INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMFINZI® (IMFINZI®)

Composition:

Active substance: durvalumab;

1 ml of concentrate for infusion solution contains 50 mg of durvalumab;

1 vial containing 2.4 ml of concentrate for infusion solution contains 120 mg of durvalumab;

1 vial containing 10 ml of concentrate for infusion solution contains 500 mg of durvalumab;

Excipients: L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, polysorbate 80, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: solution ranging from clear to opalescent, colorless to light yellow, free or practically free from visible particles.

Pharmacotherapeutic group. Antineoplastic agents, monoclonal antibodies and antibody-drug conjugates. PD-1/PD-L1 (programmed cell death protein 1/ligand 1) inhibitors. ATC code L01F F03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Expression of programmed death-ligand 1 (PD-L1) is induced by inflammatory signals (e.g., gamma interferons) and may occur on both tumor cells and tumor-associated immune cells within the tumor microenvironment. PD-L1 inhibits T-cell function and activation through interaction with PD-1 and CD80 (B7.1) receptors. By binding to these 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 its interaction with PD-1 or CD80 (B7.1). Blockade of the PD-L1/PD-1 and PD-L1/CD80 interactions reverses immune suppression without inducing antibody-dependent cell-mediated cytotoxicity (ADCC).

In vitro studies and human tumor xenograft models in mice have shown that durvalumab-mediated blockade of PD-L1 leads to enhanced T-cell activation and reduced tumor growth in immune cell xenograft models.

At steady state, AUC, Ctrough, and Cmax values in patients receiving 1500 mg every 4 weeks were 6% higher, 19% lower, and 55% higher, respectively, compared to corresponding values in patients receiving 10 mg/kg every 2 weeks. Based on pharmacokinetic modeling and safety impact assessments, there are no predicted clinically meaningful differences in efficacy and safety between the dosing regimens of 1500 mg every 4 weeks and 10 mg/kg every 2 weeks in patients with body weight > 30 kg with non-small cell lung cancer (NSCLC).

Clinical studies

Non-small cell lung cancer (NSCLC)

Neoadjuvant and adjuvant treatment of resectable NSCLC — the AEGEAN study

The efficacy of IMFINZI in combination with neoadjuvant chemotherapy followed by surgery and continuation of IMFINZI monotherapy in the adjuvant setting was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial AEGEAN (NCT03800134), which included 802 patients with previously untreated, resectable squamous or non-squamous NSCLC (Stage IIA–IIIB according to the American Joint Committee on Cancer (AJCC) 8th edition). Patients were enrolled regardless of tumor PD-L1 expression. Eligible patients had not received prior immunomodulatory therapy, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had at least one measurable lesion per RECIST 1.1 criteria.

Patients with active or previously documented autoimmune disease or those who had received any immunosuppressive agents within 14 days prior to the first dose of IMFINZI were excluded from the study. The efficacy analysis population was the modified intent-to-treat (mITT) population, which excluded patients with known EGFR mutations or ALK gene rearrangements.

Cross-over between treatment arms was not permitted. Randomization was stratified by disease stage (Stage II vs. Stage III) and PD-L1 expression status (tumor cells (TC) < 1% vs. TC ≥ 1%). Patients were randomized in a 1:1 ratio to one of the following treatment groups:

• Group 1. Neoadjuvant treatment with IMFINZI 1500 mg once every 3 weeks for up to 4 cycles in combination with:
  • For squamous histology: carboplatin AUC 6 and paclitaxel 200 mg/m² on Day 1 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;
  • For non-squamous 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.

This was followed by adjuvant monotherapy with IMFINZI 1500 mg for 12 cycles after surgery.

• Group 2. Neoadjuvant treatment with placebo in combination with 4 cycles of chemotherapy (as described above) prior to surgery.

This was followed by placebo for 12 cycles after surgery.

All study drugs were administered via intravenous infusion. Patients meeting eligibility criteria who experienced poor tolerability could be switched from cisplatin to carboplatin at any time during the study. For patients with comorbidities or cisplatin intolerance, carboplatin AUC 5 could be initiated starting from Cycle 1 at the investigator’s discretion.

Treatment with IMFINZI or placebo continued until completion of therapy, disease progression precluding curative surgery, inability to undergo curative surgery, disease recurrence during the adjuvant phase, or development of unacceptable toxicity. Tumor assessments per RECIST 1.1 were performed at baseline and after completion of the neoadjuvant phase (prior to surgery). Tumor assessments were conducted 5 weeks after surgery, prior to initiation of adjuvant therapy, every 12 weeks until Week 48, every 24 weeks for approximately 4 years, and then every 48 weeks until disease progression, withdrawal of consent, or death.

The study was not designed to determine the effect of IMFINZI during each phase (neoadjuvant or adjuvant) separately.

The primary efficacy endpoints were pathological complete response (pCR) and event-free survival (EFS) assessed by blinded independent central review (BICR). Secondary efficacy endpoints included major pathological response (MPR) by BICR, disease-free survival (DFS) by BICR, and overall survival (OS).

Demographic and baseline disease characteristics were as follows: male sex (72%); median age 65 years (range: 30–88); age ≥ 65 years (52%); ECOG performance status 0 (68%), ECOG performance status 1 (32%); White (54%), Asian (41%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), other race (2.6%); non-Hispanic and non-Spanish (84%); current or former smokers (86%); squamous cell carcinoma (49%), non-squamous carcinoma (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 Group 1 underwent curative surgery compared to 77% in Group 2.

The study demonstrated statistically significant improvements in EFS and pCR (see Table 1 and Figure 1) in the IMFINZI plus chemotherapy group compared to the placebo plus chemotherapy group.

Table 1

Efficacy results from the AEGEAN study (mITT population [modified intent-to-treat population: all randomized patients who received treatment])

* Results are based on the pre-planned interim analysis of PFS and final analysis of OS (data cutoff date [DCD]: November 10, 2022), occurring 46.3 months after the start of the study.

† Compared to the two-sided p-value of 0.00989.

‡ Based on the pre-specified interim analysis of OS (DCD: January 14, 2022), n = 402, the OS rate was statistically significant (p = 0.000036) compared to the significance level of 0.0082%.

§ The two-sided p-value for OS was calculated based on the stratified Cochran-Mantel-Haenszel test. The two-sided p-value for PFS was calculated based on the stratified log-rank test. Stratification factors included PD-L1 and disease stage.

¥ The confidence interval for the difference between proportions was calculated using the stratified method of Miettinen and Nurminen.

Figure 1. Kaplan-Meier curve for PFS

At the interim analysis, the study demonstrated a statistically significant difference in the rate of ORR (34% vs. 14%; p < 0.0001). At the time of the pre-specified interim analyses, overall survival (OS) had not been formally tested for statistical significance.

Unresectable Stage III NSCLC – PACIFIC

The efficacy of IMFINZI was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled trial involving patients with unresectable Stage III NSCLC who had completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiotherapy within 42 days prior to the initiation of study treatment, and who had a WHO performance status of 0 or 1. Patients with disease progression after concurrent chemoradiotherapy, active or documented history of autoimmune disease within 2 years prior to study initiation, or conditions requiring systemic immunosuppressive therapy were excluded from this study. Prior to randomization, patients were stratified by sex, age (<65 and ≥65 years), and smoking history (current and former smokers). Patients were randomized in a 2:1 ratio to receive either IMFINZI at a dose of 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed disease progression per RECIST 1.1 criteria. Tumor status was assessed every 8 weeks. The primary efficacy endpoints were progression-free survival (PFS), assessed by BICR per RECIST 1.1, and overall survival (OS). Secondary efficacy endpoints included ORR and DoR, both assessed by BICR.

