Imfinzi

IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution in a single-dose vial.
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 1,500 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 1,500 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): Neoadjuvant and Adjuvant Treatment of Resectable NSCLC-AEGEAN Study: The efficacy of IMFINZI in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with IMFINZI as a single agent was investigated in AEGEAN (NCT03800134), a randomized, double-blind, placebo-controlled, multicenter trial conducted in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). Patients were enrolled regardless of tumor PD-L1 expression. Eligible patients had no prior exposure to immune-mediated therapy, a WHO/ECOG Performance status of 0 or 1, and at least one RECIST 1.1 target lesion.
Patients with active or prior documented autoimmune disease, or use of any immunosuppressive medication within 14 days of the first dose of IMFINZI were ineligible. The population for efficacy analyses was a modified intent-to-treat [mITT] which excluded patients with known EGFR mutations or ALK rearrangements.
Crossover between the study arms was not permitted. Randomization was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC <1% vs. TC ≥1%) status. Patients were randomized 1:1 to one of the following treatment arms: Arm 1: Neoadjuvant IMFINZI 1,500 mg once every 3 weeks for up to 4 cycles in combination with: Squamous tumor histology: carboplatin AUC 6 and paclitaxel 200 mg/m² on Day1 of each 3-week cycle, OR cisplatin 75 mg/m² on Day 1 and gemcitabine 1250 mg/m² on Day 1 and Day 8 of each 3-week cycle, for 4 cycles.
Non-squamous tumor histology: pemetrexed 500 mg/m² and cisplatin 75 mg/m² on Day 1 of each 3-week cycle, for 4 cycles OR pemetrexed 500 mg/m² and carboplatin AUC 5 on Day 1 of each 3-week cycle, for 4 cycles.
Followed by adjuvant IMFINZI 1,500 mg as a single agent for up to 12 cycles post-surgery.
Arm 2: Neoadjuvant placebo in combination with 4 cycles of chemotherapy (see previously mentioned) prior to surgery.
Followed by placebo for up to 12 cycles post-surgery.
All study medications were administered via intravenous infusion. In the event of unfavorable tolerability, patients who met the eligibility criteria were switched from cisplatin to carboplatin therapy at any point during the study. In patients with comorbidities or unable to tolerate cisplatin as per Investigators judgment, carboplatin AUC 5 could be administered from cycle 1. Treatment with IMFINZI or placebo continued until completion of the treatment, disease progression that precluded definitive surgery, inability to complete definitive surgery, disease recurrence in the adjuvant phase, or unacceptable toxicity. A RECIST 1.1 tumor assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). Tumor assessments were conducted at 5 weeks postoperatively, prior to the start of adjuvant therapy and every 12 weeks until week 48, every 24 weeks for approximately 4 years, and then every 48 weeks thereafter until disease progression, consent withdrawal, or death.
The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment.
The major efficacy outcome measures of the study were pathological complete response (pCR) by blinded central pathology review and event-free survival (EFS) by blinded independent central review (BICR) assessment. Additional efficacy outcome measures were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS.
The demographics and baseline disease characteristics were as follows: male (72%); median age 65 years (range: 30 to 88); age ≥65 years (52%); WHO/ECOG PS 0 (68%), WHO/ECOG PS 1 (32); White (54%), Asian (41%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%); Not Hispanic or Latino (84%); current or past smokers (86%); squamous histology (49%) and non-squamous histology (51%); Stage II (28%), Stage III (71%); PD-L1 expression status TC ≥1% (67%), PD-L1 expression status TC <1% (33%).
In the mITT population, 78% of patients in Arm 1 completed definitive surgery compared to 77% of patients in Arm 2.
The trial demonstrated statistically significant improvements in EFS and pCR rate (see Table 1 and Figure 1) in the IMFINZI in combination with chemotherapy arm compared to the placebo in combination with chemotherapy arm. (See Table 1 and Figure 1.)

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At the interim analysis, the trial demonstrated a statistically significant difference in MPR rate (34% vs. 14%; p <0.0001). At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance.
PACIFIC Study: The efficacy of IMFINZI was evaluated in the PACIFIC Study, a randomised, double-blind, placebo-controlled, multicentre study in 713 patients with 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 a 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%), age ≥75 years (8%), White (69%), Asian (27%), other (4%), current smoker (16%), past-smoker (75%), never smoker (9%), ECOG Performance Status 0 (49%), ECOG Performance Status 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 v1.1.
The study demonstrated a statistically significant improvement in PFS in the IMFINZI-treated group compared with the placebo group [hazard ratio (HR)=0.52 (95% CI: 0.42, 0.65), p <0.0001]. The study demonstrated a statistically significant improvement in OS in the IMFINZI-treated group compared with the placebo group [HR=0.68 (95% CI: 0.53, 0.87), p=0.00251].
In the 5 year follow-up analysis, with a median follow-up of 34.2 months, IMFINZI continued to demonstrate improved OS and PFS compared to placebo. The OS and PFS results from the primary analysis and the follow-up analysis are summarized in Table 2. (See Table 2.)

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Kaplan-Meier curves for OS and PFS from the 5 year follow-up analysis are presented in Figures 2 and 3. (See Figures 2 and 3.)

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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.
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 cannot be established (PD-L1 unknown). PFS and OS results from the 5 year follow-up analysis are summarised in Figures 4, 5, 6, and 7. (See Figures 4, 5, 6, and 7.)

