Imfinzi

Durvalumab.

Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution.
Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution.
Durvalumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture.
IMFINZI (durvalumab) CONCENTRATE FOR SOLUTION FOR INFUSION is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles.
Excipients/Inactive Ingredients: Each mL contains L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection.

Pharmacology: Pharmacodynamics: Mechanism of Action: Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production.
Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). 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.
Clinical Studies: Non-Small Cell Lung Cancer (NSCLC): The efficacy of IMFINZI was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (<65 years vs. ≥ 65 years), and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive IMFINZI 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST v1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST v1.1, and overall survival (OS). Additional efficacy outcome measures included ORR and DoR assessed by BICR.
A total of 713 patients were randomized: 476 patients to the IMFINZI arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers, and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy, and 2% switched between cisplatin and carboplatin).
At a pre-specified interim analysis for OS based on 299 events (61% of total planned events), the study demonstrated a statistically significant improvement in OS in patients randomized to IMFINZI compared to placebo. The pre-specified interim analysis of PFS based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to IMFINZI compared to placebo. Table 1 and Figure 1 summarizes the efficacy results for PACIFIC. (See Table 1 and Figure 1.)

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Click on icon to see table/diagram/image

Small Cell Lung Cancer (SCLC): The efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was investigated in CASPIAN, a randomized, multicenter, active-controlled, open-label trial (NCT03043872). Eligible patients had WHO Performance Status of 0 or 1 and were suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC. Patients with asymptomatic or treated brain metastases were eligible. Choice of platinum agent was at the investigator's discretion, taking into consideration the calculated creatinine clearance. Patients with history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome; active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible.
Randomization was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin).
The evaluation of efficacy for ES-SCLC relied on comparison between: IMFINZI 1500 mg, and investigator's choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m²) on Day 1 and etoposide (80-100 mg/m²) intravenously on Days 1, 2, and 3 of each 21-day cycle for 4 cycles, followed by IMFINZI 1500 mg every 4 weeks until disease progression or unacceptable toxicity; or Investigator's choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m²) on Day 1 and etoposide (80-100 mg/m²) intravenously on Days 1, 2, and 3 of each 21-day cycle, up to 6 cycles. After completion of chemotherapy, prophylactic cranial irradiation (PCI) as administered per investigator discretion.
Administration of IMFINZI as a single agent was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
The major efficacy outcome measure was overall survival (OS) of IMFINZI plus chemotherapy vs. chemotherapy alone. Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1.
The study population characteristics were: median age of 63 years (range: 28 to 82); 40% age 65 or older; 70% male; 84% White, 15% Asian, and 0.9% Black; 65% WHO/ECOG PS of 1; and 93% were former/current smokers. Ninety percent of patients had Stage IV disease and 10% had brain metastasis at baseline. A total of 25% of the patients received cisplatin and 74% of the patients received carboplatin. In the chemotherapy alone arm, 57% of the patients received 6 cycles of chemotherapy, and 8% of the patients received PCI.
The OS results are summarized in Table 2 and Figure 2. (See Table 2 and Figure 2.)

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Click on icon to see table/diagram/image

Investigator-assessed PFS (96% of total planned events) showed a HR of 0.78 (95% CI: 0.65, 0.94), with median PFS of 5.1 months (95% CI: 4.7, 6.2) in the IMFINZI plus chemotherapy arm and 5.4 months (95% CI: 4.8, 6.2) in the chemotherapy alone arm. The investigator-assessed confirmed ORR was 68% (95% CI: 62%, 73%) in the IMFINZI plus chemotherapy arm and 58% (95% CI: 52%, 63%) in the chemotherapy alone arm.
In the exploratory subgroup analyses of OS based on the planned platinum chemotherapy received at cycle 1, the HR was 0.70 (95% CI 0.55, 0.89) in patients who received carboplatin, and the HR was 0.88 (95% CI 0.55, 1.41) in patients who received cisplatin.
Pharmacokinetics: The pharmacokinetics of durvalumab as a single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three, or four weeks.
PK exposure increased more than dose-proportionally at doses < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks.
The pharmacokinetics of durvalumab is similar when assessed as a single agent and when in combination with chemotherapy.
Distribution: The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.6 (18%) L.
Elimination: Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.2 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 18 (24%) days.
Specific Populations: Age (19-96 years), body weight (31-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST), or ECOG/WHO performance status had no clinically significant effect on the pharmacokinetics of durvalumab.
The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin > 1.5 to 3x ULN and any AST) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic and genotoxic potential of durvalumab have not been evaluated.
Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.
Animal Toxicology and/or Pharmacology: In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

Non-Small Cell Lung Cancer: IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
Small Cell Lung Cancer: IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Recommended Dosage: The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with chemotherapy are presented in Table 3 [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
IMFINZI is administered as an intravenous infusion over 60 minutes. (See Table 3.)

