Imfinzi 50 mg/mL concentrate for solution for infusion

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 mutations or ALK rearrangements.

Non-Small Cell Lung Cancer (NSCLC)

IMFINZI as monotherapy is indicated for the treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥ 1% of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy (see section 5.1).

Small Cell Lung Cancer (SCLC)

IMFINZI in combination with etoposide and either carboplatin or cisplatin is indicated for the first-line treatment of adults 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 locally advanced, 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).

Treatment must be initiated and supervised by a physician experienced in the treatment of cancer.

PD-L1 testing for patients with locally advanced NSCLC

Patients with locally advanced NSCLC should be evaluated for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).

Posology

The recommended dose for IMFINZI monotherapy and IMFINZI combination therapy is presented in Table 1. IMFINZI is administered as an intravenous infusion over 1 hour.

When IMFINZI is administered in combination with other therapeutic agents, refer to the summary of product characteristics (SmPC) of the therapeutic agents for further information.

Table 1. Recommended dose of IMFINZI monotherapy and combination therapy

^a Patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 30kg.

^b It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

^c Patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. In combination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 30 kg.

^d BTC patients with a body weight of 36 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. In combination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 36 kg.

^e HCC patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI 20 mg/kg until weight is greater than 30 kg. Patients with a body weight of 40 kg or less must receive weight-based dosing, equivalent to tremelimumab 4 mg/kg until weight is greater than 40 kg.

^f Resectable NSCLC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. In combination with platinum-based chemotherapy dose at 20 mg/kg every 3 weeks (21 days) prior to surgery, followed by monotherapy at 20 mg/kg every 4 weeks after surgery until weight increases to greater than 30 kg.

Dose escalation or reduction is not recommended. Treatment withholding or discontinuation may be required based on individual safety and tolerability.

Guidelines for management of immune-mediated adverse reactions are described in Table 2 (refer to section 4.4 for further management recommendations, monitoring and evaluation information).

Table 2. Treatment modifications for IMFINZI or IMFINZI in combination with tremelimumab

^a Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal; BLV: baseline value.

^b For patients with alternative cause follow the recommendations for AST or ALT increases without concurrent bilirubin elevations.

^c If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.

^d Adverse drug reaction is only associated with IMFINZI in combination with tremelimumab.

^e Permanently discontinue trememlimumab for Grade 3; however, treatment with durvalumab can be resumed once event has resolved.

^f Permanently discontinue IMFINZI if adverse reaction does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency.

^g Includes immune thrombocytopenia, pancreatitis, immune-mediated arthritis, uveitis and cystitis noninfective.

Based on the severity of the adverse reaction, IMFINZI and/or tremelimumab should be withheld and corticosteroids administered (refer to section 4.4). After withhold, IMFINZI and/or tremelimumab can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day. IMFINZI and tremelimumab should be permanently discontinued for recurrent Grade 3 (severe) immune-mediated adverse reactions and for any Grade 4 (life-threatening) immune-mediated adverse reactions, except for endocrinopathies that are controlled with replacement hormones.

For non-immune-mediated adverse reactions, withhold IMFINZI for Grade 2 and 3 adverse reactions until ≤ Grade 1 or baseline. IMFINZI should be discontinued for Grade 4 adverse reactions (with the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue should be based on accompanying clinical signs/symptoms and clinical judgment).

Special populations

Paediatric population

The safety and efficacy of IMFINZI in children and adolescents aged below 18 years of age have not been established. No data are available.

Elderly

No dose adjustment is required for elderly patients (≥ 65 years of age) (see section 5.1).

Renal impairment

No dose adjustment of IMFINZI is recommended in patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to draw conclusions on this population (see section 5.2).

Hepatic impairment

Data from patients with severe hepatic impairment are limited. Due to minor involvement of hepatic processes in the clearance of durvalumab no dose adjustment of IMFINZI is recommended for patients with hepatic impairment as no difference in exposure is expected (see section 5.2).

Paediatric population

The safety and efficacy of IMFINZI in children and adolescents aged below 18 years of age has not been established with regard to NSCLC, SCLC, BTC and HCC. No data are available. Outside its authorised indications, IMFINZI in combination with tremelimumab has been studied in children aged 1 to 17 years with neuroblastoma, solid tumour and sarcoma, however the results of the study did not allow to conclude that the benefits of such use outweigh the risks. Currently available data are described in sections 5.1 and 5.2.

Method of administration

IMFINZI is for intravenous use. It is to be administered as an intravenous infusion solution over 1 hour (see section 6.6).

For instructions on dilution of the medicinal product before administration, see section 6.6.

IMFINZI in combination with chemotherapy

For NSCLC, ES-SCLC and BTC, when IMFINZI is administered in combination with chemotherapy, administer IMFINZI prior to chemotherapy on the same day.

IMFINZI in combination with tremelimumab

For uHCC, when IMFINZI is administered in combination with tremelimumab, administer tremelimumab prior to IMFINZI on the same day. IMFINZI and tremelimumab are administered as separate intravenous infusions. Refer to the summary of product characteristics (SmPC) for tremelimumab dosing information.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Refer to section 4.2, Table 2 for recommended treatment modifications.

For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm etiology or exclude alternate 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.

Traceability

In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.

Immune-mediated pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). 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 at least 2 cycles of concurrent chemoradiation within 1 to 42 days prior to initiation of the trial, pneumonitis or radiation pneumonitis occurred in 161 (33.9%) patients in the IMFINZI-treated group and 58 (24.8%) in the placebo group, including Grade 3 (3.4% vs. 3.0%) and Grade 5 (1.1% vs. 1.7%).

Patients should be monitored for signs and symptoms of pneumonitis or radiation pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related aetiologies excluded, and managed as recommended in section 4.2.

Immune-mediated hepatitis

Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). 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 section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for all grades.

Immune-mediated colitis

Immune-mediated colitis or diarrhoea, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Adverse drug reactions of 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/diarrhoea and intestinal perforation and managed as recommended in section 4.2. 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.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab, and hypothyroidism may follow hyperthyroidism (see section 4.8). Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and as indicated based on clinical evaluation. Immune-mediated hypothyroidism, hyperthyroidism, and thyroiditis should be managed as recommended in section 4.2. For immune-mediated hypothyroidism, initiate thyroid hormone replacement as clinically indicated for Grades 2-4. For immune-mediated hyperthyroidism/thyroiditis, symptomatic management can be implemented for Grades 2-4.