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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.
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, every 4 weeks for the first 8 weeks, followed by every 8 weeks until completion of the treatment period or discontinuation of IMFINZI 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 and 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).
Small Cell Lung Cancer (SCLC): CASPIAN Study: CASPIAN was a study designed to evaluate the efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin. CASPIAN was a randomized, open-label, multicentre study in 805 treatment naïve ES-SCLC patients with WHO/ECOG Performance status of 0 or 1, body weight >30 kg, 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.
Randomization was stratified by the planned platinum-based (carboplatin or cisplatin) therapy in cycle 1.
Patients were randomised 1:1:1 to receive: Arm 1: IMFINZI 1,500 mg + tremelimumab 75 mg + etoposide and either carboplatin or cisplatin.
Arm 2: IMFINZI 1,500 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 every 4 weeks 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 etoposide + platinum, PCI was permitted only in Arm 3 per investigator discretion.
Tumour assessments were conducted at Week 6 and Week 12 from the date of randomization, 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 + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3) and IMFINZI + tremelimumab + etoposide + platinum (Arm 1) vs. etoposide + platinum 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]. Although not formally tested for significance, IMFINZI + etoposide + platinum demonstrated an improvement in PFS vs. etoposide + platinum alone [HR=0.78 (95% CI: 0.645, 0.936)].
The PFS, ORR, and DoR results from the planned final analysis (DCO: 27 Jan 2020) are summarized in Table 3. Kaplan-Meier curve for PFS is presented in Figure 9.
The OS results with the planned long-term OS follow-up analysis (DCO: 22 March 2021) (median follow-up: 39.3 months) are presented in Table 3. IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum (Arm 3) continued to demonstrate sustained improvement in OS. Kaplan-Meier curve for OS is presented in Figure 8. (See Table 3, Figures 8 and 9.)

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Subgroup analysis: The improvements in OS in favour of patients receiving IMFINZI + etoposide + platinum compared to those receiving etoposide + platinum alone, were consistently observed across the prespecified subgroups based on demographics, geographical region, carboplatin or cisplatin use and disease characteristics.
Metastatic NSCLC-POSEIDON Study: POSEIDON was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab in combination with platinum-based chemotherapy. POSEIDON was a randomized, open-label, multicenter study in 1013 metastatic NSCLC patients with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. Patients with histologically or cytologically documented metastatic NSCLC were eligible for enrolment. Patients had no prior chemotherapy or any other systemic therapy for metastatic NSCLC. Prior to randomization, patients had tumour PD-L1 status confirmed by using the Ventana PD-L1 (SP263) assay. Patients had a World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrolment.
The study excluded patients with active or prior documented autoimmune disease; active and/or untreated brain metastases; a history of immunodeficiency; administration of systemic immunosuppression within 14 days before the start of IMFINZI or tremelimumab, 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 and/or tremelimumab.
Randomisation was stratified by tumour cells (TC) PD-L1 expression (TC ≥50% vs. TS <8th 50%), disease stage (Stage IVA vs. Stage IVB, per the 8^th edition of American Joint Committeeon Cancer), and histology (non-squamous and squamous).
Patients were randomized 1:1:1 to receive: Arm1: IMFINZI 1,500 mg with tremelimumab 75 mg and platinum-based chemotherapy every 3 weeks for 4 cycles followed by, IMFINZI 1,500 mg every 4weeks as monotherapy. A fifth dose of tremelimumab 75 mg was given at Week 16 alongside IMFINZI dose 6.
Arm 2: IMFINZI 1,500 mg and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks as monotherapy.
Arm 3: Platinum-based chemotherapy every 3 weeks for 4 cycles. Patient could receive 2 additional cycles (a total of 6 cycles post-randomisation), as clinically indicated, atthe Investigator's discretion.
In the 3 treatment arms, patients received one of the following histology-based chemotherapy regimens: Non-squamous NSCLC: Pemetrexed 500 mg/m² with carboplatin AUC 5-6 or cisplatin 75 mg/m² every 3 weeks. Unless contraindicated by the investigator, pemetrexed maintenance could be given.
Squamous NSCLC: Gemcitabine 1000 or 1,250 mg/m² on Days 1 and 8 with cisplatin 75 mg/m² or carboplatin AUC 5-6 on Day 1 every 3 weeks.
Non-squamous or squamous NSCLC: Nab-paclitaxel 100 mg/m² on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day 1 every 3 weeks.
Tremelimumab was given up to a maximum of 5 doses unless there was disease progression or unacceptable toxicity, IMFINZI and histology-based pemetrexed maintenance therapy (when applicable) was continued until disease progression or unacceptable toxicity.
Tumour assessments were conducted at Week 6 and Week 12 from the date of randomization, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.
The dual primary endpoints of the study were progression-free survival (PFS) and overall survival (OS) for IMFINZI + platinum-based chemotherapy vs. platinum-based chemotherapy alone. The key secondary endpoints of the study were PFS and OS for IMFINZI + tremelimumab + platinum-based chemotherapy and platinum-based chemotherapy alone. The secondary endpoints included objection response rate (ORR) and Duration of Response (DoR). PFS, ORR, and DoR, were assessed using Blinded Independent Central Review (BICR)according to RECIST v1.1.
The demographic and baseline disease characteristics were well-balanced between study arms. Baseline demographic of the overall study population were as follows: male (76.0%), age ≥65 years (47.1%), age ≥75 years (11.3%) median age 64 years (range: 27 to 87 years), White (55.9%), Asian (34.6%), Black or African American (2.0%), Other (7.6%), non-Hispanic or Latino (84.2%), current smoker or past-smoker (78.0%), WHO/ECOG PS 0 (33.4%), WHO/ECOG PS 1 (66.5%). Disease characteristics as follows: Stage IVA (50.0%), Stage IVB (49.6%), histological sub-groups of squamous (36.9%), non-squamous (62.9%), brain metastases (10.5%), PD-L1 expression TC ≥50% (28.8), PD-L1 expression TC <50% (71.1%).
The study showed a statistically significant improved in OS with IMFINZI + tremelimumab + platinum-based chemotherapy vs. platinum-based chemotherapy. IMFINZI + tremelimumab + platinum-based chemotherapy showed a statistically significant improvement in PFS vs. platinum-based chemotherapy alone. The results are summarized as follows: (See Table 4, Figures 10 and 11.)

