Imfinzi - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

IMFINZI 50 mg/mL concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of concentrate for solution for infusion contains 50 mg of durvalumab.

One vial of 2.4 mL of concentrate contains 120 mg of durvalumab.

One vial of 10 mL of concentrate contains 500 mg of durvalumab.

Durvalumab is produced in mammalian (Chinese hamster ovary) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to slightly yellow solution, free from visible particles. The solution has a pH of approximately 6.0 and an osmolality of approximately 400 mOsm/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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).

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).

4.2 Posology and method of administration

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 (section 5.1).

Posology

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

Table 1. Recommended Dose of IMFINZI

Indication	Recommended IMFINZI dose	Duration of Therapy
Locally Advanced NSCLC	10 mg/kg every 2 weeks or 1500 mg every 4 weeksa	Until disease progression, unacceptable toxicity, or a maximum of 12 monthsb
ES-SCLC	1500 mgc in combination with chemotherapyd,e every 3 weeks (21 days) for 4 cycles, followed by 1500 mg every 4 weeks as monotherapy	Until disease progression or unacceptable toxicity

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 30 kg.

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, equivalent to IMFINZI 20 mg/kg in combination with chemotherapy every 3 weeks (21 days) for 4 cycles, followed by 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 30 kg.

d Administer IMFINZI prior to chemotherapy on the same day.

e When IMFINZI is administered in combination with chemotherapy, refer to the Prescribing Information for etoposide and carboplatin or cisplatin for dosing information.

Dose escalation or reduction is not recommended. Dose 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 (see section 4.4).

Table 2. Recommended treatment modifications for IMFINZI and management recommendations

Adverse reactions	Severity a	IMFINZI treatment modification	Corticosteroid treatment unless otherwise specified
Immune-mediated pneumonitis/in­terstitial lung disease	Grade 2	Withhold dose	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 or 4	Permanently discontinue	1 to 2 mg/kg/day prednisone or equivalent followed by a taper
Immune-mediated hepatitis	Grade 2 with ALT or AST > 3–5 x ULN and/or total bilirubin > 1.5–3 x ULN	Withhold dose	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 with AST or ALT > 5-< 8 x ULN or total bilirubin > 3-< 5× ULN

Adverse reactions	Severity a	IMFINZI treatment modification	Corticosteroid treatment unless otherwise specified
	Grade 3 with AST or ALT > 8 x ULN or total bilirubin > 5 x ULN	Permanently discontinue
	Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULN with no other cause
Immune-mediated colitis or diarrhoea	Grade 2 or 3	Withhold dose	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 4	Permanently discontinue
Immune-mediated hyperthyroidism, thyroiditis	Grade 2–4	Withhold dose until clinically stable	Symptomatic treatment, see section 4.8
Immune-mediated hypothyroidism	Grade 2–4	No changes	Initiate thyroid hormone replacement as clinically indicated
Immune-mediated adrenal insufficiency or hypophysitis/hy­popituitarism	Grade 2–4	Withhold dose until clinically stable	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated
Immune-mediated type 1 diabetes mellitus	Grade 2–4	No changes	Initiate treatment with insulin as clinically indicated
Immune-mediated nephritis	Grade 2 with serum creatinine > 1.5–3 x (ULN or baseline)	Withhold dose	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 with serum creatinine > 3 x baseline or > 3–6 x ULN; Grade 4 with serum creatinine > 6 x ULN	Permanently discontinue