A total of 713 patients were randomized: 476 to the IMFINZI group and 237 to the placebo group. Patient population characteristics were as follows: median age 64 years (range 23 to 90 years); 70% male; 69% White, 27% Asian; 16% current smokers, 75% former smokers, 9% never smokers; 51% had a WHO performance status of 1; 53% had Stage IIIA and 45% had Stage IIIB; 46% had squamous and 54% had non-squamous NSCLC. All patients received definitive radiotherapy per protocol, with 92% receiving a total radiation dose between 54 and 66 Gy; 99% of patients received concurrent platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based, and 2% switched from cisplatin to carboplatin).

The pre-specified interim analysis of OS, which included 299 events (61% of the total planned number of events), demonstrated a statistically significant improvement in OS in patients randomized to the IMFINZI group compared to the placebo group. The pre-specified interim analysis of PFS, which included 371 events (81% of the total planned number of events), demonstrated a statistically significant improvement in PFS in patients randomized to the IMFINZI group compared to the placebo group. Efficacy results from the PACIFIC study are summarized in Table 1 and the figure.

Table 2

Efficacy results from the PACIFIC study

* In the intent-to-treat (ITT) population of all patients requiring treatment, 7% of participants in the IMFINZI group and 10% in the placebo group had no evidence of disease per RECIST 1.1 criteria as assessed by BICR.

† OS estimates are based on results from the interim OS analysis conducted after 299 deaths were observed during 46 months of follow-up from study initiation.

‡ Two-sided p-value was calculated using the stratified log-rank test, stratified by sex, age, and smoking history.

§ Compared with the pre-specified interim analysis significance level of α = 0.00274 (O'Brien-Fleming boundaries using Lan-DeMets spending function).

¶ Assessed by BICR per RECIST 1.1 criteria.

PFS estimates are based on results from the interim PFS analysis conducted after 371 progression events or deaths were observed during 33 months of follow-up from study initiation.

Þ Puckered distribution estimate.

ß Compared with the pre-specified interim analysis significance level of α = 0.011035 (O'Brien-Fleming boundaries using Lan-DeMets spending function).

Figure 2. Overall survival curves for patients in the PACIFIC trial, estimated using the Kaplan-Meier method.

Number of patients at risk

Small cell lung cancer (SCLC)

The efficacy of the medicinal product IMFINZI in combination with etoposide and carboplatin or cisplatin was evaluated in patients with extensive-stage SCLC (ES-SCLC) who had not received prior treatment, in a randomized, multicenter, active-controlled, open-label study CASPIAN (NCT03043872). Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and were candidates for platinum-based chemotherapy as first-line treatment for SCLC. Patients with asymptomatic or previously treated brain metastases were included in the study. The choice of platinum agent was at the investigator’s discretion, taking into account the calculated creatinine clearance. Patients who had previously received thoracic radiotherapy; had active primary immunodeficiency, autoimmune diseases including paraneoplastic syndromes, or active or previously documented autoimmune or inflammatory disorders; or who had received systemic immunosuppressive agents within 14 days prior to the first dose of study drug, except for physiological doses of systemic corticosteroids, were excluded from the study.

Randomization was stratified by planned platinum agent in the first treatment cycle (carboplatin or cisplatin).

For efficacy evaluation in ES-SCLC, the following treatment regimens were compared:

• IMFINZI 1500 mg plus, at the investigator’s choice, carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75–80 mg/m²) on day 1, and etoposide (80–100 mg/m²) administered intravenously on days 1, 2, and 3 of each 21-day cycle for 4 cycles, followed by IMFINZI 1500 mg every 4 weeks until disease progression or unacceptable toxicity; or
• at the investigator’s choice, carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75–80 mg/m²) on day 1, and etoposide (80–100 mg/m²) administered intravenously on days 1, 2, and 3 of each 21-day cycle for 6 cycles. After completion of chemotherapy, prophylactic cranial irradiation (PCI) was permitted at the investigator’s discretion.

Continuation of IMFINZI monotherapy after disease progression was allowed if the patient’s clinical condition remained stable and, in the investigator’s opinion, the patient was deriving clinical benefit.

The primary efficacy endpoint was overall survival (OS) with IMFINZI in combination with chemotherapy compared to chemotherapy alone. Secondary efficacy endpoints included investigator-assessed progression-free survival (PFS) and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Patient baseline characteristics were as follows: median age 63 years (range: 28–82); 40% were aged ≥65 years; 70% were male; 84% were White, 15% were Asian, and 0.9% were Black; 65% had an ECOG performance status of 1; 93% were current or former smokers. At baseline, 90% of patients had stage IV disease and 10% had brain metastases. Overall, 25% of patients received cisplatin and 74% received carboplatin. In the chemotherapy-only group, 57% of patients completed 6 cycles of chemotherapy, and 8% underwent PCI.

OS data are presented in Table 3 and Figure 3.

Table 3

Overall survival data from the CASPIAN study

* At the time of the planned interim analysis, 336 AEs (79% of the total planned number of events) had been recorded, and the boundary value for declaring efficacy (0.0178) was set based on the Lan-DeMets alpha-spending function with O'Brien-Fleming boundary criteria.

† The analysis was performed using a stratified log-rank test, adjusted for planned platinum-based therapy in cycle 1 (carboplatin or cisplatin), and applying a rank-based correlation coefficient.

Figure 3. Overall survival curves for patients in the CASPIAN trial, obtained by the Kaplan-Meier method.

The risk ratio (RR) based on investigator-assessed PFS (96% of the planned number of events) was 0.78 (95% CI: 0.65–0.94), with median PFS of 5.1 months (95% CI: 4.7–6.2) in the IMFINZI plus chemotherapy group and 5.4 months (95% CI: 4.8–6.2) in the chemotherapy alone group. Investigator-assessed confirmed ORR was 68% (95% CI: 62–73%) in the IMFINZI plus chemotherapy group and 58% (95% CI: 52–63%) in the chemotherapy alone group.

In a subgroup analysis of OS by planned platinum-based chemotherapy used in cycle 1, the HR was 0.70 (95% CI 0.55–0.89) in patients who received carboplatin and 0.88 (95% CI 0.55–1.41) in those who received cisplatin.

Biliary tract cancer (BTC)

The efficacy of IMFINZI in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic BTC was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial TOPAZ-1 (NCT03875235), which included 685 patients with histologically confirmed locally advanced unresectable or metastatic BTC who had not received prior systemic therapy. Eligible patients had disease recurrence >6 months after surgery and/or completion of adjuvant therapy. Patients had an ECOG performance status of 0 or 1 and at least one target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients were excluded if they had ampullary carcinoma; active or previously documented autoimmune or inflammatory disorders; HIV infection or active infections, including tuberculosis or hepatitis C; or current or prior use of immunosuppressive medications within 14 days prior to the first dose of IMFINZI.

