Imjudo (Tremelimumab) for HCC: FDA Prescribing Information

Tremelimumab, also known as Imjudo, is a monoclonal antibody that inhibits the activity of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a protein that regulates the immune response to cancer cells.

By blocking CTLA-4, Tremelimumab can enhance the immune response against cancer cells, which can potentially slow or halt the growth and spread of tumors.

Imjudo (Tremelimumab) FDA-Approved Indications:

The FDA has approved Imjudo for the following cancers:

• Hepatocellular Carcinoma:

It has been approved for the treatment of unresectable Hepatocellular carcinoma (uHCC) in combination with Imfinzi (durvalumab).

• Non-small cell carcinoma:

It has been approved by the FDA for the treatment of patients with metastatic non-small cell carcinoma without EGFR mutations or ALK (anaplastic lymphoma kinase) genomic tumor aberrations.

Tremelimumab is to be given to these patients in combination with Imfinzi (Durvalumab) and platinum-based chemotherapy.

Imjudo (Tremelimumab) Dose:

For the treatment of uHCC (unresectable hepatocellular carcinoma), it is administered in the following dose in combination with Duvalumab [Ref]:

For the treatment of non-small cell carcinoma, the following dosing regimen should be followed:

Recommended Dosage Schedule (Manufacturer’s Recommendations):

How to adjust Imjudo Dose if the patient develops adverse drug reactions:

Here is a table summarizing dosage adjustments in case a person develops adverse drug reactions:

Imjudo (Tremelimumab) use in pregnancy and breastfeeding:

IMJUDO can harm fetuses when administered to pregnant women, and there are no available data on its use in pregnant women.

Animal studies have shown an increased risk of immune-mediated rejection of the developing fetus and fetal death with CTLA-4 blockade.

Pregnant women and females of reproductive potential should be advised of the potential risk to a fetus.

In a reproduction study with pregnant monkeys, tremelimumab-actl did not cause maternal toxicity or harm to embryo-fetal development at levels up to 31 times higher than the recommended dose range for humans.

However, in a murine model of pregnancy, blockade of CTLA-4 resulted in increased fetal resorptions and reduced live fetuses.

Fetal exposure to tremelimumab-actl may increase the risk of immune-mediated disorders or alter the normal immune response based on its mechanism of action.

IMJUDO (Tremelimumab) use during lactation:

There is no information on whether tremelimumab-actl is present in human milk or its effects on breastfed infants.

Maternal IgG is present in human milk, but the effects of IMJUDO on breastfed infants are unknown. Due to the potential for serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with IMJUDO and for 3 months after the last dose.

Contraindications to the use of Imjudo (Tremelimumab):

There are no contraindications mentioned in the manufacturer’s labeling. However, Tremelimumab is associated with severe immune-mediated toxicities for which close monitoring is recommended.

IMJUDO is a monoclonal antibody that, in combination with durvalumab, blocks T-cell inhibitory signals induced by the CTLA-4 pathway, removing inhibition of the immune response.

However, these drugs have the potential to induce immune-mediated adverse reactions, which can be severe or fatal and can occur in any organ system or tissue.

Early identification and management of these adverse reactions are essential, and monitoring for signs and symptoms is recommended.

Clinical chemistries should be evaluated at baseline and before each dose. If adverse reactions occur, IMJUDO and durvalumab may need to be withheld or permanently discontinued, and corticosteroid therapy should be administered until improvement to Grade 1 or less.

Other systemic immunosuppressants may be considered for patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-mediated pneumonitis:

• Imjudo + Imfinzi (Durvalumab):

The combination of IMJUDO and durvalumab can lead to immune-mediated pneumonitis, which can be fatal.

Among patients receiving this combination, 1.3% (5/388) developed immune-mediated pneumonitis, including fatal and Grade 3 adverse reactions.

All patients required systemic corticosteroids, and one patient also needed other immunosuppressants. Events resolved in 3 of the 5 patients, but in 1 patient, it resulted in permanent discontinuation of treatment.

• Imjudo + Imfinzi (Durvalumab) + Platinum-based Chemo:

Among patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, immune-mediated pneumonitis occurred in 3.5% (21/596), including fatal and Grade 3 adverse reactions.