Immune-mediated adrenal insufficiency

Immune-mediated adrenal insufficiency occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and a hormone replacement as clinically indicated for Grades 2-4.

Immune-mediated type 1 diabetes mellitus

Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can be fatal if not detected early, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). 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 section 4.2. Treatment with insulin can be initiated as clinically indicated for Grades 2-4.

Immune-mediated hypophysitis/hypopituitarism

Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). 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 section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and a hormone replacement as clinically indicated for Grades 2-4.

Immune-mediated nephritis

Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Patients should be monitored for abnormal renal function tests prior to and periodically during treatment with IMFINZI or IMFINZI in combination with tremelimumab and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.

Immune-mediated rash

Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Events of Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported in patients treated with PD-1 inhibitors. Patients should be monitored for signs and symptoms of rash or dermatitis and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grade 2 > 1 week or Grade 3 and 4.

Immune-mediated myocarditis

Immune-mediated myocarditis, which can be fatal, occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managed as recommended in section 4.2. 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. The following immune-related adverse reactions have been observed in patients treated with IMFINZI monotherapy or IMFINZI in combination with tremelimumab: myasthenia gravis, myelitis transverse, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, immune-mediated arthritis, uveitis and cystitis noninfective and pancreatitis (see section 4.8). Patients should be monitored for signs and symptoms and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.

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 section 4.8). Infusion-related reactions should be managed as recommended in section 4.2. 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 insititutional standard, appropriate clinical practice guidelines and/or society guidelines.

Patients with pre-existing autoimmune disease

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest an increased risk of immune-related adverse reactions following immune-checkpoint inhibitor therapy as compared with patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

Disease-specific precaution (BTC)

Cholangitis and biliary tract infections

Cholangitis and biliary tract infections are not uncommon in patients with advanced BTC. Cholangitis events were reported in TOPAZ-1 in both treatment groups (14.5% [IMFINZI + chemotherapy] vs. 8.2% [placebo + chemotherapy]); these were mostly in association with biliary stents and were not immune-mediated in aetiology. Patients with BTC (especially those with biliary stents) should be closely monitored for development of cholangitis or biliary tract infections before initiation of treatment and, regularly, thereafter.

Patients excluded from clinical trials

Patients with the following were excluded from clinical trials: a baseline ECOG performance score ≥ 2; active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions that required systemic immunosuppression, except physiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent); uncontrolled intercurrent illnesses; active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI. In the absence of data, durvalumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

The safety of concurrent prophylactic cranial irradiation (PCI) with IMFINZI in patients with ES-SCLC is unknown.

For more information on exclusion criteria for each specific study see section 5.1.

The use of systemic corticosteroids or immunosuppressants before starting durvalumab, except physiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent), is not recommended because of their potential interference with the pharmacodynamic activity and efficacy of durvalumab. However, systemic corticosteroids or other immunosuppressants can be used after starting durvalumab to treat immune-related adverse reactions (see section 4.4).

No formal pharmacokinetic (PK) drug-drug interaction studies have been conducted with durvalumab. Since the primary elimination pathways of durvalumab are protein catabolism via reticuloendothelial system or target-mediated disposition, no metabolic drug-drug interactions are expected. PK drug-drug interaction between durvalumab and chemotherapy was assessed in the CASPIAN study and showed concomitant treatment with durvalumab did not impact the PK of etoposide, carboplatin or cisplatin. Additionally, based on population PK analysis, concomitant chemotherapy treatment did not meaningfully impact the PK of durvalumab.

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with durvalumab and for at least 3 months after the last dose of durvalumab.

Pregnancy

There are no data on the use of durvalumab in pregnant women. Based on its mechanism of action, durvalumab has the potential to impact maintenance of pregnancy, and in a mouse allogeneic pregnancy model, disruption of PD-L1 signaling was shown to result in an increase in foetal loss. Animal studies with durvalumab are not indicative of reproductive toxicity (see section 5.3). Human IgG1 is known to cross the placental barrier and placental transfer of durvalumab was confirmed in animal studies. Durvalumab may cause foetal harm when administered to a pregnant woman and is not recommended during pregnancy and in women of childbearing potential not using effective contraception during treatment and for at least 3 months after the last dose.

Breast-feeding

It is unknown whether durvalumab is secreted in human breast milk. Available toxicological data in cynomolgus monkeys have shown low levels of durvalumab in breast milk on Day 28 after birth (see section 5.3). In humans, antibodies may be transferred to breast milk, but the potential for absorption and harm to the newborn is unknown. However, a potential risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast feeding or to discontinue or abstain from durvalumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the potential effects of durvalumab on fertility in humans or animals.

Durvalumab has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

IMFINZI as monotherapy

The safety of IMFINZI as monotherapy is based on pooled data in 3006 patients across multiple tumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks. The most common (>10%) adverse reactions were cough/productive cough (21.5%), diarrhoea (16.3%), rash (16.2%), pyrexia (13.8%), upper respiratory tract infections (13.5%), abdominal pain (12.7%), pruritus (10.8%), and hypothyroidism (10.1%). The most common (> 2%) Grade ≥ 3 adverse reactions were pneumonia (3.5%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.3%).

IMFINZI was discontinued due to adverse reactions in 3.6% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (1.1%) and pneumonia (0.8%).

IMFINZI was delayed or interrupted due to adverse reactions in 13.7% of patients. The most common adverse reactions leading to dose delay or interruption were pneumonia (2.7%) and aspartate aminotransferase increased/alanine aminotransferase increased (1.7%).

The most frequent (>1%) serious adverse reactions were pneumonia (4.5%), abdominal pain (1.6%), pneumonitis (1.3%), and pyrexia (1.2%).

Treatment was discontinued due to adverse reactions in 4.1% of patients. The most frequent adverse reaction leading to discontinuation was pneumonitis (1.1%).