Randomization was stratified by disease status (recurrent vs. initially unresectable) and primary tumor location (intrahepatic cholangiocarcinoma [IHCC] vs. extrahepatic cholangiocarcinoma [EHCC] vs. gallbladder cancer [GBC]). Patients were randomized in a 1:1 ratio to receive:

• IMFINZI 1500 mg on Day 1 + gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on Days 1 and 8 of each 21-day cycle — for up to 8 cycles, followed by IMFINZI 1500 mg every 4 weeks

or

• placebo on Day 1 + gemcitabine 1000 mg/m² and cisplatin 25 mg/m² on Days 1 and 8 of each 21-day cycle — for up to 8 cycles, followed by placebo every 4 weeks.

Treatment with IMFINZI or placebo was continued until disease progression or unacceptable toxicity. Post-progression therapy was permitted if the patient’s clinical condition was stable and, in the investigator’s opinion, clinical benefit was being derived.

The primary efficacy endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS) as assessed by the investigator, objective response rate (ORR), and duration of response (DOR). Tumor assessments were performed every 6 weeks for the first 24 weeks after randomization, and then every 8 weeks until confirmed objective disease progression.

The baseline characteristics of the study population were as follows: 50% male, median age 64 years (range 20–85), 47% aged ≥65 years; 56% Asian, 37% White, 2% Black or African American, 0.1% American Indian or Alaska Native, and 4% other; 51% had ECOG performance status of 1; primary tumor location: IHCC 56%, EHCC 18%, GBC 25%; 20% had recurrent disease; 86% had metastatic disease and 14% had locally advanced disease.

At the time of the pre-planned interim analysis, statistically significant improvements in OS and PFS were demonstrated in patients randomized to the IMFINZI plus chemotherapy group compared to the placebo plus chemotherapy group. Efficacy results from the TOPAZ-1 trial are summarized in Table 4.

Table 4

Efficacy results from the TOPAZ-1 trial

* Median calculated using the Kaplan-Meier method, with 95% CI obtained using the Brookmeyer-Crowley method.

† Based on the Cox proportional hazards model, stratified by disease status and primary tumor location.

‡ Two-sided p-value was calculated using the stratified log-rank test, compared with the significance level alpha of 0.030.

§ Two-sided p-value was calculated using the stratified log-rank test, compared with the significance level alpha of 0.048.

Investigator-assessed ORR was 27% (95% CI: 22–32%) in the IMFINZI plus chemotherapy group and 19% (95% CI: 15–23%) in the chemotherapy alone group.

Figure 4. Kaplan-Meier curve for OS in the TOPAZ-1 study

Pharmacokinetics.

The pharmacokinetics (PK) of durvalumab as a single agent were studied in patients at doses ranging from 0.1 mg/kg (0.01 of the approved recommended dose) to 20 mg/kg (2 times the approved recommended dose), administered once every two, three, or four weeks.

Plasma concentrations of the drug increased more than dose-proportionally when doses <3 mg/kg (0.3 of the approved recommended dose) were administered, and dose-proportionally when doses ≥3 mg/kg were given every two weeks. Steady-state concentrations were reached approximately by week 16.

The pharmacokinetics of durvalumab are similar when evaluated during administration as monotherapy or in combination with chemotherapy.

Distribution

The geometric mean (% coefficient of variation [CV %]) value of the volume of distribution at steady state was 5.6 L (18%).

Elimination

Durvalumab clearance decreased over time, with a mean maximum reduction (CV %) of approximately 23% (57%) compared to baseline values, resulting in a geometric mean (CV %) steady-state clearance (CLss) of 8.2 mL/hour (39%) on day 365 of therapy; the reduction in CLss is not considered clinically significant. The geometric mean (CV %) terminal half-life, adjusted for baseline clearance values, was approximately 18 (24%) days.

Pharmacokinetics in special patient populations

Clinically significant differences in the pharmacokinetics of durvalumab were not observed based on age (19–96 years), body weight (31–149 kg), sex, race (among Caucasian, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian populations), albumin concentration (4–57 g/L), lactate dehydrogenase concentration (18–15,800 U/L), creatinine concentration, soluble PD-L1 concentration (67–3,470 pg/mL), tumor type (NSCLC, SCLC, or biliary tract cancer), or organ impairment of various degrees, including mild to moderate renal impairment (creatinine clearance [CrCl] of 30–89 mL/min), mild to moderate hepatic impairment (bilirubin ≤ 3 × ULN [upper limit of normal] and any AST [aspartate aminotransferase] activity), or ECOG/WHO performance status. The impact of severe renal impairment (CrCl 15–29 mL/min) or severe hepatic impairment (bilirubin > 3 × ULN with any AST activity) on the pharmacokinetics of durvalumab is unknown.

Clinical characteristics.

Indications.

Non-small cell lung cancer

• The medicinal product IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by administration of the medicinal product IMFINZI as monotherapy in the adjuvant setting after surgical intervention is indicated for the treatment of adult patients with resectable (tumors ≥ 4 cm in size and/or lymph node involvement) non-small cell lung cancer (NSCLC) and without known epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene rearrangements.
• 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 radiotherapy.

Small cell lung cancer

IMFINZI in combination with etoposide and carboplatin or cisplatin is indicated as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC) in adult patients.

Biliary tract cancer

IMFINZI in combination with gemcitabine and cisplatin is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

The use of systemic corticosteroids or immunosuppressants prior to initiation of durvalumab therapy is not recommended, except for physiological doses of systemic corticosteroids (≤ 10 mg/day prednisolone or equivalent corticosteroids), due to the potential impact on the pharmacodynamic activity and efficacy of durvalumab. However, systemic corticosteroids or other immunosuppressants may be used after initiation of durvalumab therapy to manage immune-mediated adverse reactions (see section "Special warnings and precautions for use").

Formal pharmacokinetic drug interaction studies with durvalumab have not been conducted.

Since the primary elimination pathway of durvalumab involves protein catabolism in the reticuloendothelial system or target-mediated distribution, drug interactions related to metabolism are not expected.

Special precautions for use.

Immune-mediated adverse reactions

IMFINZI is a monoclonal antibody belonging to the class of medicinal products that bind to programmed death-1 (PD-1) receptors or PD-1 ligand (PD-L1), blocking the PD-1/PD-L1 pathway, thereby releasing inhibition of the immune response. This may potentially disrupt peripheral tolerance and induce immune-mediated adverse reactions. The important immune-mediated adverse reactions listed in this section may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, including severe or fatal ones, may develop in any organ system or tissue. Immune-mediated adverse reactions may occur at any time from the initiation of treatment with PD-1/PD-L1 blocking antibodies. Although immune-mediated adverse reactions typically occur during treatment with PD-1/PD-L1 blocking antibodies, these reactions may also occur after discontinuation of PD-1/PD-L1 blocking antibodies.

Early detection and management of immune-mediated adverse reactions are critical to ensure safe use of PD-1/PD-L1 blocking antibodies. Careful monitoring for symptoms and signs that may represent clinical manifestations of immune-mediated adverse reactions is required. Baseline and periodic assessments of liver enzymes, creatinine, and thyroid function should be performed during treatment. If immune-mediated adverse reactions are suspected, appropriate investigations should be initiated to exclude alternative causes, including infection. Prompt initiation of treatment and specialist consultations, if necessary, are required.