Events resolved in 11 patients, but in 7 patients, it resulted in permanent discontinuation of treatment. All patients with immune-mediated pneumonitis required systemic corticosteroids, and one patient also needed other immunosuppressants.

Immune-mediated colitis:

IMJUDO in combination with durvalumab can cause immune-mediated colitis frequently associated with diarrhea, which may result in cytomegalovirus (CMV) infection/reactivation.

Immune-mediated colitis occurred in 6% and 6.5% of patients receiving IMJUDO in combination with durvalumab, and platinum-based chemotherapy, respectively.

These events may require high-dose corticosteroid treatment, and some patients may need other immunosuppressants.

Intestinal perforation and large intestine perforation were also reported in some patients. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated hepatitis:

IMJUDO in combination with durvalumab can cause immune-mediated hepatitis, which can be fatal.

In patients receiving IMJUDO with durvalumab, 7.5% experienced immune-mediated hepatitis, and in those receiving IMJUDO with durvalumab and platinum-based chemotherapy, 3.9% experienced immune-mediated hepatitis.

All patients with immune-mediated hepatitis required systemic corticosteroids and some required other immunosuppressants. Events resolved in some patients, but others resulted in permanent discontinuation.

Endocrinopathies:

IMJUDO in combination with durvalumab can cause immune-mediated adrenal insufficiency. In patients with Grade 2 or higher adrenal insufficiency, symptomatic treatment including hormone replacement should be initiated.

Immune-mediated adrenal insufficiency occurred in 1.5% and 2.2% of patients receiving IMJUDO in combination with durvalumab or durvalumab and platinum-based chemotherapy, respectively.

Systemic corticosteroids were required in all patients, and some patients also required high-dose corticosteroid treatment and/or endocrine therapy. Events resolved in some patients, while others resulted in permanent discontinuation.

Hypophysitis:

IMJUDO in combination with durvalumab can cause immune-mediated hypophysitis, which can present with acute symptoms and hypopituitarism. Symptomatic treatment including hormone replacement is recommended.

Immune-mediated hypophysitis occurred in 1-1.3% of patients receiving IMJUDO in combination with durvalumab, with systemic corticosteroids and endocrine therapy required in some cases. Withhold or permanently discontinue IMJUDO based on severity.

Thyroid disorders:

The combination of IMJUDO and durvalumab can cause immune-mediated thyroid disorders, including thyroiditis, which can present with or without endocrinopathy.

Hypothyroidism can follow hyperthyroidism, and hormone replacement therapy or medical management of hyperthyroidism should be initiated as clinically indicated.

Immune-mediated thyroiditis occurred in 1.5% of patients receiving IMJUDO in combination with durvalumab, and systemic corticosteroids were required in 2 patients.

In patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, immune-mediated thyroiditis occurred in 1.2% of patients, and systemic corticosteroids were required in 2 patients.

All patients required other therapy, including hormone replacement therapy and endocrine therapy. Treatment with IMJUDO should be withheld or discontinued based on severity.

Hyperthyroidism:

The combination of IMJUDO and durvalumab can also cause immune-mediated hyperthyroidism, which occurred in 4.6% of patients receiving IMJUDO in combination with durvalumab and in 5% of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy.

Systemic corticosteroids were required in 2 patients with immune-mediated hyperthyroidism in the former group and in 5 patients in the latter group.

Endocrine therapy was required in all patients, and other therapies were used as well, including thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. The events are resolved in most patients.

Hypothyroidism:

The combination of IMJUDO and durvalumab can cause immune-mediated hypothyroidism, which occurred in 11% of patients receiving IMJUDO in combination with durvalumab and in 8.6% of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy.

One patient in the former group received high-dose corticosteroid treatment, and two patients in the latter group required systemic corticosteroids.

All patients required endocrine therapy, and other therapies were also used, including thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.

Events resolved in 5 of the 42 patients in the former group, and the severity of the events was Grade 3 in 0.5% of patients in the latter group.

Type 1 Diabetes Mellitus:

Patients receiving IMJUDO in combination with durvalumab are at risk of developing thyroid disorders, including thyroiditis, hyperthyroidism, and hypothyroidism.

