durvalumab: prescribing information – dosing, contraindications, interactions, side effects

Non-Small Cell Lung Cancer (NSCLC)
IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by IMFINZI as monotherapy as adjuvant treatment, is indicated for the treatment of adults with resectable NSCLC at high risk of recurrence and no EGFR mutations or ALK rearrangements (for selection criteria, see section 5.1).

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 tremelimumab and platinum-based chemotherapy is indicated for the first-line treatment of adults with metastatic NSCLC with no sensitising EGFR mutations or ALK positive mutations.

Small Cell Lung Cancer (SCLC)
IMFINZI as monotherapy is indicated for the treatment of adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following platinum-based chemoradiation therapy.

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 unresectable or metastatic biliary tract cancer (BTC).

Hepatocellular Carcinoma (HCC)
IMFINZI as monotherapy is indicated for the first line treatment of adults with advanced or unresectable hepatocellular carcinoma (HCC).

IMFINZI in combination with tremelimumab is indicated for the first line treatment of adults with advanced or unresectable hepatocellular carcinoma (HCC).

Endometrial Cancer
IMFINZI in combination with carboplatin and paclitaxel is indicated for the first-line treatment of adults with primary advanced or recurrent endometrial cancer who are candidates for systemic therapy, followed by maintenance treatment with:
- IMFINZI as monotherapy in endometrial cancer that is mismatch repair deficient (dMMR)
- IMFINZI in combination with olaparib in endometrial cancer that is mismatch repair proficient (pMMR).

Muscle Invasive Bladder Cancer (MIBC)
IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by IMFINZI as monotherapy adjuvant treatment after radical cystectomy, is indicated for the treatment of adults with resectable muscle invasive bladder cancer (MIBC).

Gastric or Gastro-oesophageal Junction Adenocarcinoma (GC/GEJC)
IMFINZI in combination with FLOT chemotherapy as neoadjuvant and adjuvant treatment, followed by adjuvant IMFINZI monotherapy, is indicated for the treatment of adults with resectable gastric or gastro-oesophageal junction adenocarcinoma.

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).

MMR testing for patients with endometrial cancer
Patients with endometrial cancer should be evaluated for treatment based on tumour MMR status confirmed by a validated test (see 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
Indication
Recommended IMFINZI dose Duration of therapy
Monotherapy
Locally Advanced NSCLC
10 mg/kg every 2 weeks or
1 500 mg every 4 weeksa
Until disease progression, unacceptable toxicity, or a maximum of 12 monthsb
LS-SCLC
1 500 mg every 4 weeksa
Until disease progression, unacceptable toxicity, or a maximum of 24 months
HCC
1 500 mg every 4 weeksa
Until disease progression or until unacceptable toxicity

Indication
Recommended IMFINZI dose Duration of therapy
Combination therapy
Resectable NSCLC
1 500 mgc in combination with platinum-based chemotherapy every 3 weeks for up to 4 cycles prior to surgery, followed by 1 500 mg monotherapy every 4 weeks for up to 12 cycles after surgery.
Neoadjuvant phase: until disease progression that precludes definitive surgery or unacceptable toxicity.
Adjuvant phase: until recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery.
Metastatic NSCLC
During platinum chemotherapy:
1 500 mgd in combination with tremelimumab 75 mgd and platinum-based chemotherapy every 3 weeks (21 days) for 4 cycles (12 weeks) Post-platinum chemotherapy:
1 500 mg every 4 weeks as monotherapy and histology-based pemetrexed maintenancee therapy every 4 weeks A fifth dose of tremelimumab 75 mgf,g should be given at week 16 alongside IMFINZI Until disease progression or unacceptable toxicity ES-SCLC 1 500 mgh in combination with chemotherapy every 3 weeks (21 days) for 4 cycles, followed by 1 500 mg every 4 weeks as monotherapy Until disease progression or unacceptable toxicity BTC 1 500 mgi in combination with chemotherapy every 3 weeks (21 days) up to 8 cycles, followed by 1 500 mg every 4 weeks as monotherapy Until disease progression or until unacceptable toxicity HCC IMFINZI 1 500 mgj administered in combination with 300 mgj tremelimumab as a single dose at Cycle 1/Day 1, followed by IMFINZI as monotherapy every 4 weeks Until disease progression or unacceptable toxicity Endometrial Cancer 1 120 mg in combination with carboplatin and paclitaxel every 3 weeks (21 days) for a minimum of 4 and up to 6 cycles, followed by IMFINZI 1 500 mgk every 4 weeks as monotherapy (dMMR patients) or in combination with olaparib Until disease progression or unacceptable toxicity

