Imfinzi

Durvalumab.

Sterile, preservative free, clear to opalescent and free from visible particles, colourless to slightly yellow.
Each vial of IMFINZI concentrated solution for infusion contains either 120 mg or 500 mg of durvalumab.
Excipients/Inactive Ingredients: Histidine, Histidine hydrochloride monohydrate, Trehalose dihydrate, Polysorbate 80, Water for injection.

Pharmacology: Pharmacodynamics: Mechanism of action: Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response that helps tumours evade detection and elimination by the immune system. PD-L1 expression can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumour cells and tumour-associated immune cells in tumour 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 fully human, high affinity, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Durvalumab does not induce antibody dependent cell-mediated cytotoxicity (ADCC). Blockade of PD-L1/PD-1 and PDL1/CD80 interactions enhances antitumour immune responses. These antitumour responses may result in tumour elimination.
In preclinical studies, PD-L1 blockade by durvalumab led to increased T-cell activation and decreased tumour size in xenograft mouse models of human melanoma and/or pancreatic cancer cells as well as mouse syngeneic colorectal cancer.
Clinical trials: Durvalumab doses of 10 mg/kg every 2 weeks or 1500 mg every 4 weeks were evaluated in NSCLC and ES-SCLC clinical studies. Based on the modelling and simulation of exposure, exposure-safety relationships and exposure-efficacy data comparisons, there are no anticipated clinically significant differences in efficacy and safety between durvalumab doses of 10 mg/kg every 2 weeks or 1500 mg every weeks. Non-small cell lung cancer (NSCLC): Randomised, placebo-controlled phase 3 study in patients with locally advanced, unresectable NSCLC after chemoradiation (PACIFIC study): The efficacy of IMFINZI was evaluated in the PACIFIC study, a randomised, double-blind, placebo-controlled, multicentre study in 713 patients with histologically or cytologically confirmed locally advanced, unresectable NSCLC. Patients had completed at least 2 cycles of definitive platinum-based chemotherapy with radiation therapy within 1 to 42 days prior to initiation of the study and had an ECOG performance status of 0 or 1. Ninety-two percent of patients had received a total dose of 54 to 66 Gy of radiation. The study excluded patients who had progressed following chemoradiation therapy, patients with prior exposure to any anti-PD-1 or anti-PD-L1 antibody, patients with active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions that required systemic immunosuppression (except physiological dose of systemic corticosteroids); active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI. Patients were randomised 2:1 to receive 10 mg/kg IMFINZI (n=476) or 10 mg/kg placebo (n=237) via intravenous infusion every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression. Randomisation was stratified by gender, age (<65 years vs. ≥65 years) and smoking status (smoker vs. non- smoker). Patients with disease control at 12 months were given the option to be re-treated upon disease progression. Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter.
Patients were enrolled regardless of their tumour PD-L1 expression level. Where available, archival tumour tissue specimens taken prior to chemoradiation therapy were retrospectively tested for PD-L1 expression on tumour cells (TC) using the VENTANA PD-L1 (SP263) IHC assay. Of the 713 patients randomised, 63% of patients provided a tissue sample of sufficient quality and quantity to determine PD-L1 expression and 37% were unknown.
The demographics and baseline disease characteristics were well balanced between study arms. Baseline demographics of the overall study population were as follows: male (70%), age ≥65 years (45%), white (69%), Asian (27%), other (4%), current smoker (16%), past-smoker (75%), and never smoker (9%), WHO/ECOG PS 0 (49%), WHO/ECOG PS 1 (51%). Disease characteristics were as follows: Stage IIIA (53%), Stage IIIB (45%), histological sub-groups of squamous (46%), non-squamous (54%). Of 451 patients with PD L1 expression available, 67% were TC ≥1% [PD-L1 TC 1-24% (32%), PD L1 TC ≥25% (35%)] and 33% were TC <1%.
The two primary endpoints of the study were progression-free survival (PFS) and overall survival (OS) of IMFINZI vs. placebo. Secondary efficacy endpoints included PFS at 12 months (PFS 12) and 18 months (PFS 18) from randomisation and Time from Randomisation to Second Progression (PFS2). PFS was assessed by Blinded Independent Central Review (BICR) according to RECIST 1.1.
The study demonstrated a statistically significant improvement in PFS and OS in the IMFINZI-treated group compared with the placebo group (see Table 1 and Figures 1 and 2).