IMFINZI should be temporarily withheld or permanently discontinued depending on the severity of the adverse reaction (see section "Dosage and administration"). In general, if treatment with IMFINZI needs to be withheld or discontinued, systemic corticosteroids (1–2 mg/kg/day of prednisone or its equivalent) should be initiated until the severity of symptoms decreases to Grade 1 or lower, after which a gradual corticosteroid taper should be initiated and continued for at least 1 month. Consideration should be given to initiating other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids.

Clinical recommendations for managing adverse reactions presenting with toxicity where systemic steroids are not necessarily required (e.g., endocrinopathies and dermatological reactions) are discussed below.

Immune-mediated pneumonitis

The medicinal product IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have previously received thoracic radiation therapy.

Patients who have not recently received radiation therapy

In patients treated with IMFINZI in clinical trials where radiation therapy was generally not used immediately prior to initiation of IMFINZI therapy, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal adverse reactions (<0.1%) and Grade 3–4 adverse reactions (0.4%). Adverse reactions resolved in 15 out of 28 patients and led to permanent discontinuation of the medicinal product in 5 patients. Systemic corticosteroids were required in 19 patients (19/34) with pneumonitis who did not receive chemoradiotherapy prior to initiation of IMFINZI treatment.

Patients who recently received radiation therapy

The incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable stage III NSCLC after definitive chemoradiotherapy within 42 days prior to initiation of IMFINZI treatment in the PACIFIC trial was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. In patients receiving IMFINZI (475), 1.1% of adverse reactions were fatal and 2.7% were Grade 3 adverse reactions. Adverse reactions resolved in 50 out of 87 patients and led to permanent discontinuation of the medicinal product in 27 patients.

Systemic corticosteroids were required in 64 patients (64/87) with pneumonitis who received chemoradiotherapy prior to initiation of IMFINZI treatment, and 2 patients required infliximab in addition to high-dose steroids.

When definitive chemoradiotherapy was not administered prior to initiation of IMFINZI treatment, the incidence and severity of immune-mediated pneumonitis were similar in patients with various cancer types in a pooled data set receiving IMFINZI as monotherapy and in patients with NSCLC or biliary tract cancer receiving IMFINZI in combination with chemotherapy.

Immune-mediated colitis

The medicinal product IMFINZI can cause immune-mediated colitis, which is often associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with immune-mediated colitis refractory to corticosteroid treatment. In cases of colitis refractory to corticosteroid treatment, repeat evaluation by an infectious disease specialist should be considered to exclude alternative causes.

Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions. Adverse reactions resolved in 27 out of 37 patients and led to permanent discontinuation of the medicinal product in 8 patients. All patients with immune-mediated colitis required systemic corticosteroids, and 2 patients (2/37) required additional immunosuppressants (e.g., infliximab, mycophenolate).

Immune-mediated hepatitis

The medicinal product IMFINZI can cause immune-mediated hepatitis.

Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal adverse reactions (0.2%), Grade 4 adverse reactions (0.3%), and Grade 3 adverse reactions (1.4%). Adverse reactions resolved in 21 out of 52 patients and led to permanent discontinuation of IMFINZI in 6 patients. All patients with immune-mediated hepatitis required systemic corticosteroids, and 2 patients (2/52) required mycophenolate in addition to high-dose steroids.

Immune-mediated endocrinopathies

Adrenal insufficiency

IMFINZI can cause primary or secondary adrenal insufficiency. In cases of Grade 2 or higher adrenal insufficiency, symptomatic treatment, including replacement hormone therapy, should be initiated if clinically indicated. IMFINZI should be temporarily withheld or permanently discontinued depending on the severity of the adverse reaction (see section "Dosage and administration").

Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 adverse reactions (<0.1%). Adrenal insufficiency resolved in 1 out of 9 patients and did not lead to permanent discontinuation of IMFINZI in any patient. All patients with adrenal insufficiency required systemic corticosteroids. Most of these patients continued to receive systemic corticosteroids.

Hypophysitis

IMFINZI can cause immune-mediated hypophysitis. Hypophysitis may present with acute symptoms associated with mass effect in the cranial cavity, such as headache, photophobia, or visual field defects. Hypophysitis may lead to hypopituitarism. Symptomatic treatment, including replacement hormone therapy if clinically indicated, should be initiated. IMFINZI should be temporarily withheld or permanently discontinued depending on the severity of the adverse reaction (see section "Dosage and administration").

Hypophysitis/hypopituitarism of Grade 3 occurred in <0.1% (1/1889) of patients receiving IMFINZI. Systemic corticosteroids were administered to this patient. This event did not lead to permanent discontinuation of IMFINZI.

Thyroid dysfunction

IMFINZI can cause immune-mediated thyroid dysfunction. Thyroiditis may present with or without endocrinopathy. Hypothyroidism may develop after hyperthyroidism. Replacement hormone therapy should be initiated in cases of hypothyroidism or antithyroid medication should be initiated for hyperthyroidism if clinically indicated. IMFINZI should be temporarily withheld or permanently discontinued depending on the severity of the adverse reaction (see section "Dosage and administration").

Thyroiditis. Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 adverse reactions (<0.1%).

Adverse reactions resolved in 4 out of 9 patients and led to permanent discontinuation of the medicinal product in 1 patient. Systemic corticosteroids were required in 3 patients (3/9) with immune-mediated thyroiditis, while 8 patients (8/9) required endocrine therapy.

Hyperthyroidism. Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Reactions resolved in 30 out of 39 patients and did not lead to discontinuation of IMFINZI in any patient. Systemic corticosteroids were required in 9 patients (9/39) with immune-mediated hyperthyroidism, while 35 patients (35/39) required endocrine therapy.

Hypothyroidism. Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 adverse reactions (<0.1%). Adverse reactions resolved in 31 out of 156 patients and did not lead to discontinuation of IMFINZI in any patient. Systemic corticosteroids were required in 11 patients (11/156), and most patients (152/156) required long-term thyroid hormone replacement therapy.

Type 1 diabetes mellitus

Type 1 diabetes mellitus, which may present with diabetic ketoacidosis.

Patients should be monitored for signs of hyperglycemia or other symptoms of diabetes mellitus. Insulin therapy should be initiated if clinically indicated. IMFINZI treatment should be temporarily withheld or permanently discontinued depending on the severity of diabetes symptoms (see section "Dosage and administration").

Immune-mediated type 1 diabetes mellitus of Grade 3 severity occurred in <0.1% (1/1889) of patients receiving IMFINZI. This patient required long-term insulin therapy and IMFINZI treatment was permanently discontinued. Hyperglycemia requiring insulin therapy was also observed in two additional patients (0.1%, 2/1889), which persisted during the reporting period.

Immune-mediated nephritis with renal dysfunction

The medicinal product IMFINZI can cause immune-mediated nephritis.

Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 adverse reactions (<0.1%). Adverse reactions resolved in 5 out of 10 patients and led to permanent discontinuation of the medicinal product in 3 patients. All patients with immune-mediated nephritis required systemic corticosteroids.