Indication
Recommended IMFINZI dose Duration of therapy
300 mg twice daily (pMMR patients)
MIBC
1 500 mgl in combination with chemotherapy every 3 weeks for
4 cycles prior to surgery, followed by 1 500 mgl every 4 weeks as monotherapy for up to 8 cycles after surgery Neoadjuvant phase: until disease progression that precludes definitive surgery or unacceptable toxicity Adjuvant phase: until recurrence, unacceptable toxicity, or a maximum of 8 cycles after surgery GC/GEJC 1 500 mgm in combination with FLOT chemotherapy every 4 weeks for up to 2 cycles prior to surgery, followed by 1 500 mgm, with FLOT chemotherapy, every 4 weeks for up to 2 cycles and then as 1 500 mg monotherapy every 4 weeks for up to 10 cycles, for a total of up to 12 cycles after surgery Neoadjuvant phase: until disease progression that precludes definitive surgery or unacceptable toxicity Adjuvant phase: until progression or recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery 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 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.
d Metastatic NSCLC patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI 20 mg/kg until weight increases to greater than 30 kg. Patients with a body weight of 34 kg or less must receive weight-based dosing equivalent to tremelimumab 1 mg/kg until weight increases to greater than 34 kg.
e Consider maintenance administration of pemetrexed for patients with non-squamous tumours who received treatment with pemetrexed and carboplatin/cisplatin during the platinum-based chemotherapy stage.
f In the case of dose delay(s), a fifth dose of tremelimumab can be given after Week 16, alongside IMFINZI.
g If patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of tremelimumab (up to a total of 5) alongside IMFINZI should be given during the post-platinum chemotherapy phase.
h ES-SCLC 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.
i 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.
j HCC patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI 20 mg/kg until weight increases to 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 increases to greater than 40 kg.
k Endometrial cancer patients with a body weight of 30 kg or less during maintenance phase must receive weight-based dosing equivalent to IMFINZI at 20 mg/kg, until weight increases to greater than 30 kg.
l MIBC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg.

m GC/GEJC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg.

Dose escalation or reduction is not recommended. Treatment withholding or discontinuation may be required based on individual safety and tolerability, see Table 2.

Guidelines for management of immune-mediated and non-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 other products Adverse reactions Severitya Treatment modification Immune-mediated adverse reactions Immune-mediated pneumonitis/interstitial lung disease Grade 2 Withhold dose Grade 3 or 4 Permanently discontinue Immune-mediated hepatitis ALT or AST > 3 - ≤ 5 x ULN or total bilirubin > 1.5 - ≤ 3 x ULN Withhold dose ALT or AST > 5 - ≤ 10 x ULN Withhold IMFINZI and permanently discontinue tremelimumab (where appropriate) Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULNb Permanently discontinue ALT or AST > 10 x ULN or total bilirubin > 3 x ULN Immune-mediated hepatitis in HCC (or secondary tumour involvement of the liver with abnormal baseline values)c

ALT or AST
> 2.5 - ≤ 5 x BLV and
≤ 20 x ULN
Withhold dose
ALT or AST
> 5 - 7 x BLV and
≤ 20 x ULN
Withhold IMFINZI and permanently discontinue

Adverse reactions
Severitya
Treatment modification or concurrent ALT or
AST 2.5 - 5 x BLV and ≤ 20 x ULN and total bilirubin
> 1.5 - < 2 x ULNb tremelimumab (where appropriate).
ALT or AST
> 7 x BLV or
> 20 ULN whichever occurs first or bilirubin
> 3 X ULN
Permanently discontinue
Immune-mediated colitis or diarrhoea
Grade 2
Withhold dose
Grade 3 for IMFINZI monotherapy
Withhold dose
Grade 3 for IMFINZI
+ tremelimumab
Permanently discontinue tremelimumabd
Grade 4
Permanently discontinue
Intestinal perforatione
Any grade
Permanently discontinue
Immune-mediated hyperthyroidism, thyroiditis
Grade 2-4
Withhold dose until clinically stable
Immune-mediated hypothyroidism
Grade 2-4
No changes
Immune-mediated adrenal insufficiency or hypophysitis/hypopituitarism
Grade 2-4
Withhold dose until clinically stable
Immune-mediated type 1 diabetes mellitus
Grade 2-4
No changes
Immune-mediated nephritis
Grade 2 with serum creatinine
> 1.5 - 3 x (ULN or baseline)
Withhold dose

