CLASSES
Antineoplastic Monoclonal Antibodies Targeting Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways
DESCRIPTION
Programmed death-ligand 1 (PD-L1) blocking monoclonal antibody
Used for certain types of NSCLC, SCLC, and biliary tract cancer
Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued
COMMON BRAND NAMES
IMFINZI
HOW SUPPLIED
IMFINZI Intravenous Inj Sol: 1mL, 50mg
DOSAGE & INDICATIONS
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).[62499] [61913]
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 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 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.
†Indicates off-label use
MAXIMUM DOSAGE
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.
DOSING CONSIDERATIONS
Hepatic Impairment
Treatment-Related Immune-Mediated HepatitisNo Tumor Involvement of the LiverAST 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 LiverBaseline 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 ULNAST 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 ULNAST 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 levelAST 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).
Renal Impairment
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).
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.
STORAGE
IMFINZI:
- Discard partially used or empty vials
- Discard product if it contains particulate matter, is cloudy, or discolored
- Do not freeze
- Prepared infusion solution may be stored from vial puncture to administration not to exceed 8 hours at room temperature up to 25 degrees C (77 degrees F)
- Prior to dilution store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)
- See package insert for detailed storage information
- Store diluted product in accordance with package insert instructions
- Store in the original carton to protect from light
CONTRAINDICATIONS / PRECAUTIONS
Immune-mediated reactions
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.
Pneumonitis, radiation 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.
Hepatitis
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.
Colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, viral infection
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.
Hyperthyroidism, hypothyroidism
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.
Adrenal insufficiency, hypophysitis, hypopituitarism
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.
Autoimmune disease, organ transplant, systemic lupus erythematosus (SLE)
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.
Diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus
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.
Serious rash
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.
Renal impairment
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.
Infusion-related reactions
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).
Guillain-Barre syndrome, myasthenia gravis, neurological disease
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.
Allogeneic stem cell transplant
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.
Pregnancy
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.
Contraception requirements, pregnancy testing, reproductive risk
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.
Breast-feeding
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.
ADVERSE REACTIONS
Severe
neutropenia / Delayed / 0-48.0
hyperkalemia / Delayed / 0-30.9
leukopenia / Delayed / 0-28.0
lymphopenia / Delayed / 14.0-23.0
hypomagnesemia / Delayed / 0-11.0
hyponatremia / Delayed / 3.6-11.0
hyperglycemia / Delayed / 5.0-8.0
infection / Delayed / 0-7.0
fatigue / Early / 0.8-6.0
elevated hepatic enzymes / Delayed / 2.3-4.9
pneumonitis / Delayed / 0.5-3.6
hypoalbuminemia / Delayed / 0-3.6
hypocalcemia / Delayed / 0.2-3.5
anorexia / Delayed / 0-2.1
hepatitis / Delayed / 1.7-1.8
dyspnea / Early / 0-1.5
vomiting / Early / 0-1.5
nausea / Early / 0-1.5
fever / Early / 0.2-1.5
diarrhea / Early / 0.6-1.2
toxic epidermal necrolysis / Delayed / 0-1.0
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / 0-1.0
Stevens-Johnson syndrome / Delayed / 0-1.0
exfoliative dermatitis / Delayed / 0-1.0
uveitis / Delayed / 0-1.0
aplastic anemia / Delayed / 0-1.0
hemolytic anemia / Delayed / 0-1.0
pericarditis / Delayed / 0-1.0
myocarditis / Delayed / 0-1.0
aseptic meningitis / Delayed / 0-1.0
pancreatitis / Delayed / 0-1.0
myasthenia gravis / Delayed / 0-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
organ transplant rejection / Delayed / 0-1.0
cough / Delayed / 0.6-0.8
constipation / Delayed / 0.6-0.8
abdominal pain / Early / 0.4-0.6
rash / Early / 0-0.6
colitis / Delayed / 0.4-0.5
interstitial nephritis / Delayed / 0.5-0.5
adrenocortical insufficiency / Delayed / 0-0.1
pulmonary fibrosis / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
Vogt-Koyanagi-Harada syndrome / Delayed / Incidence not known
myelitis / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
graft-versus-host disease (GVHD) / Delayed / Incidence not known
veno-occlusive disease (VOD) / Delayed / Incidence not known
Moderate
thrombocytopenia / Delayed / 0-18.0
anemia / Delayed / 0-13.0
dysuria / Early / 0-10.0
dysphonia / Delayed / 0-10.0
cholangitis / Delayed / 0-7.0
antibody formation / Delayed / 2.9-2.9
hypoparathyroidism / Delayed / 0-1.0
ocular inflammation / Early / 0-1.0
iritis / Delayed / 0-1.0
gastritis / Delayed / 0-1.0
paresis / Delayed / 0-1.0
infusion-related reactions / Rapid / 0.3-0.3
hypopituitarism / Delayed / 0-0.1
diabetes mellitus / Delayed / 0-0.1
interstitial lung disease / Delayed / Incidence not known
flank pain / Delayed / Incidence not known
hypophysitis / Delayed / Incidence not known
erythema / Early / Incidence not known
Mild
pruritus / Rapid / 0-12.0
night sweats / Early / 0-10.0
insomnia / Early / 0-10.0
maculopapular rash / Early / Incidence not known
pharyngitis / Delayed / Incidence not known
sinusitis / Delayed / Incidence not known
rhinitis / Early / Incidence not known
laryngitis / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
malaise / Early / Incidence not known
alopecia / Delayed / Incidence not known
DRUG INTERACTIONS
Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
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.
PREGNANCY AND LACTATION
Pregnancy
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.
MECHANISM OF ACTION
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.
PHARMACOKINETICS
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.