Immune-mediated dermatologic reactions

The medicinal product IMFINZI can cause immune-mediated rash or dermatitis (including pemphigoid). In patients receiving PD-1/L-1 blocking antibodies, exfoliative dermatitis has been reported, including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN). Topical emollients and/or topical corticosteroids may be appropriate for the treatment of non-exfoliative rashes of mild to moderate severity. IMFINZI should be temporarily withheld or permanently discontinued depending on the severity of the adverse reaction (see section "Dosage and administration").

Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 adverse reactions (0.4%). Adverse reactions resolved in 19 out of 34 patients and led to permanent discontinuation of the medicinal product in 2 patients. All patients with immune-mediated rash or dermatitis required systemic corticosteroids.

Other immune-mediated adverse reactions

The following clinically significant immune-mediated adverse reactions occurred at a frequency of less than 1% in patients receiving IMFINZI or have been reported with other PD-1/PD-L1 blocking antibodies.

Cardiovascular system: myocarditis, pericarditis, vasculitis.

Nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbations), transverse myelitis, Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Eyes: uveitis, iritis, and other inflammatory toxicities affecting ocular structures. Some cases may be associated with retinal detachment. Visual impairment of varying severity, including blindness, may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, differential diagnosis of a Vogt-Koyanagi-Harada-like syndrome should be considered, as systemic steroids may be required to reduce the risk of irreversible vision loss.

Gastrointestinal tract: pancreatitis, including elevated serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.

Endocrine system: hypoparathyroidism.

Other (hematological/immune system): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, rejection of other transplants (including corneal transplant).

Infusion reactions

The medicinal product IMFINZI can cause severe or life-threatening infusion reactions.

Symptoms of infusion reactions should be monitored. IMFINZI should be temporarily withheld, the infusion rate reduced, or administration permanently discontinued depending on the severity of the adverse reaction (see section "Dosage and administration"). Premedication should be considered for patients experiencing Grade 1 or 2 infusion reactions before subsequent doses of IMFINZI are administered.

Infusion reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 adverse reactions (0.3%).

Complications of allogeneic HSCT after treatment with IMFINZI

Serious complications, including fatal ones, may occur in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) either before or after treatment with PD-1/L-1 blocking antibodies. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, veno-occlusive disease (VOD) of the liver after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without identified infectious cause). These complications may occur despite an intervening therapy between PD-1/L-1 blockade and allogeneic HSCT.

Careful monitoring for signs of transplant-related complications is required, with prompt intervention. The benefit-risk balance of treatment with PD-1/L-1 blocking antibodies before or after allogeneic HSCT should be carefully considered.

Embryo-fetal toxicity

Based on the mechanism of action and animal study data, the medicinal product IMFINZI may harm fetal development if administered to a pregnant woman. In reproductive studies in animals, administration of durvalumab to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased rates of preterm delivery, fetal death, and death of premature newborns. Pregnant women should be informed of the potential risk to the fetus. Women of reproductive potential are advised to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of this medicinal product (see section "Use during pregnancy or breastfeeding").

Patients of advanced age

Among 476 patients who received IMFINZI treatment in the PACIFIC trial, 45% were aged ≥65 years and 7.6% were aged ≥75 years. Overall, no differences in safety or efficacy were observed between patients aged ≥65 years and younger patients. The PACIFIC trial did not include a sufficient number of patients aged ≥75 years to determine whether they respond differently compared to younger patients.

In patients with NSCLC who received IMFINZI in combination with chemotherapy, safety and efficacy were similar in patients aged under and over 65 years. Among 265 NSCLC patients, 101 (38%) were over 65 years of age and 19 (7.2%) were over 75 years of age.

Among 338 patients with biliary tract cancer who received IMFINZI in combination with chemotherapy in the TOPAZ-1 trial, 158 (47%) were over 65 years of age and 38 (11%) were over 75 years of age. No overall differences in safety or efficacy of IMFINZI were observed between patients over 65 years of age and younger adult patients.

Use during pregnancy or breastfeeding.

Pregnancy

Summary of risk

Based on the mechanism of action and animal study data, the medicinal product IMFINZI may harm fetal development if administered to a pregnant woman (see section "Pharmacological properties"). Data on the use of IMFINZI in pregnant women are lacking.

In reproductive studies in animals, administration of durvalumab to pregnant cynomolgus monkeys from the time of pregnancy confirmation through delivery, at plasma concentrations approximately 6–20 times higher than those achieved with the recommended clinical dose of 10 mg/kg (based on area under the plasma concentration-time curve, AUC), resulted in increased rates of preterm delivery, fetal death, and death of premature newborns (see subsection "Animal study data"). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab may be transferred from the pregnant woman to the developing fetus. Pregnant women should be informed of the potential risks to the fetus.

In the general US population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal study data

Published reports indicate that the PD-1/PD-L1 signaling pathway plays a key role in maintaining pregnancy by supporting maternal immunological tolerance to the fetus. In allogeneic mouse models of pregnancy, disruption of the PD-L1 signaling pathway has been shown to increase the rate of fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproductive studies in cynomolgus monkeys. Durvalumab was administered from the time of pregnancy confirmation through delivery, at plasma concentrations approximately 6–20 times higher than those achieved with the clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in preterm delivery, fetal loss (abortion and stillbirth), and increased neonatal mortality. Durvalumab was detected in neonatal plasma on day 1 postpartum, indicating that durvalumab can cross the placenta. Due to the mechanism of action of the drug, the effects of durvalumab on the fetus may increase the risk of immune-mediated disorders or disrupt normal immune responses, leading to immune-mediated disorders observed in mice with blocked PD-1 gene expression.

Breastfeeding women

Summary of risk

There is currently no information on the presence of durvalumab in human breast milk, its effects on breastfed infants, or its effects on milk production. Human IgG1 is excreted into human breast milk. Durvalumab was detected in the milk of lactating cynomolgus monkeys and was associated with premature death of newborns (see subsection "Data").

Due to the potential risk of adverse reactions in breastfed infants, women should be advised not to breastfeed during treatment with IMFINZI and for at least 3 months after the last dose of this medicinal product.

Data

In lactating cynomolgus monkeys, after administration of durvalumab from the time of pregnancy confirmation through delivery, the concentration of the drug in breast milk was 0.15% of the maternal plasma concentration; plasma concentrations were approximately 6–20 times higher than those achieved with the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature death of newborns.

Men and women of reproductive potential

The medicinal product IMFINZI may harm fetal development if administered to a pregnant woman (see section "Pregnancy").

Pregnancy testing

Pregnancy status should be verified in women of reproductive potential prior to initiation of IMFINZI treatment.

Contraception

Women

Women of reproductive potential are advised to use effective contraception during treatment with IMFINZI and for at least 3 months after the last dose of this medicinal product.

Ability to drive and use machines

Due to the pharmacodynamic properties, it is unlikely that durvalumab will affect the ability to drive or operate machinery. However, if adverse reactions affecting concentration or reaction speed occur, patients should be advised to exercise caution when driving or operating machinery.

Administration and Dosage

The medicinal product IMFINZI is administered as an intravenous infusion lasting more than 60 minutes after dilution.