Adverse reactions	Severity a	IMFINZI treatment modification	Corticosteroid treatment unless otherwise specified
Immune-mediated rash or dermatitis (including pemphigoid)	Grade 2 for >1 week	Withhold dose	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3
	Grade 4	Permanently discontinue
Immune-mediated myocarditis	Grade 2	Withhold doseb	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 3 or 4, or any Grade with positive biopsy	Permanently discontinue
Immune-mediated myositis/poly­myositis	Grade 2 or 3	Withhold dosec	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Grade 4	Permanently discontinue
Infusion-related reactions	Grade 1 or 2	Interrupt or slow the rate of infusion	May consider pre-medications for prophylaxis of subsequent infusion reactions
	Grade 3 or 4	Permanently discontinue
Infection	Grade 3 or 4	Withhold dose until clinically stable
Myasthenia gravis	Grade 2	Withhold dose	Initiate 1 to 2 mg/kg/day prednisone or equivalent followed by a taper
	Any Grade with signs of respiratory or autonomic insufficiency	Permanently discontinue
	Grade 3 or 4
Other immune-mediated adverse reactions	Grade 3	Withhold dose	Initiate 1 mg/kg/day to 2 mg/kg/day prednisone or equivalent followed by taper
	Grade 4	Permanently discontinue

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

b 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, after which IMFINZI can be resumed based on clinical judgment.

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

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 should be withheld and corticosteroids administered. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement. Upon improvement to < Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. After withhold, IMFINZI can be resumed within 12 weeks if the adverse reactions improved to < Grade 1 and the corticosteroid dose has been reduced to < 10 mg prednisone or equivalent per day. IMFINZI should be permanently discontinued for recurrent Grade 3 (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). Data on patients aged 75 years of age or older are limited.

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 moderate and 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).

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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Traceability

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

Immune-mediated pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI.

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%) (see section 4.8).

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 etiology, occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for abnormal liver tests prior to and periodically during treatment with IMFINZI, and as indicated based on clinical evaluation. Immune-mediated hepatitis should be managed as recommended in section 4.2.

Immune-mediated colitis

Immune-mediated colitis or diarrhoea, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for signs and symptoms of colitis or diarrhoea and managed as recommended in section 4.2.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receiving IMFINZI, 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.

Immune-mediated adrenal insufficiency

Immune-mediated adrenal insufficiency occurred in patients receiving IMFINZI (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.

Immune-mediated type 1 diabetes mellitus

Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can be fatal if not detected early, occurred in patients receiving IMFINZI (see 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.

Immune-mediated hypophysitis/hy­popituitarism

Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMFINZI (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.

Immune-mediated nephritis

Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for abnormal renal function tests prior to and periodically during treatment with IMFINZI and managed as recommended in section 4.2.

Immune-mediated rash

Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (see 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.

Other immune-mediated adverse reactions

Given the mechanism of action of IMFINZI, other potential immune-mediated adverse reactions may occur. The following immune-related adverse reactions have been observed in patients treated with IMFINZI monotherapy: myasthenia gravis, myocarditis, myositis, polymyositis, meningitis, encephalitis, Guillain-Barre syndrome, immune thrombocytopenia and cystitis noninfective (see section 4.8). Events of pancreatitis have been reported in patients in the clinical study programme. Patients should be monitored for signs and symptoms and managed as recommended for other immune-mediated adverse reactions, in section 4.2.

Infusion-related reactions

Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusion-related reactions have been reported in patients receiving IMFINZI (see section 4.8). Infusion-related reactions should be managed as recommended in section 4.2

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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety of IMFINZI as monotherapy is based on pooled data in 3006 patients across multiple tumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks. The most frequent (>10%) adverse reactions were cough/productive cough (21.5%), diarrhoea (16.3%), rash (16.0%), pyrexia (13.8%), upper respiratory tract infections (13.5%), abdominal pain (12.7%), pruritus (10.8%), and hypothyroidism (10.1%).

The safety of IMFINZI given in combination with chemotherapy is based on data in 265 patients with SCLC. IMFINZI was administered at a dose of 1500 mg every 3 weeks in combination with chemotherapy followed by monotherapy every 4 weeks. The most frequent (>20%) adverse reactions were neutropenia (48.7%), anaemia (38.5%), nausea (33.6%), fatigue (32.1%), alopecia (31.3%), thrombocytopenia (21.1%), and leukopenia (20.0%).

Tabulated list of adverse reactions

Table 3 lists the incidence of adverse reactions in the monotherapy safety dataset and in patients treated with IMFINZI in combination with chemotherapy in the CASPIAN study. Adverse drug reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse drug reactions are presented in decreasing frequency. The corresponding frequency category for each ADR is defined as: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 3. Adverse drug reactions in patients treated with IMFINZI monotherapy and IMFINZI in combination with chemotherapy

	IMFINZI Monotherapy			IMFINZI Combined with Chemotherapy
	Any Grade (%)		Grade 3–4 (%)	Any Grade (%)		Grade 3–4 (%)
Infections and infestations
Upper respiratory tract infections3	Very common	13.5	0.2	Common	9.1	0.4

	IMFINZI Monotherapy			IMFINZI Combined with Chemotherapy
	Any Grade (%)		Grade 3–4 (%)	Any Grade (%)		Grade 3–4 (%)
Pneumoniab,c	Common	8.9	3.5	Common	5.7	1.9
Oral candidiasis	Common	2.1	0	Uncommon	0.8	0
Dental and oral soft tissue infectionsd	Common	1.7	<0.1	Common	1.1	0
Influenza	Common	1.6	<0.1	Uncommon	0.4	0
Blood and lymphatic system disorders
Neutropeniae				Very common	48.7	29.1
Anaemia				Very common	38.5	9.1
Thrombocytopeniaf				Very common	21.1	6.8
Leukopeniag				Very common	20.0	7.9
Febrile neutropenia				Common	6.4	5.3
Pancytopenia				Common	3.0	1.5
Immune thrombocytopenia0	Rare	<0.1	<0.1
Endocrine disorders
Hypothyroidism11	Very common	10.1	0.2	Common	9.4	0
Hyperthyroidismi	Common	4.6	0	Common	9.8	0
Thyroiditisj	Uncommon	0.8	<0.1	Common	1.5	0
Adrenal insufficiency	Uncommon	0.6	<0.1	Common	1.1	0
Type 1 diabetes mellitus	Rare	<0.1	<0.1	Uncommon	0.8	0.8
Hypophysitis/ Hypopituitarism	Rare	<0.1	<0.1
Diabetes insipidus	Rare	<0.1	<0.1
Metabolism and nutrition disorders
Decreased appetite				Very common	18.1	0.8
Nervous System Disorders
Myasthenia gravis	Rarek	<0.1
Noninfective encephalitis1	Not known
Meningitism	Rare	<0.1	<0.1
Guillain-Barré syndrome	Not known
Cardiac disorders
Myocarditis	Rare	<0.1	<0.1
Respiratory, thoracic and mediastina		disorders
Cough/Productive Cough	Very common	21.5	0.4	Very common	14.7	0.8
Pneumonitis0	Common	3.8	0.9	Common	2.6	0.8
Dysphonia	Common	3.1	<0.1	Uncommon	0.8	0
Interstitial lung disease	Uncommon	0.6	0.1	Uncommon	0.8	0
Gastrointestinal disorders
Diarrhoea	Very common	16.3	0.6	Common	9.8	1.1
Abdominal painn	Very common	12.7	1.8	Common	8.7	0.4
Colitis0	Uncommon	0.9	0.3	Uncommon	0.8	0
Nausea				Very common	33.6	0.4
Constipation				Very common	16.6	0.8

	IMFINZI Monotherapy			IMFINZI Combined with Chemotherapy
	Any Grade (%)		Grade 3–4 (%)	Any Grade (%)		Grade 3–4 (%)
Vomiting				Very common	14.7	0
Stomatitisp				Common	6.0	0.4
Hepatobiliary disorders
Aspartate aminotransferase increased or Alanine aminotransferase increasedc,q	Common	8.1	2.3	Common	8.7	1.9
Hepatitisc,r	Uncommon	0.8	0.4	Common	1.9	1.1
Skin and subcutaneous tissue disorders
Rashs	Very common	16.0	0.6	Common	9.4	0
Pruritust	Very common	10.8	<0.1	Common	7.5	0
Night sweats	Common	1.6	<0.1	Uncommon	0.4	0
Dermatitis	Uncommon	0.7	<0.1	Common	1.5	0
Alopecia				Very common	31.3	1.1
Pemphigoidu	Rare	<0.1	0
Musculoskeletal and connective tissue disorders
Myalgia	Common	5.9	<0.1	Common	3.4	0
Myositis	Uncommon	0.2	<0.1
Polymyositis	Rarev	<0.1	<0.1
Renal and urinary disorders
Blood creatinine increased	Common	3.5	<0.1	Common	1.9	0
Dysuria	Common	1.3	0	Common	1.9	0
Nephritisw	Uncommon	0.3	<0.1
Cystitis noninfective	Rare	<0.1	0
General disorders and administration site cone			itions
Pyrexia	Very common	13.8	0.3	Common	8.3	0
Peripheral oedemax	Common	9.7	0.3	Common	6.4	0.8
Fatiguey				Very common	32.1	3.4
Injury, poisoning and procedural complications
Infusion-related reactionz	Common	1.6	0.2	Common	1.9	0.4

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

b includes lung infection, 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 neutropenia and neutrophil count decreased.

f includes thrombocytopenia and platelet count decreased.

g includes leukopenia and white blood cell count decreased.

h includes autoimmune hypothyroidism, hypothyroidism.

i includes hyperthyroidism and Basedow's disease.

j includes autoimmune thyroiditis, thyroiditis, and thyroiditis subacute.

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

l includes autoimmune encephalitis and encephalitis. m includes meningitis and noninfective meningitis. n includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain. o includes colitis, enteritis, enterocolitis, and proctitis.

p includes stomatitis and mucosal inflammation.

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

r includes hepatitis, autoimmune hepatitis, hepatitis toxic, hepatocellular injury, hepatitis acute, hepatotoxicity and immune-mediated hepatitis.

s includes rash erythematous, rash generalised, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema and rash.

t includes pruritus generalised and pruritus.

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

vpolymyositis (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.

w includes autoimmune nephritis, tubulointerstitial nephritis, nephritis, glomerulonephritis and glomerulonephritis membranous.

x includes oedema peripheral and peripheral swelling. y includes fatigue and asthenia.

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

Description of selected adverse reactions

IMFINZI is most commonly associated with immune-mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of IMFINZI. The data for the following immune-mediated adverse reactions reflect the combined safety database of 3006 patients which includes the PACIFIC Study and additional studies in patients with various solid tumours, in indications for which durvalumab is not approved. Across all studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks, or 1500 mg every 3 or 4 weeks. Details for the significant adverse reactions for IMFINZI when given in combination with chemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI monotherapy. The management guidelines for these adverse reactions are described in section 4.4.

Immune-mediated pneumonitis

In the combined safety database with IMFINZI monotherapy, (n = 3006 multiple tumour types), immune-mediated pneumonitis occurred in 107 (3.6%) patients, including Grade 3 in 23 (0.8%) patients, Grade 4 in 2 (< 0.1%) patients, and Grade 5 in 6 (0.2%) patients. The median time to onset was 57 days (range: 2–785 days). Sixty-four of the 107 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 58 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 (10.7%), than in the other patients in the combined safety database (2.2%).

In the PACIFIC Study, (n = 475 in the IMFINZI arm, and n = 234 in the placebo arm) immune-mediated pneumonitis occurred in 51 (10.7%) patients in the IMFINZI-treated group and 16 (6.8%) patients in the placebo group, including Grade 3 in 8 (1.7%) 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 53 days (range: 1–341 days) vs. 55.5 days (range: 0–231 days) in the placebo group. In the IMFINZI-treated group, 44 of the 51 patients received systemic corticosteroids, including 28 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, 11 of the 16 patients received systemic corticosteroids, including 9 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred for 27 patients in the IMFINZI treated group vs. 6 in placebo.

Immune-mediated hepatitis

In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in 36 (1.2%) patients, including Grade 3 in 19 (0.6%) patients, Grade 4 in 1 (<0.1%) patients and Grade 5 (fatal) in 2 (<0.1%) patients. The median time to onset was 67 days (range: 7–333 days). Twenty-five of the 36 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patients also received mycophenolate treatment. IMFINZI was discontinued in 7 patients. Resolution occurred in 22 patients.

Immune-mediated colitis

In the combined safety database with IMFINZI monotherapy, immune-mediated colitis or diarrhoea occurred in 52 (1.7%) patients, including Grade 3 in 9 (0.3%) patients and Grade 4 in 2 (<0.1%) patients. The median time to onset was 73 days (range: 1–394 days). Thirty-four of the 52 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 39 patients.

Immune-mediated endocrinopathies

Immune-mediated hypothyroidism

In the combined safety database with IMFINZI monotherapy, immune-mediated hypothyroidism occurred in 222 (7.4%) patients, including Grade 3 in 4 (0.1%) patients. The median time to onset was 85 days (range: 1–562 days). Of the 222 patients, 218 patients received hormone replacement therapy, 5 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism followed by hormone replacement. No patients discontinued IMFINZI due to immune-mediated hypothyroidism.

Immune-mediated hyperthyroidism

In the combined safety database with IMFINZI monotherapy, immune-mediated hyperthyroidism occurred in 43 (1.4%) patients, there were no Grade 3 or 4 cases. The median time to onset was 43 days (range: 1–196 days). 39 of the 43 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 hyperthyroidism. Resolution occurred in 35 patients. Eighteen patients experienced hypothyroidism following hyperthyroidism.

Immune-mediated thyroiditis

In the combined safety database with IMFINZI monotherapy, immune-mediated thyroiditis occurred in 11 (0.4%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 41 days (range: 14–106 days). Of the 11 patients, 9 patients received hormone replacement therapy, 1 patient received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) followed by hormone replacement. One patient discontinued IMFINZI due to immune-mediated thyroiditis. Two patients experienced hypothyroidism following thyroiditis.

Immune-mediated adrenal insufficiency

In the combined safety database with IMFINZI monotherapy, immune-mediated adrenal insufficiency occurred in 12 (0.4%) patients, including Grade 3 in 3 (<0.1%) patients. The median time to onset was 145.5 days (range: 20–547 days). All 12 patients received systemic corticosteroids; 4 of the 12 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). No patients discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 3 patients.

Immune-mediated type 1 diabetes mellitus

In the combined safety database with IMFINZI monotherapy, immune-mediated type 1 diabetes mellitus occurred in 1 (<0.1%) patient, (Grade 3). The time to onset was 43 days. The patient received endocrine therapy and discontinued IMFINZI due to immune-mediated type 1 diabetes mellitus. The event resolved for the patient.

Immune mediated hypophysitis/hy­popituitarism

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

Immune-mediated nephritis

In the combined safety database with IMFINZI monotherapy, immune-mediated nephritis occurred in 9 (0.3%) patients, including Grade 3 in 2 (< 0.1%) patients. The median time to onset was 87 days (range: 29–393 days). Six (0.2%) 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 6 patients.

Immune-mediated rash

In the combined safety database with IMFINZI monotherapy, immune-mediated rash or dermatitis (including pemphigoid) occurred in 45 (1.5%) patients, including Grade 3 in 12 (0.4%) patients. The median time to onset was 41 days (range: 4–333 days). Twenty of the 45 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 3 patients. Resolution occurred in 31 patients.