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The improvements in PFS and OS in favour of patients receiving IMFINZI compared to those receiving placebo were consistently observed in all predefined subgroups analysed, including ethnicity, age, gender, smoking history, EGFR mutation status and histology. ALK mutation status was not analysed in this study.
Post-hoc subgroup analysis by PD-L1 expression: Additional subgroup analyses were conducted to evaluate the efficacy by tumour PD-L1 expression (≥25%, 1-24%, ≥1%, <1%) and for patients whose PD-L1 status could not be established (PD-L1 unknown). PFS and OS results are summarised in Figures 3 and 4. Overall the safety profile of durvalumab in PD-L1 TC ≥1% subgroup was consistent with the intent to treat population, as was the PD-L1 TC <1% subgroup. (See Figures 3 and 4.)


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Patient reported outcomes: Patient-reported symptoms, function and health-related quality of life (HRQoL) were collected using the EORTC QLQ-C30 and its lung cancer module (EORTC QLQ-LC13). The LC13 and C30 were assessed at baseline and every 4 weeks for the first 8 weeks, then every 8 weeks until completion of the treatment period or discontinuation of study drug due to toxicity or disease progression. Compliance was similar between the IMFINZI and placebo treatment groups (83% vs 85.1% overall of evaluable forms completed).
At baseline, no differences in patient reported symptoms, function or HRQoL were observed between IMFINZI and placebo groups. Throughout the duration of the study to week 48, there was no clinically meaningful difference between IMFINZI and placebo groups in symptoms, functioning and HRQoL (as assessed by a difference of greater than or equal to 10 points).
SCLC-CASPIAN Study: CASPIAN was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab in combination with etoposide and either carboplatin or cisplatin. CASPIAN was a randomized, open-label, multicenter study in 805 treatment naïve ES-SCLC patients with WHO/ECOG Performance status of 0 or 1, suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC, with life expectancy ≥12 weeks, at least one target lesion by RECIST 1.1 and adequate organ and bone marrow function. Patients with asymptomatic or treated brain metastases were eligible. The study excluded patients with a history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome (PNS); 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; active tuberculosis or hepatitis B or C or HIV infection; or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI.
Randomisation was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin).
Patients were randomised 1:1:1 to receive: Arm 1: IMFINZI 1500 mg + tremelimumab 75 mg + etoposide and either carboplatin or cisplatin; Arm 2: IMFINZI 1500 mg + etoposide and either carboplatin or cisplatin; Arm 3: Either 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 between 4-6 cycles.
For patients randomised to Arm 1 and 2, etoposide and either carboplatin or cisplatin was limited to 4 cycles on an every 3 week schedule subsequent to randomisation. IMFINZI monotherapy continued until disease progression or unacceptable toxicity. Administration of IMFINZI monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.
Patients randomised to Arm 3, were permitted to receive a total of up to 6 cycles of etoposide and either carboplatin or cisplatin. After completion of chemotherapy, prophylactic cranial irradiation (PCI) was permitted only in Arm 3 per investigator discretion.
Tumour assessments were conducted at Week 6 and Week 12 from the date of randomisation, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.
The primary endpoints of the study were Overall Survival (OS) of IMFINZI + chemotherapy (Arm 2) vs. chemotherapy alone (Arm 3) and IMFINZI + tremelimumab + chemotherapy (Arm 1) vs. chemotherapy alone (Arm 3). The key secondary endpoint was progression-free survival (PFS). Other secondary endpoints were Objective Response Rate (ORR), OS and PFS landmarks and Patient-Reported Outcomes (PRO). PFS and ORR were assessed using Investigator assessments according to RECIST v1.1.
The demographics and baseline disease characteristics were well balanced between the two study arms (268 patients in Arm 2 and 269 patients in Arm 3). Baseline demographics of the overall study population were as follows: male (69.6%), age ≥65 years (39.6%), median age 63 years (range: 28 to 82 years), white (83.8%), Asian (14.5%), black or African American (0.9%), other (0.6%), non-Hispanic or Latino (96.1%), current or past-smoker (93.1%), never smoker (6.9%), WHO/ECOG PS 0 (35.2%), WHO/ECOG PS 1 (64.8%), Stage IV 90.3%, 24.6% of the patients received cisplatin and 74.1% of the patients received carboplatin. In Arm 3, 56.8% of the patients received 6 cycles of etoposide + platinum and 7.8% of the patients received PCI.
At a planned interim (primary) analysis the study demonstrated a statistically significant improvement in OS with IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3) [HR=0.73 (95% CI: 0.591, 0.909), p=0.0047]. IMFINZI + etoposide + platinum demonstrated an improvement in PFS vs. etoposide + platinum alone [HR=0.78 (95% CI: 0.645, 0.936). See Table 2 and Figures 5 and 6.
In the planned follow-up analysis (median: 25.1 months), IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum (Arm 3) continued to demonstrate improved OS. The OS, PFS, ORR and DoR results from the planned follow-up analysis are summarized in Table 5; Kaplan-Meier curves for OS and PFS are presented in Figures 5 and 6. (See Table 2 and Figures 5 and 6.)


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Subgroup analysis: The improvements in OS in favor of patients receiving IMFINZI + chemotherapy compared to those receiving chemotherapy alone, were consistently observed across the prespecified subgroups based on demographics, geographical region, carboplatin or cisplatin use and disease characteristics.
Pharmacokinetics: The pharmacokinetics (PK) of durvalumab was assessed for both IMFINZI monotherapy and in combination with chemotherapy.
The pharmacokinetics of IMFINZI was studied in 2903 patients with solid tumours with doses ranging from 0.1 to 20 mg/kg administered once every two, three or four weeks as monotherapy.
Distribution: PK exposure increased more than dose-proportionally (non-linear PK) at doses <3 mg/kg and dose proportionally (linear PK) at doses ≥3 mg/kg. Steady state was achieved at approximately 16 weeks. Based on population PK analysis that included 1878 patients who received durvalumab monotherapy in the dose range of ≥10 mg/kg Q2W, the steady state volume of distribution (Vss) was 5.64 L.
Excretion: Durvalumab clearance (CL) decreased over time resulting in a geometric mean steady state clearance (CLss) of 8.16 mL/h at Day 365; the decrease in CLss was not considered clinically relevant. The terminal half-life (t1/2), based on baseline CL, was approximately 18 days. There was no clinically meaningful difference between the PK of durvalumab as a single agent and in combination with chemotherapy.
Special Populations: Age (19-96 years), body weight (34-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, soluble PD-L1, tumour type, race, mild renal impairment (creatinine clearance (CRCL) 60 to 89 mL/min), moderate renal impairment (creatinine clearance (CRCL) 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ULN and AST >ULN or bilirubin >1.0 to 1.5 × ULN and any AST) and ECOG/WHO status had no clinically significant effect on the pharmacokinetics of durvalumab.
The effect of severe renal impairment (CRCL 15 to 29 mL/min) or moderate (bilirubin >1.5 to 3 x ULN and any AST) or severe (bilirubin >3.0 x ULN and any AST) hepatic impairment on the pharmacokinetics of durvalumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence durvalumab exposure.
Laboratory abnormalities: In patients treated with durvalumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.4% for alanine aminotransferase increased, 3.6% for aspartate aminotransferase increased, 0.5% for blood creatinine increased, 5.7% for amylase increased and 5.6% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 18.8% and a TSH shift from baseline that was ≥LLN to any grade <LLN was 18.1%.
In patients treated with durvalumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.9% for alanine aminotransferase increased, 4.6% for aspartate aminotransferase increased, 3.4% for blood creatinine increased, 4.8% for amylase increased and 8.1% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ULN to any grade >ULN was 17.7% and a TSH shift from baseline that was ≥LLN to any grade <LLN was 31.3%.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. Of the 2280 patients who were treated with IMFINZI 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADA). Sixty nine patients (3.0%) tested positive for treatment emergent ADA. Neutralising antibodies against durvalumab were detected in 0.5% (12/2280) patients. The presence of ADAs did not have a clinically relevant effect on pharmacokinetics or safety.
In the CASPIAN study, of the 201 patients who were treated with IMFINZI 1500 mg every 3 weeks in combination with chemotherapy and evaluable for the presence of ADAs, 0 (0%) patients tested positive for treatment-emergent ADAs. The impact of treatment-emergent ADA on pharmacokinetics and clinical safety of durvalumab was not evaluable as no patient samples tested positive for treatment-emergent durvalumab ADA.
Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease.
For these reasons, comparison of incidence of antibodies to IMFINZI with the incidence of antibodies to other products may be misleading.
Toxicology: Preclinical safety data: Genotoxicity: The genotoxic potential of durvalumab has not been evaluated. As a large protein molecule, durvalumab is not expected to interact directly with DNA or other chromosomal material.
Carcinogenicity: The carcinogenic potential of durvalumab has not been evaluated.

Locally advanced non-small cell lung cancer (NSCLC): IMFINZI (durvalumab) is indicated for the treatment of patients with locally advanced, unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy.
Small Cell Lung Cancer (SCLC): 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).

IMFINZI is for single use in one patient only. Discard any residue.
Posology: The recommended dose for IMFINZI monotherapy and IMFINZI in combination with chemotherapy is presented in Table 3. IMFINZI is administered as an intravenous infusion over 1 hour. (See Table 3.)


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It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.
Dose escalation or reduction is not recommended. Dose withholding, or discontinuation may be required based on individual safety and tolerability.
Guidelines for management of adverse reactions are described in Table 4.
Refer to Precautions for further monitoring and evaluation information. (See Table 4.)


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For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude alternate aetiologies. Based on the severity of the adverse reaction, IMFINZI should be withheld and corticosteroids administered. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement. Upon improvement to ≤Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. After withhold, IMFINZI can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤10 mg prednisone or equivalent per day. IMFINZI should be permanently discontinued for recurrent Grade 3 or 4 (severe or life-threatening) immune-mediated adverse reactions and for any Grade 4 (life-threatening) immune-mediated adverse reactions, except for endocrinopathies that are controlled with replacement hormones.
For non-immune-mediated adverse reactions, withhold IMFINZI for Grade 2 and 3 adverse reactions until ≤Grade 1 or baseline. IMFINZI should be discontinued for Grade 4 adverse reactions (with the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue should be based on accompanying clinical signs/symptoms and clinical judgment).
Special patient populations: Renal impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (see Pharmacology: Pharmacokinetics under Actions). Durvalumab has not been studied in subjects with severe renal impairment.
Hepatic impairment: No dose adjustment is recommended for patients with hepatic impairment. Data from patients with moderate and severe hepatic impairment are limited, however, due to minor involvement of hepatic processes in the clearance of durvalumab, no difference in exposure is expected for these patients (see Pharmacology: Pharmacokinetics under Actions).
Use in paediatric patients: The safety and efficacy of durvalumab have not been established in patients younger than 18 years of age.
Use in the elderly: No dose adjustment is required for elderly patients (≥65 years of age) (see Pharmacology: Pharmacodynamics: Clinical trials and Pharmacokinetics under Actions).
Method of administration: Preparation of solution: IMFINZI is supplied as single-dose vials and does not contain any preservatives. Aseptic technique must be observed.
Visually inspect drug product for particulate matter and discolouration. IMFINZI is a clear to opalescent, colourless to slightly yellow solution. Discard the vial if the solution is cloudy, discoloured 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 (IV) bag containing 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. Do not freeze or shake the solution.
Care must be taken to ensure the sterility of prepared solutions.
Do not re-enter the vial after withdrawal of drug; only withdraw one dose per vial.
Discard any unused portion left in the vial.
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.
After preparation of infusion solution: IMFINZI does not contain a preservative. Chemical and physical in-use stability has been demonstrated for up to 30 days at 2ºC to 8ºC and for up to 24 hours at room temperature (up to 25ºC) from the time of preparation.
From a microbiological point of view, the prepared solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2ºC to 8ºC or 12 hours at room temperature (up to 25ºC), unless dilution has taken place in controlled and validated aseptic conditions.
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 specific treatment in the event of durvalumab overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Traceability: In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
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).
Pneumonitis and radiation pneumonitis: Radiated 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 at least 2 cycles of concurrent chemoradiation within 1 to 42 days prior to initiation of the trial, 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 (3.4% vs 3.0%) and Grade 5 (1.1% vs 1.7%).
Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related aetiologies excluded, and managed as recommended in Dosage & Administration.
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, and as indicated based on clinical evaluation. Immune-mediated hepatitis should be managed as recommended in Dosage & Administration.
Immune-mediated colitis: Immune-mediated colitis or diarrhoea, 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 diarrhoea and managed as recommended in Dosage & Administration.
Immune-mediated endocrinopathies: Immune-mediated hypothyroidism/hyperthyroidism/thyroiditis: Immune-mediated hypothyroidism, hyperthyroidism, or thyroiditis occurred in patients receiving IMFINZI, and hypothyroidism may follow hyperthyroidism (see Adverse Reactions). Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment as indicated based on clinical evaluation. Immune-mediated hypothyroidism, hyperthyroidism, and thyroiditis should be managed as recommended in Dosage & Administration.
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.
Immune-mediated type 1 diabetes mellitus: Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can be fatal if not detected early, 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.
Immune-mediated hypophysitis/hypopituitarism: Immune-mediated hypophysitis/hypopituitarism occurred in patients receiving IMFINZI (see Adverse Reactions). Patients should be monitored for clinical signs and symptoms of hypophysitis. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in Dosage & Administration.
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 durvalumab and managed as recommended in Dosage & Administration.
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. Events of Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis have been reported in patients treated with PD-1 inhibitors. Patients should be monitored for signs and symptoms of rash or dermatitis and managed as recommended in Dosage & Administration.
Other immune mediated adverse reactions: Given the mechanism of action of IMFINZI, other potential immune-mediated adverse reactions may occur. The following immune-related adverse reactions have been observed in patients treated with IMFINZI monotherapy: myasthenia gravis, myocarditis, myositis, polymyositis, meningitis, Guillain-Barré syndrome, immune thrombocytopenia and pancreatitis (see Adverse Reactions). Events of pancreatitis have been reported in patients in the clinical study programme. Patients should be monitored for signs and symptoms and managed as recommended for other immune-mediated adverse reactions, in Dosage & Administration.
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). Infusion-related reactions should be managed as recommended in Dosage & Administration.
Patients excluded from clinical trials: Patients with the following were excluded from clinical trials: a baseline ECOG performance score ≥2; active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions that required systemic immunosuppression, except physiological dose of systemic corticosteroids (≤10 mg/day prednisone or equivalent); uncontrolled intercurrent illnesses; active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI. In the absence of data, durvalumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis. The safety of concurrent prophylactic cranial irradiation (PCI) with IMFINZI in patients with ES-SCLC is unknown.
Effects on ability to drive and use machines: Based on its pharmacodynamic properties, durvalumab is unlikely to affect the ability to drive and use machines. However, if patients experience adverse reactions affecting their ability to concentrate and react, they should be advised to use caution when driving or operating machinery.

Effects on fertility: There are no data on the effects of durvalumab on fertility in humans. In repeat-dose toxicology studies of durvalumab up to 3 months duration in sexually mature cynomolgus monkeys, there were no notable effects on the male and female reproductive organs. These animals received weekly doses of durvalumab yielding 23 times the exposure (based on AUC) in humans at the recommended clinical dose.
Use in pregnancy - Category D: There are no data on the use of durvalumab in pregnant women. Based on its mechanism of action, durvalumab has the potential to impact maintenance of pregnancy and may cause foetal harm when administered to a pregnant woman. Human IgG1 is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing foetus.
Durvalumab use is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose.
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 foetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signalling was shown to result in an increase in foetal 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 in humans at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, foetal loss (abortion and stillbirth) and increase in neonatal deaths compared to concurrent controls. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, foetal 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.
Use in lactation: There is no information regarding the presence of durvalumab in human milk, the absorption and effects on the breastfed infant, or the effects on milk production. Human IgG is excreted in human milk. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys was associated with dose-related low-level excretion of durvalumab in breast milk and was associated with premature neonatal death compared to concurrent controls. Because of the potential for adverse reactions in breastfed infants from durvalumab, lactating women should be advised not to breastfeed during treatment and for at least 3 months after the last dose.

Summary of the safety profile: The safety of IMFINZI as monotherapy is based on pooled data in 3006 patients across multiple tumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks. The most frequent (>10%) adverse reactions were cough/productive cough (21.5%), diarrhoea (16.3%), rash (16.0%), pyrexia (13.8%), upper respiratory tract infections (13.5%), abdominal pain (12.7%), pruritus (10.8%), and hypothyroidism (10.1%).
The safety of IMFINZI given in combination with chemotherapy is based on data in 265 patients with SCLC. IMFINZI was administered at a dose of 1500 mg every 3 weeks in combination with chemotherapy followed by monotherapy every 4 weeks. The most frequent (>20%) adverse reactions were neutropenia (48.7%), anaemia (38.5%), nausea (33.6%), fatigue (32.1%), alopecia (31.3%), thrombocytopenia (21.1%), and leukopenia (20.0%).
Tabulated list of adverse reactions: Table 5 lists the incidence of adverse reactions in the monotherapy safety dataset and in patients treated with IMFINZI in combination with chemotherapy in the CASPIAN study. Adverse drug reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse drug reactions are presented in decreasing frequency. The corresponding frequency category for each ADR is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. (See Table 5.)


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Description of selected adverse reactions: IMFINZI is most commonly associated with immune-mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal and/or treatment modifications. The data for the following immune-mediated adverse reactions reflect the combined safety database of 3006 patients which includes the PACIFIC Study and additional studies in patients with various solid tumours, in indications for which durvalumab is not approved. Across all studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks, or 1500 mg every 3 or 4 weeks. Details for the significant adverse reactions for IMFINZI when given in combination with chemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI monotherapy. The management guidelines for these adverse reactions are described in Dosage & Administration and Precautions.
Immune-mediated pneumonitis: In the combined safety database with IMFINZI monotherapy, (n=3006 multiple tumour types), immune-mediated pneumonitis occurred in 92 (3.1%) patients, including Grade 3 in 25 (0.8%) patients, Grade 4 in 2 (<0.1%) patient, 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), and 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 the PACIFIC study who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of the study (9.9%), than in the other patients in the combined safety database (1.8%).
In the PACIFIC Study, (n=475 in the IMFINZI arm, and n=234 in the placebo arm) 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 (fatal) 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, all patients received systemic corticosteroids, including 30 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), and 2 patients also received infliximab. In the placebo group, all patients received systemic corticosteroids, including 12 patients who 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: In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in 68 (2.3%) patients, including Grade 3 in 35 (1.2%) patient, Grade 4 in 6 (<0.2%) and Grade 5 (fatal) in 4 (<0.1%) patient. The median time to onset was 33 days (range: 3-333 days). Forty-five of the 68 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patient also received mycophenolate treatment. IMFINZI was discontinued in 9 patients. Resolution occurred in 31 patients.
Immune-mediated colitis: In the combined safety database with IMFINZI monotherapy, immune-mediated colitis or diarrhoea occurred in 58 (1.9%) patients, including Grade 3 in 9 (0.3%) patients and Grade 4 in 2 (<0.1%) patient. 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 1 patient also received mycophenolate. IMFINZI was discontinued in 9 patients. Resolution occurred in 43 patients.
Immune-mediated endocrinopathies: Immune-mediated hypothyroidism: In the combined safety database with 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 and 6 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism. No patients discontinued IMFINZI due to immune-mediated hypothyroidism.
Immune-mediated hyperthyroidism: In the combined safety database with 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: 1-196 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. Twenty patients experienced hypothyroidism following hyperthyroidism.
Immune-mediated thyroiditis: In the combined safety database with 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 and 1 patient received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated thyroiditis. Three patients experienced hypothyroidism following thyroiditis.
Immune-mediated adrenal insufficiency: In the combined safety database with 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: In one study with 475 locally advance, unresectable NSCLC patients, Grade-3 immune-mediated type 1 diabetes mellitus occurred in 1 (<0.1%) patient. The time to onset was 43 days. This patient recovered with sequelae, required long-term insulin therapy and IMFINZI was permanently discontinued due to immune-mediated type 1 diabetes mellitus.
Immune-mediated hypophysitis/hypopituitarism: In the combined safety database with 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: In the combined safety database with 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: In the combined safety database with IMFINZI monotherapy, immune-mediated rash or dermatitis 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-three 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 32 patients.
Infusion-related reactions: In the combined safety database with 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.
Laboratory abnormalities: In patients treated with durvalumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.4% for alanine aminotransferase increased, 3.6% for aspartate aminotransferase increased, 0.5% for blood creatinine increased, 5.7% for amylase increased and 5.6% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ULN to any grade >ULN was 18.8% and a TSH shift from baseline was ≥LLN to any grade <LLN was 18.1%.
In patients treated with durvalumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.9% for alanine aminotransferase increased, 4.6% for aspartate aminotransferase increased, 3.4% for blood creatinine increased, 4.8% for amylase increased and 8.1% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ULN to any grade >ULN was 17.7% and a TSH shift from baseline that was ≥LLN to any grade <LLN was 31.3%.
Immunogenicity: Immunogenicity of IMFINZI as monotherapy is based on pooled data in 2280 patients who were treated with IMFINZI 10 mg/kg every 2 weeks, or 20 mg/kg every 4 weeks as a single-agent and evaluable for the presence of anti-drug antibodies (ADA). Sixty nine patients (3.0%) tested positive for treatment emergent ADA. Neutralising antibodies (nAb) against durvalumab were detected in 0.5% (12/2280) of patients. The presence of ADA did not have a clinically relevant effect on safety. There are insufficient number of patients to determine ADA impact on efficacy. Based on population PK analysis, slightly lower exposure are expected in ADA-positive patients however, the reduction of PK exposure is less than 30% compared to a typical patient and is not considered clinically relevant.
In the CASPIAN study, of 201 patients who were treated with IMFINZI 1500 mg every 3 weeks in combination with chemotherapy and evaluable for the presence of ADAs, 0 (0%) patients tested positive for treatment-emergent ADAs. The impact of treatment-emergent ADA on PK, clinical safety and efficacy of durvalumab was not evaluable as no patient samples tested positive for treatment-emergent durvalumab ADA.
Elderly: No overall differences in safety were reported between elderly (≥65 years) and younger patients. Data from NSCLC and ES-SCLC patients 75 years of age or older are limited.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at e-meso.pom.go.id.

Durvalumab is an immunoglobulin, therefore no formal pharmacokinetic drug-drug interaction studies have been conducted. PK drug-drug interaction between durvalumab and chemotherapy was assessed in the CASPIAN study and showed concomitant treatment with durvalumab did not impact the PK of etoposide, carboplatin or cisplatin. Additionally, based on population PK analysis, concomitant chemotherapy treatment did not meaningfully impact the PK of durvalumab.

Incompatibilities: Incompatibilities were either not assessed or not identified as part of registration of this medicine.

Store unopened vials under refrigeration at 2°C to 8°C in the original carton to protect from light.
Do not freeze. Do not shake.
Shelf life: 36 months.

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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