Tremelimumab-actl (Monograph)

Brand name: Imjudo
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 21, 2023. Written by ASHP.

Introduction

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody; antineoplastic agent.

Uses for Tremelimumab-actl

Hepatocellular Carcinoma

Used in combination with durvalumab for the treatment of adults with unresectable hepatocellular carcinoma (uHCC). Designated an orphan drug by FDA for treatment of this cancer in combination with durvalumab.

Current US guidelines do not address use of tremelimumab for treatment of HCC.

Non-small Cell Lung Cancer

Used in combination with durvalumab and platinum-based chemotherapy for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

Most recent update of the ASCO living guideline states that clinicians may offer durvalumab and tremelimumab plus platinum-based chemotherapy to patients with non-squamous or squamous cell carcinoma, a PD-L1 tumor proportion score of 0%-49%, and performance status of 0-1.

Tremelimumab-actl Dosage and Administration

General

Pretreatment Screening

• Perform pregnancy testing for females of reproductive potential prior to treatment with tremelimumab.

• Assess baseline liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function prior to treatment with tremelimumab.

Patient Monitoring

• Monitor for signs and symptoms of underlying immune-mediated adverse reactions during treatment with tremelimumab. Assess liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function before each dose of tremelimumab.

• Monitor for signs and symptoms of infusion-related reactions during treatment with tremelimumab.

• Monitor patients for hyperglycemia or other signs and symptoms of diabetes during treatment with tremelimumab.

• When tremelimumab is used in combination with durvalumab plus cisplatin-based chemotherapy, monitor weight prior to each infusion of tremelimumab.

Dispensing and Administration Precautions

• Tremelimumab is administered in combination with durvalumab and/or platinum-based chemotherapy regimens. Consult the full prescribing information for dosage, administration, safety, and other important information of the agent(s) used in combination with tremelimumab.

• Based on the Institute for Safe Medication Practices (ISMP), tremelimumab-actl is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

IV Administration

Available as an injection concentrate in single-dose vials containing 25 mg/1.25 mL (20 mg/mL) or 300 mg/15 mL (20 mg/mL). The drug is administered as an IV infusion after dilution.

Dilution

Prior to dilution, visually inspect the injection for particulate matter and discoloration; discard vial if the solution is cloudy, discolored, or has visible particles. Do not shake vial.

Withdraw required volume from vial(s) and transfer into an IV bag containing 0.9% sodium chloride or 5% dextrose. Mix diluted solution by gentle inversion; do not shake. The maximum final concentration of the diluted solution should not exceed 10 mg/mL. Discard partially used or empty vials of tremelimumab.

Administer diluted solution immediately once prepared; tremelimumab does not contain a preservative. Do not shake or freeze diluted solution.

Rate of Administration

Administer tremelimumab IV over 60 minutes through IV line containing a sterile, low-protein binding 0.2- or 0.22-micron filter.

Use separate infusion bags and filters for each drug. Do not coadminister other drugs through same infusion line.

When tremelimumab is used in combination with durvalumab, infuse tremelimumab over 60 minutes, observe patient for 60 minutes following completion of the infusion, then infuse durvalumab as a separate infusion over 60 minutes on same day of dosing.

When tremelimumab is used in combination with durvalumab plus platinum-based chemotherapy/pemetrexed, infuse tremelimumab first, followed by durvalumab, and then platinum-based chemotherapy/pemetrexed on day of dosing. During cycle 1, first infuse tremelimumab over 60 minutes; then, 1–2 hours after completion of tremelimumab infusion, infuse durvalumab over 60 minutes; and 1–2 hours after completion of durvalumab infusion, infuse platinum-based chemotherapy. For subsequent cycles, if no infusion reactions occur during cycle 1, durvalumab may be infused immediately after tremelimumab, and time between end of durvalumab infusion and start of chemotherapy can be reduced to 30 minutes.