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: 4.9% for alanine aminotransferase increased, 4.6% for aspartate aminotransferase increased, 3.4% for blood creatinine increased, 4.8% for amylase increased and 8.1% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was < ULN to any grade > ULN was 17.7% and a TSH shift from baseline that was > LLN to any grade < LLN was 31.3%.

Immunogenicity

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

In the CASPIAN study, of 201 patients who were treated with IMFINZI 1500 mg every 3 weeks in combination with chemotherapy and evaluable for the presence of ADAs, 0 (0%) patients tested positive for treatment-emergent ADAs. The impact of treatment-emergent ADA on PK, clinical safety and efficacy of durvalumab was not evaluable as no patient samples tested positive for treatment-emergent durvalumab ADA.

Elderly

No overall differences in safety were reported between elderly (> 65 years) and younger patients. Data from NSCLC and ES-SCLC patients 75 years of age or older are limited.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after 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 the national reporting system listed in

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC28

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 (IgG1K) 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.

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 4 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 4.

Table 4. Efficacy results for the PACIFIC Study

	Primary Analysis3		4 Year Follow-up Analysis b
	IMFINZI (n = 476)	Placebo (n = 237)	IMFINZI (n = 476)	Placebo (n = 237)
OS
Number of deaths (%)	183 (38.4%)	116 (48.9%)	247 (51.9%)	149 (62.9%)
Median (months) (95% CI)	NR (34.7, NR)	28.7 (22.9, NR)	47.5 (38.4, 52.6)	29.1 (22.1, 35.1)
HR (95% CI)	0.68 (0.53, 0.87)		0.71 (0.57, 0.88)
2– sided p-value	0.00251
OS at 24 months (%) (95% CI)	66.3% (61.7%, 70.4%)	55.6% (48.9%, 61.3%)	66.3% (61.8%, 70.4%)	55.3% (48.6%, 61.4%)
p-value	0.005

	Primary Analysis3		4 Year Follow-up Analysis b
	IMFINZI (n = 476)	Placebo (n = 237)	IMFINZI (n = 476)	Placebo (n = 237)
OS at 48 months (%) (95% CI)			49.6% (44.9%, 54.1%)	36.3% (30.1%, 42.6%)
PFS
Number of events (%)	214 (45.0%)	157 (66.2%)	266 (55.9%)	174 (73.4%)
Median PFS (months) (95% CI)	16.8 (13.0, 18.1)	5.6 (4.6, 7.8)	17.2 (12.3, 23.8)	5.6 (4.6, 7.7)
HR (95% CI)	0.52 (0.4	12, 0.65)	0.55 (0.4	t4, 0.67)
p-value	p < 0.0001
PFS at 12 months (%) (95% CI)	55.9% (51.0%, 60.4%)	35.3% (29.0%, 41.7%)	55.3% (50.5%, 59.8%)	34.4% (28.2%, 40.7%)
PFS at 18 months (%) (95% CI)	44.2% (37.7%, 50.5%)	27.0% (19.9%, 34.5%)	49.2% (44.3%, 53.8%)	27.3% (21.4%, 33.5%)
PFS at 48 months (%) (95% CI)			35.3% (30.3%, 40.4%)	19.5% (14.1%, 25.7%)
PFS2 c
Median PFS2 (months) (95% CI)	28.3 (25.1, 34.7)	17.1 (14.5, 20.7)
HR (95% CI)	0.58 (0.4	16, 0.73)
p-value	p < 0.0001

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 20 March 2020.

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 4 year follow-up analysis are presented in Figures 1 and 2.

Number of patients at risk

Month	0	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	51	54	57	60	63	66
IMFINZI	476	464	431	414	385	364	343	319	299	290	274	265	252	241	235	225	195	138	75	36	15	2	0
Placebo	237	220	199	179	171	156	143	133	123	116	107	99	97	93	91	83	75	53	29	15	7	2	0

Figure 2. Kaplan-Meier curve of PFS

Time from randomisation (months)

Number of patients at risk

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 4 year follow-up analysis are summarised in Figures 3, 4, 5 and 6.