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Figure 12 summarises efficacy results of OS by tumour PD-L1 expression in prespecified subgroup analyses. (See Figure 12.)

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Elderly population: A total of 75 patients aged ≥75 years were enrolled in the IMFINZI in combination with tremelimumab and chemotherapy (n=35) and platinum-based chemotherapy only (n=40) arms of the POSEIDON study. An exploratory HR of 1.05 (95% CI: 0.64, 1.71) for OS was observed for the IMFINZI in combination with tremelimumab and platinum-based chemotherapy vs. platinum-based chemotherapy within this study subgroup. Due to the exploratory nature of this subgroup analysis no definitive conclusions can be drawn, but caution is suggested when considering this regimen for elderly patients.
BTC: TOPAZ-1 Study: TOPAZ-1 was a study designed to evaluate the efficacy of IMFINZI in combination with gemcitabine and cisplatin. TOPAZ-1 was a randomised, double-blind, placebo-controlled, multicentre study in 685 patients with unresectable or metastatic BTC (including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder carcinoma) and ECOG Performance status of 0 or 1. Patients had not received previous therapy in the advanced/unresectable setting. Patients who developed recurrent disease >6 months after surgery and/or completion of adjuvant therapy were included. Patients must have had an adequate organ and bone marrow function, and have had acceptable serum bilirubin levels (≤2.0 x the upper limit of normal (ULN)), and any clinically significant biliary obstruction had to be resolved before randomisation.
The study excluded patients with ampullary carcinoma, with brain metastases, active or prior documented autoimmune or inflammatory disorders, HIV infection or active infections, including tuberculosis or hepatitis C or patients with current or prior use of immunosuppressive medication within 14 days before the first dose of IMFINZI. Patients with active HBV were allowed to participate if they were on antiviral therapy.
Randomisation was stratified by disease status (initially unresectable vs. recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder carcinoma).
Patients were randomised 1:1 to receive: Arm 1: IMFINZI 1,500 mg administered on Day 1 + gemcitabine 1,000 mg/m² and cisplatin 25 mg/m² (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles, followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity, or Arm 2: Placebo administered on Day 1 + gemcitabine 1,000 mg/m² and cisplatin 25 mg/m² (each administered on Days 1 and 8) every 3 weeks (21 days) for up to 8 cycles, followed by placebo every 4 weeks until disease progression or unacceptable toxicity.
Tumour assessments were conducted every 6 weeks for the first 24 weeks after the date of randomisation, and then every 8 weeks until confirmed objective disease progression.
The primary endpoint of the study was OS, the key secondary endpoint was PFS. Other secondary endpoints were ORR, DoR, and PRO. PFS, ORR, and DoR were investigator-assessed according to RECIST v1.1.
The demographics and baseline disease characteristics were well balanced between the two study arms (341 patients in Arm 1 and 344 patients in Arm 2). Baseline demographics of the overall study population were as follows: male (50.4%), age <65 years (53.3%), white (37.2%), Asian (56.4%), Black or African American (2.0%), other (4.2%), non-Hispanic or Latino (93.1%), ECOG PS 0 (49.1%), vs. PS 1 (50.9%), primary tumour location (intrahepatic bile duct 55.9%, extrahepatic bile duct 19.1% and gallbladder 25.0%), disease status [recurrent (19.1%) vs. unresectable (80.7%), metastatic (86.0%) vs. locally advanced (13.9%)]. PD-L1 expression was evaluated on tumour and immune cells using the Ventana PD-L1 (SP263) assay and the TAP (tumour area positivity) algorithm, 58.7% patients had TAP ≥1% and 30.1% TAP <1%.
OS and PFS were formally tested at a pre-planned interim analysis (data cut-off 11 Aug 2021) after a median follow-up of 9.8 months. Efficacy results are shown in Table 5 and Figure 13. The maturity for OS was 62% and the maturity for PFS was 84%. IMFINZI + chemotherapy (Arm 1) showed statistically significant improvement vs. placebo + chemotherapy (Arm 2) in OS and in PFS. (See Table 5.)

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An additional planned follow-up analysis of OS (data cut-off 25 Feb 2022) was performed 6.5 months after the interim analysis with an OS maturity of 77%. IMFINZI + chemotherapy continued to demonstrate improved OS vs. chemotherapy alone [HR=0.76, (95% CI: 0.64, 0.91)] and the median follow-up increased to 12 months. (See Figures 13 and 14.)

