe hepatic impairment (bilirubin > 3.0 x ULN and any AST) on the PK of tremelimumab is unknown; the potential need for dose adjustment cannot be determined. 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.

 

For HIMALAYA:

 

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 requiring supportive care. This dose provided an exposure-based safety margin of 3 to clinical relevant exposure (taking species difference in potency into account).

 

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.

 

Disposal

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