Recommended doses for treatment in the neoadjuvant and adjuvant setting for resectable non-small cell lung cancer

Patients with body weight ≥ 30 kg

Neoadjuvant therapy: IMFINZI 1500 mg in combination with chemotherapy* every 3 weeks for up to 4 cycles prior to surgery; adjuvant therapy: IMFINZI 1500 mg as monotherapy every 4 weeks for up to 12 cycles following surgery.

Patients with body weight < 30 kg

Neoadjuvant therapy: IMFINZI 20 mg/kg in combination with chemotherapy* every 3 weeks for up to 4 cycles prior to surgery; adjuvant therapy: IMFINZI 20 mg/kg every 4 weeks for up to 12 cycles as monotherapy following surgery.

The medicinal product should be administered until disease progression precluding curative surgery, recurrence, development of unacceptable toxicity, or for a maximum of 12 cycles after surgery.

Recommended doses for treatment of unresectable stage III NSCLC

Patients with body weight 30 kg and above: 10 mg/kg every 2 weeks or 1500 mg every 4 weeks. Patients with body weight less than 30 kg: 10 mg/kg every 2 weeks.

The medicinal product should be administered until disease progression, occurrence of unacceptable toxicities, or for a maximum duration of 12 months.

Recommended doses for treatment of metastatic NSCLC

Patients with body weight 30 kg and above: 1500 mg in combination with chemotherapy* every 3 weeks (21 days) for 4 cycles, followed by 1500 mg every 4 weeks as monotherapy.

Patients with body weight less than 30 kg: 20 mg/kg in combination with chemotherapy* every 3 weeks (21 days) for 4 cycles, followed by 10 mg/kg every 2 weeks as monotherapy.

Biliary tract cancer (BTC)

Patients with body weight 30 kg and above: 1500 mg in combination with chemotherapy* every 3 weeks (21 days) for 8 cycles, followed by 1500 mg every 4 weeks as monotherapy.

Patients with body weight less than 30 kg: 20 mg/kg in combination with chemotherapy* every 3 weeks (21 days) for 8 cycles, followed by 20 mg/kg every 4 weeks as monotherapy.

Treatment should be continued until disease progression or occurrence of unacceptable toxicities.

*IMFINZI should be administered before chemotherapy on the same day. For recommended dosing of the medicinal product used in combination with IMFINZI, refer to the respective summary of product characteristics.

Dose adjustments for adverse reactions

Dose reduction of the medicinal product is not recommended.

In general, treatment with IMFINZI should be discontinued in case of severe (Grade 3) immune-mediated adverse reactions. IMFINZI treatment should be permanently discontinued for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions requiring systemic immunosuppressive treatment, or if corticosteroid dose cannot be tapered to 10 mg per day or less (prednisone or equivalent) within 12 weeks from initiation of corticosteroid therapy.

Dose modifications of IMFINZI due to adverse reactions requiring treatment differing from these general clinical recommendations are described in Table 5.

Table 5

Recommended dose modifications for adverse reactions

ALT — alanine aminotransferase; AST — aspartate aminotransferase; DRESS — drug rash with eosinophilia and systemic symptoms; SJS — Stevens-Johnson syndrome; TEN — toxic epidermal necrolysis; ULN — upper limit of normal.

* National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

† Resumption of treatment in patients with complete or partial regression (grade 0–1) after gradual tapering of corticosteroids. Permanent discontinuation of the medicinal product if complete or partial regression does not occur within 12 weeks from the initiation of steroid therapy, or if the prednisone dose (or equivalent) cannot be reduced to 10 mg per day or less within 12 weeks from the initiation of steroid therapy.

‡ If AST or ALT levels are ≤ ULN at baseline in patients with hepatic involvement, suspend or permanently discontinue IMFINZI treatment according to recommendations for hepatitis without hepatic involvement.

Preparation and administration of the solution

Preparation

• Prior to administration, visually inspect the medicinal product for the presence of particulate matter and discoloration, if the solution and container permit. Discard the vial if the solution is cloudy or discolored, or if particulate matter is visible.
• Do not shake the vial.
• Withdraw the required volume of IMFINZI medicinal product from the vial(s) and add it to an intravenous infusion container containing 0.9% sodium chloride solution or 5% dextrose solution. Mix the resulting diluted solution by gentle inversion of the container. Do not shake this 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 the infusion solution

• IMFINZI does not contain preservatives.
• The infusion solution should be administered immediately after preparation. If the infusion solution is not administered immediately and needs to be stored, the total time from preparation to completion of infusion must not exceed:
  • 28 days if stored refrigerated at 2° to 8 °C;
  • 8 hours if stored at room temperature up to 25 °C.
• Do not freeze.
• Do not shake.

Administration

The infusion solution should be administered intravenously over more than 60 minutes through an infusion set containing a sterile filter with a pore size of 0.2 or 0.22 µm for low molecular weight proteins.

Other medicinal products must not be administered through the same infusion set.

Children.

The safety and efficacy of IMFINZI in children have not yet been established.

Overdose.

There is no information available on overdose with IMFINZI.

Adverse reactions.

The adverse reactions listed below are described in more detail in the section "Special warnings and precautions for use" of this medicinal product information:

• Immune-mediated adverse reactions;
• Infusion reactions.

Clinical trial experience

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of a particular medicinal product cannot be directly compared with the frequency of adverse reactions in clinical trials of other medicinal products, and may not reflect the frequency of adverse reactions observed in clinical practice.

The data described in the section "Special warnings and precautions for use" reflect the use of the medicinal product IMFINZI in 1889 patients from the PACIFIC study (a randomized, placebo-controlled study involving 475 patients with stage III NSCLC), Study 1108 (an open-label, uncontrolled, multi-cohort study involving 970 patients with advanced solid tumors), and an additional open-label, uncontrolled study involving 444 patients with metastatic lung cancer for which durvalumab is not currently approved. In all these studies, IMFINZI was administered at a dose of 10 mg/kg intravenously every 2 weeks. Of the 1889 patients, 38% were treated for ≥6 months and 18% for ≥12 months. The data also reflect the use of IMFINZI in combination with chemotherapy in 265 patients in the CASPIAN study (a randomized, open-label study in patients with extensive-stage small cell lung cancer [ES-SCLC]) and in 338 patients from the TOPAZ-1 study (a randomized, double-blind study in patients with biliary tract cancer [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 the use of IMFINZI in patients with stage III NSCLC from the PACIFIC study, patients with ES-SCLC from the CASPIAN study, and patients with BTC from the TOPAZ-1 study.

Non-small cell lung cancer

Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer — AEGEAN study

The safety of IMFINZI in combination with neoadjuvant platinum-based chemotherapy followed by surgical intervention and continuation of IMFINZI monotherapy in the adjuvant setting after surgery was evaluated in a randomized, double-blind, placebo-controlled, multicenter AEGEAN study in patients with resectable non-small cell lung cancer (stage IIA–IIIB [according to the AJCC 8th edition tumor classification], squamous or non-squamous histology), see section "Pharmacological properties".

Safety data are available for 799 patients who received IMFINZI in combination with chemotherapy (n = 401) or placebo in combination with chemotherapy (n = 398).

