Imjudo®
Tremelimumab-actl, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody, is an antineoplastic agent.1
Tremelimumab-actl is used in combination with durvalumab for the treatment of adults with unresectable hepatocellular carcinoma (uHCC).1, 3 Tremelimumab has been designated an orphan drug by the FDA for treatment of this cancer in combination with durvalumab.2, 100
Tremelimumab-actl in combination with durvalumab was compared to sorafenib in adults with uHCC who had not previously received systemic therapy and were ineligible for locoregional therapy in the randomized, open-label, multicenter, phase 3 HIMALAYA trial.1, 3 Patients were randomized 1:1:1 to receive durvalumab monotherapy (1500 mg IV every 4 weeks), durvalumab (1500 mg IV every 4 weeks) in combination with tremelimumab (300 mg IV as a single dose on the first day of treatment only), or sorafenib monotherapy (400 mg orally twice daily).1 Treatment continued until disease progression or unacceptable toxicity.1 The primary efficacy outcome was overall survival; the primary analysis was performed in patients randomized to receive tremelimumab in combination with durvalumab or sorafenib.1
Among patients randomized to tremelimumab in combination with durvalumab (n=393) or sorafenib (n=389) in HIMALAYA, the median age was 65 years, 85% were male, 49% were Asian, and 46% were white.1 Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.1, 3
In the primary analysis of HIMALAYA, median overall survival was substantially prolonged in patients randomized to tremelimumab in combination with durvalumab (16.4 months) compared to those randomized to sorafenib (13.8 months).1 Median progression-free survival was similar between these groups.1 A substantially higher proportion of patients receiving tremelimumab-containing therapy experienced an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST).1
Guidelines for systemic treatment of HCC have been published by the American Gastroenterological Association (AGA) and the American Society of Clinical Oncology (ASCO).23, 100 Both guidelines were published before tremelimumab was approved and do not address its use for HCC.23, 100
Tremelimumab is 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.1
Tremelimumab-actl in combination with durvalumab and investigator's-choice platinum-based chemotherapy was compared to platinum-based chemotherapy alone in adults with previously untreated metastatic NSCLC without sensitizing EGFR mutations or ALK genomic tumor aberrations in the randomized, open-label, multicenter, phase 3 POSEIDON trial.1, 4 Patients were randomized 1:1:1 to receive durvalumab (1500 mg once per chemotherapy cycle, followed by 1500 mg every 4 weeks) with platinum-based chemotherapy (four 21-day cycles), tremelimumab (75 mg, or 1 mg/kg in patients weighing <30 kg, once per chemotherapy cycle, plus 1 dose in cycle 6 at week 16; total of 5 doses) in combination with durvalumab (1500 mg once per chemotherapy cycle, followed by 1500 mg every 4 weeks) and platinum-based chemotherapy (four 21-day cycles), or platinum-based chemotherapy alone (four to six 21-day cycles).1, 4 Following initial fixed-duration combination treatment, patients assigned to either durvalumab arm continued durvalumab monotherapy until disease progression, loss of clinical benefit, or unacceptable toxicity.1, 4 Additionally, patients with non-squamous cell NSCLC who received pemetrexed as part of platinum-based chemotherapy continued to receive pemetrexed, alone or in combination with durvalumab according to treatment assignment, every 4 weeks until disease progression or unacceptable toxicity.1, 4 The primary efficacy outcomes were progression-free and overall survival; the primary analysis was performed in patients randomized to tremelimumab in combination with durvalumab and platinum-based chemotherapy or platinum-based chemotherapy alone.1
Among 675 patients randomized to tremelimumab in combination with durvalumab and platinum-based therapy or platinum-based therapy alone in POSEIDON, the median age was 63 years, 77% were male, 57% were white, and 34% were Asian.1 All patients had an ECOG PS of 0 or 1.1
In the primary analysis of POSEIDON, median progression-free and overall survival were substantially prolonged in patients who received tremelimumab in combination with durvalumab and platinum-based chemotherapy (6.2 and 14 months, respectively) compared to those who received platinum-based chemotherapy alone (4.8 months and 11.7 months, respectively).1 Patients who received tremelimumab-containing therapy were substantially more likely to experience an objective response by RECIST, and experienced a substantially longer median duration of response, than those who received platinum-based chemotherapy alone.1
A living guideline for the treatment of patients with stage IV NSCLC without driver mutations has been published by ASCO.102 The most recent update of this 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 0-1.102
Dispensing and Administration Precautions
Tremelimumab injection concentrate for IV infusion is available as single-dose vials containing 25 mg/1.25 mL (20 mg/mL) or 300 mg/15 mL (20 mg/mL).1 The drug is administered as an IV infusion after dilution.1 Store vials in a refrigerator at 2-8ºC in original carton to protect from light; do not freeze.1 Do not shake.1
Prior to dilution, visually inspect the injection for particulate matter and discoloration; discard the vial if the solution is cloudy, discolored, or has visible particles.1