Dosage

Adults

Hepatocellular Carcinoma

IV

Recommended dosage based on body weight.

Weight <30 kg: Administer tremelimumab 4 mg/kg by IV infusion as a single dose followed by durvalumab 20 mg/kg by IV infusion on day 1 of cycle 1, followed by durvalumab 20 mg/kg by IV infusion as a single agent every 4 weeks until disease progression or unacceptable toxicity.

Weight ≥30 kg: Administer tremelimumab 300 mg by IV infusion as a single dose followed by durvalumab 1,500 mg by IV infusion on day 1 of cycle 1, followed by durvalumab 1,500 mg by IV infusion as a single agent every 4 weeks until disease progression or unacceptable toxicity.

Non-small Cell Lung Cancer

IV

Recommended dosage of tremelimumab is based on tumor histology and body weight. Weigh patients prior to each infusion. Recommended regimens and dosage schedule are provided in Tables 1 and 2.

Consult the full prescribing information for dosing information.

Dosing interval change from every 3 weeks to every 4 weeks starting at cycle 5.

IV infusion over 60 minutes.

If patients receive <4 cycles of platinum-based chemotherapy, administer the remaining cycles of tremelimumab (up to a total of 5) after the platinum-based chemotherapy phase, in combination with durvalumab, every 4 weeks.

Continue durvalumab until disease progression or intolerable toxicity.

In patients with non-squamous disease who received treatment with pemetrexed and carboplatin/cisplatin, optional pemetrexed therapy may be administered from week 12 until disease progression or intolerable toxicity.

^eIn patients with non-squamous disease who received treatment with pemetrexed and carboplatin/cisplatin, optional pemetrexed therapy may be administered from week 12 until disease progression or intolerable toxicity.

Therapy Modification for Toxicity

Immune-mediated Adverse Reactions

Dosage reductions not recommended. In general, withhold treatment regimen for severe (grade 3) immune-mediated adverse reactions and administer systemic corticosteroid therapy.

Systemic corticosteroid therapy consists of prednisone 1–2 mg/kg per day or equivalent until improvement to grade 1 or less. Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over ≥1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy.

Permanently discontinue treatment regimen for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to ≤10 mg of prednisone per day (or equivalent) within 12 weeks of initiating corticosteroids.

Table 3 summarizes recommended treatment modifications for specific adverse reactions.

Resume in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to ≤10 mg of prednisone per day (or equivalent) within 12 weeks of initiating corticosteroids.

Endocrinopathies include type 1 diabetes, hypophysitis, hypothyroidism, hyperthyroidism, and adrenal insufficiency.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time.

Cautions for Tremelimumab-actl

Contraindications

• None.

Warnings/Precautions

Severe and Fatal Immune-mediated Adverse Reactions

Tremelimumab has potential for induction of immune-mediated adverse reactions.

Severe or fatal immune-mediated adverse reactions may occur in any organ system or tissue. May occur at any time after starting tremelimumab in combination with durvalumab; such reactions usually manifest during treatment but may also manifest after treatment discontinuation.

Early identification and management of immune-mediated adverse reactions are essential to ensure treatment safety. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Assess clinical chemistries, including liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function, at baseline and before each dose. Medically manage immune-mediated adverse reactions promptly, and refer for specialty consultation as appropriate

Withhold or permanently discontinue tremelimumab and durvalumab depending on severity; refer to Table 3 for recommended treatment modifications for specific immune-mediated adverse reactions. In general, if treatment interruption or discontinuation is required, administer systemic corticosteroid therapy (prednisone 1 to 2 mg/kg per day or equivalent) until improvement to grade 1 or less. Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over ≥1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-mediated adverse reactions listed below may not be inclusive of all possible immune-mediated reactions.

Immune-mediated Pneumonitis: Immune-mediated pneumonitis (including grade 3 and fatal events) has been reported in patients receiving tremelimumab in combination with durvalumab and/or platinum-based chemotherapy. All patients received systemic corticosteroids to treat immune-mediated pneumonitis; some required other immunosuppressants. While pneumonitis resolved in most cases, it led to treatment discontinuation in some patients.