Adverse reactions
Severitya
Treatment modification
Grade 3 with serum creatinine
> 3 x baseline or
> 3-6 x ULN; Grade 4 with serum creatinine
> 6 x ULN
Permanently discontinue
Immune-mediated rash or dermatitis
(including pemphigoid)
Grade 2 for > 1 week
Withhold dose
Grade 3
Grade 4
Permanently discontinue
Immune-mediated myocarditis
Grade 2-4
Permanently discontinue
Immune-mediated myositis/polymyositis/rhabdomyolysis
Grade 2 or 3
Withhold dosef
Grade 4
Permanently discontinue
Infusion-related reactions
Grade 1 or 2
Interrupt or slow the rate of infusion
Grade 3 or 4
Permanently discontinue
Infection
Grade 3 or 4
Withhold dose until clinically stable
Immune-mediated myasthenia gravis
Grade 2-4
Permanently discontinue
Immune-mediated Myelitis transverse
Any grade
Permanently discontinue
Immune-mediated meningitis
Grade 2
Withhold dose
Grade 3 or 4
Permanently discontinue
Immune-mediated encephalitis
Grade 2-4
Permanently discontinue
Immune-mediated Guillain-Barré syndrome
Grade 2-4
Permanently discontinue
Other immune-mediated adverse reactionsg
Grade 2 or 3
Withhold dose
Grade 4
Permanently discontinue

Adverse reactions
Severitya
Treatment modification
Non-immune-mediated adverse reactions
Pure red cell aplasia (PRCA)h
Any Grade
Permanently discontinue
Other non-immune-mediated adverse reactions
Grade 2 and 3
Withhold dose until
≤ Grade 1 or return to baseline
Grade 4
Permanently discontinuei 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 Permanently discontinue tremelimumab for Grade 3; however, treatment with durvalumab can be resumed once event has resolved.
e Adverse drug reaction is only associated with IMFINZI in combination with tremelimumab.
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, cystitis noninfective and polymyalgia rheumatica.
h Adverse drug reaction is only associated when olaparib maintenance treatment is used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy.
i 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.

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.

Special populations
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
No dose adjustment of IMFINZI is recommended for patients with mild or moderate hepatic impairment. Data from patients with severe hepatic impairment are too limited to draw conclusions on this population (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, HCC, endometrial cancer and GC/GEJC. 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
When IMFINZI is administered in combination with chemotherapy, administer IMFINZI prior to chemotherapy on the same day.

IMFINZI in combination with tremelimumab and platinum-based chemotherapy
When IMFINZI is administered in combination with tremelimumab and platinum-based chemotherapy, tremelimumab is given first, followed by IMFINZI and then platinum-based chemotherapy on the same day of dosing.

When IMFINZI is administered in combination with a fifth dose of tremelimumab and pemetrexed maintenance therapy at week 16, tremelimumab is given first, followed by IMFINZI and then pemetrexed maintenance therapy on the same day of dosing.

IMFINZI, tremelimumab, and platinum-based chemotherapy are administered as separate intravenous infusions. IMFINZI and tremelimumab are each given over 1 hour. For platinum-based chemotherapy, refer to the SmPC for administration information. For pemetrexed maintenance therapy, refer to the SmPC for administration information. Separate infusion bags and filters for each infusion should be used.

During cycle 1, tremelimumab is to be followed by IMFINZI starting approximately 1 hour (maximum 2 hours) after the end of the tremelimumab infusion. Platinum-based chemotherapy infusion should start approximately 1 hour (maximum 2 hours) after the end of the IMFINZI infusion. If there are no clinically significant concerns during cycle 1, then at the physician’s discretion, subsequent cycles of IMFINZI can be given immediately after tremelimumab and the time period between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes.