Treatment with hormone replacement therapy or other medical management is indicated based on clinical presentation and severity.

Patients should be monitored for hyperglycemia and signs of Type 1 Diabetes Mellitus, and insulin therapy should be initiated as clinically necessary. IMJUDO may need to be withheld or permanently discontinued based on the severity of the adverse reactions.

Immune-mediated nephritis with renal dysfunction:

IMJUDO in combination with durvalumab can cause immune-mediated nephritis in some patients.

In clinical trials, 1-1.7% of patients experienced immune-mediated nephritis, which resolved in some cases but resulted in permanent discontinuation of treatment in others.

All patients with immune-mediated nephritis required systemic corticosteroids, and some required high-dose treatment.

Immune-mediated skin reactions:

IMJUDO in combination with durvalumab can cause immune-mediated rash or dermatitis, including exfoliative dermatitis, SJS, DRESS, and TEN.

Topical emollients and/or corticosteroids may be used for mild to moderate non-exfoliative rashes. Immune-mediated rash or dermatitis occurred in 4.9% and 7.2% of patients receiving IMJUDO in combination with durvalumab or durvalumab and platinum-based chemotherapy, respectively.

Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis, and some patients required high-dose corticosteroid treatment or other immunosuppressants. Permanent discontinuation of treatment was required in some cases.

Immune-mediated pancreatitis:

IMJUDO in combination with durvalumab can cause immune-mediated pancreatitis. In clinical studies, immune-mediated pancreatitis occurred in 2.3% of patients receiving IMJUDO in combination with durvalumab, including Grade 4 and Grade 3 adverse reactions.

Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all 9 patients, and of these, 7 patients required high-dose corticosteroid treatment.

Other adverse drug reactions:

IMJUDO in combination with durvalumab can cause various clinically significant, immune-mediated adverse reactions.

These adverse reactions occurred at an incidence of less than 1% each and include:

• Cardiovascular:

  • myocarditis,
  • pericarditis,
  • vasculitis,

• Nervous System-related:

  • meningitis,
  • encephalitis,
  • myelitis,
  • demyelination,
  • myasthenic syndrome/myasthenia gravis,
  • Guillain-Barré syndrome,
  • nerve paresis,
  • autoimmune neuropathy,

• Ocular:

  • uveitis,
  • iritis,
  • retinal detachment,

• Gastrointestinal:

  • gastritis,
  • duodenitis,

• Musculoskeletal:

  • myositis/polymyositis,
  • rhabdomyolysis,
  • arthritis,
  • polymyalgia rheumatica,

• Endocrine:

  • hypoparathyroidism,

• Other:

  • hemolytic anemia,
  • aplastic anemia,
  • hemophagocytic lymphohistiocytosis,
  • systemic inflammatory response syndrome,
  • histiocytic necrotizing lymphadenitis,
  • sarcoidosis, and
  • immune thrombocytopenia.

Infusion-related adverse reactions:

IMJUDO in combination with durvalumab can cause severe or life-threatening infusion-related reactions.

These reactions should be monitored for signs and symptoms, and treatment should be interrupted, slowed, or permanently discontinued based on severity.

Pre-medications may be considered for Grade 1 or 2 reactions. Infusion-related reactions occurred in 2.6% of patients receiving IMJUDO in combination with durvalumab and in 2.9% of patients receiving IMJUDO in combination with durvalumab and platinum-based chemotherapy, including Grade 3 adverse reactions.

Side effects of Imjudo (Tremelimumab):

common side effects of Tremelimumab organized by system:

Gastrointestinal system

• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Stomatitis (inflammation of the mouth)

Hepatic system

• Increased liver enzymes (AST, ALT, ALP)
• Hepatitis

Dermatological system

• Rash
• Itching
• Dermatitis
• Eczema
• Skin dryness

Endocrine system

• Hypophysitis (inflammation of the pituitary gland)
• Hypothyroidism (underactive thyroid gland)
• Hyperthyroidism (overactive thyroid gland)

Immune system

• Immune-related adverse events
• Autoimmune disorders
• Hypersensitivity reactions

Musculoskeletal system

• Arthralgia (joint pain)
• Myalgia (muscle pain)

Nervous system

• Headache
• Dizziness
• Fatigue
• Insomnia
• Peripheral neuropathy

How to administer Imjudo (Tremelimumab)?