Withdraw the required volume from the vial(s) and transfer into an IV bag containing 0.9% sodium chloride or 5% dextrose.1 Mix the diluted solution by gentle inversion; do not shake.1 The maximum final concentration of the diluted solution should not exceed 10 mg/mL.1 Discard partially used or empty vials of tremelimumab.1
Administer the diluted solution immediately once prepared; tremelimumab does not contain a preservative.1 If the solution is not administered immediately and storage is necessary, the total time from preparation to the start of administration should not exceed 24 hours when stored under refrigeration at 2-8ºC or at room temperature of ≤30°C.1 Do not shake or freeze the diluted solution.1
Administer tremelimumab IV over 60 minutes through an IV line containing a sterile, low-protein binding 0.2- or 0.22-micron filter.1
Use separate infusion bags and filters for each drug.1 Administer all drugs in the combination regimen as separate IV infusions; do not coadminister other drugs through the same infusion line.1
When tremelimumab is used in combination with durvalumab, administer tremelimumab by IV infusion over 60 minutes, observe the patient for 60 minutes following completion of the infusion, then infuse durvalumab as a separate infusion over 60 minutes on the same day of dosing.1
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 the day of dosing.1 During cycle 1, first infuse tremelimumab over 60 minutes; then, 1-2 hours after completion of the tremelimumab infusion, infuse durvalumab over 60 minutes; 1-2 hours after completion of the durvalumab infusion, infuse platinum-based chemotherapy.1 For subsequent cycles, if no infusion reactions occurred during cycle 1, durvalumab may be infused immediately after tremelimumab, and the time between the end of the durvalumab infusion and the start of chemotherapy can be reduced to 30 minutes.1
For the treatment of unresectable hepatocellular carcinoma, the dosage of tremelimumab is 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.1
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.1
For the treatment of metastatic non-small cell cancer, the dosage of tremelimumab is based on tumor histology and body weight.1 Patients should be weighed prior to each infusion.1 The recommended regimens and dosage schedule are provided in Tables 1 and 2.1
On the day of dosing, infuse tremelimumab first, followed by durvalumab, and then platinum-based chemotherapy or pemetrexed.1
Tumor Histology | Patient Weight | Tremelimumab Dosage | Durvalumab Dosage | Platinum-based Chemotherapy Regimena a |
|---|---|---|---|---|
Non-squamous | <30 kg | 1 mg/kg | 20 mg/kg | Carboplatin and albumin-bound paclitaxel OR Carboplatin or cisplatin and pemetrexed |
≥30 kg | 75 mg | 1500 mg | ||
Squamous | <30 kg | 1 mg/kg | 20 mg/kg | Carboplatin and albumin-bound paclitaxel OR Carboplatin or cisplatin and gemcitabine |
≥30 kg | 75 mg | 1500 mg |
aConsult the full prescribing information for dosing information.8, 9, 10, 11, 12, 13, 8
aDosing interval change from every 3 weeks to every 4 weeks starting at cycle 5.
cIf 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.
dContinue durvalumab 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 of tremelimumab are not recommended.1 In general, withhold treatment regimen for severe (grade 3) immune-mediated adverse reactions and administer systemic corticosteroid therapy.1 Systemic corticosteroid therapy consists of prednisone 1-2 mg/kg per day or equivalent until improvement to grade 1 or less.1 Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over ≥1 month.1 Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy.1
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.1
Table 3 summarizes recommended treatment modifications for specific adverse reactions.1
Adverse Reaction | Severity | Treatment Modification |
|---|---|---|
Immune-mediated Adverse Reactions | ||
Colitis | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | |
Endocrinopathiesb | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
Exfoliative dermatologic conditions | Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) | Withholda a |
Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
Hepatitis with no tumor involvement of the liver | ALT or AST increases to >3 and up to 8 times ULN, or total bilirubin increases to >1.5 and up to 3 times ULN | Withholda |
ALT or AST increases to >8 times ULN or total bilirubin increases to >3 times ULN | Permanently discontinue | |
Hepatitis with tumor involvement of the liver | AST and ALT less than or equal to ULN at baseline | Withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement |
AST or ALT >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times ULN, or AST or ALT >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times ULN | Withholda | |
ALT or AST increases to >10 times ULN or total bilirubin increases to >3 times ULN | Permanently discontinue | |
Intestinal perforation | Any grade | Permanently discontinue |
Myocarditis | Grade 2, 3, or 4 | Permanently discontinue |
Nephritis with renal dysfunction | Grade 2 or 3 increased blood creatinine | Withholda |
Grade 4 increased blood creatinine | Permanently discontinue | |
Neurological toxicities | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | |
Pneumonitis | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | |
Other Adverse Reactions | ||
Infusion-related reactions | Grade 1 or 2 | Interrupt or slow infusion rate |
Grade 3 or 4 | Permanently discontinue |
aResume 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.