IMFINZI in combination with tremelimumab
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 SmPC for tremelimumab dosing information.

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

Summary of the safety profile
IMFINZI as monotherapy
The safety of IMFINZI as monotherapy is based on pooled data in 4 642 patients across multiple tumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks or 1 500 mg every 4 weeks. The most common (> 10%) adverse reactions were cough/productive cough (18.1%), diarrhoea (15.1%), rash (15.0%), arthralgia (12.4%), pyrexia (12.5%), abdominal pain (11.8%), upper respiratory tract infections (11.8%), pruritus (11.1%), and hypothyroidism (11.6%). The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were pneumonia (3.4%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.5%).

IMFINZI was discontinued due to adverse reactions in 3.9% of patients. The most common adverse reactions leading to treatment discontinuation were pneumonitis (1.1%) and pneumonia (0.8%).

IMFINZI was delayed or interrupted due to adverse reactions in 13.1% of patients. The most common adverse reactions leading to dose delay or interruption were pneumonia (2.3%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.0%).

The safety of IMFINZI as monotherapy in patients treated for HCC is based on data in 492 patients and was consistent with the overall safety profile in the IMFINZI monotherapy pool (N=4 642). The most common (> 10%) adverse reactions were AST increased/ALT increased (20.3%), abdominal pain (17.9%), diarrhoea (15.9%), pruritus (15.4%), and rash (15.2%). The most common (> 2%) Grade ≥ 3 adverse reactions were AST increased/ALT increased (8.1%) and abdominal pain (2.2%).

IMFINZI was discontinued due to adverse reactions in 3.7% of patients. The most common adverse reactions leading to treatment discontinuation were AST increased/ALT increased (0.8%) and hepatitis (0.6%).

IMFINZI was delayed or interrupted due to adverse reactions in 11.6% of patients. The most common adverse reaction leading to dose delay or interruption was AST increased/ALT increased (5.9%).

IMFINZI in combination with chemotherapy

The safety of IMFINZI in combination with chemotherapy is based on pooled data in 2 244 patients from 6 studies (TOPAZ-1, CASPIAN, DUO-E, AEGEAN, NIAGARA and MATTERHORN). The most common (> 10%) adverse reactions were neutropenia (44.6%), nausea (42.4%), fatigue (41.2%), anaemia (37.4%), diarrhoea (27.5%), constipation (26.7%), decreased appetite (24.0%), alopecia (22.0%), neuropathy peripheral (21.6%), thrombocytopenia (19.7%), rash (19.7%), vomiting (18.8%), abdominal pain (17.9%), pyrexia (15.2%), leukopenia (14.9%), pruritus (12.5%), hypothyroidism (11.1%), arthralgia (10.9%), cough/productive cough (10.8%), and aspartate aminotransferase increased/alanine aminotransferase increased (10.5%). The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were neutropenia (28.5%), anaemia (11.9%), thrombocytopenia (5.6%), leukopenia (4.9%), fatigue (3.3%), pneumonia (2.5%), febrile neutropenia (2.4%), and diarrhoea (2.3%).

IMFINZI was discontinued due to adverse reactions in 6.2% of patients. The most common adverse reactions leading to treatment discontinuation were pneumonitis (0.8%), rash (0.6%), hepatitis (0.5%), and fatigue (0.5%).

IMFINZI was delayed or interrupted due to adverse reactions in 32.4% of patients. The most common adverse reactions leading to dose delay or interruption were neutropenia (15.5%), thrombocytopenia (4.1%), anaemia (3.3%), leukopenia (2.0%), fatigue (2.0%), and aspartate aminotransferase increased/alanine aminotransferase increased (2.0%).

IMFINZI in combination with tremelimumab 75 mg and platinum-based chemotherapy
The safety of IMFINZI given in combination with tremelimumab 75 mg and chemotherapy is based on data in 330 patients with metastatic NSCLC. The most common (> 20%) adverse reactions were anaemia (49.7%), nausea (41.5%), neutropenia (41.2%), fatigue (36.1%), rash (25.8%), thrombocytopenia (24.5%) and diarrhoea (21.5%). The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were neutropenia (23.9%), anaemia (20.6%), pneumonia (9.4%), thrombocytopenia (8.2%), leukopenia (5.5%), fatigue (5.2%), lipase increased (3.9%), amylase increased (3.6%), febrile neutropenia (2.4%), colitis (2.1%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.1%).