The median duration of IMFINZI treatment at a dose of 1500 mg every 3 weeks during the neoadjuvant phase was 12 weeks (range: 0 to 19 weeks). The median duration of IMFINZI treatment at a dose of 1500 mg every 4 weeks during 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 years); patients aged ≥65 years accounted for 52%, and those aged ≥75 years for 12%; male patients accounted for 65%; Caucasian patients accounted for 54%, Asian patients for 41%, Black patients for 1%, and other races for 3%; Hispanic or Latino patients accounted for 17%.

The most common adverse reactions (occurring in ≥20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash.

Table 6 lists adverse reactions that occurred in ≥10% of patients receiving IMFINZI in combination with chemotherapy.

Table 6

Adverse reactions occurring in ≥10% of patients in the AEGEAN study

• Includes colitis, diarrhea, enteritis, and proctitis.

† Includes fatigue and asthenia.

Þ Includes dermatitis, acneiform dermatitis, drug eruption, eczema, asteatotic eczema, erythema, palmar-plantar erythrodysesthesia syndrome, pemphigoid, rash, erythematous, macular, maculopapular, papular, pruritic, and pustular rash, skin exfoliation, and urticaria.

ß Includes arthralgia, arthritis, back pain, bone pain, chest pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, limb pain, and back pain.

α Includes dysesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paresthesia, peripheral sensory neuropathy, and polyneuropathy.

¶ Includes increased blood thyroid-stimulating hormone levels and hypothyroidism.

Includes lower respiratory tract infection, lung abscess, paracancerous pneumonia, aspiration pneumonia, bacterial pneumonia, chlamydial pneumonia, cryptococcal pneumonia, fungal pneumonia, pseudomonal pneumonia, streptococcal pneumonia, viral pneumonia, and post-procedural pneumonia.

‡ Five grade 5 events in the IMFINZI group and four grade 5 events in the placebo group.

§ Includes COVID-19 and pneumonia due to COVID-19. Five grade 5 events in the IMFINZI group and one grade 5 event in the placebo group.

Table 7 presents laboratory abnormalities that occurred in patients receiving IMFINZI in combination with chemotherapy.

Table 7

Selected laboratory abnormalities (≥ 20%) that worsened from baseline in participants of the AEGEAN study receiving IMFINZI in combination with chemotherapy

*Classified according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.

† Denominator used to calculate the rate varied from 349 to 399 depending on the number of patients with a baseline value and at least one post-treatment value.

Þ Denominator used to calculate the rate varied from 333 to 398 depending on the number of patients with a baseline value and at least one post-treatment value.

Neoadjuvant phase in the AEGEAN study

A total of 401 patients received at least one dose of IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, and 398 patients received at least one dose of placebo in combination with platinum-based chemotherapy as neoadjuvant treatment.

Serious adverse reactions occurred in 21% of patients who received IMFINZI in combination with platinum-based 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 (1.0%), and acute kidney injury (1.0%). 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 of unknown etiology (0.2%).

Permanently discontinued any investigational medicinal product due to an adverse reaction in 14% of patients who received IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment; the most frequent (>0.5%) adverse reactions leading to permanent discontinuation of any investigational medicinal product were anemia (1.5%), neutropenia (0.7%), myelosuppression (0.7%), and peripheral sensory neuropathy (0.7%). IMFINZI was permanently discontinued due to an adverse reaction in 6.7% of patients who received IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment; the most frequent (≥0.5%) adverse reactions leading to permanent discontinuation of IMFINZI were peripheral sensory neuropathy (0.7%) and pneumonitis (0.5%).

Among the 401 patients who received neoadjuvant IMFINZI treatment and the 398 patients who received neoadjuvant placebo treatment, 1.7% (n=7) and 1.0% (n=4), respectively, did not undergo surgery due to adverse reactions. The adverse reactions leading to cancellation of surgery in the IMFINZI group were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colorectal cancer, pruritus, and colitis.

Among 325 patients who received IMFINZI and underwent surgery, 4% (n=15) had delayed surgery (delayed surgery defined as surgery occurring more than 40 days after the last dose of investigational treatment received during the neoadjuvant phase) due to adverse reactions. Among 326 patients who received placebo and underwent surgery, 4% (n=16) had delayed surgery due to adverse reactions.

Among 325 patients who received IMFINZI and underwent surgery, 6.5% (n=21) did not receive adjuvant treatment due to adverse reactions. Among 326 patients who received placebo and underwent surgery, 5.8% (n=19) did not receive adjuvant treatment due to adverse reactions.

Adjuvant phase in the AEGEAN study

A total of 265 patients in the IMFINZI group and 254 patients in the placebo group received at least one dose of adjuvant treatment.

Among patients who received IMFINZI monotherapy as adjuvant treatment, serious adverse reactions occurred in 13%. 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: pneumonia due to COVID-19, aspiration pneumonia, interstitial lung disease, and aortic aneurysm. Adjuvant therapy with IMFINZI was permanently discontinued due to an adverse reaction in 8% of patients. The most frequent (≥0.5%) adverse reactions leading to permanent discontinuation of adjuvant IMFINZI therapy were pneumonitis (1.1%) and rash (0.8%).

Unresectable Stage III NSCLC – PACIFIC

The safety of IMFINZI in patients with Stage III unresectable NSCLC who had completed definitive platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial, PACIFIC. A total of 475 patients received IMFINZI 10 mg/kg intravenously every 2 weeks. Patients with disease progression after chemoradiotherapy, active or within 2 years prior to study entry autoimmune disease, or conditions requiring systemic immunosuppressive therapy were excluded from this study (see section "Pharmacodynamics. Clinical studies").

Patient population characteristics were as follows: median age 64 years (range 23–90 years), 45% aged ≥65 years, 70% male, 69% White, 27% Asian, 75% former smokers, 16% current smokers, 51% with WHO performance status of 1. All patients completed definitive radiotherapy per protocol, with 92% receiving a total radiation dose of 54–66 Gy. The median duration of treatment with IMFINZI was 10 months (range 0.2–12.6).

15% of patients discontinued IMFINZI due to adverse reactions. The most frequent adverse reactions leading to discontinuation of IMFINZI were pneumonitis or radiation pneumonitis, occurring in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions, occurring in at least 2% of patients, were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis/radiation pneumonitis and fatal pneumonia were reported in <2% of patients, with a similar incidence across all study groups. 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 8 summarizes adverse reactions that occurred in at least 10% of patients who received IMFINZI.

Table 8

Adverse reactions occurring in ≥10% of patients in the PACIFIC study

*Includes acute interstitial pneumonia, interstitial lung disease, pneumonitis, and pulmonary fibrosis.

†Includes dyspnea and dyspnea on exertion.

‡Includes abdominal pain, lower abdominal pain, upper abdominal pain, and flank pain.

§Includes autoimmune hypothyroidism and hypothyroidism.

¶Includes erythematous, generalized, macular, maculopapular, papular, pruritic, and pustular rashes, erythema, eczema, rash, and dermatitis.

#Includes generalized and localized pruritus.

ÞIncludes asthenia and fatigue.

ßIncludes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis, and upper respiratory tract infection.

àIncludes pulmonary infections, Pneumocystis, adenoviral, bacterial, cytomegaloviral, Haemophilus, Klebsiella, necrotizing, pneumococcal, and streptococcal pneumonia.