bEndocrinopathies include type 1 diabetes, hypophysitis, hypothyroidism, hyperthyroidism, and adrenal insufficiency.
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe and Fatal Immune-mediated Adverse Reactions
Tremelimumab blocks T-cell inhibitory signals induced by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathway, thus removing inhibition of the immune response.1 In combination with durvalumab, tremelimumab has the potential for induction of immune-mediated adverse reactions.1
Severe or fatal immune-mediated adverse reactions may occur in any organ system or tissue.1 These reactions may occur at any time after starting tremelimumab in combination with durvalumab; while the reactions usually manifest during treatment, they may also manifest after discontinuation of tremelimumab and/or durvalumab.1
Early identification and management of immune-mediated adverse reactions are essential to ensure treatment safety.1 Monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions.1 Assess clinical chemistries, including liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function, at baseline and before each dose.1 Medically manage immune-mediated adverse reactions promptly, and refer for specialty consultation as appropriate. 1
Withhold or permanently discontinue tremelimumab and durvalumab depending on severity; refer to Table 3 for recommended treatment modifications for specific immune-mediated adverse reactions.1 In general, if treatment interruption or discontinuation is required, administer systemic corticosteroid therapy (prednisone 1-2 mg/kg per day or equivalent) until improvement to grade 1 or less.1 Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over ≥1 month.1 Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy.1
The immune-mediated adverse reactions listed below may not be inclusive of all possible immune-mediated reactions.1
Immune-mediated Pneumonitis: Immune-mediated pneumonitis (including grade 3 and fatal events) has occurred in the primary efficacy studies in patients receiving tremelimumab in combination with durvalumab and/or platinum-based chemotherapy.1 All patients received systemic corticosteroids to treat immune-mediated pneumonitis; some patients required other immunosuppressants.1 While pneumonitis resolved in most cases, it led to treatment discontinuation in some patients.1
Immune-mediated Colitis: Tremelimumab in combination with durvalumab may cause immune-mediated colitis (including grade 3 events) that is frequently associated with diarrhea.1 In clinical studies, all patients received systemic corticosteroids to manage colitis and most patients required high-dose corticosteroids (at least 40 mg of prednisone or equivalent daily); some patients also received other immunosuppressants.1 While events resolved in most patients, they resulted in permanent discontinuation in some patients.1
Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis.1 In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. 1 Intestinal perforation has been observed in other studies of tremelimumab in combination with durvalumab. 1
Immune-mediated Hepatitis: Immune-mediated hepatitis (including grade 3 and 4 and fatal events) has occurred with tremelimumab in combination with durvalumab.1 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.1 Hepatitis resolved in under half of patients, but led to permanent discontinuation in some patients. 1
Immune-mediated Adrenal Insufficiency: Primary and secondary adrenal insufficiency, including grade 3 events, has occurred with tremelimumab in combination with durvalumab.1 For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated.1 In clinical studies, systemic corticosteroids were required in all patients.1
Immune-mediated Hypophysitis: Tremelimumab in combination with durvalumab may cause immune-mediated hypophysitis (including grade 3 events).1 Hypophysitis may present with acute symptoms associated with mass effect (e.g., headache, photophobia, or visual field cuts).1 Hypophysitis may lead to hypopituitarism.1 Initiate symptomatic treatment, including hormone replacement, as clinically indicated.1 In clinical studies, most patients with immune-mediated hypophysitis and hypopituitarism required systemic corticosteroids and some patients also required endocrine therapy.1 These events resolved in some patients.1
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).1 Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.1 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).1 Hyperthyroidism resolved in most patients while hypothyroidism and thyroiditis resolved in some patients.1
Type 1 Diabetes Mellitus:Type 1 diabetes mellitus can present with diabetic ketoacidosis.1 Monitor patients for hyperglycemia and other signs and symptoms of diabetes.1 Initiate treatment with insulin as clinically indicated.1
Immune-mediated Nephritis with Renal Dysfunction:Immune-mediated nephritis with renal dysfunction (including grade 3 events) has occurred in clinical studies of tremelimumab in combination with durvalumab. 1 Systemic corticosteroids were required in all patients. 1 In some patients, events resolved; immune-mediated nephritis resulted in permanent discontinuation in some patients.1
Immune-mediated Dermatologic Reactions: Tremelimumab in combination with durvalumab may cause immune-mediated rash or dermatitis, including grade 3 and 4 events.1 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.1 Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.1 In clinical studies, all patients received systemic corticosteroids to manage immune-mediated rash or dermatitis; other immunosuppressants were required rarely.1 Dermatologic events resolved in most patients, although permanent discontinuation was required in some cases.1
Immune-mediated Pancreatitis: Tremelimumab in combination with durvalumab may cause immune-mediated pancreatitis, including grade 3 or 4 events.1 In clinical studies, all patients required management with systemic corticosteroids (high-dose corticosteroid therapy was necessary in most patients); pancreatitis resolved in most patients.1, 1
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. 1
Cardiac/vascular: Myocarditis, pericarditis, vasculitis.1
Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.1
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities have been observed; some cases can be associated with retinal detachment.1 Various degrees of visual impairment, including blindness, may occur. 1 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.1
Gastrointestinal: Gastritis, duodenitis.1
Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.1
Endocrine: Hypoparathyroidism.1
Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia.1
Severe or life-threatening infusion-related reactions have been reported with tremelimumab in combination with durvalumab.1
Monitor for signs and symptoms of infusion-related reactions.1 Depending on the severity of the reaction, interrupt, slow the rate of, or permanently discontinue tremelimumab and durvalumab; refer to Table 3 for specific recommendations.1 For grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.1
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.1 Animal studies have found that CTLA-4 blockade is associated with a higher incidence of pregnancy loss. 1
Advise pregnant women and females of reproductive potential of the potential risk to the fetus.1 Advise females of reproductive potential to use effective contraception during treatment with tremelimumab and for 3 months after the last dose of the drug. 1
There is a potential for immunogenicity with tremelimumab therapy.1 In the HIMALAYA and POSEIDON studies, anti-tremelimumab antibodies were detected in 20 of 182 patients (11%) and 38 of 278 patients (14%). respectively.1 These anti-tremelimumab antibodies did not have a clinically significant effect on the pharmacokinetics or safety of tremelimumab; however, the effect of anti-drug antibodies and neutralizing antibodies on the efficacy of the drug is unknown.1
There are no available data on the use of tremelimumab in pregnant women.1 However, based on findings from animal studies and its mechanism of action, tremelimumab can cause fetal harm when administered to a pregnant woman.1
Administration of tremelimumab to pregnant cynomolgus monkeys during the period of organogenesis was not associated with adverse maternal or embryo-fetal effects at exposure levels approximately 4-31 times higher than those observed at a recommended dose range of 75-300 mg based on AUC.1 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.1 Based on the mechanism of action of tremelimumab, fetal exposure to the drug may increase the risk of developing immune-mediated disorders or altering the normal immune response.1
Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, tremelimumab may be transmitted from the mother to the developing fetus.1 Advise pregnant women and females of reproductive potential of the potential risk to the fetus.1
It is not known whether tremelimumab is distributed into human milk; the effects of the drug on breast-fed infants or on milk production also are unknown.1 Maternal IgG is known to be present in human milk.1 The effects of local GI exposure and limited systemic exposure in the breast-fed child to tremelimumab are unknown.1 Due to the potential for serious adverse reactions in the breast-fed child, advise women not to breast-feed during treatment with tremelimumab and for 3 months after the last dose.1
Consult the full prescribing information for breast-feeding considerations of agents administered in combination with tremelimumab.8, 9, 10, 11, 12, 13
Females and Males of Reproductive Potential
Tremelimumab can cause fetal harm when administered to a pregnant woman.1 Perform pregnancy testing in females of reproductive potential before initiating tremelimumab therapy.1
Advise females of reproductive potential to use effective contraception during treatment with tremelimumab and for 3 months after the last dose.1
Consult the full prescribing information for recommended contraceptive duration of agents administered in combination with tremelimumab.8, 9, 10, 11, 12, 13
The safety and efficacy of tremelimumab have not been established in pediatric patients.1
