durvalumab

Antineoplastic Monoclonal Antibodies Targeting Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways

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.

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.

neutropenia / Delayed / 37.0-48.0
anemia / Delayed / 4.8-31.0
leukopenia / Delayed / 0.8-28.0
elevated hepatic enzymes / Delayed / 1.8-27.0
lymphopenia / Delayed / 11.0-23.0
thrombocytopenia / Delayed / 1.6-18.0
hyponatremia / Delayed / 3.6-18.0
hyperglycemia / Delayed / 0-14.0
hypomagnesemia / Delayed / 4.0-11.0
hyperbilirubinemia / Delayed / 0.9-10.0
hyperamylasemia / Delayed / 0-9.0
infection / Delayed / 0.4-8.0
hypokalemia / Delayed / 0-8.0
diarrhea / Early / 0.6-6.0
fatigue / Early / 0.8-6.0
hepatitis / Delayed / 1.9-5.2
nephrotoxicity / Delayed / 1.3-5.0
asthenia / Delayed / 0-5.0
pneumonitis / Delayed / 0.4-3.8
hyperkalemia / Delayed / 1.1-3.8
colitis / Delayed / 0.4-3.6
hypoalbuminemia / Delayed / 0.5-3.6
hypocalcemia / Delayed / 0-3.5
sepsis / Delayed / 0-3.3
rash / Early / 0-2.8
musculoskeletal pain / Early / 0-2.6
anorexia / Delayed / 0.8-2.1
abdominal pain / Early / 0.4-1.8
nausea / Early / 0-1.8
pancreatitis / Delayed / 0-1.8
dyspnea / Early / 0-1.5
vomiting / Early / 0-1.5
fever / Early / 0-1.5
alopecia / Delayed / 0-1.1
uveitis / Delayed / 0-1.0
hemolytic anemia / Delayed / 0-1.0
aplastic anemia / Delayed / 0-1.0
hemophagocytic lymphohistiocytosis / Delayed / 0-1.0
myocarditis / Delayed / 0-1.0
pericarditis / Delayed / 0-1.0
vasculitis / Delayed / 0-1.0
rhabdomyolysis / Delayed / 0-1.0
myelitis / Delayed / 0-1.0
aseptic meningitis / 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 / 0-0.8
constipation / Delayed / 0-0.8
adrenocortical insufficiency / Delayed / 0-0.8
hypophysitis / Delayed / 0-0.5
hypothyroidism / Delayed / 0-0.5
interstitial nephritis / Delayed / 0-0.5
hyperthyroidism / Delayed / 0-0.3
diabetes mellitus / Delayed / 0-0.3
infusion-related reactions / Rapid / 0-0.3
insomnia / Early / 0-0.3
GI perforation / Delayed / 0-0.1
thyroiditis / Delayed / 0-0.1
immune-mediated reactions / Delayed / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
visual impairment / Early / Incidence not known
retinal detachment / Delayed / Incidence not known
Vogt-Koyanagi-Harada syndrome / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
renal failure / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
intracranial bleeding / Delayed / Incidence not known

hypernatremia / Delayed / 0-15.0
stomatitis / Delayed / 0-10.0
dysuria / Early / 0-10.0
peripheral edema / Delayed / 0-10.0
edema / Delayed / 0-10.0
dysphonia / Delayed / 0-10.0
antibody formation / Delayed / 0-10.0
cholangitis / Delayed / 0-7.0
gastritis / Delayed / 0-1.0
hypoparathyroidism / Delayed / 0-1.0
ocular inflammation / Early / 0-1.0
iritis / Delayed / 0-1.0
peripheral neuropathy / Delayed / 0-1.0
paresis / Delayed / 0-1.0
sarcoidosis / Delayed / 0-1.0
interstitial lung disease / Delayed / Incidence not known
hypopituitarism / Delayed / Incidence not known
bullous rash / Early / Incidence not known
erythema / Early / Incidence not known
bone pain / Delayed / Incidence not known
migraine / Early / Incidence not known
hyperthermia / Delayed / Incidence not known

pruritus / Rapid / 11.0-23.0
headache / Early / 0-11.0
night sweats / Early / 0-10.0
purpura / Delayed / 0-1.0
maculopapular rash / Early / Incidence not known
acneiform rash / Delayed / Incidence not known
myalgia / Early / Incidence not known
back pain / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known
laryngitis / Delayed / Incidence not known
rhinitis / Early / Incidence not known
sinusitis / Delayed / Incidence not known
malaise / Early / Incidence not known

IMFINZI

Rx

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

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]

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.

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.

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.

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.

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. 

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. 

Dosage not established.

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.

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

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).

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).

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.

IMFINZI Intravenous Inj Sol: 1mL, 50mg

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.

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.

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.