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HCC: HIMALAYA Study: The efficacy of IMFINZI given in combination with a single dose of tremelimumab 300 mg was evaluated in the HIMALAYA Study, a randomized, open-label, multicentre study in patients with confirmed uHCC who did not receive prior systemic treatment for HCC. The study included patients with Barcelona Clinic Liver Cancer (BLCC) Stage C or B (not eligible for locoregional therapy) and Child-Pugh Score Class A.
The study excluded patients with brain metastases or a history of brain metastases, co-infection of viral hepatitis B and hepatitis C; active or prior documented gastrointestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disease.
Patients with oesophageal varices were included except those with active or prior documented GI bleeding within 12 months prior to study entry.
Randomisation was stratified by macrovascular invasion (MVI) (yes vs. no), aetiology of liver disease (confirmed hepatitis B virus vs. confirmed hepatitis C virus vs. others) and ECOG performance status (0 vs. 1). The HIMALAYA study randomized 1171 patients 1:1:1 to receive: IMFINZI: durvalumab 1,500 mg every 4 weeks; Tremelimumab 300 mg as a single dose + IMFINZI 1,500 mg; followed by IMFINZI 1,500 mg every 4 weeks; S: Sorafenib 400 mg twice daily.
Tumour assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter. Survival assessments were conducted every month for the first 3 months following treatment discontinuation and then every 2 months.
The primary endpoint was OS. Secondary endpoints included PFS, Investigator-assessed ORR and DoR according to RECIST v1.1.The demographics and baseline disease characteristics were well balanced between study arms. The baseline demographics of the overall study population were as follows: male (83.7%), age <65 years (50.4%), White (44.6%), Asian (50.7%), Black or African American (1.7%), Other race (2.3%), ECOG PS 0 (62.6%); Child-Pugh Class score A (99.5%), macrovascular invasion (25.2%), extrahepatic spread (53.4%), baseline AFP <400 ng/mL (63.7%), baseline AFP ≥400 ng/mL (34.5%), viral aetiology; hepatitis B (30.6%), hepatitis C (27.2%), uninfected (42.2%), evaluable PD-L1 data (86.3%), PD-L1 Tumour area positivity (TAP) ≥1% (38.9%), PD-L1 TAP <1% (48.3%) [Ventana PD-L1 (SP263) assay].
Results are presented in Table 6 and Figure 15. (See Table 6 and Figure 15.)

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Endometrial Cancer: DUO-E Study: DUO-E was a randomised, multicentre, double-blind, placebo-controlled Phase III study of first-line platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI with or without olaparib in patients with advanced or recurrent endometrial cancer. Patients had to have endometrial cancer in one of the following categories: newly diagnosed Stage III disease (measurable disease per RECIST v1.1 following surgery or diagnostic biopsy), newly diagnosed Stage IV disease (with or without disease following surgery or diagnostic biopsy), or recurrence of disease (measurable or nonmeasurable disease per RECIST v1.1) where the potential for cure by surgery alone or in combination is poor. For patients with recurrent disease, prior chemotherapy was allowed only if it was administered in the adjuvant setting and there was at least 12 months from the date of last dose of chemotherapy administered to the date of subsequent relapse. The study included patients with epithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients with endometrial sarcoma were excluded.
Randomisation was stratified by tumour tissue's mismatch repair (MMR) status (proficient versus deficient), disease status (recurrent versus newly diagnosed), and geographic region (Asia versus rest of the world). Patients were randomised 1:1:1 to one of the following arms: Arm 1 (Platinum-based chemotherapy): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with durvalumab placebo every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received durvalumab placebo every 4 weeks and olaparib placebo tablets twice daily as maintenance treatment until disease progression.
Arm 2 (Platinum-based chemotherapy + IMFINZI): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1,120 mg durvalumab every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1,500 mg durvalumab every 4 weeks with olaparib placebo tablets twice daily as maintenance treatment until disease progression.
Arm 3 (Platinum-based chemotherapy + IMFINZI + olaparib): Platinum-based chemotherapy (paclitaxel and carboplatin) every 3 weeks for a maximum of 6 cycles with 1,120 mg durvalumab every 3 weeks. Following completion of chemotherapy treatment, patients without objective disease progression received 1,500 mg durvalumab every 4 weeks with 300 mg olaparib tablets twice daily as maintenance treatment until disease progression.
Patients who discontinued either product (IMFINZI/placebo or olaparib/placebo) for reasons other than disease progression could continue treatment with the other product if appropriate based on toxicity considerations and investigator discretion.
Treatment was continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Assessment of tumour status was performed every 9 weeks for the first 18 weeks relative to randomisation and every 12 weeks thereafter.
The primary endpoint was PFS, determined by investigator assessment using RECIST v1.1. Secondary efficacy endpoints included OS, ORR and DoR.
The study demonstrated a statistically significant improvement in PFS in the ITT population, for patients treated with platinum-based chemotherapy + IMFINZI + olaparib compared to platinum-based chemotherapy [HR=0.55 (95% CI: 0.43, 0.69), p=<0.0001], and for patients treated with platinum-based chemotherapy + IMFINZI compared to platinum-based chemotherapy [HR=0.71 (95% CI: 0.57, 0.89), p=0.003]. At the time of PFS analysis, interim OS data were 28% mature with events in 199 of 718 patients.
Mismatch repair (MMR) status was determined centrally using an MMR immunohistochemistry panel assay. Of a total of 718 patients randomized in the study, 575 (80%) patients had MMR-proficient (pMMR) tumour status and 143 (20%) patients had MMR-deficient (dMMR) tumour status.
Patients with MMR-deficient (dMMR) endometrial cancer: Among patients with dMMR tumour status, demographic and baseline characteristics were generally well balanced between the treatment arms. Baseline demographics across all three arms were as follows: median age of 62 years (range: 34 to 85), 41% age 65 or older, 1.5% age 75 or older, 62% White, 29% Asian, and 2% Black or African American. Disease characteristics were as follows: ECOG PS of 0 (58%) or 1 (42%), 46% newly diagnosed and 54% recurrent disease. The histologic subtypes were endometrioid (83%), mixed epithelial (5%), serous (3%), carcinosarcoma (3%), undifferentiated (2%), and other (3%).
In patients with dMMR tumour status, the results are summarised in Table 7 and Figure 16. The median follow-up time for PFS in censored patients with dMMR tumour status was 15.5 months in the platinum-based chemotherapy + IMFINZI arm and 10.2 months in the platinum-based chemotherapy arm. At the time of PFS analysis, interim OS data were 26% mature with events in 25 of 95 patients treated with platinum-based chemotherapy + IMFINZI and platinum-based chemotherapy. (See Table 7 and Figure 16.)

