Durvalumab is a human IgG1 kappa monoclonal antibody that binds to and blocks programmed death-ligand 1 (PD-L1). It is indicated as monotherapy for the treatment of patients with unresectable stage III non-small cell lung cancer whose disease has not progressed following concurrent platinum-based chemoradiotherapy, in combination with etoposide and either cisplatin or carboplatin for the first-line treatment of extensive-stage small cell lung cancer, and in combination with gemcitabine and cisplatin for the treatment of locally advanced or metastatic biliary tract cancer. Immune-mediated adverse reactions including colitis, pneumonitis, hepatitis, endocrinopathies, and nephritis have been reported with 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. Durvalumab is clear to opalescent, colorless to slightly yellow solution, free from visible particles. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
-Do not shake durvalumab.
-Administer durvalumab prior to chemotherapy when given on the same day.
Intravenous Administration
Preparation:
-Withdraw the required volume of drug and transfer into an intravenous container containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection, to prepare an infusion with a final concentration ranging from 1 mg/mL to 15 mg/mL.
-Mix diluted solution by gentle inversion. Do not shake.
-Discard partially used or empty vials of durvalumab.
-Storage after dilution: Durvalumab does not contain a preservative; administer immediately after preparation. If unable to be administered immediately, the storage time of diluted durvalumab from preparation until completion of the infusion should not exceed 28 days under refrigeration (2 to 8 degrees C; 36 to 46 degrees F) or 8 hours at room temperature (up to 25 degrees C; up to 77 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.
-Do not coadminister with other drugs through the same intravenous line.
Immune-mediated reactions have been reported with programmed death-receptor 1/PD-ligand 1 (PD1/PD-L1) inhibitors, including durvalumab; some cases were severe or fatal. Hold or permanently discontinue durvalumab depending on toxicity severity. Immune reactions may occur in any organ system or tissue during therapy or after therapy is discontinued. Monitor patients for signs and symptoms of immune-mediated reactions. Obtain [liver function tests, serum creatinine, and thyroid function tests] prior to and periodically during therapy. Initiate appropriate workup to exclude alternative etiologies, particularly infectious etiologies. If an immune-mediated reaction is confirmed, begin medical management promptly; obtain a specialty consultation as appropriate. If durvalumab is held or discontinued, administer systemic corticosteroid therapy (i.e., 1 to 2 mg/kg per day of prednisone or equivalent) until the toxicity improves to grade 1 or less. When the toxicity improves to grade 1 or less, begin a steroid taper over at least 1 month. If the immune-mediated toxicity is not improved with systemic corticosteroids, consider administering other systemic immunosuppressants.
Immune-mediated pneumonitis was reported in 1.3% to 3.5% (grade 3 or higher, 0.4% to 1.5%) of patients who received durvalumab in combination with other agents. In a pooled analysis of patients who received single-agent durvalumab therapy, immune-mediated pneumonitis occurred in 2.4% (grade 3 or higher, 0.4%) of patients who had not received recent prior radiation (n = 1,414) compared with 18.3% (grade 3 or higher, 3.8%) of patients who received recent prior radiation (n = 475). Fatal immune-related pneumonitis was reported in 1.1% or less of patients who received durvalumab. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary. Pneumonitis/radiation pneumonitis occurred in 34% (grade 3 or 4, 3.4%) of patients with advanced non-small cell lung cancer who received adjuvant therapy with single-agent durvalumab (n = 475) in a randomized trial; fatal pneumonitis occurred in less than 2% of patients. In this trial, the term pneumonitis included acute interstitial pneumonitis, interstitial lung disease, and pulmonary fibrosis.
Cough occurred in 12% to 40% (grade 3 or 4, 0.8% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Dyspnea was reported in 25% (grade 3 or 4, 1.5%) of patients with advanced non-small cell lung cancer who received adjuvant therapy with single-agent durvalumab (n = 475) in a randomized, placebo-controlled trial. Fatal chronic obstructive pulmonary disease and dyspnea occurred in 1 patient each with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial.