Number of patients at risk

Month	0	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	51	54	57	60	63	66
IMFINZI	212	208	193	186	178	171	165	156	146	141	132	129	123	117	116	113	99	75	45	24	9	1	0
Placebo	91	81	75	67	64	58	52	47	45	44	41	38	38	37	36	33	29	22	13	7	5	2	0

1.0

0.8

CZ) °-7

----------------1----------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------1----------------T"

1    3      6      9      12     15     18     21     24     27     30     33     36     39     42     45     48     51     54     57 60

Time from randomisation (months)

Number of patients at risk

Month	0	3	6	9	12	15	18	21	24	27	30	33	36	39	42	45	48	51	54	57	60
IMFINZI	212	175	142	126	105	94	82	69	66	62	57	55	50	47	45	40	30	20	12	7	0
Placebo	91	59	39	34	26	22	19	16	15	15	12	11	10	10	9	9	7	4	1	1	0

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).

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, openlabel, multicentre study in 805 treatment naïve ES-SCLC patients with WHO/ECOG Performance status of 0 or 1, body weight >30 kg, suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC, with life expectancy >12 weeks, at least one target lesion by RECIST 1.1 and adequate organ and bone marrow function. Patients with asymptomatic or treated brain metastases were eligible. The study excluded patients with a history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome (PNS); active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids; active tuberculosis or hepatitis B or C or HIV infection; or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI.

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 1500 mg + tremelimumab 75 mg + etoposide and either carboplatin or

cisplatin

• • Arm 2: IMFINZI 1500 mg + etoposide and either carboplatin or cisplatin
• • Arm 3: Either carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75–80 mg/m2) on Day 1 and

etoposide (80–100 mg/m2) intravenously on Days 1, 2, and 3 of each 21-day cycle for between 4 – 6 cycles.

For patients randomised to Arm 1 and 2, etoposide and either carboplatin or cisplatin was limited to 4 cycles on an every 3 week schedule subsequent to randomisation. IMFINZI monotherapy continued every 4 weeks until disease progression or unacceptable toxicity. Administration of IMFINZI monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator.

Patients randomised to Arm 3 were permitted to receive a total of up to 6 cycles of etoposide and either carboplatin or cisplatin. After completion of etoposide + platinum, PCI was permitted only in Arm 3 per investigator discretion.

Tumour assessments were conducted at Week 6 and Week 12 from the date of randomization, and then every 8 weeks until confirmed objective disease progression. Survival assessments were conducted every 2 months following treatment discontinuation.

The primary endpoints of the study were Overall Survival (OS) of IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3) and IMFINZI + tremelimumab + etoposide + platinum (Arm 1) vs. etoposide + platinum alone (Arm 3). The key secondary endpoint was

progression-free survival (PFS). Other secondary endpoints were Objective Response Rate (ORR), OS and PFS landmarks and Patient-Reported Outcomes (PRO). PFS and ORR were assessed using Investigator assessments according to RECIST v1.1.

The demographics and baseline disease characteristics were well balanced between the two study arms (268 patients in Arm 2 and 269 patients in Arm 3). Baseline demographics of the overall study population were as follows: male (69.6%), age > 65 years (39.6%), median age 63 years (range: 28 to 82 years), white (83.8%), Asian (14.5%), black or African American (0.9%), other (0.6 %), non-Hispanic or Latino (96.1%), current or past-smoker (93.1%), never smoker (6.9%), WHO/ECOG PS 0 (35.2%), WHO/ECOG PS 1 (64.8%), Stage IV 90.3%, 24.6% of the patients received cisplatin and 74.1% of the patients received carboplatin. In Arm 3, 56.8% of the patients received 6 cycles of etoposide + platinum and 7.8% of the patients received PCI.

At a planned interim (primary) analysis the study demonstrated a statistically significant improvement in OS with IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum alone (Arm 3) [HR=0.73 (95% CI: 0.591, 0.909), p=0.0047]. Although not formally tested for significance, IMFINZI + etoposide + platinum demonstrated an improvement in PFS vs. etoposide + platinum alone [HR=0.78 (95% CI: 0.645, 0.936)].

In the planned follow-up analysis (median: 25.1 months), IMFINZI + etoposide + platinum (Arm 2) vs. etoposide + platinum (Arm 3) continued to demonstrate improved OS. The OS, PFS, ORR and DoR results from the planned follow-up analysis are summarized in Table 5; Kaplan-Meier curves for OS and PFS are presented in Figures 7 and 8.

Table 5. Efficacy Results for the CASPIAN Studya

	Arm 2: IMFINZI + etoposide and either carboplatin or cisplatin (n=268)	Arm 3: etoposide + and either carboplatin or cisplatin (n=269)
OS
Number of deaths (%)	210 (78.4)	231 (85.9)
Median OS (months) (95% CI)	12.9 (11.3, 14.7)	10.5 (9.3, 11.2)
HR (95% CI)b	0.75 (0.625, 0.910)
p-valuec	0.0032
OS at 18 months (%) (95% CI)	32.0 (26.5, 37.7)	24.8 (19.7, 30.1)
PFS
Number of events (%)	234 (87.3)	236 (87.7)
Median PFS (months) (95% CI)	5.1 (4.7, 6.2)	5.4 (4.8, 6.2)
HR (95% CI)b	0.80 (0.665, 0.959)
PFS at 6 months (%) (95% CI)	45.4 (39.3, 51.3)	45.8 (39.5, 51.9)
PFS at 12 months (%) (95% CI)	17.9 (13.5, 22.8)	5.3 (2.9, 8.8)
ORR n(%) (95% CI)d	182 (67.9) (62.0, 73.5)	156 (58.0) (51.8, 64.0)
Complete Response n (%)	7 (2.6)	2 (0.7)
Partial Response n (%)	175 (65.3)	154 (57.2)
Median DoR (months) (95% CI)d,e	5.1 (4.9, 5.3)	5.1 (4.8, 5.3)

a Follow-up OS, PFS, ORR and DoR analysis at data cut-off 27 January 2020.

b 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.

c 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.

d Confirmed Objective Response.

e Post-hoc analysis.

Figure 7. Kaplan-Meier curve of OS

Number of patients at risk	0	3	6	9	12	15	18	21	24	27	30	33	36
IMFINZI + etoposide + platinum	268	244	214	177	140	109	85	66	41	21	8	2	0
etoposide + platinum	269	243	212	156	104	82	64	48	24	8	0	0	0

Figure 8. Kaplan-Meier curve of PFS

Probability of PFS

Number of patients at risk	0	3	6	9	12	15	18	21	24	27	30	33
IMFINZI + etoposide + platinum	268	220	119	55	45	40	35	24	18	8	5	0
etoposide + platinum	269	195	110	33	12	9	7	7	6	1	0	0

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.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with durvalumab in all subsets of the paediatric population in the treatment of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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

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 (Vss) was 5.64 L. Durvalumab clearance (CL) decreased over time resulting in a geometric mean steady state clearance (CLss) of 8.16 mL/h at Day 365; the decrease in CLss was not considered clinically relevant. The terminal half-life (t1/2), based on baseline CL, was approximately 18 days. There was no clinically meaningful difference between the PK of durvalumab as a single agent and in combination with chemotherapy. 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) had no clinically significant effect on the PK of durvalumab. The effect of moderate hepatic impairment (bilirubin > 1.5 to 3 x ULN and any AST) or 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.

5.3 Preclinical safety data

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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Histidine

Histidine hydrochloride monohydrate

Trehalose dihydrate Polysorbate 80 Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

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.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

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

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Södertälje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1322/­002 120 mg vial

EU/1/18/1322/­001 500 mg vial

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 September 2018