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Dosage Modifications for Adverse Reactions: No dose reductions are recommended. Withhold or discontinue IMFINZI to manage adverse reactions as described in Table 4. (See Table 4.)

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Preparation and Administration: Preparation: Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.
Do not shake the vial.
Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL.
Discard partially used or empty vials of IMFINZI.
Storage of Infusion Solution: IMFINZI does not contain a preservative.
Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from vial puncture to the start of the administration should not exceed: 24 hours in a refrigerator at 2°C to 8°C; 8 hours at room temperature up to 25°C.
Do not freeze.
Do not shake.
Administration: Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
Do not co-administer other drugs through the same infusion line.

None.

Immune-Mediated Pneumonitis: IMFINZI can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported.
Monitor patients for signs and symptoms of pneumonitis. Confirm patients with suspected pneumonitis with radiographic imaging and other infectious and disease-related aetiologies excluded. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent for moderate (Grade 2) pneumonitis or prednisone 1 to 4 mg per kg per day or equivalent for more severe (Grade 3-4) pneumonitis, followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (< 0.1%) and Grade 5 (0.3%). The median time to onset was 1.8 months (range: 1 day to 13.9 months) and the median time to resolution was 4.9 months (range: 0 days to 13.7 months). Pneumonitis led to discontinuation of IMFINZI in 1.5% of the 1889 patients. Pneumonitis was resolved in 54% of patients. Systemic corticosteroids were required in 3.5% of the 1889 patients, with 2.5% requiring high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) and 0.1% requiring infliximab.
The frequency and severity of immune-mediated pneumonitis were similar whether IMFINZI was given as a single agent in patients with various cancers or in combination with chemotherapy in patients with ES-SCLC.
The incidence of pneumonitis (including radiation pneumonitis) was higher in patients in the PACIFIC study who completed treatment with definitive chemoradiation within 42 days prior to initiation of IMFINZI (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI.
In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and the incidence of Grade 5 pneumonitis was 1.1% in the IMFINZI arm. The median time to onset of pneumonitis was 1.8 months and the median duration was 2.1 months (range: 3 days to 18.7 months). Pneumonitis led to discontinuation of IMFINZI in 6% of patients. Pneumonitis resolved in 47% of patients experiencing pneumonitis. Systemic corticosteroids were required in 21% of patients, with 12% requiring high-dose corticosteroids and 0.1% requiring infliximab.
Immune-Mediated Hepatitis: IMFINZI can cause immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported.
Monitor patients for signs and symptoms of hepatitis, during and after discontinuation of IMFINZI, including clinical chemistry monitoring. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, followed by taper for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin. Interrupt or permanently discontinue IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%) and Grade 5 (0.2%) immune-mediated hepatitis. The median time to onset was 1.2 months (range: 1 day to 13.6 months). Hepatitis led to discontinuation of IMFINZI in 0.7% of the 1889 patients. Hepatitis resolved in 49% of patients. Systemic corticosteroids were required in 2.7% of patients, with 1.7% requiring high-dose corticosteroids and 0.1% requiring mycophenolate.
Immune-Mediated Colitis: IMFINZI can cause immune-mediated colitis, defined as requiring use of corticosteroids.
Monitor patients for signs and symptoms of diarrhea or colitis. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or more severe (Grade 3-4) colitis, followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], diarrhea or colitis occurred in 18% of patients, including Grade 3 (1%) and Grade 4 (0.1%) immune-mediated colitis. The median time to onset was 1.4 months (range: 1 day to 14 months). Diarrhea or colitis lead to discontinuation of IMFINZI in 0.4% of the 1889 patients. Diarrhea or colitis resolved in 78% of the patients. Systemic corticosteroids were required in 1.9% of patients, with 1% requiring high-dose corticosteroids and 0.1% requiring other immunosuppressants (e.g., infliximab, mycophenolate).
Immune-Mediated Endocrinopathies: IMFINZI can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism.
Thyroid Disorders: Monitor thyroid function prior to and periodically during treatment with IMFINZI. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Continue IMFINZI for hypothyroidism and interrupt for hyperthyroidism based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], hypothyroidism occurred in 11% of patients and hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (< 0.1%) thyroiditis. Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients.