Immune-mediated hepatitis was reported in 2.8% to 7.5% (grade 3 or higher, 1.9% to 5.2%) of patients who received durvalumab as monotherapy or in combination with other agents. Fatal immune-related hepatitis was reported in 0.2% to 0.8% of patients who received durvalumab. Monitor hepatic function (e.g., liver function tests, bilirubin) during therapy. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Elevated hepatic enzymes including increased ALT (39% to 64%; grade 3 or 4, 2.3% to 18%), AST (36% to 63%; grade 3 or 4, 2.8% to 27%), alkaline phosphatase (41% or less; grade 3 or 4, 1.8% to 8%), and gamma glutamyl transferase (38% or less; grade 3 or 4, 2.2% to 12%) levels and hyperbilirubinemia (41% or less; grade 3 or 4, 0.9% to 10%) were reported in patients who received durvalumab as monotherapy or in combination with other agents. Severe cholangitis was reported in 7% of patients with advanced biliary tract cancer who received durvalumab in combination with gemcitabine and cisplatin (n = 338) in a randomized placebo-controlled trial. Fatal hepatic failure occurred in 0.5% of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) in a randomized clinical trial.
Immune-mediated colitis was reported in 2% to 6.5% (grade 3 and higher, 0.4% to 3.6%) of patients who received durvalumab as monotherapy or in combination with other agents. Fatal colitis occurred in 0.2% of patients with lung cancer who received durvalumab in combination with tremelimumab and/or platinum-containing therapy (n = 596) in pooled analysis. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary. Consider repeating the infectious workup to exclude alternative etiologies in durvalumab-treated patients who have corticosteroid-refractory immune-mediated colitis.
Diarrhea (10% to 27%; grade 3 or 4, 0.6% to 6%), abdominal pain including flank pain (10% to 24%; grade 3 or 4, 0.4% to 1.8%), nausea (12% to 42%; grade 3 or 4, 1.8% or less), constipation (17% to 32%; grade 3 or 4, 0.8% or less), vomiting (15% to 18%; grade 3 or 4, 1.5% or less), and anorexia/decreased appetite (17% to 28%; grade 3 or 4, 0.8% to 2.1%) occurred in patients who received durvalumab as monotherapy or in combination with other agents. Stomatitis including mucosal inflammation was reported in 10% of patients with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial.
Immune-mediated gastrointestinal toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies included duodenitis and gastritis; cases may be severe or fatal. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Intestinal/GI perforation occurred in 0.1% of patients with who received durvalumab in combination with tremelimumab. Permanently discontinue durvalumab in patients who develop an intestinal perforation. Fatal upper GI bleeding occurred in 2 patients with advanced biliary tract cancer who received durvalumab in combination with gemcitabine and cisplatin (n = 338) in a randomized placebo-controlled trial.
Immune-mediated hyperthyroidism was reported in 2.1% to 5% (grade 3, 0.3% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Monitor thyroid function tests during therapy. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with endocrine therapy/antithyroid agents or systemic corticosteroids may be necessary. Hyperthyroidism including Basedow disease occurred in 10% of patients with extensive-stage small cell lung cancer who received durvalumab in combination with etoposide and carboplatin or cisplatin (n = 265) in a randomized trial.
Immune-mediated primary or secondary adrenal/adrenocortical insufficiency was reported in 0.5% to 2.2% (grade 3, 0.8% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with hormone replacement/endocrine therapy or systemic corticosteroids may be necessary.
Immune-mediated hypophysitis was reported in 1.3% or less (grade 3, 0.5% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with hormone replacement/endocrine therapy or systemic corticosteroids may be necessary.
Immune-mediated thyroiditis was reported in 0.5% to 1.5% (grade 3, less than 0.1%) of patients who received durvalumab as monotherapy or in combination with other agents. Thyroiditis can present with or without endocrinopathy. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with hormone replacement/endocrine therapy or systemic corticosteroids may be necessary.
Immune-mediated hypothyroidism was reported in 8.3% to 11% (grade 3, 0.5% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Hypothyroidism may follow hyperthyroidism. Monitor thyroid function tests during therapy. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with hormone replacement/endocrine therapy or systemic corticosteroids may be necessary. Hypothyroidism was reported in 14% of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) and 12% (grade 3 or 4, 0.2%) of patients who received adjuvant therapy with single-agent durvalumab (n = 475) in 2 randomized trials.
Immune-mediated hypoparathyroidism was reported in less than 1% of patients who received durvalumab or other PD1/PD-L1 blocking antibodies. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Immune-mediated type 1 diabetes mellitus (0.5% or less; grade 3, 0.3% or less), hyperglycemia (52% or less; grade 3 or 4, 14% or less), and hyperglycemia requiring insulin therapy (0.5% or less) were reported in patients who received durvalumab as monotherapy or in combination with other agents. Patients may present with diabetic ketoacidosis. Monitor patients for signs and symptoms of diabetes including blood glucose levels during therapy. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with insulin may be necessary.
Rash (11% to 32%; grade 3 or 4, 2.8% or less) including immune-mediated rash or dermatitis (1.8% to 7.2%; grade 3 or 4, 0.3% to 1.8%) was reported in patients who received durvalumab as monotherapy or in combination with other agents. Exfoliative dermatitis including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN) has occurred with PD1/PD-L1-blocking antibodies. Hold durvalumab therapy for suspected SJS, TEN, or DRESS; permanently discontinue durvalumab therapy for confirmed SJS, TEN, or DRESS. Mild to moderate non-exfoliative rashes may respond to topical emollients and/or topical corticosteroids. Treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary to treat exfoliative rashes. The term rash included maculopapular rash, morbilliform rash, pustular rash, erythematous rash or erythema, acneiform rash/dermatitis, bullous rash/dermatitis, erythema multiforme, pemphigoid, and eczema.
Pruritus (11% to 23%) and alopecia (31% or less; grade 3 or 4, 1.1% or less) occurred in patients who received durvalumab as monotherapy or in combination with other agents. Night sweats were reported in less than 10% of patients with advanced non-small cell lung cancer who received adjuvant therapy with single-agent durvalumab (n = 475) in a randomized, placebo-controlled trial.
Immune-mediated interstitial nephritis was reported in 0.5% to 1% (grade 3, 0.5% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Fatal nephritis was reported in 1 patient with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial. Monitor renal function during therapy. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Nephrotoxicity including increased serum creatinine level (89% or less; grade 3 or 4, 1.3% to 5%), serious acute kidney injury (2.4% or less), and dysuria (less than 10%) occurred in patients who received durvalumab as monotherapy or in combination with other agents. Fatal acute kidney injury was reported in 2 patients with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial.
Immune-mediated ocular toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD1/PD-L1-blocking antibodies included uveitis, iritis, and other ocular inflammation toxicity; some cases were associated with retinal detachment. Visual impairment including vision loss/blindness may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a diagnosis of Vogt-Koyanagi-Harada syndrome. Patients may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
Immune-mediated hematologic toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD1/PD-L1 blocking antibodies included hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis) and immune thrombocytopenic purpura; cases may be severe or fatal. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Lymphopenia (67% or less; grade 3 or 4, 11% to 23%), neutropenia (71% or less; grade 3 or 4, 37% to 48%), anemia (84% or less; grade 3 or 4, 4.8% to 31%), leukopenia (77% or less; grade 3 or 4, 0.8% to 28%), and thrombocytopenia (53% or less; grade 3 or 4, 1.6% to 18%) occurred in patients who received durvalumab as monotherapy or in combination with other agents. Fatal pancytopenia occurred in 1 patient with extensive-stage small cell lung cancer who received durvalumab in combination with etoposide and carboplatin or cisplatin (n = 265) in a randomized trial. Additionally, fatal febrile neutropenia occurred in 1 patient with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in another randomized trial.
Immune-mediated cardiovascular toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD1/PD-L1 blocking antibodies included myocarditis, pericarditis, and vasculitis; cases may be severe or fatal. Fatal myocarditis was reported in 1 patient with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Fatal cardiac arrest was reported in 0.5% of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) in a randomized clinical trial.
Immune-mediated musculoskeletal toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD1/PD-L1 blocking antibodies included myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, and polymyalgia rheumatica; cases may be severe or fatal. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Musculoskeletal pain occurred in 29% (grade 3 or 4, 0.6%) of patients with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) and 22% (grade 3 or 4, 2.6%) of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) in 2 randomized trials. The term musculoskeletal pain includes arthralgia, arthritis, back pain, bone pain, neck pain, myalgia, and musculoskeletal/noncardiac chest pain.
Immune-mediated pancreatitis occurred in 2.3% (grade 3 or 4, 1.8%) of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) in a randomized clinical trial. Additionally, fatal pancreatitis was reported in 1 patient with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial. Immune-mediated increased amylase or lipase levels were reported in less than 1% of patients who received durvalumab or other PD1/PD-L1 blocking antibodies. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Increased lipase level (35%; grade 3 or 4, 14%) and hyperamylasemia (41%; grade 3 or 4, 9%) were reported in patients with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial.
Immune-mediated neurologic toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD1/PD-L1-blocking antibodies included aseptic meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, and autoimmune peripheral neuropathy; cases may be severe or fatal. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Headache including migraine was reported in 11% of patients with metastatic non-small cell lung cancer (NSCLC) who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial.
Other immune-mediated toxicity that was reported in less than 1% of patients who received durvalumab or that occurred with the use of other PD1/PD-L1 blocking antibodies included systemic inflammatory response syndrome, sarcoidosis, and solid organ transplant rejection; cases may be severe or fatal. Hold or permanently discontinue durvalumab depending on toxicity severity; treatment with systemic corticosteroids or other systemic immunosuppressants may be necessary.
Infusion-related reactions were reported in 2.2% to 2.9% (grade 3 or 4, 0.3% or less) of patients who received durvalumab as monotherapy or in combination with other agents. Monitor patients for signs and symptoms of infusion reactions. Hold, slow the rate of, or permanently discontinue durvalumab depending on toxicity severity; consider premedication with subsequent durvalumab doses in patients who developed a grade 1 or 2 infusion-related reactions.
Infection including upper respiratory tract infection (26% or less; grade 3 or 4, 0.6% or less), pneumonia (17% or less; grade 3 or 4, 2.1% to 8%), and sepsis (serious, 3.3% or less) occurred in patients who received durvalumab as monotherapy or in combination with other agents. The term upper respiratory tract infection included laryngitis, pharyngitis/nasopharyngitis, peritonsillar abscess, rhinitis, sinusitis, tonsillitis, and tracheobronchitis. Increased susceptibility to infections was reported in less than 10% of patients with advanced non-small cell lung cancer who received adjuvant therapy with single-agent durvalumab (n = 475) in a randomized, placebo-controlled trial. Fatal sepsis or septic shock occurred in less than 1% of patients.
Fatigue (26% to 42%; grade 3 or 4%, 0.8% to 6%) and asthenia (36% or less; grade 3 or 4, 5% or less) occurred in patients who received durvalumab as monotherapy or in combination with other agents. The term fatigue included asthenia and malaise.
Peripheral edema occurred in less than 10% of patients with advanced non-small cell lung cancer (NSCLC) who received adjuvant therapy with single-agent durvalumab (n = 475) and edema occurred in 10% of patients with metastatic NSCLC who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in 2 randomized trials. The term edema included face edema, localized edema, and peripheral edema.
Fever (13% to 20%; grade 3 or 4, 1.5% or less) occurred in patients who received durvalumab as monotherapy or in combination with other agents. The term fever included increased body temperature, hyperpyrexia, and hyperthermia.
Dysphonia occurred in less than 10% of patients with advanced non-small cell lung cancer who received adjuvant therapy with single-agent durvalumab (n = 475) in a randomized, placebo-controlled trial.
Insomnia occurred in 10% of patients with advanced biliary tract cancer who received durvalumab in combination with gemcitabine and cisplatin (n = 338) and 10% (grade 3 or 4, 0.3%) of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) in 2 randomized trials.
Hypocalcemia (34% to 58% or less; grade 3 or 4, 3.5% or less), hyponatremia (33% to 55% or less; grade 3 or 4, 3.6% to 18%), hypokalemia (21% or less; grade 3 or 4, 8% or less), hypomagnesemia (12% or less; grade 3 or 4, 4 to 11%) occurred in patients who received durvalumab as monotherapy or in combination with other agents.
Hypoalbuminemia was reported in 31% or less (grade 3 or 4, 0.5% to 3.6%) of patients who received durvalumab as monotherapy or in combination with other agents.
Hyperkalemia occurred in 28% to 49% (grade 3 or 4, 1.1% to 3.8%) of patients who received durvalumab as monotherapy or in combination with other agents. Hypernatremia was reported in 15% of patients with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in a randomized trial.
Fatal pulmonary embolism and pulmonary artery thrombosis occurred in 1 patient each with extensive-stage small cell lung cancer who received durvalumab in combination with etoposide and carboplatin or cisplatin (n = 265) in a randomized trial.
Fatal ischemic or hemorrhagic stroke occurred in 4 patients with advanced biliary tract cancer who received durvalumab in combination with gemcitabine and cisplatin (n = 338) and fatal ischemic stroke occurred in 1 patient with metastatic non-small cell lung cancer who received durvalumab plus tremelimumab and platinum-based chemotherapy (n = 330) in 2 randomized trials.
Fatal intracranial bleeding was reported in 0.5% of patients with unresectable hepatocellular carcinoma who received durvalumab plus tremelimumab (n = 388) in a randomized clinical trial.
Antibody formation occurred in 3% of patients who received single-agent durvalumab and 10% or less of patients who received durvalumab in combination with other agents; neutralizing antibodies were reported in 0.5% and 1.7% or less, respectively.
Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as durvalumab. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, 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 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 has been reported with durvalumab therapy; some cases were fatal. The incidence of pneumonitis was higher in durvalumab-treated patients who have received prior thoracic radiation therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, durvalumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated hepatitis has been reported with durvalumab therapy; some cases were fatal. Monitor hepatic function at baseline and periodically during treatment. 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.
Immune-mediated colitis has been reported with durvalumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use durvalumab 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.
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. Durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with durvalumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Durvalumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Use durvalumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1 inhibitor therapy.
Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, has been reported with durvalumab therapy. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold durvalumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
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 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. Durvalumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.
Immune-mediated nephritis has been reported with durvalumab therapy; renal failure may occur. Monitor renal function at baseline and periodically during treatment. Durvalumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Severe infusion-related reactions have occurred with durvalumab. Monitor patients for signs and symptoms of infusion reactions including fever, chills, wheezing, pruritus, flushing, and rash. Consider premedication with subsequent doses in patients who develop a reaction. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions (grade 1 or 2); stop the infusion and permanently discontinue durvalumab for severe or life-threatening infusion-related reactions (grade 3 or 4).
Immune-mediated neurotoxicity has been reported with durvalumab or other PD-1/PD-L1 inhibitors. Use durvalumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Durvalumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.
Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as durvalumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.
Based on its mechanism of action and data from animal studies, durvalumab may cause fetal harm if used during pregnancy. Durvalumab is an immunoglobulin G1 antibody and may cross the placental barrier. Fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Advise pregnant women of the potential risk to a fetus. The PD-1 pathway is associated with decidual CD8-positive T-cell function and the PD1/PD-L1 interaction may be important in maintaining fetal tolerance during pregnancy. PD1/PDL1 Inhibitors, such as durvalumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia. In animal reproduction studies in pregnant cynomolgus monkeys, premature delivery, fetal loss, and an increase in neonatal death were observed when durvalumab was administered at doses resulting in AUC values of 6 to 20 times higher than the clinical human dose of 10 mg/kg.
Counsel patients about the reproductive risk and contraception requirements during durvalumab treatment. Durvalumab can be teratogenic 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 durvalumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of durvalumab. Women who become pregnant while receiving durvalumab should be apprised of the potential hazard to the fetus.
Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during durvalumab therapy and for at least 3 months after the final dose. It is not known if durvalumab is present in human milk or if it has effects on the breastfed child or on milk production. Use durvalumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because durvalumab is a large protein molecule (molecular weight of 146,000 Daltons), the amount of drug in milk is likely to be very low. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.
For the treatment of urothelial carcinoma*:
-for the treatment of locally advanced or metastatic urothelial carcinoma, in patients with disease progression on or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy*:
NOTE: FDA approval was removed for this indication in February 2021 after initial accelerated approval due to failure improve overall survival in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma compared with gemcitabine plus cisplatin or carboplatin in a phase 3 clinical trial (the DANUBE trial).
Intravenous dosage:
Adults: Dosage not established.
For the treatment of unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemoradiotherapy:
Intravenous dosage:
Adults: 10 mg/kg IV over 60 minutes, every 2 weeks until disease progression or unacceptable toxicity for up to 12 months. In a planned interim analysis of a multicenter, randomized, double-blind, phase 3 clinical trial (the PACIFIC trial), consolidation treatment for up to 12 months with durvalumab after standard platinum-based chemoradiotherapy significantly prolonged median PFS by blinded independent central review (BICR) in patients with locally advanced or unresectable non-small cell lung cancer (NSCLC) compared with placebo (16.8 months vs. 5.6 months). The benefit in PFS was consistent across 35 prespecified subgroups, including PD-L1 25% or higher, PD-L1 less than 25%, and never smokers; hazard ratios for patients who were EGFR mutation-positive or -unknown were not clinically significant. Median overall survival was also significantly improved in the durvalumab arm (not reached vs. 28.7 months).
For the treatment of small cell lung cancer (SCLC):
NOTE: Durvalumab has been designated by the FDA as an orphan drug for the treatment of SCLC.
-for the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with carboplatin and etoposide:
Intravenous dosage:
Adults weighing more than 30 kg: 1,500 mg IV over 60 minutes on day 1, followed by carboplatin (AUC 5 to 6 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.
Adults weighing 30 kg or less: 20 mg/kg IV over 60 minutes on day 1, followed by carboplatin (AUC 5 to 6 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.
-for the first-line treatment of extensive-stage small cell lung cancer (SCLC), in combination with cisplatin and etoposide:
Intravenous dosage:
Adults weighing more than 30 kg: 1,500 mg IV over 60 minutes on day 1, followed by cisplatin (75 to 80 mg/m2 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.
Adults weighing 30 kg or less: 20 mg/kg IV over 60 minutes on day 1, followed by cisplatin (75 to 80 mg/m2 IV on day 1) and etoposide (80 to 100 mg/m2 IV on days 1 to 3), every 3 weeks for 4 cycles; administer durvalumab prior to chemotherapy when given on the same day. Administer appropriate hydration prior to cisplatin administration and maintain hydration and adequate urinary output for 24 hours after cisplatin administration. After completion of 4 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. Durvalumab significantly improved overall survival by approximately 3 months when added to platinum-etoposide chemotherapy compared with platinum-etoposide alone in patients with extensive-stage SCLC in a randomized clinical trial.
For the treatment of biliary tract cancer:
NOTE: Durvalumab has been designated as an orphan drug by the FDA for the treatment of biliary tract cancer.
-for the treatment of locally advanced or metastatic biliary tract cancer, in combination with gemcitabine and cisplatin:
Intravenous dosage:
Adults weighing 30 kg or more: 1,500 mg IV over 60 minutes on day 1, followed by gemcitabine (1,000 mg/m2 IV on days 1 and 8) and cisplatin (25 mg/m2 IV on days 1 and 8), every 3 weeks for up to 8 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 8 cycles of durvalumab plus chemotherapy, continue durvalumab 1,500 mg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. At a planned interim analysis of a multicenter, randomized, double-blind, phase 3 clinical trial (TOPAZ-1), treatment with durvalumab plus gemcitabine and cisplatin significantly improved overall survival (12.8 months vs. 11.5 months) and progression-free survival (7.2 months vs. 5.7 months) compared with placebo plus gemcitabine and cisplatin in patients with locally advanced/unresectable or metastatic biliary tract cancer who had not previously received systemic therapy. The investigator-assessed objective response rate was 27% versus 19%, respectively.