IMFINZI in combination with chemotherapy

The safety of IMFINZI in combination with chemotherapy is based on pooled data in 1004 patients from 3 studies (AEGEAN, TOPAZ-1 and CASPIAN). The most common (> 10%) adverse reactions were neutropenia (44.5%), anaemia (39.9%), nausea (32.6%), fatigue (32.2%), constipation (25.2%), thrombocytopenia (22.2%), decreased appetite (20.8%), alopecia (18.0%), rash (16.7%), leukopenia (16.1%), vomiting (14.6%), diarrhoea (13.7%), abdominal pain (12.6%), pyrexia (11.6%), cough or productive cough (11.1%), pruritus (11.0%), and aspartate aminotransferase increased or alanine aminotransferase increased (10.5%).

The most common (> 2%) Grade ≥ 3 adverse reactions were neutropenia (35.2%), anaemia (17.4%), thrombocytopenia (11.1%), leukopenia (7.1%), fatigue (5.0%), febrile neutropenia (3.0%), aspartate aminotransferase increased or alanine aminotransferase increased (2.8%) and pneumonia (2.5%).

IMFINZI was discontinued due to adverse reactions in 2.0% of patients. The most common adverse reaction leading to treatment discontinuation was fatigue (0.3%).

IMFINZI was delayed or interrupted due to adverse reactions in 29.2% of patients. The most common adverse reactions leading to dose delay or interruption were neutropenia (17.1%), anaemia (3.8%), thrombocytopenia (4.3%), leukopenia (3.5%), fatigue (1.7%) and pyrexia (1.3).

The most frequent (>1%) serious adverse reactions were anaemia (2.8%), febrile neutropenia (2.7%), pyrexia (2.5%), pneumonia (2.2%), thrombocytopenia (1.3%), fatigue (1.3%), and neutropenia (1.2%).

Treatment was discontinued due to adverse reactions in 5.5% of patients. The most frequent adverse reaction leading to discontinuation was neutropenia (1.2%).

IMFINZI in combination with tremelimumab 300 mg

The safety of IMFINZI given in combination with a single dose of tremelimumab 300 mg is based on pooled data (HCC pool) in 462 HCC patients from the HIMALAYA Study and another study in HCC patients, Study 22. The most common (> 10%) adverse reactions were rash (32.5%), pruritus (25.5%), diarrhoea (25.3%), abdominal pain (19.7%), aspartate aminotransferase increased/alanine aminotransferase increased (18.0%), pyrexia (13.9%), hypothyroidism (13.0%), cough/productive cough (10.8%), oedema peripheral (10.4%) and lipase increased (10.0%) (see Table 4). The most common severe adverse reactions (NCI CTCAE Grade ≥ 3) are aspartate aminotransferase increased/alanine aminotransferase increased (8.9%), lipase increased (7.1%), amylase increased (4.3%) and diarrhoea (3.9%).

The most common serious adverse reactions are colitis (2.6%), diarrhoea (2.4%), pneumonia (2.2%), and hepatitis (1.7%).

The frequency of treatment discontinuation due to adverse reactions is 6.5%. The most common adverse reactions leading to treatment discontinuation are hepatitis (1.5%) and aspartate aminotransferase increased/alanine aminotransferase increased (1.3%).

The severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life threatening and grade 5=death.

Tabulated list of adverse reactions

Table 3 lists the incidence of adverse reactions in the IMFINZI monotherapy pooled safety dataset and Tables 4 and 5 in patients treated with IMFINZI in combination with chemotherapy in the CASPIAN and TOPAZ-1 studies respectively. Table 4 lists the incidence of adverse reactions in patients treated with IMFINZI in combination with a single dose of tremelimumab 300 mg in the HCC pool (N=462). Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in decreasing frequency. The corresponding frequency category for each ADR is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 3. Adverse drug reactions in patients treated with IMFINZI

Adverse reaction frequencies may not be fully attributed to durvalumab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.

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

^b includes pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia pneumococcal, pneumonia streptococcal, candida pneumonia and pneumonia legionella.

^c including fatal outcome.

^d includes gingivitis, oral infection, periodontitis, pulpitis dental, tooth abscess and tooth infection.

^e includes autoimmune hypothyroidism, hypothyroidism, immune-mediated hypothyroidism, blood thyroid stimulating hormone increased.

^f includes hyperthyroidism, Basedow's disease, immune-mediated hyperthyroidism and blood thyroid stimulating hormone decreased.

^g includes autoimmune thyroiditis, thyroiditis, and thyroiditis subacute.

^h reported frequency from AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare, with no events at Grade > 2.

ⁱ includes meningitis and noninfective meningitis.

^j reported frequency from ongoing AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare and includes two events of encephalitis, one was Grade 5 fatal (immune-mediated encephalitis) and one was Grade 2 (autoimmune encephalitis).

^k includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.

^l includes colitis, enteritis, enterocolitis, and proctitis.

^m includes pancreatitis, pancreatitis acute, and immune-mediated pancreatitis.

ⁿ includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.

^o includes hepatitis, autoimmune hepatitis, hepatitis toxic, hepatic cytolysis, hepatocellular injury, hepatitis acute, hepatotoxicity and immune-mediated hepatitis.

^p includes drug eruption, eczema, erythema, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash vesicular.

^q includes pemphigoid, dermatitis bullous and pemphigus. Reported frequency from completed and ongoing trials is uncommon.

^r includes rhabdomyolysis, myositis, and polymyositis.

^s polymyositis (fatal) was observed in a patient treated with IMFINZI from an ongoing sponsored clinical study outside of the pooled dataset: rare in any grade, rare in Grade 3 or 4 or 5.

^t includes autoimmune nephritis, tubulointerstitial nephritis, nephritis, glomerulonephritis and glomerulonephritis membranous.

^u includes fatigue and asthenia.

^v includes oedema peripheral and peripheral swelling.

^w includes infusion-related reaction and urticaria with onset on the day of dosing or 1 day after dosing.

^x includes stomatitis and mucosal inflammation.

^y includes peripheral neuropathy, paraesthesia and peripheral sensory neuropathy.

^z includes leukopenia and white blood cell count decreased.

^aa includes neutropenia and neutrophil count decreased.

^bb includes thrombocytopenia and platelet count decreased.

^cc includes dermatitis, dermatitis acneiform, urticarial dermatitis

^dd events were reported from post-marketing data

^ee includes myocarditis.

^ff includes adrenal insufficiency.

^gg includes hypophysitis.

^hh includes myasthenia gravis.

ⁱⁱ includes pneumonitis and immune-mediated lung disease.