Adrenal Insufficiency: Monitor patients for clinical signs and symptoms of adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement as clinically indicated. Interrupt IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients who received IMFINZI, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (< 0.1%). Systemic corticosteroids were required in 0.4% of patients, including 0.1% of patients who required high-dose corticosteroids.
Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Interrupt IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients who received IMFINZI, type 1 diabetes mellitus occurred in < 0.1 % of patients. The median time to onset was 1.4 months.
Hypophysitis: For Grade 2 or higher hypophysitis, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement therapy as clinically indicated. Interrupt IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in < 0.1% of 1889 patients who received IMFINZI in clinical studies.
Immune-Mediated Nephritis: IMFINZI can cause immune-mediated nephritis defined as evidence of renal dysfunction requiring use of corticosteroids. Fatal cases have occurred.
Monitor patients for abnormal renal function tests prior to and periodically during treatment with IMFINZI. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or severe (Grade 3-4) nephritis, followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], nephritis (reported as any of the following increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of patients including Grade 3 (1.1%), Grade 4 (0.2%), and Grade 5 (0.1%) immune-mediated nephritis. The median time to onset was 2 months (range: 1 day to 14.2 months). IMFINZI was discontinued in 0.3% of the 1889 patients. Nephritis resolved in 50% of patients. Systemic corticosteroids were required in 0.6% of patients, with 0.4% receiving high-dose corticosteroids.
Immune-Mediated Dermatologic Reactions: IMFINZI can cause immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate etiology. Other dermatologic reactions have occurred with other products in this class including Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Other Immune-Mediated Adverse Reactions as follows].
Monitor for signs and symptoms of rash. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) rash or dermatitis lasting for more than 1 week or severe (Grade 3-4) rash or dermatitis followed by taper. Interrupt or permanently discontinue IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], 26% of patients developed rash or dermatitis. Rash or dermatitis led to discontinuation of IMFINZI in 0.1% of the 1889 patients. Rash resolved in 62% of patients. Systemic corticosteroids were required in 2% of patients, including high-dose corticosteroids in 1% of patients.
Other Immune-Mediated Adverse Reactions: IMFINZI can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with IMFINZI, immune-mediated adverse reactions can also manifest after discontinuation of IMFINZI.
For suspected Grade 2 immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. For severe (Grade 3 or 4) adverse reactions, administer corticosteroids, prednisone 1 to 4 mg per kg per day or equivalent, followed by taper. Interrupt or permanently discontinue IMFINZI, based on the severity of the reaction [see Dosage Modifications for Adverse Reactions under Dosage & Administration]. If uveitis occurs in combination with other immune-mediated adverse reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received IMFINZI: aseptic meningitis, hemolytic anemia, immune thrombocytopenia, myocarditis, myositis/polymyositis, and ocular inflammatory toxicity, including uveitis and keratitis [see Clinical Trials Experience under Adverse Reactions]. In patients who received IMFINZI in clinical studies outside of the pooled dataset, myasthenia gravis occurred at an incidence of less than 0.1%. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, histiocytic necrotizing lymphadenitis, vasculitis, hemolytic anemia, iritis, encephalitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome and Vogt-Koyanagi-Harada syndrome.
Infection: IMFINZI can cause serious infections, including fatal cases.
Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold IMFINZI and resume once clinically stable [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
In clinical studies enrolling 1889 patients with various cancers who received IMFINZI [see Clinical Trials Experience under Adverse Reactions], infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1%). In the PACIFIC study the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients. The overall incidence of infections in IMFINZI-treated patients (56%) in the PACIFIC study was higher compared to patients in other studies (38%) in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI.
Infusion-Related Reactions: IMFINZI can cause severe or life-threatening infusion-related reactions.
Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
In clinical studies enrolling 1889 patients with various cancers [see Clinical Trials Experience under Adverse Reactions], infusion-related reactions occurred in 2.2% of patients, including Grade 3 (0.3%).
Embryo-Fetal Toxicity: Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of IMFINZI [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Use in Children: The safety and effectiveness of IMFINZI have not been established in pediatric patients.
Use in the Elderly: Of the 476 patients treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients.
Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy, 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients.