Adults weighing less than 30 kg: 20 mg/kg IV over 60 minutes on day 1, followed by gemcitabine (1,000 mg/m2 IV on days 1 and 8) and cisplatin (25 mg/m2 IV on days 1 and 8), every 3 weeks for up to 8 cycles; administer durvalumab prior to chemotherapy when given on the same day. After completion of 8 cycles of durvalumab plus chemotherapy, continue durvalumab 20 mg/kg IV every 4 weeks as a single agent until disease progression or unacceptable toxicity. At a planned interim analysis of a multicenter, randomized, double-blind, phase 3 clinical trial (TOPAZ-1), treatment with durvalumab plus gemcitabine and cisplatin significantly improved overall survival (12.8 months vs. 11.5 months) and progression-free survival (7.2 months vs. 5.7 months) compared with placebo plus gemcitabine and cisplatin in patients with locally advanced/unresectable or metastatic biliary tract cancer who had not previously received systemic therapy. The investigator-assessed objective response rate was 27% versus 19%, respectively.
For the treatment of hepatocellular cancer*:
NOTE: Durvalumab is designated by the FDA as an orphan drug for this indication.
-for the treatment of unresectable hepatocellular cancer, in combination with tremelimumab*:
NOTE: Tremelimumab is FDA-approved for this indication.
Intravenous dosage:
Adults weighing less than 30 kg: 20 mg/kg IV on day 1. Begin durvalumab 60 minutes after the completion of tremelimumab 4 mg/kg IV on day 1. 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 plus durvalumab (n = 393), durvalumab, or sorafenib (n = 389). Treatment with tremelimumab 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 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: 1,500 mg IV on day 1. Begin durvalumab 60 minutes after the completion of tremelimumab 300 mg IV on day 1. 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 plus durvalumab (n = 393), durvalumab, or sorafenib (n = 389). Treatment with tremelimumab 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 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.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Immune-Mediated Reactions
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 durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Colitis
Grade 2 or 3 toxicity: Hold durvalumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 4 toxicity: Permanently discontinue durvalumab and administer corticosteroids.
Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
Grade 3 or 4 toxicity: Hold durvalumab until the patient is clinically stable; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Permanently discontinue durvalumab 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 durvalumab and administer corticosteroids as applicable.
Confirmed SJS, TEN, or DRESS: Permanently discontinue durvalumab and administer corticosteroids.
Infusion-Related Reactions
Grade 1 or 2 toxicity: Hold durvalumab or slow the infusion rate.
Grade 3 or 4 toxicity: Permanently discontinue durvalumab.
Myocarditis
Grade 2, 3, or 4 toxicity: Permanently discontinue durvalumab and administer corticosteroids.
Neurologic Toxicity
Grade 2 toxicity: Hold durvalumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue durvalumab and administer corticosteroids.
Pneumonitis
Grade 2 toxicity: Hold durvalumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue durvalumab and administer corticosteroids.
Other Immune-Mediated Adverse Reactions
Grade 3 toxicity: Hold durvalumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Recurrent grade 3 toxicity that requires treatment with other systemic immunosuppressants: Permanently discontinue durvalumab.
Grade 4 toxicity: Permanently discontinue durvalumab and administer corticosteroids.
Maximum Dosage Limits:
-Adults
NSCLC: 10 mg/kg IV every 2 weeks or 1,500 mg IV every 4 weeks.
SCLC: 1,500 mg IV every 3 or 4 weeks.
-Geriatric
NSCLC: 10 mg/kg IV every 2 weeks or 1,500 mg IV every 4 weeks.
SCLC: 1,500 mg IV every 3 or 4 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Treatment-Related Immune-Mediated Hepatitis
No Tumor Involvement of the Liver
AST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue durvalumab and administer corticosteroids (i.e., 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).
Tumor Involvement of the Liver
Baseline AST or ALT level at the ULN or less: Hold or permanently discontinue durvalumab based on recommendations for hepatitis with no tumor involvement of the liver.
Baseline AST or ALT level of more than 1 to 3 times the ULN
AST or ALT level of more than 5 to 10 times the ULN: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Baseline AST or ALT level of more than 3 to 5 times the ULN
AST or ALT level of more than 8 to 10 times the ULN: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Any Baseline AST or ALT level
AST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue durvalumab and administer corticosteroids (i.e., 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).
Patients with Renal Impairment Dosing
Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction
Grade 2 or 3 increased serum creatinine (SCr) level: Hold durvalumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue durvalumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Grade 4 increased SCr level: Permanently discontinue durvalumab and administer corticosteroids (i.e., 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).
*non-FDA-approved indication
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Durvalumab is a human IgG1 kappa (IgG1k) monoclonal antibody, produced in Chinese Hamster Ovary (CHO) cell suspension culture, that inhibits programmed death ligand 1 (PD-L1) interactions with the PD-1 and CD80 (B7.1) molecules. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells, can be induced by inflammatory signals (e.g., IFN-gamma), and can contribute to inhibition of the anti-tumor immune response in the tumor microenvironment; PD-1 and B7.1 receptors are found on T-cells and antigen-presenting cells. The PD-1 pathway regulates the balance between T-cell activation and protection of healthy tissues from immune-mediated damage. In cancer, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.
Durvalumab is administered intravenously. Exposure to durvalumab increases more than dose-proportionally at doses less than 3 mg/kg (0.3 times the approved dosage), but increases in a dose-proportional manner at doses greater than or equal to 3 mg/kg every 2 weeks. In a pharmacokinetic study (n = 1,902), steady-state was reached in approximately 16 weeks when administered at doses up to 2 times the recommended dosage every 2, 3, or 4 weeks. The geometric mean volume of distribution at steady state (% coefficient of variation, CV%) was 5.6 liters (CV%, 18%). The mean clearance of durvalumab at steady-state is 8.2 mL/hour (CV%, 39%). Clearance decreases over time, with a mean maximal reduction from baseline of approximately 23% (CV%, 57%); however, the decrease in clearance at steady state is not clinically relevant. The mean terminal half-life was 18 days (CV%, 24%). The pharmacokinetics of durvalumab are similar when assessed as a single-agent and when given in combination with chemotherapy.
Affected cytochrome P450 isoenzymes and transporters: None.
-Special Populations
Hepatic Impairment
Mild to moderate hepatic impairment (bilirubin less than or equal to 3 times the upper limit of normal (ULN) and any AST) does not significantly affect the pharmacokinetics of durvalumab. The effects of severe (bilirubin greater than 3 times ULN and any AST) hepatic impairment on the pharmacokinetics of durvalumab are unknown.
Renal Impairment
Neither creatinine levels nor mild to moderate renal impairment (CrCL 30 to 89 mL/min) had a clinically significant effect the pharmacokinetics of durvalumab. The effect of severe renal impairment (CrCL 15 to 29 mL/min) on the pharmacokinetics of durvalumab is unknown.
Geriatric
Age (19 to 96 years) does not significantly affect the pharmacokinetics of durvalumab.
Gender Differences
Sex does not significantly affect the pharmacokinetics of durvalumab.
Ethnic Differences
Race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American) does not significantly affect the pharmacokinetics of durvalumab.
Obesity
Body weight (31 to 149 kg) does not significantly affect the pharmacokinetics of durvalumab.
Other
Neither albumin levels (4 to 57 g/dL), lactate dehydrogenase (LDH) levels (18 to 15,800 units/L), creatinine levels, soluble PD-L1 (67 to 3,470 pg/mL), tumor type, nor ECOG/WHO performance status had a clinically significant effect on the pharmacokinetics of durvalumab.