Table 4. Adverse drug reactions in patients treated with IMFINZI in combination with tremelimumab

^a Includes nasopharyngitis, pharyngitis, rhinitis, tracheobronchitis and upper respiratory tract infection.

^b Includes pneumocystis jirovecii pneumonia and pneumonia.

^c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.

^d Adverse reaction was not observed in the HCC pool, but was reported in patients treated with IMFINZI or IMFINZI+tremelimumab in AstraZeneca-sponsored clinical studies.

^e Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.

^f Includes blood thyroid stimulating hormone decreased and hyperthyroidism.

^g Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.

^h Includes immune-mediated pneumonitis and pneumonitis.

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

^j Includes colitis, enteritis and enterocolitis.

^k Includes pancreatitis and pancreatitis acute.

^l Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.

^m Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity and immune-mediated hepatitis.

ⁿ Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular and rash pruritic.

^o Includes dermatitis and immune-mediated dermatitis.

^p Includes rhabdomyolysis, myositis, and polymyositis.

^q Includes autoimmune nephritis and immune-mediated nephritis.

^r Includes oedema peripheral and peripheral swelling.

^s Includes infusion-related reaction and urticaria.

Description of selected adverse reactions

IMFINZI is associated with immune-mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy and/or treatment modifications. The data for the following immune-mediated adverse reactions reflect the IMFINZI monotherapy combined safety database of 3006 patients which includes the PACIFIC Study and additional studies in patients with various solid tumours, in indications for which durvalumab is not approved. Across all studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks, or 1500 mg every 3 or 4 weeks. Details for the significant adverse reactions for IMFINZI when given in combination with chemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI monotherapy.

The data for the following immune-mediated adverse reactions also reflect the IMFINZI in combination with tremelimumab 300 mg combined safety database of 462 patients with HCC (the HCC pool). In these two studies, IMFINZI was administered at a dose of 1500 mg in combination with tremelimumab 300 mg every 4 weeks.

The management guidelines for these adverse reactions are described in section 4.2 and 4.4.

Immune-mediated pneumonitis

In the combined safety database with IMFINZI monotherapy, (n = 3006 multiple tumour types), immune-mediated pneumonitis occurred in 92 (3.1%) patients, including Grade 3 in 25 (0.8%) patients, Grade 4 in 2 (< 0.1%) 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%), than in the other patients in the combined safety database (1.8%).

In the PACIFIC Study, (n = 475 in the IMFINZI arm, and n = 234 in the placebo arm) immune-mediated pneumonitis occurred in 47 (9.9%) patients in the IMFINZI-treated group and 14 (6.0%) patients in the placebo group, including Grade 3 in 9 (1.9%) patients on IMFINZI vs. 6 (2.6%) patients on placebo and Grade 5 (fatal) in 4 (0.8%) patients on IMFINZI vs. 3 (1.3%) patients on placebo. The median time to onset in the IMFINZI-treated group was 46 days (range: 2-342 days) vs. 57 days (range: 26-253 days) in the placebo group. In the IMFINZI-treated group, all patients received systemic corticosteroids, including 30 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), and 2 patients also received infliximab. In the placebo group, all patients received systemic corticosteroids, including 12 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the IMFINZI treated group vs. 6 in placebo.

In the HCC pool (n=462), immune-mediated pneumonitis occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient and Grade 5 (fatal) in 1 (0.2%) patient. The median time to onset was 29 days (range: 5-774 days). Six patients received systemic corticosteroids, and 5 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received other immunosuppressants. Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.

Immune-mediated hepatitis

In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in 68 (2.3%) patients, including Grade 3 in 35 (1.2%) patients, Grade 4 in 6 (0.2%) patients and Grade 5 (fatal) in 4 (0.1%) patients. The median time to onset was 33 days (range: 3-333 days). Forty-five of the 68 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received mycophenolate treatment. IMFINZI was discontinued in 9 patients. Resolution occurred in 31 patients.

In the HCC pool (n=462), immune-mediated hepatitis occurred in 34 (7.4%) patients, including Grade 3 in 20 (4.3%) patients, Grade 4 in 1 (0.2%) patient and Grade 5 (fatal) in 3 (0.6%) patients. The median time to onset was 29 days (range: 13-313 days). All patients received systemic corticosteroids, and 32 of the 34 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants. Treatment was discontinued in 10 patients. Resolution occurred in 13 patients.

Immune-mediated colitis

In the combined safety database with IMFINZI monotherapy, immune-mediated colitis or diarrhoea occurred in 58 (1.9%) patients, including Grade 3 in 9 (0.3%) patients and Grade 4 in 2 (<0.1%) 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 1 patient also received mycophenolate. IMFINZI was discontinued in 9 patients. Resolution occurred in 43 patients.

In the HCC pool (n=462), immune mediated colitis or diarrhoea occurred in 31 (6.7%) patients, including Grade 3 in 17 (3.7%) patients. The median time to onset was 23 days (range: 2-479 days). All patients received systemic corticosteroids, and 28 of the 31 patients received high dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also received other immunosuppressants. Treatment was discontinued in 5 patients. Resolution occurred in 29 patients.

Intestinal perforation was observed in patients receiving IMFINZI in combination with tremelimumab (rare) in studies outside of the HCC pool.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism

In the combined safety database with IMFINZI monotherapy, immune-mediated hypothyroidism occurred in 245 (8.2%) patients, including Grade 3 in 4 (0.1%) patients. The median time to onset was 85 days (range: 1-562 days). Of the 245 patients, 240 patients received hormone replacement therapy and 6 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism. No patients discontinued IMFINZI due to immune-mediated hypothyroidism.

In the HCC pool (n=462), immune-mediated hypothyroidism occurred in 46 (10.0%) patients. The median time to onset was 85 days (range: 26-763 days). One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy. Resolution occurred in 6 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 4 patients.

Immune-mediated hyperthyroidism

In the combined safety database with IMFINZI monotherapy, immune-mediated hyperthyroidism occurred in 50 (1.7%) patients, there were no Grade 3 or 4 cases. The median time to onset was 43 days (range: 1-196 days). Forty-six of the 50 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), 11 patients received systemic corticosteroids and 4 of the 11 patients received high-dose systemic corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated hyperthyroidism. Resolution occurred in 39 patients. Twenty patients experienced hypothyroidism following hyperthyroidism.