Before using IMJUDO, visually inspect the drug product and discard it if it appears cloudy, discolored, or contains visible particles.

Do not shake the vial. Withdraw the required volume from the vial(s) and transfer it to an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

Mix the solution by gentle inversion, but do not shake it. The maximum final concentration of the diluted solution should not exceed 10 mg/mL. Discard partially used or empty vials of IMJUDO.

IMJUDO does not contain preservatives, so the infusion solution should be administered immediately after it’s prepared.

If it needs to be stored, it should not exceed 24 hours from preparation to administration and can be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature up to 30°C (86°F). Do not freeze or shake the solution.

IMJUDO infusion solution should be administered intravenously over 60 minutes using a low-protein binding filter.

It should be administered separately from other drug products, and separate infusion bags and filters should be used for each product.

Administering IMJUDO in combination with other drugs:

The infusion solution should be administered intravenously over 60 minutes using a sterile low-protein binding filter.

Each drug should be infused separately, and separate infusion bags and filters should be used.

IMJUDO should be infused first, followed by durvalumab, platinum-based chemotherapy, or pemetrexed therapy.

The patient should be observed for 60 minutes following completion of the IMJUDO infusion, and subsequent cycles of durvalumab can be given immediately after IMJUDO if there are no infusion reactions.

Imjudo (Tremelimumab) MOA (Mechanism of Action):

CTLA-4, or Cytotoxic T-Lymphocyte Antigen-4, is a protein receptor found on the surface of T cells, a type of white blood cell that plays a crucial role in the immune system’s response to foreign pathogens and cancer cells.

When T cells are activated, CTLA-4 acts as a negative regulator to help prevent excessive immune response and damage to healthy tissues.

Tremelimumab-actl is a monoclonal antibody designed to bind to CTLA-4 and block its inhibitory activity.

By blocking the interaction between CTLA-4 and its ligands CD80 and CD86, tremelimumab-actl releases the inhibition of T-cell activation, allowing for increased T-cell proliferation and activity.

In animal models, blocking CTLA-4 with tremelimumab-actl has been shown to result in decreased tumor growth and increased proliferation of T cells within tumors.

Pharmacokinetics:

The pharmacokinetics of tremelimumab-actl were studied in patients with other solid tumors and in patients with HCC.

The AUC of tremelimumab-actl increased proportionally from 1 mg/kg to 10 mg/kg every 4 weeks, and steady-state was achieved at approximately 12 weeks.

The distribution and elimination of tremelimumab-actl were also evaluated, and there were no clinically significant differences in the pharmacokinetics based on body weight, age, sex, race, serum albumin levels, lactate dehydrogenase levels, soluble PD-L1, tumor type, or mild to moderate organ dysfunction.

However, the effect of severe renal impairment or severe hepatic impairment on the pharmacokinetics of tremelimumab-actl is unknown.

Absorption:

• Tremelimumab is administered intravenously, so it is 100% bioavailable.

Distribution:

• The volume of distribution of Tremelimumab is approximately equal to the plasma volume, indicating that it is distributed evenly throughout the extracellular fluid compartment. Tremelimumab binds to CTLA-4 receptors on T cells, where it exerts its therapeutic effect.

Metabolism:

• Tremelimumab is a protein-based drug and is not metabolized in the traditional sense.
• Instead, it is broken down by proteolytic enzymes into small peptides and amino acids, which are then eliminated by the body.

Elimination:

• The elimination half-life of Tremelimumab is approximately 22 days.
• Tremelimumab is eliminated primarily through proteolytic breakdown and excretion in the urine and feces.
• There is no evidence of accumulation of Tremelimumab with repeated doses.

Special populations:

There is limited information on the pharmacokinetics of Tremelimumab in special populations, such as elderly patients or those with renal or hepatic impairment.

However, no dose adjustment is currently recommended based on age or renal or hepatic function.