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Patients with MMR-proficient (pMMR) endometrial cancer: Among patients with pMMR tumour status, demographic and baseline characteristics were generally well balanced between the treatment arms. Baseline demographics across all three arms were as follows: median age of 64 years (range: 22 to 86), 48% age 65 or older, 8.1% age 75 or older, 56% White, 30% Asian, and 6% Black or African American. Disease characteristics were as follows: ECOG PS of 0 (69%) or 1 (31%), 47% newly diagnosed and 53% recurrent disease. The histologic subtypes were endometrioid (54%), serous (26%), carcinosarcoma (8%), mixed epithelial (4%), clear cell (3%), undifferentiated (2%), mucinous (<1%), and other (3%).
Results in patients with pMMR tumour status are summarised in Table 8 and Figure 17. The median follow-up time in censored patients with pMMR tumour status was 15.2 months in the platinum-based chemotherapy + IMFINZI + olaparib arm, and 12.8 months in the platinum-based chemotherapy arm. At the time of PFS analysis, interim OS data were 29% mature with events in 110 of 383 patients treated with platinum-based chemotherapy + IMFINZI + olaparib and platinum-based chemotherapy. (See Table 8 and Figure 17.)

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Among patients with pMMR tumour status, the PFS HRs were 0.44 (95% CI: 0.31, 0.61) in patients with PD-L1 expression positive status (236/383; 62%) and 0.87 (95% CI: 0.59, 1.28) in patients with PD-L1 expression negative status (140/383; 37%), for the platinum-based chemotherapy + IMFINZI + olaparib arm compared to the platinum-based chemotherapy arm. PD-L1 expression positive was defined as tumour area positive (TAP) ≥1%.
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 and in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib.
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: There were no clinically significant differences in pharmacokinetics of durvalumab based on body weight (31-175 kg), age (18-96 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4-57 g/L), lactate dehydrogenase (LDH) levels (18-15,800 U/L), creatinine levels, soluble PD-L1 (67-3,470 pg/mL), tumor type (NSCLC, SCLC and BTC), mild or moderate renal impairment (CL_cr 30 to 89 mL/min), mild or moderate hepatic impairment (bilirubin ≤3x ULN and any AST). The effect of severe renal impairment (CL_cr 15 to 29 mL/min) or severe hepatic impairment (bilirubin >3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown.
Immunogenicity: The observed incidence of anti-drug antibodies (ADA) highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of the incidence of ADAs in the studies described as follows with the incidence of ADAs in other studies including those of IMFINZI.
During the 10 to 48 week treatment period across PACIFIC, CASPIAN, TOPAZ-1, HIMALAYA, POSEIDON, DUO-E, AEGEAN and other clinical trials, in patients who received IMFINZI at dosages of 1,500 mg every 4 hours, 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks as a single agent or 1,120 mg every 3 weeks, or 1,500 mg every 3 weeks in the combination therapies, 3.2% (151/4668) of evaluable patients tested positive for anti-durvalumab antibodies, and 19.2% (29/151) of ADA positive patients had neutralizing antibodies against durvalumab. There were no identified clinically significant effects of ADAs on durvalumab pharmacokinetics or safety; however, the effect of these ADAs on the effectiveness of IMFINZI is unknown.
In the DUO-E study, the number of patients who were treated with platinum-based chemotherapy + IMFINZI (n=198) or platinum-based chemotherapy + IMFINZI + Olaparib (n=207) and evaluable for the presence of ADAs, 2 (1.0%) patients tested positive for treatment-emergent ADAs in the platinum-based chemotherapy + IMFINZI arm and no patients tested positive for treatment-emergent ADAs in the platinum-based chemotherapy + IMFINZI + olaparib arm. Neutralizing antibodies against durvalumab were detected in 1 (0.5%) patient in the platinum-based chemotherapy + IMFINZI arm and 0 patients in the platinum-based chemotherapy + IMFINZI + olaparib arm. There were insufficient number of patients with treatment-emergent ADAs or neutralizing antibodies to determine whether ADAs have an impact on pharmacokinetics or safety of durvalumab.
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.
IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by IMFINZI as monotherapy after surgery, is indicated for the treatment of adults with resectable (tumours ≥4 cm and/or node positive) NSCLC and no known EGFR mutation or ALK rearrangements.
IMFINZI in combination with tremelimumab and platinum-based chemotherapy is indicated for the first-line treatment of adults with metastatic NSCLC with no sensitizing EGFR mutations or ALK positive mutations.
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).
Hepatocellular Carcinoma (HCC): IMFINZI in combination with tremelimumab is indicated for the first-line treatment of adults with advanced or unresectable hepatocellular carcinoma (HCC).
Endometrial Cancer: IMFINZI in combination with carboplatin and paclitaxel is indicated for the first-line treatment of adults with primary advanced or recurrent endometrial cancer who are candidates for systemic therapy, followed by maintenance treatment with: IMFINZI as monotherapy in endometrial cancer that is mismatch repair deficient (dMMR); IMFINZI in combination with olaparib in endometrial cancer that is mismatch repair proficient (pMMR).

