Introduction

Tremelimumab-actl, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody, is an antineoplastic agent.

Uses for Tremelimumab

Tremelimumab-actl has the following uses:

Tremelimumab-actl is indicated, in combination with durvalumab, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).

Tremelimumab Dosage and Administration

General

Tremelimumab-actl is available in the following dosage form(s) and strength(s):

• Injection: 25 mg/1.25 mL (20 mg/mL) solution in a single-dose vial.

• Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer tremelimumab-actl as an intravenous infusion over 60 minutes after dilution.

• The recommended dosage of tremelimumab-actl for the treatment of uHCC in adults is based on body weight as follows:

• Body weight 30 kg and more: tremelimumab-actl 300 mg as a single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab 1,500 mg as a single agent every 4 weeks.

• Body weight less than 30 kg: tremelimumab-actl 4 mg/kg as a single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab 20 mg/kg as a single agent every 4 weeks.

• After Cycle 1 of combination therapy, administer durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity occurs.

• See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

Contraindications

• None.

Warnings/Precautions

Severe and Fatal Immune-mediated Adverse Reactions

Tremelimumab-actl is a monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response. In combination with durvalumab, a PD-L1 inhibitor, these drugs have the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting tremelimumab-actl in combination with durvalumab. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of tremelimumab-actl and/or durvalumab.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of tremelimumab-actl in combination with durvalumab. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue tremelimumab-actl and durvalumab depending on severity. In general, if combination of tremelimumab-actl and durvalumab requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis: Tremelimumab-actl in combination with durvalumab can cause immune-mediated pneumonitis, which may be fatal. Immune mediated pneumonitis occurred in 1.3% (5/388) of patients receiving tremelimumab-actl in combination with durvalumab, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients, of these 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants.

Immune-Mediated Colitis: Tremelimumab-actl in combination with durvalumab can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving tremelimumab-actl in combination with durvalumab, including Grade 3 (3.6%) adverse reactions. Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants. Intestinal perforation has been observed in other studies of tremelimumab-actl in combination with durvalumab.

Immune-Mediated Hepatitis: Tremelimumab-actl in combination with durvalumab can cause immune-mediated hepatitis, which may be fatal. Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving tremelimumab-actl in combination with durvalumab, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions. Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants.

Immune-Mediated Adrenal Insufficiency: Tremelimumab-actl in combination with durvalumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue tremelimumab-actl in combination with durvalumab based on the severity Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving tremelimumab-actl in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in all 6 patients and of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Immune-Mediated Hypophysitis: Tremelimumab-actl in combination with durvalumab can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue tremelimumab-actl in combination with durvalumab depending on severity Immune-mediated hypophysitis/hypopituitarism occurred in 1.1% (5/462) of patients receiving the STRIDE regimen (combination of tremelimumab-actl with durvalumab). Events resolved in 2 of the 5 patients. Systemic corticosteroids were required in 4 patients (4/5) with hypophysitis, of these 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.

Thyroid Disorders: Tremelimumab-actl in combination with durvalumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue tremelimumab-actl in combination with durvalumab based on the severity.

Immune-mediated Thyroiditis: Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving tremelimumab-actl in combination with durvalumab. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in 2 patients (2/6) with immune-mediated thyroiditis, of these 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.

Immune-mediated Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving tremelimumab-actl in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).

Immune-mediated Hypothyroidism: Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving tremelimumab-actl in combination with durvalumab. Events resolved in 5 of the 42 patients. One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).

Type 1 Diabetes Mellitus: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue tremelimumab-actl in combination with durvalumab based on the severity. Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.

Immune-Mediated Nephritis with Renal Dysfunction: Tremelimumab-actl in combination with durvalumab can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 1% (4/388) of patients receiving tremelimumab-actl in combination with durvalumab, including Grade 3 (0.5%) adverse reactions. Events resolved in 3 of the 4 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis, of these 3 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Immune-Mediated Dermatology Reactions: Tremelimumab-actl in combination with durvalumab can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with CTLA-4 and PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue tremelimumab-actl in combination with durvalumab depending on severity. Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving tremelimumab-actl in combination with durvalumab, including Grade 4 (0.3%) and Grade 3 (1.5%) 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 (at least 40 mg prednisone or equivalent per day).

