Imfinzi

Durvalumab.

Each mL contains durvalumab, 50 mg.
Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution.
Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 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) Injection for intravenous use 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, USP.

Pharmacology: 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.
Pharmacodynamics: The steady state AUC, C_trough, and C_max in patients administered with 1500 mg every 4 weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every 2 weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1500 mg every 4 weeks compared to 10 mg/kg every 2 weeks in patients weighing > 30 kg with NSCLC.
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 1.1-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 1.1 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 PFS analysis 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 Arms 2 and 3: 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 for are summarized in Table 2 and Figure 2. (See Table 2 and Figure 2.)

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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.
Biliary Tract Cancer (BTC): The efficacy of IMFINZI in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic BTC was investigated in TOPAZ-1 (NCT03875235), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 685 patients with histologically confirmed locally advanced unresectable or metastatic BTC who have not previously received systemic therapy. Patients with recurrent disease > 6 months after surgery and/or completion of adjuvant therapy were eligible. Patients had an ECOG Performance status of 0 and 1 and least one target lesion by RECIST 1.1. Patients with ampullary carcinoma; active or prior documented autoimmune or inflammatory disorders; HIV infection or active infections, including tuberculosis or hepatitis C; current or prior use of immunosuppressive medication within 14 days before the first dose of IMFINZI were ineligible.
Randomization was stratified by disease status (recurrent vs. initially unresectable) and primary tumor location (intrahepatic cholangiocarcinoma [ICCA] vs. extrahepatic cholangiocarcinoma [ECCA] vs. gallbladder cancer [GBC]). Patients were randomized 1:1 to receive: IMFINZI 1500 mg on Day 1+ gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by IMFINZI 1500 mg every 4 weeks, or; Placebo on Day 1+ gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by placebo every 4 weeks.
Treatment with IMFINZI or placebo continued until disease progression, or unacceptable toxicity. Treatment beyond disease progression was permitted if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR). Tumor assessments were conducted every 6 weeks for the first 24 weeks after the date of randomization, and then every 8 weeks until confirmed objective disease progression.
The study population characteristics were: 50% male, median age of 64 years (range 20-85), 47% age 65 or older; 56% Asian, 37% White, 2% Black or African American, 0.1% American Indian or Alaskan Native, and 4% other; 51% had an ECOG PS of 1; primary tumor location was ICCA 56%, ECCA 18% and GBC 25%); 20% of patients had recurrent disease; 86% of patients had metastatic and 14% had locally advanced disease.
At a pre-specified interim analysis, the trial demonstrated a statistically significant improvement in OS and PFS in patients randomized to IMFINZI in combination with chemotherapy compared to placebo in combination with chemotherapy. Table 3 summarizes the efficacy results for TOPAZ-1. (See Table 3.)

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The investigator-assessed ORR was 27% (95% CI: 22%-32%) in the IMFINZI plus chemotherapy arm and 19% (95% CI: 15%-23%) in the chemotherapy alone arm. (See Figure 3.)

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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 ≥ to 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 (V_ss) 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 (CL_ss) of 8.2 mL/h (39%) at day 365; the decrease in CL_ss 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.
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 (NSCLC): IMFINZI is indicated for the treatment of 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 (SCLC): IMFINZI in combination with etoposide and either carboplatin or cisplatin is indicated for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).
Biliary Tract Cancer (BTC): IMFINZI in combination with gemcitabine and cisplatin is indicated for the first-line treatment of adults with unresectable or metastatic biliary tract cancer (BTC).

The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with chemotherapy are presented in Table 4 [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
IMFINZI is administered as an intravenous infusion over 60 minutes. (See Table 4.)

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Dosage Modifications for Adverse Reactions: No dose reductions are recommended. In general, withhold or discontinue IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.
Immune-mediated adverse reactions requiring specific management are summarized in Table 5. Refer to Precautions for further monitoring and evaluation information. (See Table 5.)

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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, USP or 5% Dextrose Injection, USP. 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 (36°F to 46°F); 12 hours at room temperature up to 25°C (77°F).
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.

There is no information on overdose with IMFINZI.

None.

Refer to Table 5 under Dosage & Administration for recommended treatment modifications and management of immune-mediated adverse reactions.
Immune-mediated pneumonitis: Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related etiologies excluded, and managed as recommended in Dosage & Administration [see Dosage & Administration].
Pneumonitis and radiation pneumonitis: Radiation pneumonitis is frequently observed in patients receiving radiation therapy to the lung and the clinical presentation of pneumonitis and radiation pneumonitis is very similar. In the PACIFIC Study, in patients who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the trial, pneumonitis and radiation pneumonitis occurred in patients receiving IMFINZI. Pneumonitis or radiation pneumonitis occurred in 161 (33.9%) patients in the IMFINZI-treated group and 58 (24.8%) in the placebo group; including Grade 3 in 16 (3.4%) patients on IMFINZI vs. 7 (3.0%) patients on placebo and Grade 5 in 5 (1.1%) patients on IMFINZI vs. 4 (1.7%) patients on placebo. The median time to onset in the IMFINZI-treated group was 55 days (range: 1-406 days) vs. 55 days (range: 1-255 days) in the placebo group.
In patients receiving IMFINZI monotherapy, immune-mediated pneumonitis occurred in 92 (3.1%) patients, including Grade 3 in 25 (0.8%) patients, Grade 4 in 2 (<0.1%) patients, and Grade 5 in 6 (0.2%) patients. The median time to onset was 55 days (range: 2-785 days). Sixty-nine of the 92 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), 2 patients also received infliximab and 1 patient also received cyclosporine. IMFINZI was discontinued in 38 patients. Resolution occurred in 53 patients. Immune-mediated pneumonitis occurred more frequently in patients in the PACIFIC Study who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the study (9.9%), compared to the other patients in the combined safety database (1.8%).
In the PACIFIC Study, in patients with locally advanced, unresectable NSCLC (n=475 in the IMFINZI arm, and n=234 in the placebo arm) who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the study, immune-mediated pneumonitis occurred in 47 (9.9%) patients in the IMFINZI-treated group and 14 (6.0%) patients in the placebo group, including Grade 3 in 9 (1.9%) patients on IMFINZI vs. 6 (2.6%) patients on placebo and Grade 5 in 4 (0.8%) patients on IMFINZI vs. 3 (1.3%) patients on placebo. The median time to onset in the IMFINZI-treated group was 46 days (range: 2-342 days) vs. 57 days (range: 26-253 days) in the placebo group. In the IMFINZI-treated group 30 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 2 patients also received infliximab. In the placebo group 12 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the IMFINZI treated group vs 6 in placebo.
Immune-mediated hepatitis: Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for abnormal liver tests prior to and periodically during treatment with IMFINZI. Immune-mediated hepatitis should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated hepatitis occurred in 67 (2.2%) patients, including Grade 3 in 35 (1.2%) patients, Grade 4 in 6 (0.2%) and Grade 5 in 4 (0.1%) patients. The median time to onset was 36 days (range: 3-333 days). Forty-four of the 67 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received mycophenolate treatment. IMFINZI was discontinued in 9 patients. Resolution occurred in 29 patients.
Immune-mediated colitis: Immune-mediated colitis or diarrhea, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for signs and symptoms of colitis or diarrhea and managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated colitis or diarrhea occurred in 58 (1.9%) patients, including Grade 3 in 9 (0.3%) patients and Grade 4 in 2 (<0.1%) patients. The median time to onset was 70 days (range: 1-394 days). Thirty-eight of the 58 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received infliximab treatment and one patient also received mycophenolate treatment. IMFINZI was discontinued in 9 patients. Resolution occurred in 43 patients.
Immune-mediated endocrinopathies: Immune-mediated hypothyroidism/hyperthyroidism/thyroiditis: Immune-mediated hypothyroidism, hyperthyroidism or thyroiditis have occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and managed as recommended in Dosage & Administration [see Dosage & Administration].
Immune-mediated hypothyroidism: In patients receiving IMFINZI monotherapy, immune-mediated hypothyroidism occurred in 245 (8.2%) patients, including Grade 3 in 4 (0.1%) patients. The median time to onset was 85 days (range: 1-562 days). Of the 245 patients, 240 patients received hormone replacement therapy, 6 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism followed by hormone replacement. No patients discontinued IMFINZI due to immune-mediated hypothyroidism. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 20 patients or immune-mediated thyroiditis in 3 patients.
Immune-mediated hyperthyroidism: In patients receiving IMFINZI monotherapy, immune-mediated hyperthyroidism occurred in 50 (1.7%) patients, there were no Grade 3 or 4 cases. The median time to onset was 43 days (range: 1-253 days). Forty-six of the 50 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker), 11 patients received systemic corticosteroids and 4 of the 11 patients received high-dose systemic corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated hyperthyroidism. Resolution occurred in 39 patients.
Immune-mediated thyroiditis: In patients receiving IMFINZI monotherapy, immune-mediated thyroiditis occurred in 12 (0.4%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 49 days (range: 14-106 days). Of the 12 patients, 10 patients received hormone replacement therapy, 1 patient received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated thyroiditis.
Immune-mediated adrenal insufficiency: Immune-mediated adrenal insufficiency occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated adrenal insufficiency occurred in 14 (0.5%) patients, including Grade 3 in 3 (<0.1%) patients. The median time to onset was 146 days (range: 20-547 days). All 14 patients received systemic corticosteroids; 4 of the 14 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). No patients discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 3 patients.
Immune-mediated type 1 diabetes mellitus: Immune-mediated type 1 diabetes mellitus, which can present with diabetic ketoacidosis, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus, patients should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, Grade 3 immune-mediated type 1 diabetes mellitus occurred in 1 (<0.1%) patient. The time to onset was 43 days. This patient required long-term insulin therapy and IMFINZI was permanently discontinued due to immune-mediated type 1 diabetes mellitus.
Immune-mediated hypophysitis/hypopituitarism: Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated hypophysitis/hypopituitarism occurred in 2 (<0.1%) patients both Grade 3. The time to onset for the events was 44 days and 50 days. Both patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and one patient discontinued IMFINZI due to immune-mediated hypophysitis/hypopituitarism.
Immune-mediated nephritis: Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for abnormal renal function tests prior to and periodically during treatment with IMFINZI and managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated nephritis occurred in 14 (0.5%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 71 days (range: 4-393 days). Nine patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received mycophenolate. IMFINZI was discontinued in 5 patients. Resolution occurred in 8 patients.
Immune-mediated rash: Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI [see Adverse Reactions]. Patients should be monitored for signs and symptoms of rash or dermatitis and managed as recommended in Dosage & Administration [see Dosage & Administration].
In patients receiving IMFINZI monotherapy, immune-mediated rash or dermatitis (including pemphigoid) occurred in 50 (1.7%) patients, including Grade 3 in 12 (0.4%) patients. The median time to onset was 43 days (range: 4-333 days). Twenty-four of the 50 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 3 patients. Resolution occurred in 31 patients.
Other immune-mediated adverse reactions: Given the mechanism of action of IMFINZI, other potential immune-mediated adverse reactions may occur. Patients should be monitored for signs and symptoms and managed as recommended in Dosage & Administration [see Dosage & Administration]. Other immune-mediated adverse reactions are myasthenia gravis, myocarditis, myositis, polymyositis and immune thrombocytopenia, pancreatitis and encephalitis.
Infusion-related reactions: Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusion-related reactions have been reported in patients receiving IMFINZI [see Adverse Reactions].
In patients receiving IMFINZI monotherapy, infusion-related reactions occurred in 49 (1.6%) patients, including Grade 3 in 5 (0.2%) patients. There were no Grade 4 or 5 events.
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 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.
Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult 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 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 [see Precautions]; Immune-mediated hepatitis [see Precautions]; Immune-mediated colitis [see Precautions]; Immune-mediated endocrinopathies [see Precautions]; Immune-mediated nephritis [see Precautions]; Immune-mediated rash [see Precautions]; Other immune-mediated adverse reactions [see Precautions]; 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), and Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumours), and additional open-label, single-arm trial that enrolled 444 patients with metastatic lung cancer, indications 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 reflects 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 338 patients from the TOPAZ-1 study (a randomized, double-blind study in patients with BTC). In the CASPIAN and TOPAZ-1 studies, 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 and in patients with BTC enrolled in the TOPAZ-1 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 6 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. (See Table 6.)

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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 7 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. (See Table 7.)

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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 8 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 8.)

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Table 9 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. (See Table 9.)

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Biliary Tract Cancer: The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomized, double-blind, placebo-controlled, multicenter trial. A total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis C were ineligible [see Pharmacology: Clinical Studies under Actions].
IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in 1 patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia. Table 10 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 10.)

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Table 11 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. (See Table 11.)

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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 profile.
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.
Of the 240 patients in the TOPAZ-1 study who received IMFINZI 1500 mg every 3 weeks in combination with chemotherapy up to 8 cycles followed by IMFINZI 1500 mg every 4 weeks, 2 (0.8%) patients tested positive for treatment emergent ADAs and neutralizing antibodies, respectively. There were insufficient numbers of patients with treatment-emergent ADAs or neutralizing antibodies (2 patients each) to determine whether ADAs have an impact on pharmacokinetics, pharmacodynamics, safety and/or effectiveness of IMFINZI.

Durvalumab is an immunoglobulin, therefore no formal pharmacokinetic drug-drug interaction studies have been conducted with durvalumab.

Incompatibilities: Durvalumab: No incompatibilities between IMFINZI and 9 g/L (0.9%) sodium chloride or 50 g/L (5%) dextrose in polyvinylchloride or polyolefin IV bags have been observed.
This drug product must not be mixed with other drug products except those mentioned in Preparation and Administration under Dosage & Administration.
Do not co-administer other drugs through the same intravenous line.

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.
Do not freeze. Do not shake.

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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