MMR testing for patients with endometrial cancer: Patients with endometrial cancer should be evaluated for treatment based on tumour MMR status confirmed by a validated test (see Pharmacology: Clinical Studies under Actions).
Posology: The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with chemotherapy are presented in Table 9 [see Pharmacology: Clinical Studies under Actions].
IMFINZI is administered as an intravenous infusion over 60 minutes. (See Table 9.)

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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 10. Refer to Precautions for further management monitoring, monitoring, and evaluation information. (See Table 10.)

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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 time from preparation until the completion of the infusion should not exceed: 28 days 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.
Use separate infusion bags and filters for each drug product.
IMFINZI in Combination with Other Products: Administer all drug products as separate infusions.
Do not co-administer other drugs through the same infusion line.
For platinum-based chemotherapy, refer to Prescribing Information for administration information.
For pemetrexed therapy, refer to Prescribing Information for administration information.
Combination Regimens: Order of Infusions: IMFINZI in Combination with Tremelimumab: Infuse tremelimumab first, followed by IMFINZI on the same day of dosing.
IMFINZI in Combination with Tremelimumab and Platinum-Based Chemotherapy: Infuse tremelimumab first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing.
IMFINZI in Combination with Tremelimumab and Pemetrexed Therapy: Infuse tremelimumab first, followed by IMFINZI and then pemetrexed therapy on the day of dosing.
IMFINZI in Combination with Carboplatin and Paclitaxel: Infuse IMFINZI first and then carboplatin and paclitaxel on the same day of dosing.
Combination Regimens: Infusion Instructions: IMFINZI in Combination with Tremelimumab: Administer tremelimumab over 60 minutes, followed by a 60-minute observation period. Then administer IMFINZI as a separate intravenous infusion over 60 minutes.
IMFINZI in Combination with Tremelimumab and Platinum-Based Chemotherapy/Pemetrexed Therapy: Cycle 1: Infuse tremelimumab over 1 hour. One to two hours after completion of tremelimumab infusion, infuse IMFINZI over 1 hour. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy.
Subsequent Cycles: If there are no infusion reactions during Cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.

There is no information on overdose with IMFINZI.

None.

Refer to Table 10 under Dosage & Administration for recommended treatment modifications.
For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm etiology or exclude external etiologies. Based on the severity of the adverse reaction, IMFINZI or IMFINZI in combination with tremelimumab should be withheld or permanently discontinued. Treatment with corticosteroids or endocrine therapy should be initiated. For events requiring corticosteroid therapy, and upon improvement to <Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement.
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 or IMFINZI in combination with tremelimumab or IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib [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]. For Grade 2 events, an initial dose of 1-2 mg/kg/day prednisone or equivalent should be initiated followed by a taper. For Grade 3 or 4 events, an initial dose of 2-4 mg/kg/day methylprednisolone or equivalent should be initiated followed by a taper.
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.
In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), immune-mediated pneumonitis occurred in 5 (2.1%) patients, including Grade 3 in 3 (1.3%) patients. The median time to onset was 85 days (range: 65-321 days). Five patients received systemic corticosteroids, including 4 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 5 patients.
Immune-mediated hepatitis: Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab [see Adverse Reactions]. Monitor alanine aminotransferase, aspartate aminotransferase, total bilirubin and alkaline phosphatase levels prior to initiation of treatment and prior to each subsequent infusion. Additional monitoring is to be considered based on clinical evaluation. Immune-mediated hepatitis should be managed as recommended in Dosage & Administration [see Dosage & Administration]. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for all grades.
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 or IMFINZI in combination with tremelimumab [see Adverse Reactions]. Intestinal perforation and large intestine perforation were reported in patients receiving IMFINZI in combination with tremelimumab. Patients should be monitored for signs and symptoms of colitis or diarrhea and intestinal perforation and managed as recommended in Dosage & Administration [see Dosage & Administration]. Corticosteroids should be administered at an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for Grades 2-4. Consult a surgeon immediately if intestinal perforation of ANY grade is suspected.
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 or IMFINZI in combination with tremelimumab [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]. For immune-mediated hypothyroidism, initiate thyroid hormone replacement as clinically indicated for Grade 2-4. For immune-mediated hyperthyroidism/thyroiditis, symptomatic management can be implemented for Grades 2-4.
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.
IMFINZI with Carboplatin and Paclitaxel: Immune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel. Events resolved in 8 of the 34 patients. Endocrine therapy was required in 34 of the 34 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 or IMFINZI in combination with tremelimumab [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]. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and hormone replacement as clinical indicated for Grade 2-4.
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 or IMFINZI in combination with tremelimumab [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]. Treatment with insulin can be initiated as clinically indicated for Grades 2-4.
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 or IMFINZI in combination with tremelimumab [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]. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and hormone replacement as clinically indicated for Grades 2-4.
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 or IMFINZI in combination with tremelimumab [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]. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.
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 or IMFINZI in combination with tremelimumab [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]. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2 > 1 week or Grade 3 and 4.
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.
In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), immune-mediated rash occurred in 8 (3.4%) patients, including Grade 3 in 2 (0.8%) patients. The median time to onset was 155 days (range: 2-308 days). All patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 8 patients.
Immune-mediated myocarditis: Immune-mediated myocarditis, which can be fatal, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see Adverse Reactions). Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managed as recommended in Dosage & Administration. Corticosteroids should be administered with an initial dose of 2-4 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4. If no improvement within 2 to 3 days despite corticosteroids, promptly start additional immunosuppressive therapy. Upon resolution (Grade 0), corticosteroid taper should be initiated and continued over at least 1 month.
Other immune-mediated adverse reactions: Given the mechanism of action of IMFINZI or IMFINZI in combination with tremelimumab, 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, myelitis transverse, myositis, polymyositis, rhabdomyolysis, Guillain-Barre syndrome, immune thrombocytopenia, pancreatitis, immune-mediated arthritis, uveitis and encephalitis (see Adverse Reactions).
Other (hematologic/immune): Haemolytic anaemia, aplastic anaemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection.
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 or IMFINZI in combination with tremelimumab [see Adverse Reactions]. For Grade 1 or 2 severity, may consider pre-medications for prophylaxis of subsequent infusion reactions. For Grade 3 or 4, manage severe infusion-related reactions per institutional standard, appropriate clinical practice guidelines and/or society guidelines.
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.
In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), infusion-related reactions occurred in 13 (5.5%) patients, including Grade 3 in 1 (0.4%) patient. There were no Grade 4 or 5 events.
Treatment-specific precaution (IMFINZI in combination with olaparib in endometrial cancer): Haematological toxicity: Pure red cell aplasia (PRCA) (see Adverse Reactions) was reported when olaparib maintenance treatment was used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy. If PRCA is confirmed, treatment with IMFINZI and olaparib should be discontinued.
Autoimmune haemolytic anemia (AIHA) was reported when olaparib maintenance treatment was used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy. If AIHA is confirmed, treatment with IMFINZI and olaparib should be discontinued.
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. The safety, preliminary efficacy and pharmacokinetics of IMFINZI in combination with tremelimumab followed by IMFINZI as a single agent were assessed but not established in a multi-centre, open-label, dose finding and dose expansion study (NCT03837899) in pediatric patients with advanced malignant solid tumours (except primary central nervous system tumours) who had disease progression and for whom no standard of care treatment exists. The study enrolled 50 pediatric patients with an age range from 1 to 17 years with primary tumour categories: neuroblastoma, solid tumour, and sarcoma. Patients received either IMFINZI 20 mg/kg in combination with tremelimumab 1 mg/kg or IMFINZI 30 mg/kg in combination with tremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by IMFINZI as a single agent every 4 weeks. In the dose finding phase, IMFINZI and tremelimumab combination therapy was preceded by a single dose of IMFINZI monotherapy; 8 patients in this phase, however, discontinued treatment prior to receiving tremelimumab. No new safety signals were observed in pediatric patients in this study, relative to the known safety profiles of IMFINZI and tremelimumab in adults. Based on population PK analysis, durvalumab systemic exposure in pediatric patients > 35 kg receiving IMFINZI 20 mg/kg every 4 weeks was similar to exposure in adults receiving IMFINZI 20 mg/kg every 4 weeks, whereas in pediatric patients (≥35 kg) receiving IMFINZI 30 mg/kg every 4 weeks, exposure was approximately 1.5 fold higher compared to exposure in adults receiving IMFINZI 20 mg/kg every 4 weeks. In pediatric patients < 35 kg receiving IMFINZI 30 mg/kg every 4 weeks, the systemic exposure was similar to exposure in adults receiving IMFINZI 20 mg/kg every 4 weeks.
Use in the Elderly: Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older, and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients ≥ 65 years of age and younger patients.
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.
Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older, and 12% of patients were 75 years of age 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 at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg (based on AUC) 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: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI.
Contraception: Females: 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.
IMFINZI can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned].