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. From post-marketing data, cases of transverse myelitis have been reported with a frequency of "Not known."

Table 9 summarizes laboratory abnormalities that occurred in at least 20% of patients receiving IMFINZI.

Table 9

Laboratory abnormalities that worsened from baseline in ≥20% of patients in the PACIFIC study

*Classified according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

†For each frequency assessment, the number of patients with laboratory results obtained prior to study initiation and at least once during the study was considered: in the IMFINZI group (range: 464–470) and the placebo group (range: 224–228).

Small cell lung cancer

The safety of IMFINZI in combination with etoposide and carboplatin or cisplatin in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) was evaluated in a randomized, open-label, multicenter, active-controlled trial CASPIAN. 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. Patients with active or prior autoimmune disease or conditions requiring treatment with systemic corticosteroids or immunosuppressants were excluded from the study (see section "Clinical studies").

Of the 265 patients who received IMFINZI, 49% were treated for ≥6 months and 19% for ≥12 months.

Of the 266 patients who received chemotherapy alone, 57% completed 6 cycles of chemotherapy, and 8% received prophylactic cranial irradiation (PCI) after chemotherapy.

In the IMFINZI plus chemotherapy treatment group, 7% of patients discontinued IMFINZI due to adverse reactions, including pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis, and pancytopenia (each occurring in no more than 1 patient). Serious adverse reactions occurred in 31% of patients receiving IMFINZI in combination with chemotherapy. The most frequent serious adverse reactions occurring in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and chronic obstructive pulmonary disease (COPD) (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI in combination with chemotherapy. These included pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (each occurring in no more than 1 patient), as well as sudden death (2 patients). The most common adverse reactions (occurring in ≥20% of patients) were nausea, fatigue/asthenia, and alopecia.

Table 10 presents adverse reactions observed in patients receiving IMFINZI in combination with chemotherapy.

Table 10

Adverse reactions occurring in ≥10% of patients enrolled in the CASPIAN study

* Includes hyperthyroidism and Graves' disease.

† Includes erythematous, generalized, macular, maculopapular, papular, pruritic, pustular rashes, erythema, eczema, rash, and dermatitis.

Table 11 lists laboratory abnormalities that worsened from baseline in ≥ 20% of patients who received IMFINZI in combination with chemotherapy.

Table 11

Laboratory abnormalities worsened from baseline in ≥20%* of patients in the CASPIAN study

* Threshold values for frequency are defined by any change (of any grade) in the parameter from baseline.

† Classified according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

‡ For each frequency assessment, the number of patients with laboratory test results obtained at baseline and at least once during the study was considered: in the IMFINZI group (range: 258–263) and the chemotherapy group (range: 253–262), except for magnesium levels in the IMFINZI + chemotherapy group (18) and the chemotherapy group (16).

§ LLN — lower limit of normal.

Bile duct cancer

The safety of IMFINZI administered in combination with gemcitabine and cisplatin for locally advanced or metastatic biliary tract cancer was evaluated in a randomized, double-blind, placebo-controlled, multicenter study TOPAZ-1. A total of 338 patients received IMFINZI 1500 mg in combination with gemcitabine and cisplatin every 3 weeks for 8 cycles, followed by IMFINZI 1500 mg every 4 weeks until disease progression or occurrence of unacceptable toxicity. Patients with active or history of autoimmune or inflammatory disorders, HIV infection, or other active infections, including tuberculosis or hepatitis C, were not included in the study (see section "Clinical studies").

In the IMFINZI plus chemotherapy treatment group, 6% of patients discontinued IMFINZI due to adverse reactions. The most frequent events leading to discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). Other events were distributed across system organ classes and occurred in one patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI in combination with 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%). Serious adverse reactions with fatal outcomes occurred in 3.6% of patients receiving IMFINZI in combination with chemotherapy. These included 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 12 lists adverse reactions observed in patients receiving IMFINZI in combination with chemotherapy.

Table 12

Adverse reactions occurring in ≥10% of patients in the TOPAZ-1 study

* Classified according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), USA, version 5.0

† Includes fatigue, general weakness, cancer-related fatigue, and asthenia.

‡ Includes abdominal pain, lower abdominal pain, upper abdominal pain, and flank pain.

§ Includes macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash, pustular rash, erythematous rash, acneiform dermatitis, bullous dermatitis, drug rash, eczema, erythema, dermatitis, and rash.

Table 13 shows laboratory abnormalities that worsened from baseline in patients receiving IMFINZI in combination with chemotherapy.

Table 13

Laboratory abnormalities that worsened from baseline in ≥ 20%* of patients in the TOPAZ-1 study

* Threshold values for frequency are defined by any change (of any grade) in the parameter from baseline

† Classified according to the National Cancer Institute (NCI) of the United States Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. For each frequency assessment, the number of patients with laboratory results obtained at baseline and at least once during the study was considered: IMFINZI + Gem/Cis (range: from 312 to 335) and placebo + Gem/Cis (range: from 319 to 341).

Immunogenicity

The frequency of detecting antibodies to medicinal products largely depends on the sensitivity and specificity of the assay. Differences in assay methods do not allow meaningful comparison of the frequency of anti-drug antibody (ADA) formation in the studies described below with ADA frequencies in other studies.

Among 2280 patients who received IMFINZI as monotherapy at a dose of 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks, 69 patients (3%) had positive test results for anti-drug antibodies (ADA), and 12 patients (0.5%) had positive results for neutralizing antibodies. The development of ADA against durvalumab is unlikely to have a clinically significant impact on its pharmacokinetics or safety.

Among 201 patients who received IMFINZI at a dose of 1500 mg every 3 weeks in combination with chemotherapy (a total of four doses) during the CASPIAN study, followed by IMFINZI at a dose of 1500 mg every 4 weeks, no patient had positive ADA test results emerging during treatment.

Among 240 patients who received IMFINZI at a dose of 1500 mg every 3 weeks in combination with chemotherapy (up to 8 cycles) during the TOPAZ-1 study, followed by IMFINZI at a dose of 1500 mg every 4 weeks, 2 patients (0.8%) had positive test results for ADA emerging during treatment and neutralizing antibodies, respectively. The number of patients developing ADA during treatment or neutralizing antibodies was too small (two patients each) to determine whether ADAs affect the pharmacokinetics, pharmacodynamics, safety, and/or efficacy of IMFINZI.

Reporting of adverse reactions

Reporting of adverse reactions following marketing authorization of the medicinal product is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

Unopened vial

36 months.

Storage conditions.

Unopened vial

Store in a refrigerator at 2 to 8 °C in the original packaging to protect from light. Do not freeze. Do not shake.

Keep out of reach of children.

Reconstituted solution

The infusion solution should be administered immediately after preparation. If the infusion solution is not administered immediately and requires storage, the total time from preparation must not exceed:

• 28 days if stored refrigerated at 2 to 8 °C;
• 8 hours if stored at room temperature up to 25 °C.

Packaging.

1 vial (120 mg/2.4 mL) with stopper and flip-off cap in a cardboard box or 1 vial (500 mg/10 mL) with stopper and flip-off cap in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca AB.

Manufacturer's address and location of its business operations.

Gertrud Svenssons väg, Södertälje, 152 57, Sweden.