Pregnancy: Risk summary: Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman [see Pharmacology: Pharmacodynamics: Mechanism of Action under Actions]. There are no data on the use of IMFINZI in pregnant women.
In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery resulted in an increase in premature delivery, fetal loss and premature neonatal death [see Data as follows]. Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data: Animal Data: As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth) and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice.
Lactation: Risk Summary: There is no information regarding the presence of durvalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG1 is excreted in human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death [see Data as follows].
Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IMFINZI and for at least 3 months after the last dose.
Data: In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death.
Females and Males of Reproductive Potential: Contraception: Females: Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned]. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for at least 3 months following the last dose of IMFINZI.

The following adverse reactions are discussed in greater detail in Precautions: Immune-Mediated Pneumonitis; Immune-Mediated Hepatitis; Immune-Mediated Colitis; Immune-Mediated Endocrinopathies; Immune-Mediated Nephritis; Immune-Mediated Dermatologic Reactions; Other Immune-Mediated Adverse Reactions; Infection; Infusion-Related Reactions. [See Precautions.]
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in Precautions reflect exposure to IMFINZI in 1889 patients from the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open-label, single-arm trial that enrolled 444 patients with metastatic lung cancer, an indication for which durvalumab is not approved. In these trials, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. The data also reflect exposure to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC). In the CASPIAN study, IMFINZI was administered at a dose of 1500 mg every 3 or 4 weeks.
The data described in this section reflect exposure to IMFINZI in patients with Stage III NSCLC enrolled in the PACIFIC study and in patients with ES-SCLC enrolled in the CASPIAN study.
Non-Small Cell Lung Cancer: The safety of IMFINZI in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received IMFINZI 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to IMFINZI was 10 months (range: 0.2 to 12.6).
IMFINZI was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to IMFINZI discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea and rash.
Table 5 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. (See Table 5.)

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Other adverse reactions occurring in less than 10% of patients treated with IMFINZI were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections.
Table 6 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. (See Table 6.)

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Small Cell Lung Cancer: The safety of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, a randomized, open-label, multicenter, active-controlled trial. A total of 265 patients received IMFINZI 1500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by IMFINZI 1500 mg every 4 weeks until disease progression or unacceptable toxicity. The trial excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Among 265 patients receiving IMFINZI, 49% were exposed for 6 months or longer and 19% were exposed for 12 months or longer.
Among 266 patients receiving chemotherapy alone, 57% of the patients received 6 cycles of chemotherapy and 8% of the patients received PCI after chemotherapy.
IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue/asthenia and alopecia.
Table 7 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 7.)

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Table 8 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. (See Table 8.)

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Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to durvalumab to the incidence of antibodies to other products may be misleading.
Of 2280 patients who received IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as a single-agent, 69 patients (3%) tested positive for treatment-emergent anti-drug antibodies (ADA) and 12 (0.5%) tested positive for neutralizing antibodies. The development of ADA against durvalumab appears to have no clinically relevant effect on its pharmacokinetics or safety.
Of 201 patients in the CASPIAN study who received IMFINZI 1500 mg every 3 weeks in combination with chemotherapy for four doses followed by IMFINZI 1500 mg every 4 weeks no patients tested positive for treatment-emergent ADA.

Store at 2°C to 8°C in the original carton to protect from light.
Do not freeze or shake.

Advise the patient to read the Medication Guide.
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI, including: Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Precautions].
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Precautions].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain [see Precautions].
Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis [see Precautions].
Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Precautions].
Dermatological Reactions: Advise patients to contact their healthcare provider immediately signs or symptoms of severe dermatological reactions [see Precautions].
Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis [see Precautions].
Infection: Advise patients to contact their healthcare provider immediately for infection [see Precautions].
Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Precautions].
Embryo-Fetal Toxicity: Advise females of reproductive potential that IMFINZI can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Precautions and Use in Pregnancy & Lactation].
Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of IMFINZI [see Use in Pregnancy & Lactation].
Lactation: Advise female patients not to breastfeed while taking IMFINZI and for at least 3 months after the last dose [see Precautions and Use in Pregnancy & Lactation].

Targeted Cancer Therapy / Cancer Immunotherapy

L01FF03 - durvalumab ; Belongs to the class of PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. Used in the treatment of cancer.

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