In the HCC pool (n=462), immune-mediated hyperthyroidism occurred in 21 (4.5%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 30 days (range: 13-60 days). Four patients received systemic corticosteriods, and all of the four patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 17 patients.

Immune-mediated thyroiditis

In the combined safety database with IMFINZI monotherapy, immune-mediated thyroiditis occurred in 12 (0.4%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 49 days (range: 14-106 days). Of the 12 patients, 10 patients received hormone replacement therapy and 1 patient received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated thyroiditis. Three patients experienced hypothyroidism following thyroiditis.

In the HCC pool (n=462), immune-mediated thyroiditis occurred in 6 (1.3%) patients. The median time to onset was 56 days (range: 7-84 days). Two patients received systemic corticosteroids, and 1 of the 2 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy. Resolution occurred in 2 patients.

Immune-mediated adrenal insufficiency

In the combined safety database with IMFINZI monotherapy, immune-mediated adrenal insufficiency occurred in 14 (0.5%) patients, including Grade 3 in 3 (<0.1%) patients. The median time to onset was 146 days (range: 20-547 days). All 14 patients received systemic corticosteroids; 4 of the 14 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). No patients discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 3 patients.

In the HCC pool (n=462), immune-mediated adrenal insufficiency occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 64 days (range: 43-504 days). All patients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.

Immune-mediated type 1 diabetes mellitus

In the combined safety database with 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 recovered with sequelae, required long-term insulin therapy and IMFINZI was permanently discontinued due to immune-mediated type 1 diabetes mellitus.

Immune-mediated hypophysitis/hypopituitarism

In the combined safety database with IMFINZI monotherapy, immune-mediated hypophysitis/hypopituitarism occurred in 2 (< 0.1%) patients both Grade 3. The time to onset for the events was 44 days and 50 days. Both patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and one patient discontinued IMFINZI due to immune-mediated hypophysitis/hypopituitarism.

In the HCC pool (n=462), immune-mediated hypophysitis/hypopituitarism occurred in 5 (1.1%) patients. The median time to onset for the events was 149 days (range: 27-242 days). Four patients received systemic corticosteroids, and 1 of the 4 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also required endocrine therapy. Resolution occurred in 2 patients.

Immune-mediated nephritis

In the combined safety database with IMFINZI monotherapy, immune-mediated nephritis occurred in 14 (0.5%) patients, including Grade 3 in 2 (< 0.1%) patients. The median time to onset was 71 days (range: 4-393 days). Nine patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received mycophenolate. IMFINZI was discontinued in 5 patients. Resolution occurred in 8 patients.

In the HCC pool (n=462), immune-mediated nephritis occurred in 4 (0.9%) patients, including Grade 3 in 2 (0.4%) patients. The median time to onset was 53 days (range: 26-242 days). All patients received systemic corticosteroids, and 3 of the 4 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.

Immune-mediated rash

In the combined safety database with 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-three of the 50 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 3 patients. Resolution occurred in 32 patients.

In the HCC pool (n=462), immune-mediated rash or dermatitis (including pemphigoid) occurred in 26 (5.6%) patients, including Grade 3 in 9 (1.9%) patients and Grade 4 in 1 (0.2%) patient. The median time to onset was 25 days (range: 2-933 days). All patients received systemic corticosteroids and 14 of the 26 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants. Treatment was discontinued in 3 patients. Resolution occurred in 19 patients.

Infusion related reactions

In the combined safety database with IMFINZI monotherapy, infusion-related reactions occurred in 49 (1.6%) patients, including Grade 3 in 5 (0.2%) patients. There were no Grade 4 or 5 events.

Laboratory abnormalities

In patients treated with durvalumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 2.4% for alanine aminotransferase increased, 3.6% for aspartate aminotransferase increased, 0.5% for blood creatinine increased, 5.7% for amylase increased and 5.6% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 18.8% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 18.1%.

In patients treated with durvalumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 6.4% for alanine aminotransferase increased, 6.5% for aspartate aminotransferase increased, 4.2% for blood creatinine increased, 6.4% for amylase increased, and 11.7% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 20.3% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 24.1%.

In patients treated with IMFINZI in combination with tremelimumab, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 5.1% for alanine aminotransferase increased, 5.8% for aspartate aminotransferase, 1.0% for blood creatinine increased, 5.9% for amylase increased and 11.3% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 4.2% and a TSH shift from baseline that was ≥ LLN to < LLN was 17.2%.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with durvalumab: pancreatic exocrine insufficiency.

Immunogenicity

Immunogenicity of IMFINZI as monotherapy is based on pooled data in 2280 patients who were treated with IMFINZI 10 mg/kg every 2 weeks, or 20 mg/kg every 4 weeks as a single-agent and evaluable for the presence of anti-drug antibodies (ADAs). Sixty-nine patients (3.0%) tested positive for treatment emergent ADAs. Neutralising antibodies (nAb) against durvalumab were detected in 0.5% (12/2280) of patients. The presence of ADAs did not have a clinically relevant effect on safety. There are insufficient number of patients to determine ADA impact on efficacy. Based on population PK analysis, slightly lower exposure are expected in ADA-positive patients however, the reduction of PK exposure is less than 30% compared to a typical patient and is not considered clinically relevant.

Across multiple phase III studies, in patients treated with IMFINZI in combination with other therapeutic agents, 0% to 3.1% of patients developed treatment-emergent ADAs. Neutralizing antibodies against durvalumab were detected in 0% to 1.7% of patients treated with IMFINZI in combination with other therapeutic agents. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.

Elderly

In studies PACIFIC, CASPIAN, TOPAZ-1, and AEGEAN data on safety for patients 75 years and older are too limited to draw a conclusion on this population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no information on overdose with durvalumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code: L01FF03.

Mechanism of action

Expression of programmed cell death ligand-1 (PD-L1) protein is an adaptive immune response that helps tumours evade detection and elimination by the immune system. PD-L1 can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumour cells and tumour-associated immune cells in tumour microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation and cytokine production.

Durvalumab is a fully human, immunoglobulin G1 kappa (IgG1κ ) monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Durvalumab does not induce antibody dependent cell-mediated cytotoxicity (ADCC). Selective blockade of PD-L1/PD-1 and PD-L1/CD80 interactions enhances antitumour immune responses and increases T-cell activation.