Other Immune-Mediated Pancreatitis: Tremelimumab-actl in combination with durvalumab can cause immune-mediated pancreatitis. Immune-mediated pancreatitis occurred in 1.9% (9/462) of patients receiving the STRIDE regimen (combination of tremelimumab-actl with durvalumab), including Grade 4 (0.2%) and Grade 3 (1.3%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all patients with immune-mediated pancreatitis, of these 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).

Other Immune-Mediated Adverse Reactions: The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received tremelimumab-actl in combination with durvalumab or were reported with the use of other immune-checkpoint inhibitors.

Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Gastritis, duodenitis.

Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Endocrine: Hypoparathyroidism.

Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, and immune thrombocytopenia.

Infusion-related Reactions

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

Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue tremelimumab-actl and durvalumab based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

Infusion-related reactions occurred in 10 (2.6%) patients receiving tremelimumab-actl in combination with durvalumab.

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, tremelimumab-actl can cause fetal harm when administered to a pregnant woman. In animal studies, CTLA-4 blockade is associated with higher incidence of pregnancy loss.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with tremelimumab-actl and for 3 months after the last dose of the drug.

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, tremelimumab-actl can cause fetal harm when administered to a pregnant woman. There are no available data on the use of tremelimumab-actl in pregnant women. In animal studies, CTLA-4 blockade is associated with increased risk of immune-mediated rejection of the developing fetus and fetal death.

Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, tremelimumab-actl has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In reproduction studies, administration of tremelimumab-actl to pregnant cynomolgus monkeys during the period of organogenesis through delivery was not associated with maternal toxicity or effects on embryo-fetal development at exposure levels approximately 31-times higher than those observed at a recommended dose of 300 mg (based on AUC). CTLA-4 plays a role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and in immune regulation of the newborn. In a murine model of pregnancy, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses. Mated genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-) gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-) that appeared healthy at birth. The CTLA-4-/- homozygous negative offspring developed signs of a lymphoproliferative disorder and died by 3 to 4 weeks of age with multiorgan tissue destruction. Based on its mechanism of action, fetal exposure to tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response.

Lactation

There are no data on the presence of tremelimumab-actl in human milk, its effects on a breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to tremelimumab-actl are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with tremelimumab-actl and for 3 months after the last dose. Refer to the prescribing information for agents administered in combination with tremelimumab-actl for breastfeeding recommendations, as appropriate.

Females and Males of Reproductive Potential

Tremelimumab-actl can cause fetal harm when administered to a pregnant woman.

Verify pregnancy status of females of reproductive potential prior to initiating treatment with tremelimumab-actl.

Advise females of reproductive potential to use effective contraception during treatment with tremelimumab-actl and for 3 months after the last dose. Refer to the prescribing information for the agents administered in combination with tremelimumab-actl for recommended contraception duration, as appropriate.

Pediatric Use

The safety and effectiveness of tremelimumab-actl have not been established in pediatric patients.

Geriatric Use

Of the 393 patients with uHCC treated with tremelimumab-actl in combination with durvalumab, 50% of patients were 65 years or older and 13% of patients were 75 years or older. No overall differences in safety or efficacy of tremelimumab-actl have been observed between patients 65 years or older and younger adult patients.

Common Adverse Effects

Most common adverse reactions (≥ 20%) of patients with uHCC receiving tremelimumab-actl are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. Most common laboratory abnormalities (≥ 40%) of patients with uHCC receiving tremelimumab-actl are increased AST, increased ALT, decreased hemoglobin, decreased sodium, increased bilirubin, increased alkaline phosphatase, and decreased lymphocytes.

General

Tremelimumab-actl is available in the following dosage form(s) and strength(s):

• Injection: 25 mg/1.25 mL (20 mg/mL) solution in a single-dose vial.

• Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer tremelimumab-actl as an intravenous infusion over 60 minutes after dilution.

• The recommended dosage of tremelimumab-actl for the treatment of uHCC in adults is based on body weight as follows:

• Body weight 30 kg and more: tremelimumab-actl 300 mg as a single dose in combination with durvalumab 1,500 mg at Cycle 1/Day 1, followed by durvalumab 1,500 mg as a single agent every 4 weeks.

• Body weight less than 30 kg: tremelimumab-actl 4 mg/kg as a single dose in combination with durvalumab 20 mg/kg at Cycle 1/Day 1, followed by durvalumab 20 mg/kg as a single agent every 4 weeks.

• After Cycle 1 of combination therapy, administer durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity occurs.

• See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.