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 were observed between patients 65 years of age or older and younger adults.1
No clinically significant differences in the pharmacokinetics of tremelimumab were observed in patients with mild to moderate hepatic impairment (bilirubin <3 times the upper limit of normal [ULN] and any AST).1 The effect of severe hepatic impairment (bilirubin >3 times ULN and any AST) on the pharmacokinetics of tremelimumab is unknown.1
No clinically significant differences in the pharmacokinetics of tremelimumab were observed in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute).1 The effect of severe renal impairment (creatinine clearance 15-29 mL/minute) on the pharmacokinetics of tremelimumab is unknown.1
The most common adverse effects (≥20%) in patients with unresectable hepatocellular carcinoma (uHCC) receiving tremelimumab are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.1 The most common laboratory abnormalities (≥40%) of patients with uHCC receiving tremelimumab are increased AST, increased ALT, decreased hemoglobin, decreased sodium, increased bilirubin, increased alkaline phosphatase, and decreased lymphocytes.1
The most common adverse effects (≥20%) in patients with metastatic NSCLC are nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea.1
The manufacturer does not provide any information on drug interactions with tremelimumab in the prescribing information.1 Consult the prescribing information for drug interactions of the agents administered in combination with tremelimumab.8, 9, 10, 11, 12, 13
The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a receptor expressed on T cells.14 CTLA-4 is a negative regulator of T-cell activity;1 by competitively binding to its ligands, CD80 and CD86, CTLA-4 reduces the amplitude of CD28-mediated T-cell activation.14 Blockade of CTLA-4 results in enhanced T-cell activation, thus restoring immune control.14 In synergistic mouse tumor models, blockade of CTLA-4 resulted in decreased tumor growth and increased proliferation of T cells in tumors.1
Tremelimumab is a selective human immunoglobulin G (IgG2) monoclonal antibody against CTLA-4 that is produced by recombinant DNA technology in NS0 cell suspension culture.1 Tremelimumab binds to CTLA-4 and blocks its interaction with the CD80 and CD86 ligands, releasing CTLA-4-mediated inhibition of T-cell activation.1
The exposure-response relationship and time course of the pharmacodynamic response to tremelimumab have not been fully characterized.1 After administration of tremelimumab 1-10 mg/kg (1- to 10-times the approved recommended dosage) once every 4 weeks for 4 doses in patients with solid tumors, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks.1 The geometric mean terminal half-life of tremelimumab was 16.9 days after a single dose in patients with hepatocellular carcinoma, and 18.2 days during steady-state following doses from 1-10 mg/kg (1- to 10-times the approved dosage) in patients with other solid tumors.1
There were no clinically significant differences in the pharmacokinetics of tremelimumab based on 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 picogram/mL), or tumor type (hepatocellular carcinoma, NSCLC).1
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV Infusion | 25 mg/1.25 mL | Imjudo® | AstraZeneca |
300 mg/15 mL | Imjudo® | AstraZeneca |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions November 21, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. AstraZeneca Pharmaceuticals LP. IMJUDO® (tremelimumab) INTRAVENOUS prescribing information. 2023 June. [Web]
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2023 Feb 9.
3. Abou-Alfa GK, Lau G, Kudo M et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022; 1(8):1-12.
4. Johnson ML, Chul Cho B, Luft A et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023;41(6):1213-27.
8. AstraZeneca Pharmaceuticals LP. IMFINZI® (durvalumab) prescribing information. 2022 Nov.
9. Fresenius Kabi USA, LLC. Carboplatin prescribing information. 2021 May.
10. Abraxis BioScience, LLC. ABRAXANE® (paclitaxel protein-bound) prescribing information. 2022 Oct.
11. Fresenius Kabi USA, LLC. Cisplatin prescribing information. 2017 Mar.
12. Armas Pharmaceuticals Inc. Gemcitabine prescribing information. 2020 Jan.
13. Dr. Reddys Laboratories Inc. Pemetrexed prescribing information. 2022 Nov.
14. Sharma P, Sohn J, Shin SJ, et al. Efficacy and tolerability of tremelimumab in locally advanced or metastatic urothelial carcinoma patients who have failed first-line platinum-based chemotherapy. Clin Cancer Res. 2020;26(1):61-70.
23. Gordan JD, Kennedy EB, Abou-Alfa GK et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020; 38:4317-45.
24. Institute for Safe Medication Practices. ISMP list of high-alert medications in acute care settings. 2018. [Web]
100. Su GL, Altayar O, O'Shea R et al. AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma. Gastroenterology. 2022; 162:920-34.
102. Singh N, Jaiyesimi IA, Ismaila N, et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.1 J Clin Oncol. 2023; 41:e51-e62.