IMFINZI was discontinued due to adverse reactions in 8.5% of patients. The most common adverse reactions leading to treatment discontinuation were pneumonia (2.1%) and colitis (1.2%).

IMFINZI was interrupted due to adverse reactions in 49.4% of patients. The most common adverse reactions leading to dose interruption were neutropenia (16.1%), anaemia (10.3%), thrombocytopenia (7.3%), leukopenia (5.8%), pneumonia (5.2%), aspartate aminotransferase increased/alanine aminotransferase increased (4.8%), colitis (3.3%) and pneumonitis (3.3%).

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) were 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 were colitis (2.6%), diarrhoea (2.4%), pneumonia (2.2%), and hepatitis (1.7%).

The frequency of treatment discontinuation due to adverse reactions was 6.5%. The most common adverse reactions leading to treatment discontinuation were 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.

IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily The safety of IMFINZI given in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily is based on data in 238 patients with endometrial cancer. The most common (> 20%) adverse reactions were anaemia (61.8%), nausea (54.6%), fatigue (54.2%), neuropathy peripheral (51.7%), alopecia (50.8%), neutropenia (39.5%), constipation (32.8%), thrombocytopenia (29.8%), diarrhoea (28.2%), vomiting (25.6%), arthralgia (24.4%), rash (23.5%), abdominal pain (23.5%), decreased appetite (23.1%) and leukopenia (20.2%).

The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were neutropenia (25.2%), anaemia (23.5%), leukopenia (6.7%), thrombocytopenia (5.9%), fatigue (5.5%), febrile neutropenia (3.4%), nausea (2.9%), aspartate aminotransferase increased / alanine aminotransferase increased (2.9%) and neuropathy peripheral (2.5%).

IMFINZI was discontinued in 4.6% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (1.7%).

IMFINZI was interrupted in 38.2% of patients. The most common adverse reactions leading to dose interruption were anaemia (13.4%), thrombocytopenia (11.8%), neutropenia (10.1%), leukopenia (2.9%), hypothyroidism (2.1%) and upper respiratory tract infection (2.1%).

Tabulated list of adverse reactions
Table 3 lists the incidence of adverse reactions in the IMFINZI monotherapy pooled safety dataset (N=4 642), in patients treated with IMFINZI in combination with chemotherapy (N=2 244) and in patients treated with IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib) (N=238). Unless otherwise stated, Table 4 lists the incidence of adverse reactions in patients treated with IMFINZI in combination with tremelimumab 75 mg and platinum-based chemotherapy in the POSEIDON study (N=330) and 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 < 1/1 000); 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
IMFINZI as monotherapy IMFINZI in combination with chemotherapy
Platinum-based chemotherapy + IMFINZI
+ olaparib*
Infections and infestations
Very common Upper respiratory tract infectionsa
Upper respiratory tract infectiona
Common
Pneumoniab,c, Influenza,
Oral candidiasis, Dental and oral soft tissue infectionsd
Pneumoniab,c, Upper respiratory tract infectionsa,
Dental and oral soft tissue infectionsd
Pneumonia, Oral candidiasis, Dental and oral soft tissue infectionsd
Uncommon
Oral candidiasis, Influenza Influenza

IMFINZI as monotherapy IMFINZI in combination with chemotherapy
Platinum-based chemotherapy + IMFINZI
+ olaparib*
Blood and lymphatic system disorders
Very Common
Anaemia, Leukopeniae,
Neutropeniaf,
Thrombocytopeniag
Anaemiah, Leukopeniah
Neutropeniah,
Thrombocytopeniah
Common
Febrile neutropenia
Aplasia pure red cell,
Febrile neutropeniah,
Lymphopeniai
Uncommon
Immune thrombocytopeniac Pancytopeniac
Pancytopeniah
Rare
Immune thrombocytopenia
Immune system disorders
Common
Hypersensitivityi,j
Endocrine disorders
Very common Hypothyroidismk
Hypothyroidismk
Hypothyroidism
Common
Hyperthyroidisml
Hyperthyroidisml
Hyperthyroidism,
Thyroiditis
Uncommon
Thyroiditism, