Tremelimumab is an intravenous cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody indicated for the treatment of adults with unresectable hepatocellular carcinoma in combination with durvalumab and for the treatment of metastatic NSCLC in combination with durvalumab and platinum-based chemotherapy. Immune-mediated adverse reactions including colitis, pneumonitis, hepatitis, endocrinopathies, and nephritis have been reported with tremelimumab plus durvalumab therapy in clinical trials; treatment with high-dose corticosteroids may be necessary in patients who develop immune-mediated toxicity. Severe infusion-related reactions may also occur.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect drug product for particulate matter and discoloration. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
-Do not shake the vial of tremelimumab.
-Administer tremelimumab prior to durvalumab when given on the same day.
-Administer chemotherapy after both tremelimumab and durvalumab when given on the same day.
-Use separate infusion bags and filters for durvalumab and tremelimumab. Do not coadminister tremelimumab with other drugs through the same IV line.
Intravenous Administration
Preparation
-Withdraw the required volume of drug and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration between 0.1 mg/mL to 10 mg/mL.
-Mix by gentle inversion; do not shake.
-Discard partially used or empty vials of tremelimumab.
-Storage after dilution: Tremelimumab does not contain a preservative; administer immediately after preparation. If unable to be administered immediately, the storage time of diluted tremelimumab from start of preparation until completion of the infusion should not exceed 24 hours under refrigeration (2 to 8 degrees C; 36 to 46 degrees F) or 24 hours at room temperature (up to 30 degrees C; up to 86 degrees F). Do not freeze.
Intravenous Infusion
-Administer the diluted infusion over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
-In combination with durvalumab: Observe the patient for infusion reactions for 60 minutes following completion of the tremelimumab infusion; then administer durvalumab as a separate infusion.
-In combination with chemotherapy: For the first cycle, observe the patient for infusion reactions for 60 minutes following completion of the tremelimumab infusion; then administer durvalumab as a separate infusion. Platinum-based chemotherapy may be administered 1 to 2 hours after completion of the durvalumab infusion. If there are no infusion reactions in cycle 1, subsequent cycles of durvalumab may be given immediately after tremelimumab and chemotherapy can be started 30 minutes after durvalumab.
Immune-mediated pneumonitis/interstitial lung disease occurred in 1.3% to 3.5% of patients treated with tremelimumab in combination with durvalumab in 2 randomized, open-label clinical trials (n = 984); 0.2% to 1% of cases were grade 3 and 0.3% to 0.5% were fatal. All patients were treated with systemic corticosteroids; 2 patients required additional immunosuppressants. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, tremelimumab and/or durvalumab may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar incidence of cough in patients with metastatic NSCLC compared with platinum-based chemotherapy alone (12% vs. 8%; grade 3 or 4, 0% vs. 0.3%) in another randomized clinical trial.
Immune-mediated colitis or diarrhea occurred in 6% to 6.5% (grade 3, 2.5% to 3.6%) of patients treated with tremelimumab in combination with durvalumab in 2 randomized, open-label clinical trials (n = 984). All patients received systemic corticosteroids; 7 patients additionally received other immunosuppressants. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. The overall incidence of diarrhea in patients with treated with tremelimumab plus durvalumab was 27% (grade 3 or 4, 6%); gastritis and duodenitis were each reported in less than 1% of patients receiving combination therapy in this trial. GI perforation was reported in 0.1% of patients who received tremelimumab in combination with durvalumab. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar incidence of diarrhea (22% vs. 15%; grade 3 or 4, 1.5% vs. 1.5%) or constipation (19% vs. 24%; grade 3 or 4, 0% vs. 0.6%) compared with platinum-based chemotherapy alone.
Immune-mediated hepatitis occurred in 3.9% to 7.5% (grade 3, 2% to 4.1%; grade 4, 0.3% to 0.5%) patients treated with tremelimumab in combination with durvalumab; some cases (0.3% to 0.8%) were fatal. All patients required treatment with high-dose corticosteroids (n = 984); 10 patients additionally required other immunosuppressants. Monitor hepatic function at baseline and prior to each dose during treatment. Tremelimumab plus durvalumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary. Elevated hepatic enzymes and hyperbilirubinemia were reported with tremelimumab use in combination with durvalumab in a randomized, open-label trial of patients with hepatocellular cancer, including increases from baseline in AST (63%; grade 3 or 4, 27%), ALT (56%; grade 3 or 4, 18%), bilirubin (41%; grade 3 or 4, 8%), and alkaline phosphatase (41%; grade 3 or 4, 8%); fatal hepatic failure occurred in 0.5% of patients. The addition of tremelimumab and durvalumab to platinum-based chemotherapy in patients with metastatic NSCLC increased the incidence of increased ALT (64% vs. 56%; grade 3 or 4, 6% vs. 4.7%), increased AST (63% vs. 55%; grade 3 or 4, 5% vs. 2.2%), increased alkaline phosphatase (33% vs. 26%; grade 3 or 4, 3.4% vs. 1.2%), increased GGT (38% vs. 35%; grade 3 or 4, 2.2% vs. 4.7%), and hyperbilirubinemia (16% vs. 8%; grade 3 or 4, 0.9% vs. 0.3%) compared with platinum-based chemotherapy alone.
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with tremelimumab in combination with durvalumab. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Tremelimumab plus durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids or endocrine therapy may also be necessary. Immune-mediated adrenal insufficiency occurred in 1.5% to 2.2% of patients treated with tremelimumab in combination with durvalumab (grade 3, 0.3% to 0.8%) in 2 randomized, open-label clinical trials (n = 984); all patients required treatment with corticosteroids. Immune-mediated hypophysitis occurred in 1% to 1.3% of patients treated with tremelimumab pus durvalumab (grade 3, 0.5% or less). Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism.
Tremelimumab in combination with durvalumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Tremelimumab and/or durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. In 2 randomized, open-label clinical trials (n = 984), immune-mediated hypothyroidism (8.6% to 11%; grade 3, 0.5% or less), hyperthyroidism (4.6% to 5%; grade 3, 0.2% to 0.3%), and thyroiditis (1.2% to 1.5%) were reported; the overall incidence of hypothyroidism was 13% to 14% in these trials. Additionally, less than 1% of patients treated with tremelimumab plus durvalumab experienced hypoparathyroidism.
Hyperglycemia, including type 1 diabetes mellitus, has occurred in patients treated with tremelimumab in combination with durvalumab and may present with diabetic ketoacidosis. Increased glucose from baseline occurred in 39% to 42% (grade 3 or 4, 6% to 14%) of patients receiving combination therapy in 2 randomized, open-label clinical trials (n = 984). Immune-mediated type 1 diabetes occurred in 0.5% of patients with metastatic NSCLC treated with tremelimumab, durvalumab, and platinum-based chemotherapy. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold tremelimumab and durvalumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
Immune-mediated interstitial nephritis occurred in 0.7% to 1% of patients treated with tremelimumab in combination with durvalumab (grade 3, 0.2% to 0.5%) in 2 randomized, open-label clinical trials (n = 984); all patients required treatment with systemic corticosteroids. An increase from baseline in serum creatinine occurred in 21% (grade 3 or 4, 1.3%) and acute kidney injury (1.3%) were also reported in patients with hepatocellular cancer treated with tremelimumab plus durvalumab. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar incidence of increased creatinine in patients with metastatic NSCLC compared with platinum-based chemotherapy alone in another randomized clinical trial (89% vs. 83%; grade 3 or 4, 4% to 1.9%). Monitor renal function at baseline and prior to each dose during treatment. Therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Immune-mediated rash or dermatitis occurred in 4.9% to 7.2% (grade 3, 0.3% to 1.5%; grade 4, 0.3% or less) of patients receiving tremelimumab in combination with durvalumab in 2 randomized, open-label clinical trials (n = 984); all patients required treatment with systemic corticosteroids. Overall, rash was reported in 27% to 32% (grade 3 or 4, 2.4% to 2.8%) and pruritus in 11% to 23% of patients who received tremelimumab plus durvalumab, including eczema, erythema, dermatitis, erythema multiforme, pemphigoid, maculopapular rash, and pustular rash. Other serious rashes including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 and CTLA-4 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase in the incidence of alopecia compared with platinum-based chemotherapy alone in one randomized clinical trial.
Immune-mediated pancreatitis occurred in 2.3% (grade 3, 1.5%; grade 4, 0.3%) of patients treated with tremelimumab in combination with durvalumab in a randomized, open-label trial (n = 388). All patients required treatment with systemic corticosteroids, with 7 of 9 requiring high-dose corticosteroids. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a higher incidence of increases in lipase (35% vs. 25%; grade 3 or 4, 14 % vs. 5%) and amylase (hyperamylasemia) (41% vs. 25%; grade 3 or 4, 9% vs. 6%) compared with platinum-based chemotherapy alone in another randomized clinical trial.
Immune-mediated encephalitis, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, and autoimmune neuropathy were each reported in less than 1% of patients who received tremelimumab in combination with durvalumab or other checkpoint inhibitors in clinical trials. Therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Musculoskeletal pain occurred in 22% (grade 3 or 4, 2.6%) of patients treated with tremelimumab in combination with durvalumab in a randomized, open-label clinical trial (n = 388). Immune-mediated myositis/polymyositis, rhabdomyolysis and associate sequelae (including renal failure), arthritis, polymyalgia rheumatica, myelitis, demyelination, and sarcoidosis were each reported in less than 1% of patients who received tremelimumab in combination with durvalumab or other checkpoint inhibitors in clinical trials. Therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase in the incidence of musculoskeletal pain including arthralgia, back pain, bone pain, non-cardiac chest pain, myalgia, and neck pain in patients with metastatic NSCLC compared with platinum-based chemotherapy alone (29% vs. 22%; grade 3 or 4, 0.6% vs. 1.5%) in another randomized clinical trial.
Immune-mediated myocarditis, pericarditis, and vasculitis were each reported in less than 1% of patients who received tremelimumab in combination with durvalumab or other checkpoint inhibitors in clinical trials. Therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Immune-mediated uveitis, iritis, and other ocular inflammatory toxicities can occur in patients treated with tremelimumab in combination with durvalumab or other checkpoint inhibitors; some cases can be associated with retinal detachment. Various grades of visual impairment including blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider the possibility of Vogt-Koyanagi-Harada syndrome. Therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Abdominal pain (20%; grade 3 or 4, 1.8%), nausea (12%), and decreased appetite/anorexia (17%; grade 3 or 4, 1.3%) occurred in patients with unresectable hepatocellular cancer treated with tremelimumab in combination with durvalumab in a randomized, open-label clinical trial (n = 388). The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase to the incidence of nausea (42% vs. 37%; grade 3 or 4, 1.8% vs. 2.1%), vomiting (18% vs. 14%; grade 3 or 4, 1.2% vs. 1.5%), stomatitis (10% vs. 6%; grade 3 or 4, 0% vs. 0.3%), or decreased appetite (28% vs. 15%; grade 3 or 4, 1.5% vs. 1.2%) in patients with metastatic NSCLC compared with chemotherapy alone.
Fatigue occurred in 26% (grade 3 or 4, 3.9%) of patients with unresectable hepatocellular cancer treated with tremelimumab in combination with durvalumab in a randomized, open-label clinical trial. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase in the incidence of fatigue/asthenia in patients with metastatic NSCLC compared with platinum-based chemotherapy alone (36% vs. 32%; grade 3 or 4, 5% vs. 4.5%) in another randomized clinical trial.
Fever occurred in 13% (grade 3 or 4, 0.3%) of patients with unresectable hepatocellular cancer treated with tremelimumab in combination with durvalumab in a randomized, open-label clinical trial (n = 388); serious cases of infection including sepsis (2.1%) and pneumonia (2.1%) were also reported in these patients. Immune-mediated systemic inflammatory response syndrome was reported in less than 1% of patients who received tremelimumab in combination with durvalumab or other checkpoint inhibitors in clinical trials. The addition of tremelimumab and durvalumab to platinum-based chemotherapy did not meaningfully increase the incidence of fever (19% vs. 8%), pneumonia (17% vs. 12%; grade 3 or 4, 88% vs. 4.2%), or upper respiratory tract infections including bronchitis, laryngitis, naso-pharyngitis, rhinitis, sinusitis, tonsillitis (15% vs. 9%; grade 3 or 4, 0.6% vs. 0.9%) in patients with metastatic NSCLC compared with platinum-based chemotherapy alone (36% vs. 32%; grade 3 or 4, 5% vs. 4.5%) in another randomized clinical trial. Therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction.
Insomnia occurred in 10% (grade 3 or 4, 0.3%) of patients with unresectable hepatocellular cancer treated with tremelimumab in combination with durvalumab in a randomized, open-label clinical trial (n = 388).
Electrolyte abnormalities including hyponatremia, hypocalcemia, and hypokalemia have occurred in patients with unresectable hepatocellular cancer treated with tremelimumab in combination with durvalumab. Decreases from baseline in sodium (46%; grade 3 or 4, 15%), calcium (34%), and potassium (28%; grade 3 or 4, 3.8%) were reported in a randomized, open-label clinical trial (n = 388). The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase in the incidence of hyponatremia (55% vs. 50%; grade 3 or 4, 13% vs. 11%), hypernatremia (15% vs. 14%), or hypokalemia (21% vs. 17%; grade 3 or 4, 7 % vs. 2.8%) compared with platinum-based chemotherapy alone; hyperkalemia (49% vs. 35%; grade 3 or 4, 2.2% vs. 2.8%) and hypocalcemia (58% vs. 49%; grade 3 or 4, 0.9% vs. 0.9%) occurred more often in the tremelimumab/durvalumab arm in this trial.
Anemia, lymphopenia, thrombocytopenia, and leukopenia have been reported in patients treated with tremelimumab in combination with durvalumab. In a randomized, open-label clinical trial, patients with unresectable hepatocellular cancer who received tremelimumab plus durvalumab reported decreases from baseline in hemoglobin (52%; grade 3 or 4, 4.8%), lymphocytes (41%; grade 3 or 4, 11%), platelets (29%; grade 3 or 4, 1.6%), and leukocytes (20%; grade 3 or 4, 1.6%). Immune-mediated hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), and immune thrombocytopenia were each reported in less than 1% of patients who received tremelimumab in combination with durvalumab or other checkpoint inhibitors in clinical trials. Therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase in the incidence of neutropenia (71% vs. 69%; grade 3 or 4, 37% vs. 32%), anemia (84% vs. 84%; grade 3 or 4, 24% vs. 25%), leukopenia (77% vs. 81%; grade 3 or 4, 21% vs. 18%), lymphocytopenia (67% vs. 60%; grade 3 or 4, 20% vs. 19%), or thrombocytopenia (53% vs. 54%; grade 3 or 4, 11% vs. 12%) in patients with metastatic NSCLC compared with platinum-based chemotherapy alone.
Hypoalbuminemia has occurred in patients with unresectable hepatocellular cancer treated with tremelimumab in combination with durvalumab in a randomized, open-label clinical trial (n = 388), with 31% of patients reporting a decrease in albumin from baseline (grade 3 or 4, 0.5%). The addition of tremelimumab and durvalumab to platinum-based chemotherapy resulted in a similar increase in the incidence of decreased albumin compared with platinum-based chemotherapy alone in another randomized clinical trial (27% vs. 18%; grade 3 or 4, 1.9% vs. 0.9%).
Infusion-related reactions occurred in 2.9% to 10% (grade 3 or 4, 0.3% to 2.6%) of patients treated with tremelimumab in combination with durvalumab. Monitor patients for signs and symptoms of infusion reactions including fever, chills, wheezing, pruritus, flushing, and rash. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions (grade 1 or 2); consider premedication with subsequent doses. Stop the infusion and permanently discontinue tremelimumab plus durvalumab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Treatment-emergent antidrug antibody formation (ADA formation) occurred in 11% to 14% of patients who received tremelimumab every 3 to 4 weeks for 2 doses (n = 460); 40% to 82% tested positive for neutralizing antibodies. The development of ADAs and neutralizing antibodies appear to have no clinically relevant effect on the pharmacokinetic profile of tremelimumab or on its safety; the effect on the effectiveness of tremelimumab is unknown.
The addition of tremelimumab and durvalumab to platinum-based chemotherapy similarly increased the incidence of headache (including migraine) (11% vs. 8%; grade 3 or 4, 0% vs. 0.6%) in patients with metastatic NSCLC compared with platinum-based chemotherapy alone.
Immune-mediated reactions, which may be severe or fatal, can occur when tremelimumab is administered in combination with durvalumab, effectively removing inhibition of the body's immune response. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously; they can occur at any time after starting therapy including after discontinuation of tremelimumab and/or durvalumab. Because early identification and management is critical to safe usage of tremelimumab in combination with durvalumab, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of tremelimumab and durvalumab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.
Immune-mediated pneumonitis can occur in patients treated with tremelimumab in combination with durvalumab; some cases were fatal. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, tremelimumab and/or durvalumab may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated colitis that is frequently associated with diarrhea can occur during treatment with tremelimumab in combination with durvalumab. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use tremelimumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated hepatitis has been reported in patients treated with tremelimumab in combination with durvalumab; some cases were fatal. Monitor hepatic function at baseline and prior to each dose during treatment. Tremelimumab and/or durvalumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis and if there is tumor involvement of the liver; treatment with systemic corticosteroids may also be necessary.
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with tremelimumab in combination with durvalumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Monitor adrenocorticotropic hormone (ACTH) levels at baseline and prior to each dose. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Tremelimumab plus durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Tremelimumab in combination with durvalumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and prior to each dose during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Tremelimumab and/or durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, may occur in patients treated with tremelimumab in combination with durvalumab. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold tremelimumab and durvalumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
Immune-mediated nephritis has been reported in patients treated with tremelimumab in combination with durvalumab. Monitor renal function at baseline and prior to each dose during treatment. Therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 and CTLA-4 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.
Immune-mediated neurotoxicity has been reported in patients treated with tremelimumab in combination with durvalumab or with other checkpoint inhibitors. Use tremelimumab plus durvalumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Therapy may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.
Severe infusion-related reactions have occurred with tremelimumab in combination with durvalumab. Monitor patients for signs and symptoms of infusion reactions including fever, chills, wheezing, pruritus, flushing, and rash. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions (grade 1 or 2); consider premedication with subsequent doses. Stop the infusion and permanently discontinue tremelimumab plus durvalumab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Pregnancy should be avoided by females of reproductive potential during tremelimumab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women, tremelimumab can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving tremelimumab should be apprised of the potential hazard to the fetus. Human immunoglobulin G2 (IgG2) is known to cross the placenta and thus has the potential to be transmitted from the mother to the developing fetus. When administered to pregnant cynomolgus monkeys from organogenesis through delivery, tremelimumab was not associated with maternal toxicity or effects on embryofetal development at exposures approximately 4 to 31 times higher than those observed in humans at the recommended doses. However, 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 mouse model, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses. Genetically engineered fetuses born homozygous negative for CTLA-4 developed signs of a lymphoproliferative disorder which resulted in death by 3 to 4 weeks after birth due to multiorgan tissue destruction; human fetal exposure to tremelimumab may increase the risk of developing immune-mediated disorders or altering the normal immune response.
Counsel patients about the reproductive risk and contraception requirements during tremelimumab treatment. Tremelimumab can cause fetal harm or an increased risk of immune-mediated rejection of the developing fetus if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with tremelimumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of tremelimumab. Women who become pregnant while receiving tremelimumab should be apprised of the potential hazard to the fetus.
Due to the potential for serious adverse reactions in nursing infants from tremelimumab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether tremelimumab is present in human milk, although many maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breast-fed child are unknown.
For the treatment of hepatocellular cancer:
NOTE: Tremelimumab is designated by the FDA as an orphan drug for this indication.
-for the treatment of unresectable hepatocellular cancer:
Intravenous dosage:
Adults weighing less than 30 kg: 4 mg/kg IV on day 1. Observe the patient for signs of an infusion reaction for 60 minutes, then administer durvalumab (20 mg/kg IV). Continue durvalumab (4 mg/kg IV) as monotherapy every 4 weeks until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label phase 3 trial (HIMALAYA), patients with previously untreated unresectable hepatocellular cancer were randomized to treatment with tremelimumab-actl plus durvalumab (n = 393), durvalumab, or sorafenib (n = 389). Treatment with tremelimumab-actl plus durvalumab significantly improved median overall survival (16.4 months vs. 13.8 months) compared with those who received sorafenib. Median progression-free survival was 3.8 months in patients who received combination therapy with tremelimumab-actl compared with 4.1 months in those who received sorafenib. The objective response rate was 20.1% versus 5.1%, respectively (complete response, 12% vs. 0%), while the median duration of response was 22.3 months versus 18.4 months, respectively.
Adults weighing 30 kg or more: 300 mg IV on day 1. Observe the patient for signs of an infusion reaction for 60 minutes, then administer durvalumab (1,500 mg IV). Continue durvalumab (1,500 mg IV) as monotherapy every 4 weeks until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label phase 3 trial (HIMALAYA), patients with previously untreated unresectable hepatocellular cancer were randomized to treatment with tremelimumab-actl plus durvalumab (n = 393), durvalumab, or sorafenib (n = 389). Treatment with tremelimumab-actl plus durvalumab significantly improved median overall survival (16.4 months vs. 13.8 months) compared with those who received sorafenib. Median progression-free survival was 3.8 months in patients who received combination therapy with tremelimumab-actl compared with 4.1 months in those who received sorafenib. The objective response rate was 20.1% versus 5.1%, respectively (complete response, 12% vs. 0%), while the median duration of response was 22.3 months versus 18.4 months, respectively.
For the treatment of non-small cell lung cancer (NSCLC):
-for the treatment of metastatic squamous or non-squamous NSCLC without EGFR mutations or ALK aberrations, in combination with durvalumab, carboplatin, and nab-paclitaxel:
Intravenous dosage:
Adults weighing less than 30 kg: 1 mg/kg IV over 60 minutes on day 1 every 3 weeks for 4 cycles; infuse a fifth dose of tremelimumab 1 mg/kg IV on week 16, day 1. Observe the patient for signs of an infusion reaction for 1 hour, then administer durvalumab (20 mg/kg IV on day 1, every 3 weeks for 5 cycles, then beginning week 16, day 1, every 4 weeks until disease progression or unacceptable toxicity). During cycles 1 through 4, observe the patient for signs of an infusion reaction for another 1 to 2 hours prior to administration of nab-paclitaxel (100 mg/m2 IV on days 1, 8, and 15) followed by carboplatin (AUC 5 or 6 IV on day 1) every 3 weeks. In a randomized, multicenter, open-label clinical trial (POSEIDON), treatment with tremelimumab, durvalumab, and platinum-based chemotherapy significantly improved median overall survival (14 months vs. 11.7 months) and median progression-free survival (6.2 months vs. 4.8 months) compared with platinum-based chemotherapy alone in patients with metastatic EGFR negative and ALK negative NSCLC. The objective response rate was 39% in the tremelimumab/durvalumab arm compared with 24% in the chemotherapy alone arm; the median duration of response was 9.5 months versus 5.1 months, respectively.
Adults weighing 30 kg or more: 75 mg IV over 60 minutes on day 1, every 3 weeks for 4 cycles; infuse a fifth dose of tremelimumab 75 mg IV on week 16, day 1. Observe the patient for signs of an infusion reaction for 1 hour, then administer durvalumab (1,500 mg IV on day 1, every 3 weeks for 5 cycles, then beginning week 16, day 1, every 4 weeks until disease progression or unacceptable toxicity). During cycles 1 through 4, observe the patient for signs of an infusion reaction for another 1 to 2 hours prior to administration of nab-paclitaxel (100 mg/m2 IV on days 1, 8, and 15) followed by carboplatin (AUC 5 or 6 IV on day 1) every 3 weeks. In a randomized, multicenter, open-label clinical trial (POSEIDON), treatment with tremelimumab, durvalumab, and platinum-based chemotherapy significantly improved median overall survival (14 months vs. 11.7 months) and median progression-free survival (6.2 months vs. 4.8 months) compared with platinum-based chemotherapy alone in patients with metastatic EGFR negative and ALK negative NSCLC. The objective response rate was 39% in the tremelimumab/durvalumab arm compared with 24% in the chemotherapy alone arm; the median duration of response was 9.5 months versus 5.1 months, respectively.
-for the treatment of metastatic non-squamous NSCLC without EGFR mutations or ALK aberrations, in combination with durvalumab, carboplatin or cisplatin, and pemetrexed:
Intravenous dosage:
Adults weighing less than 30 kg: 1 mg/kg IV over 60 minutes every 3 weeks for 4 cycles; infuse a fifth dose of tremelimumab 1 mg/kg mg IV on week 16, day 1. Observe the patient for signs of an infusion reaction for 1 hour, then administer durvalumab (20 mg/kg IV on day 1, every 3 weeks for 4 cycles, then beginning week 12, day 1, every 4 weeks until disease progression or unacceptable toxicity). During cycles 1 through 4, observe the patient for signs of an infusion reaction for another 1 to 2 hours prior to administration of carboplatin (AUC 5 or 6 IV) or cisplatin (75 mg/m2 IV) and pemetrexed (500 mg/m2 IV) every 3 weeks. Pemetrexed may be continued as maintenance therapy with durvalumab (every 4 weeks beginning week 12) until disease progression or unacceptable toxicity. In a randomized, multicenter, open-label clinical trial (POSEIDON), treatment with tremelimumab, durvalumab, and platinum-based chemotherapy significantly improved median overall survival (14 months vs. 11.7 months) and median progression-free survival (6.2 months vs. 4.8 months) compared with platinum-based chemotherapy alone in patients with metastatic EGFR negative and ALK negative NSCLC. The objective response rate was 39% in the tremelimumab/durvalumab arm compared with 24% in the chemotherapy alone arm; the median duration of response was 9.5 months versus 5.1 months, respectively.
Adults weighing 30 kg or more: 75 mg IV over 60 minutes every 3 weeks for 4 cycles; infuse a fifth dose of tremelimumab 75 mg IV on week 16, day 1. Observe the patient for signs of an infusion reaction for 1 hour, then administer durvalumab (1,500 mg IV on day 1, every 3 weeks for 4 cycles, then beginning week 12, day 1, every 4 weeks until disease progression or unacceptable toxicity). During cycles 1 through 4, observe the patient for signs of an infusion reaction for another 1 to 2 hours prior to administration of carboplatin (AUC 5 or 6 IV) or cisplatin (75 mg/m2 IV) and pemetrexed (500 mg/m2 IV) every 3 weeks. Pemetrexed may be continued as maintenance therapy with durvalumab (every 4 weeks beginning week 12) until disease progression or unacceptable toxicity. In a randomized, multicenter, open-label clinical trial (POSEIDON), treatment with tremelimumab, durvalumab, and platinum-based chemotherapy significantly improved median overall survival (14 months vs. 11.7 months) and median progression-free survival (6.2 months vs. 4.8 months) compared with platinum-based chemotherapy alone in patients with metastatic EGFR negative and ALK negative NSCLC. The objective response rate was 39% in the tremelimumab/durvalumab arm compared with 24% in the chemotherapy alone arm; the median duration of response was 9.5 months versus 5.1 months, respectively.
-for the treatment of metastatic squamous NSCLC without EGFR mutations or ALK aberrations, in combination with durvalumab, carboplatin or cisplatin, and gemcitabine:
Intravenous dosage:
Adults weighing less than 30 kg: 1 mg/kg IV over 60 minutes every 3 weeks for 4 cycles; infuse a fifth dose of tremelimumab 1 mg/kg mg IV on week 16, day 1. Observe the patient for signs of an infusion reaction for 1 hour, then administer durvalumab (20 mg/kg IV on day 1, every 3 weeks for 4 cycles, then beginning week 12, day 1, every 4 weeks until disease progression or unacceptable toxicity). During cycles 1 through 4, observe the patient for signs of an infusion reaction for another 1 to 2 hours prior to administration of carboplatin (AUC 5 or 6 IV) or cisplatin (75 mg/m2 IV) and gemcitabine (1,000 mg/m2 or 1,250 mg/m2 IV on days 1 and 8) every 3 weeks. In a randomized, multicenter, open-label clinical trial (POSEIDON), treatment with tremelimumab, durvalumab, and platinum-based chemotherapy significantly improved median overall survival (14 months vs. 11.7 months) and median progression-free survival (6.2 months vs. 4.8 months) compared with platinum-based chemotherapy alone in patients with metastatic EGFR negative and ALK negative NSCLC. The objective response rate was 39% in the tremelimumab/durvalumab arm compared with 24% in the chemotherapy alone arm; the median duration of response was 9.5 months versus 5.1 months, respectively.
Adults weighing 30 kg or more: 75 mg IV over 60 minutes every 3 weeks for 4 cycles; infuse a fifth dose of tremelimumab 1 mg/kg mg IV on week 16, day 1. Observe the patient for signs of an infusion reaction for 1 hour, then administer durvalumab (1,500 mg IV on day 1, every 3 weeks for 4 cycles, then beginning week 12, day 1, every 4 weeks until disease progression or unacceptable toxicity). During cycles 1 through 4, observe the patient for signs of an infusion reaction for another 1 to 2 hours prior to administration of carboplatin (AUC 5 or 6 IV) or cisplatin (75 mg/m2 IV) and gemcitabine (1,000 mg/m2 IV or 1,250 mg/m2 IV on days 1 and 8) every 3 weeks. In a randomized, multicenter, open-label clinical trial (POSEIDON), treatment with tremelimumab, durvalumab, and platinum-based chemotherapy significantly improved median overall survival (14 months vs. 11.7 months) and median progression-free survival (6.2 months vs. 4.8 months) compared with platinum-based chemotherapy alone in patients with metastatic EGFR negative and ALK negative NSCLC. The objective response rate was 39% in the tremelimumab/durvalumab arm compared with 24% in the chemotherapy alone arm; the median duration of response was 9.5 months versus 5.1 months, respectively.
Therapeutic Drug Monitoring:
Dose Adjustments for Treatment-Related Toxicities
NOTE: Corticosteroid therapy consists of prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Permanently discontinue tremelimumab in patients who do not have a complete or partial resolution of toxicity (grade 1 or less) or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Colitis
-Grade 2: Hold tremelimumab and administer corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Grade 3 or 4: Permanently discontinue tremelimumab therapy and administer corticosteroids.
Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
-Grade 3 or 4: Hold tremelimumab until the patient is clinically stable; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Permanently discontinue tremelimumab for severe toxicity.
Exfoliative Skin Reactions
-Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Hold tremelimumab and administer corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Confirmed SJS, TEN, or DRESS: Permanently discontinue tremelimumab therapy and administer corticosteroids.
GI perforation
-Any grade: Permanently discontinue tremelimumab therapy and administer corticosteroids.
Infusion-Related Reactions
-Grade 1 or 2: Hold tremelimumab or slow the infusion rate.
-Grade 3 or 4: Permanently discontinue tremelimumab therapy.
Interstitial Lung Disease (ILD)/Pneumonitis
-Grade 2: Hold tremelimumab and administer corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Grade 3 or 4: Permanently discontinue tremelimumab therapy and administer corticosteroids.
Myocarditis
-Grade 2, 3, or 4: Permanently discontinue tremelimumab therapy and administer corticosteroids.
Neurologic Toxicities
-Grade 2: Hold tremelimumab and administer corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper.
-Grade 3 or 4: Permanently discontinue tremelimumab therapy and administer corticosteroids.
Maximum Dosage Limits:
-Adults
weight less than 30 kg: 4 mg/kg IV
weight 30 kg or more: 300 mg IV
-Geriatric
weight less than 30 kg: 4 mg/kg IV
weight 30 kg or more: 300 mg IV
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild to moderate hepatic impairment (bilirubin less than 3 times the upper limit of normal (ULN) and any AST): No dosage adjustments are needed.
-Severe hepatic impairment (bilirubin greater than 3 times ULN and any AST): The pharmacokinetics of tremelimumab are unknown.
Treatment-Related Hepatitis in patients WITHOUT tumor involvement of the liver
-AST/ALT increases to 3.1 to 8 times the upper limit of normal (ULN), or total bilirubin increases to 1.6 to 3 times ULN: Hold tremelimumab and administer corticosteroids (1 to 2 mg/kg/day of prednisone or equivalent). Upon improvement to grade 1 or less, taper steroids over at least 1 month. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue tremelimumab in patients who do not have a complete or partial resolution of toxicity (grade 1 or less) or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
-AST/ALT increases to more than 8 times ULN, or total bilirubin increases to more than 3 times ULN: Permanently discontinue tremelimumab therapy.
Treatment-Related Hepatitis in patients WITH tumor involvement of the liver
-Baseline AST and ALT are less than or equal to ULN: Follow recommendations for treatment-related hepatitis WITHOUT liver involvement.
-Baseline AST/ALT is 1 to 3 times ULN and increases to 5.1 to 10 times ULN; OR baseline AST/ALT is 3 to 5 times ULN and increases to 8.1 to 10 times ULN: Hold tremelimumab and administer corticosteroids (1 to 2 mg/kg/day of prednisone or equivalent). Upon improvement to grade 1 or less, taper steroids over at least 1 month. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue tremelimumab in patients who do not have a complete or partial resolution of toxicity (grade 1 or less) or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
-AST/ALT increases to more than 10 times ULN or total bilirubin increases to more than 3 times ULN: Permanently discontinue tremelimumab therapy.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild to moderate renal impairment (CrCl 30 to 89 mL/min): No dosage adjustments are needed.
-Severe renal impairment (CrCl 15 to 29 mL/min): The pharmacokinetics of tremelimumab are unknown.
Treatment-Related Nephritis with Renal Impairment
-Grade 2 or 3 increase in serum creatinine: Hold tremelimumab and administer corticosteroids (1 to 2 mg/kg/day of prednisone or equivalent). Upon improvement to grade 1 or less, taper steroids over at least 1 month. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Resume therapy at the same dose when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue tremelimumab in patients who do not have a complete or partial resolution of toxicity (grade 1 or less) or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
-Grade 4 increase in serum creatinine: Permanently discontinue therapy.
*non-FDA-approved indication
There are no drug interactions associated with Tremelimumab products.
Tremelimumab is a human IgG2 monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction with its ligands CD80 and CD86. CTLA-4 is a negative regulator of T-cell activity. By blocking the interaction of CTLA4 with CD80 and CD86, tremelimumab releases CTLA-4-mediated inhibition of T-cell activation. In synergistic mouse tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of T cells in tumors.
Tremelimumab is administered intravenously. The geometric mean for central volume of distribution (V1) is 3.45 liters (CV, 24%) and the geometric mean for peripheral volume of distribution (V2) is 2.66 liters (CV, 34%). The geometric mean terminal half-life of tremelimumab is 16.9 days (CV, 19%) after a single dose and 19.2 days (CV, 19%) at steady-state. Steady-state was reached approximately 12 weeks after every-4-week dosing. Tremelimumab clearance is 0.286 liters/day (CV, 32%) after a single dose and 0.263 liters/day (CV, 32%) at steady-state.
Affected cytochrome P450 isoenzymes and transporters: None
-Route-Specific Pharmacokinetics
Intravenous Route
The AUC of tremelimumab increased proportionally from 1 mg/kg to 10 mg/kg IV every 4 weeks (from 1 to 10 times the approved recommended dosage).
-Special Populations
Hepatic Impairment
Mild to moderate hepatic impairment (bilirubin less than 3 times the upper limit of normal [ULN] and any AST) does not have a clinically significant effect on the pharmacokinetics of tremelimumab. The effect of severe hepatic impairment (bilirubin greater than 3 times ULN and any AST) on the pharmacokinetics of tremelimumab is unknown.
Renal Impairment
Mild to moderate renal impairment (CrCl 30 to 89 mL/min) does not have a clinically significant effect on the pharmacokinetics of tremelimumab. The effect of severe renal impairment (CrCl 15 to 29 mL/min) on the pharmacokinetics of tremelimumab is unknown.
Geriatric
Age (18 to 87 years) does not have a clinically significant effect on the pharmacokinetics of tremelimumab.
Gender Differences
Sex does not have a clinically significant effect on the pharmacokinetics of tremelimumab.
Ethnic Differences
Race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American) does not have a clinically significant effect on the pharmacokinetics of tremelimumab.
Obesity
Body weight (34 kg to 149 kg) does not have a clinically significant effect on the pharmacokinetics of tremelimumab.
Other
Tumor type (NSCLC or HCC), serum albumin levels (0.3 to 396 g/L), lactate dehydrogenase levels (12 to 5,570 units/L), and soluble PD-L1 levels (67 to 349 pg/mL) do not have a clinically significant effect on the pharmacokinetics of tremelimumab.