Immune-mediated Colitis: Tremelimumab in combination with durvalumab may cause immune-mediated colitis (including grade 3 events) that is frequently associated with diarrhea. In clinical studies, all patients received systemic corticosteroids to manage colitis and most required high-dose corticosteroids (at least 40 mg of prednisone or equivalent daily); some patients also received other immunosuppressants. While events resolved in most patients, they resulted in permanent discontinuation in some patients.

Cytomegalovirus infection/reactivation reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Intestinal perforation observed in other studies of tremelimumab in combination with durvalumab.

Immune-mediated Hepatitis:Immune-mediated hepatitis (including grade 3 and 4 and fatal events) has occurred with tremelimumab in combination with durvalumab. In clinical studies, systemic corticosteroids were used to manage immune-mediated hepatitis in all patients and all patients required high-dose corticosteroid therapy (at least 40 mg of prednisone or equivalent daily); some patients required other immunosuppressants. Hepatitis resolved in under half of patients but led to permanent discontinuation in some patients.

Immune-mediated Adrenal Insufficiency:Primary or secondary adrenal insufficiency, including grade 3 events, reported with tremelimumab in combination with durvalumab. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. In clinical studies, systemic corticosteroids were required in all patients. Events resolved in some patients.

Immune-mediated Hypophysitis: Tremelimumab in combination with durvalumab may cause immune-mediated hypophysitis (including grade 3 events). Hypophysitis may present with acute symptoms associated with mass effect (e.g., headache, photophobia, or visual field cuts). Hypophysitis may lead to hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. In clinical studies, most patients with immune-mediated hypophysitis and hypopituitarism required systemic corticosteroids and some patients also required endocrine therapy. These events resolved in some patients.

Thyroid Disorders:Tremelimumab in combination with durvalumab may cause immune-mediated thyroid disorders, including thyroiditis (which can be present with or without endocrinopathy), hyperthyroidism (including grade 3 events), and hypothyroidism (which may follow hyperthyroidism). Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. In clinical trials, systemic corticosteroids were required in some patients with hyperthyroidism, hypothyroidism, or thyroiditis; all or most patients required other therapy (e.g., hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium-channel blockers, beta-blockers). Hyperthyroidism resolved in most patients while hypothyroidism and thyroiditis resolved in some patients.

Type 1 Diabetes Mellitus:Type 1 diabetes mellitus can present with diabetic ketoacidosis. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated.

Immune-mediated Nephritis with Renal Dysfunction:Immune-mediated nephritis with renal dysfunction (including grade 3 events) reported with tremelimumab in combination with durvalumab. Systemic corticosteroids were required in all patients. In some patients, events resolved; immune-mediated nephritis resulted in permanent discontinuation in some patients.

Immune-mediated Dermatologic Reactions: Tremelimumab in combination with durvalumab may cause immune-mediated rash or dermatitis, including grade 3 and 4 events. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with immune checkpoint inhibitors. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. In clinical studies, all patients received systemic corticosteroids to manage immune-mediated rash or dermatitis; other immunosuppressants were required rarely. Dermatologic events resolved in most patients, although permanent discontinuation was required in some cases.

Immune-mediated Pancreatitis: Tremelimumab in combination with durvalumab may cause immune-mediated pancreatitis, including grade 3 or 4 events. In clinical studies, all patients required management with systemic corticosteroids (high-dose corticosteroid therapy was necessary in most patients); pancreatitis resolved in most patients.

Other Immune-mediated Adverse Reactions:The following clinically significant, immune-mediated adverse reactions occurred at an incidence of <1% each in patients who received tremelimumab 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 observed; some cases can be associated with retinal detachment. Various degrees of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome; this condition may require systemic corticosteroid therapy to reduce the risk of permanent vision loss.

GI: 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, immune thrombocytopenia.

Infusion-related Reactions

Severe or life-threatening infusion-related reactions reported with tremelimumab in combination with durvalumab.

Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue tremelimumab and durvalumab based on severity; refer to Table 3 for specific recommendations. For Grade 1 or 2 infusion-related reactions, consider pre-medications with subsequent doses.

Embryo-fetal Toxicity

Based on findings from animal studies and the mechanism of action of tremelimumab, the drug can cause fetal harm when administered to a pregnant woman. Animal studies have found that 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 and for 3 months after the last dose of the drug.

Immunogenicity

There is a potential for immunogenicity with tremelimumab therapy. In the HIMALAYA and POSEIDON studies, anti-tremelimumab antibodies detected in 11 and 14% of patients, respectively. These anti-tremelimumab antibodies did not have a clinically significant effect on pharmacokinetics or safety of tremelimumab; however, the effect of anti-drug antibodies and neutralizing antibodies on the drug's efficacy is unknown.

Specific Populations

Pregnancy

No available data on the use of tremelimumab in pregnant women. However, based on findings from animal studies and its mechanism of action, tremelimumab can cause fetal harm when administered to a pregnant woman. In a murine model of pregnancy, CTLA-4 blockade was associated with an increased risk of immune-mediated rejection of the developing fetus and fetal death.

Human IgG₂ is known to cross the placental barrier; therefore, tremelimumab may be transmitted from mother to developing fetus. Advise pregnant women and females of reproductive potential of the potential risk tothe fetus.

Lactation

Unknown whether tremelimumab is distributed into human milk; effects of the drug on breast-fed infants or on milk production also are unknown. Maternal IgG is known to be present in human milk. Effects of local GI exposure and limited systemic exposure to tremelimumab in the breast-fed child are unknown. Because of the potential for serious adverse reactions in the breast-fed child, advise women not to breastfeed during treatment with tremelimumab and for 3 months after the last dose.

Females and Males of Reproductive Potential

Tremelimumab can cause fetal harm when administered to a pregnant woman. Perform pregnancy testing in females of reproductive potential before initiating tremelimumab.

Advise females of reproductive potential to use effective contraception during treatment with tremelimumab and for 3 months after the last dose.

Pediatric Use

Safety and efficacy of tremelimumab not established in pediatric patients.

Geriatric Use

In clinical studies of patients with unresectable hepatocellular carcinoma or metastatic non-small cell lung cancer treated with tremelimumab in combination with durvalumab, no overall differences in safety or efficacy of tremelimumab observed in patients ≥65 years of age compared to younger adults.

Hepatic Impairment

No clinically significant differences in pharmacokinetics observed in patients with mild to moderate hepatic impairment (bilirubin <3 times ULN and any AST). Effect of severe hepatic impairment (bilirubin >3 times ULN and any AST) on pharmacokinetics is unknown.

Renal Impairment

No clinically significant differences in pharmacokinetics observed in patients with mild to moderate renal impairment (Cl_cr 30–89 mL/min). Effect of severe renal impairment (Cl_cr 15–29 mL/min) on pharmacokinetics is unknown.

Common Adverse Effects

Most common adverse effects (≥20%) in patients with unresectable hepatocellular carcinoma: Rash, diarrhea, fatigue, pruritus, musculoskeletal pain, abdominal pain. Most common laboratory abnormalities (≥40%) of patients with unresectable hepatocellular carcinoma: Increased AST, increased ALT, decreased hemoglobin, decreased sodium, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes.

Most common adverse effects (≥20%) in patients with metastatic NSCLC: Nausea, fatigue, musculoskeletal pain, decreased appetite, rash, diarrhea.

Drug Interactions

The manufacturer does not provide any information on drug interactions with tremelimumab in the prescribing information. Consult the prescribing information for drug interactions of the agents administered in combination with tremelimumab.

Tremelimumab-actl Pharmacokinetics

Absorption

Bioavailability

Steady-state achieved at approximately 12 weeks after administration of tremelimumab 1–10 mg/kg (1- to 10-times the approved recommended dosage) once every 4 weeks in patients with solid tumors.

Distribution

Extent

Not known whether distributed into human milk.

Elimination

Half-life

Approximately 16.9 days after a single dose in patients with hepatocellular carcinoma.

Approximately 18.2 days during steady-state following doses ranging from 1–10 mg/kg (1- to 10-times the approved recommended dosage) in patients with other solid tumors.

Special Populations

Pharmacokinetics not affected by body weight (34–149 kg), age (18–87 years), sex, race (white, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3–396 g/L), lactate dehydrogenase levels (12–5570 units/L), soluble programmed death-ligand 1 (67–349 picograms/mL), or tumor type (hepatocellular carcinoma, NSCLC).

Stability

Storage

Parenteral

Injection Concentrate

Single-dose vials: Store in refrigerator at 2–8ºC in original carton to protect from light. Do not freeze. Do not shake.

Diluted infusion solution (if not administered immediately after preparation and storage is necessary): Total time from preparation to start of administration should not exceed 24 hours if stored in a refrigerator at 2–8ºC or at room temperature of ≤30°C. Do not freeze or shake the diluted infusion solution.

Actions

• Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a receptor expressed on T cells; it is a negative regulator of T-cell activity.

• Blockade of CTLA-4 results in enhanced T-cell activation, thus restoring immune control. In synergistic mouse tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of T cells in tumors.

• Tremelimumab is a selective human IgG₂ monoclonal antibody against CTLA-4 that is produced by recombinant DNA technology in NS0 cell suspension culture.

• Tremelimumab binds to CTLA-4 and blocks the interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation.

Advice to Patients

• Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of therapy.

• Advise patients to contact their clinician immediately for signs or symptoms of pneumonitis such as any new or worsening cough, chest pain, or shortness of breath.

• Advise patients to contact their clinician immediately for signs or symptoms of colitis such as diarrhea, blood or mucus in stools, or severe abdominal pain.

• Advise patients to contact their clinician immediately for signs or symptoms of hepatitis such as jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.

• Advise patients to contact their clinician immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis. Some signs and symptoms of these endocrinopathies include persistent or unusual headaches, eye problems (including sensitivity to light), tachycardia, increased sweating, extreme tiredness, weight gain or weight loss, excessive hunger or thirst, frequent urination, hair loss, feeling cold, constipation, deepening of voice, dizziness or fainting, and changes in mood or behavior.

• Advise patients to contact their clinician immediately for signs or symptoms of nephritis such as blood in the urine, decreased urine output, swelling of the ankles, or loss of appetite.

• Advise patients to contact their clinician immediately for signs or symptoms of severe dermatological reactions such as rash; pruritus; skin blistering or peeling; painful sores or ulcers in the mouth or nose, throat, or genital area; fever or flu-like symptoms; or swollen lymph nodes.

• Advise patients to contact their clinician immediately for signs or symptoms of pancreatitis such as abdominal pain, severe nausea or vomiting, or loss of appetite.

• Advise patients to contact their clinician immediately for signs or symptoms of other immune-mediated adverse reactions such as aseptic meningitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, or myasthenia gravis.

• Advise patients to contact their clinician immediately for signs or symptoms of infusion-related reactions such as chills or shaking, pruritus or rash, flushing, shortness of breath or wheezing, dizziness, fever, or back or neck pain.

• Advise females of reproductive potential of the potential risks to the fetus. Advise females of reproductive potential to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Advise females of reproductive potential to use effective contraception during treatment and for ≥3 months after the last dose of tremelimumab.

• Advise female patients not to breast-feed while taking tremelimumab and for ≥3 months after the last dose.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or dietary supplements, as well as any concomitant illnesses.

• Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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