The combination of tremelimumab, a CTLA-4 inhibitor and durvalumab, a PD-L1 inhibitor functions to enhance anti-tumour T-cell activation and function at multiple stages of the immune response resulting in improved anti-tumour responses. In murine syngeneic tumour models, dual blockade of PD-L1 and CTLA-4 resulted in enhanced anti-tumour activity.

Clinical efficacy and safety

Durvalumab doses of 10 mg/kg every 2 weeks or 1500 mg every 4 weeks were evaluated in NSCLC and ES-SCLC clinical studies. Based on the modeling and simulation of exposure, exposure-safety relationships and exposure-efficacy data comparisons, there are no anticipated clinically significant differences in efficacy and safety between durvalumab doses of 10 mg/kg every 2 weeks or 1500 mg every 4 weeks.

NSCLC – 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 5.

Table 5. Efficacy results for the PACIFIC Study

^a Primary analysis of PFS at data cut-off 13 February 2017. Primary analysis of OS and PFS2 at data cut-off 22 March 2018.

^b Follow-up OS and PFS analysis at data cut-off 11 January 2021.

^c PFS2 is defined as the time from the date of randomisation until the date of second progression (defined by local standard clinical practice) or death.

NR: Not Reached

Kaplan-Meier curves for OS and PFS from the 5 year follow-up analysis are presented in Figures 1 and 2.

Figure 1. Kaplan-Meier curve of OS

Figure 2. Kaplan-Meier curve of PFS

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 3, 4, 5 and 6.

Figure 3. Kaplan-Meier curve of OS for PD-L1 TC ≥ 1%

Figure 4. Kaplan-Meier curve of PFS for PD-L1 TC ≥ 1%

Figure 5. Forest plot of OS by PD-L1 expression

Figure 6. Forest plot of PFS by PD-L1 expression

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).

Resectable NSCLC – AEGEAN Study

AEGEAN was a randomized, double-blind, placebo-controlled, multicentre, Phase III study designed to evaluate the efficacy of IMFINZI in combination with chemotherapy as neoadjuvant treatment, then continued as IMFINZI monotherapy after surgery, in patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJCC, 8^th edition]). The study enrolled previously untreated patients with documented squamous or non-squamous NSCLC and 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. Prior to randomization, patients had tumour PD-L1 expression status confirmed using the Ventana PD-L1 (SP263) Assay.

The study excluded patients with active or prior documented autoimmune disease, or use of immunosuppressive medication within 14 days of the first dose of durvalumab. The study population for efficacy analysis (modified intent-to-treat [mITT]) excluded patients with known EGFR mutations or ALK rearrangements.

Randomisation was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC <1% vs. TC ≥ 1%) status.

The AEGEAN study randomized 802 patients in a 1:1 ratio to receive perioperative IMFINZI (Arm 1) or placebo (Arm 2) in combination with neoadjuvant chemotherapy. Crossover between the study arms was not permitted. Efficacy analysis was conducted based on 740 patients in the mITT population.

• Arm 1: IMFINZI 1 500 mg + chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by IMFINZI 1 500 mg every 4 weeks for up to 12 cycles after surgery

• Arm 2: Placebo + chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by Placebo every 4 weeks for up to 12 cycles after surgery.

A RECIST 1.1 tumour assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). The first post-surgical CT/MRI scan of the chest and abdomen (including the entire liver and both adrenals) was acquired 5 weeks ± 2 weeks after surgery and prior to, but as close as possible to the start of adjuvant therapy. Tumour assessments were then conducted every 12 weeks (relative to the date of surgery) until week 48, every 24 weeks (relative to the date of surgery) until week 192 (approximately 4 years), and then every 48 weeks (relative to the date of surgery) thereafter until RECIST 1.1 defined radiological PD, consent withdrawal, or death. Survival assessments were conducted at month 2, 3, and 4 following treatment discontinuation and then every 2 months until month 12 followed by every 3 months.

The primary endpoints 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. The key secondary endpoints were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS. Other secondary efficacy objectives were EFS (PD-L1-TC ≥ 1% analysis set), pCR (PD-L1-TC ≥ 1% analysis set), and Patient Reported Outcomes (PRO).

At the planned interim analysis of pCR, the study met its prespecified boundary for declaring statistical significance for pCR and MPR. Subsequently, at the first planned interim analysis of EFS, the study met its prespecified boundary for declaring statistical significance for EFS.

The demographics and baseline disease characteristics were well balanced between the two study arms (366 patients in Arm 1 and 374 patients in Arm 2 of the mITT set). Baseline demographics and disease characteristics of the population for efficacy analysis (mITT) were as follows: male (71.6%), female (28.4%), age ≥ 65 years (51.6%), median age 65 years (range: 30 to 88), WHO/ECOG PS 0 (68.4%), WHO/ECOG PS 1 (31.6), White (53.6%), Asian (41.5%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%), Hispanic or Latino (16.1%), Not Hispanic or Latino (83.9%). current or past smokers (85.5%), never smoker (14.5%), squamous histology (48.6%) and non-squamous histology (50.7%), Stage II (28.4%), Stage III (71.6%), PD-L1 expression status TC ≥ 1% (66.6%), PD-L1 expression status TC <1% (33.4%). The demographics and baseline characteristics for the mITT population were similar to the ITT population, except for the absence of patients with known EGFR mutations or ALK rearrangements.

In the mITT population there were 295 (80.6%) patients in Arm 1 who underwent curative intent surgery compared to 302 (80.7%) patients in Arm 2. There were 284 (77.6%) patients in Arm 1 who completed curative intent surgery compared to 287 (76.7%) patients in Arm 2. The resection margin status within the mITT population, who completed surgery, was (Arm 1 vs. Arm 2):

• R0 (no residual tumour): 94.7% vs. 91.3%

• R1 (microscopic residual tumour): 4.2% vs. 7.7%

• R2 (macroscopic residual tumour): 0.7% vs. 0.7%

The study demonstrated a statistically significant and clinically meaningful improvement in EFS [HR = 0.68 (95% CI: 0.53, 0.88), p = 0.003902] in the IMFINZI arm compared to the placebo arm. The study also demonstrated a statistically significant and meaningful improved in pCR [Difference in proportions, 12.96% (95% CI: 8.67, 17.57)] in the IMFINZI arm compared to the placebo arm. Overall survival (OS) data were not mature at the time of EFS analysis. See Table 5 and Figure 7.

Table 6: Efficacy Results for the AEGEAN Study (mITT)

^a Results are based on planned EFS interim analysis and pCR/MPR final analysis (DCO: 10 November 2022) which occurred 46.3 months after study initiation.

^b Based on a pre-specified pCR interim analysis (DCO: 14 January 2022) in n =402, the pCR rate was statistically significant (p = 0.000036) compared to significance level of 0.0082%.

^c Based on a pre-specified MPR interim analysis (DCO: 14 January 2022) in n=402, the MPR rate was statistically significant (p= 0.000002) compared to significance level of 0.0082%.

^d The 2-sided p-value for pCR and MPR was calculated based on a stratified CMH test. The 2-sided p-value for EFS was calculated based on based on a stratified log-rank test. Stratification factors include PD-L1 and disease stage.

The boundary for declaring statistical significance for each of the efficacy endpoints were determined by a Lan-DeMets alpha spending function that approximates an O'Brien Fleming approach (EFS = 0.9899%, pCR = 0.0082%, MPR = 0.0082%, 2-sided).

Figure 7: Kaplan-Meier Curve of EFS

Sensitivity analysis

The improvement in EFS favouring patients in Arm 1 compared to patients in Arm 2 was consistent across prespecified sensitivity analyses. An attrition assessment, which removed censoring related to missed visits and added censoring of patients who take subsequent therapy prior to an event, resulted in a HR of 0.71 [95% CI: 0.55, 0.92].

Subgroup analysis

The improvement in EFS and pCR favouring patients in Arm 1 compared to patients in Arm 2 were consistently observed across prespecified subgroups based on demographic and baseline disease characteristics, histology, and planned chemotherapy.

Patient Reported Outcomes (PRO)

Patient-reported symptoms, function, and health related quality of life (HRQoL) were collected using the EORTC QLQ-C30, complementary EORTC QLQ-LC13, and exploratory PGIS, EQ-5D-5L, and PRO-CTCAE. These questionnaires were administered before discussion of disease progression and dosing and collected on month 1, 2, 3, and 6 post last dose. Overall compliance rates were high at neoadjuvant baseline (>90%) in the IMFINZI in combination with chemotherapy arm and the placebo in combination with chemotherapy arm.

Overall, the PRO/HRQoL data was generally similar between treatment arms throughout the neoadjuvant period. The proportion of patients with a clinically meaningful (≥ 10 point change) improvement in EORTC QLQ-C30 GHS/QoL was similar over the neoadjuvant period (reported for approximately a quarter of patients in both treatment arms). Clinically meaningful changes (≥ 10 point from baseline) were observed in only two scales: worsening fatigue (EORTC QLQ-C30) in the D + CTx arm (12.57 points [D + CTx] vs 8.50 points [placebo + CTx]) and decreased coughing (EORTC QLQ-LC13) in the placebo + CTx arm (-9.26 points [D + CTx] vs -11.60 points [placebo + CTx).

SCLC – CASPIAN Study

CASPIAN was a study designed to evaluate the efficacy of IMFINZI with or without tremelimumab in combination with etoposide and either carboplatin or cisplatin. CASPIAN was a randomized, open-label, multicentre study in 805 treatment naï ve 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.

Randomisation 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 randomisation, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.

The primary endpoints of the study were 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 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 6. Kaplan-Meier curve for PFS is presented in Figure 8.

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 6. 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.

Table 7. Efficacy Results for the CASPIAN Study

^a Final PFS, ORR and DoR analysis at data cut-off 27 January 2020.

^b Long-term follow-up OS analysis at data cut-off 22 March 2021.

^c The analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.

^d At the interim analysis (data cut-off 11 March 2019) the OS p-value was 0.0047, which met the boundary for declaring statistical significance of 0.0178 for a 4% overall 2-sided alpha, based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary with the actual number of events observed.

^e Confirmed Objective Response.

^f Post-hoc analysis.

Figure 8. Kaplan-Meier curve of OS

Figure 9. Kaplan-Meier curve of PFS

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.

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, 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 or recurrent) and primary tumour location (intrahepatic or extrahepatic cholangiocarcinoma or gall bladder cancer).

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 as long as clinical benefit is observed or until 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 as long as clinical benefit is observed or until 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, Duration of Response (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%), ECOG 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. initially unresectable (80.7%), metastatic (86.0%) vs. locally advanced (13.9%)].

At a prespecified interim analysis, there was a statistically significant improvement in OS and PFS for patients randomised to IMFINZI and chemotherapy compared to placebo and chemotherapy. See Table 8 and Figures 10 and 11.

Table 8. Efficacy Results for the TOPAZ-1 Study^a

^a Analysis at data cut-off 11 August 2021.

^b Calculated using the Kaplan-Meier technique. CI for median derived based on Brookmeyer-Crowley method.

^c The analysis for HR was performed using a stratified Cox proportional hazards model and 2-sided p-value is based on a stratified log-rank test, both are adjusted for disease status and primary tumour location.

^d At the interim analysis (data cut-off 11 August 2021) the OS p-value was 0.021, which met the boundary for declaring statistical significance of 0.03 for a 4.9% overall 2-sided alpha, based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary with the actual number of events observed.

^e At the interim analysis (data cut-off 11 August 2021) the PFS p-value was 0.001, which met the boundary for declaring statistical significance of 0.0481 for a 4.9% overall 2-sided alpha, based on a Lan-DeMets alpha spending function with Pocock-type boundary with the actual number of events observed.

^f Confirmed objective response.

Figure 10: Kaplan-Meier curve of OS

Figure 11: Kaplan-Meier curve of PFS

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 randomised, 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 (BCLC) 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 disorders.

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.

• 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 9 and Figure 12.

Table 9. Efficacy Results for the HIMALAYA Study for IMFINZI given in combination with a single dose of tremelimumab 300 mg vs. S

^a Calculated using reverse the Kaplan-Meier technique (with censor indicator reversed).

^b Based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary and the actual number of events observed, the boundary for declaring statistical significance for IMFINZI + tremelimumab 300 mg vs. S was 0.0398 (Lan◦ and◦ DeMets 1983).

^c Confirmed complete response.