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 reflect exposure to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC), in 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 and in patients with endometrial cancer enrolled in the DUO-E study.
Summary of the safety profile: IMFINZI in combination with chemotherapy: The safety of IMFINZI in combination with chemotherapy is based on pooled data in 838 patients from 3 studies (TOPAZ-1, CASPIAN and DUO-E). The most common (>10%) adverse reactions were neutropenia (47.3%), anaemia (44.9%), fatigue (38.8%), nausea (38.4%), thrombocytopenia (28.0%), alopecia (27.4%), constipation (25.9%), decreased appetite (21.2%), neuropathy peripheral (21.2%), abdominal pain (20.3%), diarrhoea (19.1%), rash (18.5%), vomiting (18.0%), leukopenia (17.2%), pyrexia (13.4%), arthralgia (12.4%), cough/productive cough (12.4%), pruritus (11.8%), hypothyroidism (11.0%), aspartate aminotransferase increased/alanine aminotransferase increased (10.7%) and oedema peripheral (10.1%). The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were neutropenia (30.7%), anaemia (17.1%), thrombocytopenia (9.9%), leukopenia (6.4%), fatigue (4.5%), febrile neutropenia (2.9%), aspartate aminotransferase increased/alanine aminotransferase increased (2.1%) and pneumonia (2.0%).
IMFINZI was discontinued due to adverse reactions in 3.6% of patients. The most common adverse reactions leading to treatment discontinuation were anaemia (0.5%), rash (0.5%) and fatigue (0.5%).
IMFINZI was delayed or interrupted due to adverse reactions in 31.0% of patients. The most common adverse reactions leading to dose delay or interruption were neutropenia (15.0%), thrombocytopenia (6.8%), anaemia (5.1%) and leukopenia (2.9%).
IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily.
The safety of IMFINZI given in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily is based on data in 238 patients with endometrial cancer. The most common (>20%) adverse reactions were anaemia (61.8%), nausea (54.6%), fatigue (54.2%), neuropathy peripheral (51.7%), alopecia (50.8%), neutropenia (39.5%), constipation (32.8%), thrombocytopenia (29.8%), diarrhoea (28.2%), vomiting (25.6%), arthralgia (24.4%), rash (23.5%), abdominal pain (23.5%), decreased appetite (23.1%) and leukopenia (20.2%).
The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were neutropenia (25.2%), anaemia (23.5%), leukopenia (6.7%), thrombocytopenia (5.9%), fatigue (5.5%), febrile neutropenia (3.4%), nausea (2.9%), aspartate aminotransferase increased/alanine aminotransferase increased (2.9%) and neuropathy peripheral (2.5%).
IMFINZI was discontinued in 4.6% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (1.7%).
IMFINZI was interrupted in 38.2% of patients. The most common adverse reactions leading to dose interruption were anaemia (13.4%), thrombocytopenia (11.8%), neutropenia (10.1%), leukopenia (2.9%), hypothyroidism (2.1%) and upper respiratory tract infection (2.1%).
Non-Small Cell Lung Cancer: AEGEAN Study: The safety of IMFINZI in combination with neoadjuvant platinum-containing chemotherapy followed by surgery, and continued adjuvant treatment with IMFINZI as a single agent after surgery, was investigated in AEGEAN, a randomized, double-blind, placebo-controlled, multicenter study for patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJC, 8th edition]; squamous or non-squamous) [see Pharmacology: Clinical Studies under Actions].
Safety data are available for the 799 patients who received IMFINZI in combination with chemotherapy (n=401) or placebo in combination with chemotherapy (n=398).
The median duration of exposure to IMFINZI 1500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 0 to 19 weeks). The median duration of exposure to IMFINZI 1500 mg every 4 weeks in the adjuvant phase was 37 weeks (range: 4 to 67 weeks). The median age of patients who received IMFINZI was 65 years (range: 30 to 88), 52% age 65 or older, 12% age 75 or older; 65% male; 54% White, 41% Asian, 1% Black, 3% Other races; and 17% Hispanic or Latino.
The most common adverse reactions (occurring in ≥20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash.
Table 11 summarizes the adverse reactions that occurred in (≥ 10%) patients treated with IMFINZI in combination with chemotherapy. (See Table 11.)

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Table 12 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy. (See Table 12.)

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Neoadjuvant Phase of AEGEAN: A total of 401 patients received at least 1 dose of IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment and 398 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.
Serious adverse reactions occurred in 21% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%).
Permanent discontinuation of any study drug due to an adverse reaction occurred in 14% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>0.5%) adverse reactions that led to permanent discontinuation of any study drug were anemia (1.5%), neutropenia (0.7%), myelosuppression (0.7%), and periphery sensory neuropathy (0.7%). Permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were peripheral sensory neuropathy (0.7%) and pneumonitis (0.5%).
Of the 401 IMFINZI-treated patients and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. Adverse reactions that led to cancellation of surgery in the IMFINZI arm were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colon cancer, pruritus, and colitis.
Of the 325 IMFINZI-treated patients who received surgery, 4% (n=15) experienced delay of surgery (a surgical delay is defined as on-study surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period) due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 4% (n=16) experienced delay of surgery due to adverse reactions.
Of the 325 IMFINZI-treated patients who received surgery, 6.5% (n=21) did not receive adjuvant treatment due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 5.8% (n=19) did not receive adjuvant treatment due to adverse reactions.
Adjuvant Phase of AEGEAN: A total of 265 patients in the IMFINZI arm and 254 patients in the placebo arm received at least 1 dose of adjuvant treatment.
Of the patients who received single agent IMFINZI as adjuvant treatment, 13% experienced serious adverse reactions. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 8% of patients. The most frequent (≥0.5%) adverse reaction that led to permanent discontinuation of adjuvant IMFINZI was pneumonitis (1.1%) and rash (0.8%).
PACIFIC Study: 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: 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 13 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. (See Table 13.)

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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 14 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. (See Table 14.)

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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: 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 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 15.)

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Table 16 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. (See Table 16.)

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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 17 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. (See Table 17.)

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Table 18 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. (See Table 18.)

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Endometrial Cancer (DUO-E): Adverse reactions known to occur with durvalumab, chemotherapy or olaparib given alone, may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. Refer to the local prescribing information for chemotherapy and olaparib. (See Tables 19 and 20.)

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Durvalumab is an immunoglobulin, therefore no formal pharmacokinetic drug-drug interaction studies have been conducted with durvalumab.
Furthermore, in the DUO-E study, the exposure to durvalumab was similar in both treatment arms which indicates that there were no clinically meaningful PK drug-drug interactions between durvalumab and olaparib, although exposure to olaparib was not measured throughout the study.

Incompatibilities: Durvalumab: No incompatibilities between IMFINZI and 9 g/L (0.9%) sodium chloride or 50 g/L (5%) dextrose in polyvinylchloride or polyolefin intravenous 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/PD-L1 (Programmed cell death protein 1/death ligand 1) inhibitors. Used in the treatment of cancer.

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