NR=Not Reached, CI=Confidence Interval

Figure 12. Kaplan-Meier curve of OS

Paediatric population

The safety and efficacy of IMFINZI in combination with tremelimumab in children and adolescents aged less than 18 years has not been established. Study D419EC00001 was a multi-centre, open-label dose finding and dose expansion study to evaluate the safety, preliminary efficacy and pharmacokinetics of IMFINZI in combination with tremelimumab followed by IMFINZI monotherapy, in paediatric 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 paediatric 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 monotherapy every 4 weeks. In the dose finding phase, IMFINZI and tremelimumab combination therapy was preceded by a single cycle of IMFINZI monotherapy; 8 patients in this phase however discontinued treatment prior to receiving tremelimumab. Thus, of the 50 patients enrolled in the study, 42 received IMFINZI in combination with tremelimumab and 8 received IMFINZI only. In the dose-expansion phase, an ORR of 5.0% (1/20 patients) was reported in the evaluable for response analysis set. No new safety signals were observed relative to the known safety profiles of IMFINZI and tremelimumab in adults. See section 4.2 for information on paediatric use.

The pharmacokinetics (PK) of durvalumab was assessed for IMFINZI, in combination with chemotherapy, and in combination with tremelimumab.

The PK of durvalumab was studied in 2903 patients with solid tumours with doses ranging from 0.1 to 20 mg/kg administered intravenously once every two, three or four weeks as monotherapy. PK exposure increased more than dose-proportionally (non-linear PK) at doses < 3 mg/kg, and dose proportionally (linear PK) at doses ≥ 3 mg/kg. Steady state was achieved at approximately 16 weeks. Based on population PK analysis that included 1878 patients who received durvalumab monotherapy in the dose range of ≥ 10 mg/kg every 2 weeks, the geometric mean steady state volume of distribution (V_ss) was 5.64 L. Durvalumab clearance (CL) decreased over time resulting in a geometric mean steady state clearance (CL_ss) of 8.16 mL/h at Day 365; the decrease in CL_ss was not considered clinically relevant. The terminal half-life (t_1/2), based on baseline CL, was approximately 18 days. There was no clinically meaningful difference between the PK of durvalumab as a single agent, in combination with chemotherapy, and in combination with tremelimumab. The primary elimination pathways of durvalumab are protein catabolism via reticuloendothelial system or target mediated disposition.

Special populations

Age (19-96 years), body weight (31-149 kg), gender, positive anti-drug antibody (ADA) status, albumin levels, LDH levels, creatinine levels, soluble PD-L1, tumour type, race or ECOG status had no clinically significant effect on the PK of durvalumab.

Patients with renal impairment

Mild (creatinine clearance (CrCL) 60 to 89 mL/min) and moderate renal impairment (creatinine clearance (CrCL) 30 to 59 mL/min) had no clinically significant effect on the PK of durvalumab.The effect of severe renal impairment (CrCL 15 to 29 mL/min) on the PK of durvalumab is unknown.

Patients with hepatic impairment

Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1.0 to 1.5 x ULN and any AST) or moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) had no clinically significant effect on the PK of durvalumab. The effect of severe hepatic impairment (bilirubin > 3.0 x ULN and any AST) on the pharmacokinetics of durvalumab is unknown; however, as IgG monoclonal antibodies are not primarily cleared via hepatic pathways, a change in hepatic function is not expected to influence durvalumab exposure.

Paediatric population

The PK of durvalumab in combination with tremelimumab was evaluated in a study of 50 paediatric patients with an age range from 1 to 17 years in study D419EC00001. Patients received either durvalumab 20 mg/kg in combination with tremelimumab 1 mg/kg or durvalumab 30 mg/kg in combination with tremelimumab 1 mg/kg intravenously every 4 weeks for 4 cycles, followed by durvalumab as monotherapy every 4 weeks. Based on population PK analysis, durvalumab systemic exposure in paediatric patients ≥ 35kg receiving durvalumab 20 mg/kg every 4 weeks was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks, whereas in paediatric patients (≥ 35kg) receiving durvalumab 30mg/kg every 4 weeks, exposure was approximately 1.5 fold higher compared to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks. In paediatric patients < 35kg receiving durvalumab 30 mg/kg every 4 weeks, the systemic exposure was similar to exposure in adults receiving durvalumab 20 mg/kg every 4 weeks.

Carcinogenicity and mutagenicity

The carcinogenic and genotoxic potential of durvalumab has not been evaluated.

Reproductive toxicology

As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the foetus, and in mouse allogeneic pregnancy models disruption of PD-L1 signalling was shown to result in an increase in foetal loss. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery, at exposure levels approximately 18 times higher than those observed at the clinical dose of 10 mg/kg of durvalumab (based on AUC), was associated with placental transfer but not with maternal toxicity or effects on embryofoetal development, pregnancy outcome or postnatal development. Negligible levels of durvalumab was found in milk of cynomolgous monkey on Day 28 after birth.

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial

3 years.

Diluted solution

Chemical and physical in-use stability has been demonstrated for up to 30 days at 2° C to 8° C and for up to 24 hours at room temperature (up to 25° C) from the time of preparation.

From a microbiological point of view, the prepared solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C to 8° C or 12 hours at room temperature (up to 25° C), unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2° C – 8° C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Two pack sizes of IMFINZI are available:

2.4 mL (a total of 120 mg durvalumab) of concentrate in a Type 1 glass vial with an elastomeric stopper and a gray flip-off aluminium seal. Pack size of 1 vial.

10 mL (a total of 500 mg durvalumab) of concentrate in a Type 1 glass vial with an elastomeric stopper and a white flip-off aluminium seal. Pack size of 1 vial.

Not all pack sizes may be marketed.

Preparation of solution

IMFINZI is supplied as a single-dose vial and does not contain any preservatives, aseptic technique must be observed.

• Visually inspect the medicinal product for particulate matter and discolouration. IMFINZI is clear to opalescent, colourless to slightly yellow solution. Discard the vial if the solution is cloudy, discoloured or visible particles are observed. Do not shake the vial.

• Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous (IV) bag containing sodium chloride 9 mg/mL (0.9%) solution for injection, or glucose 50 mg/mL (5%) solution for injection. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. Do not freeze or shake the solution.

• Discard any unused portion left in the vial.

Administration

• Administer the infusion solution intravenously over 1 hour through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

• Do not co-administer other medicinal products through the same infusion line.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.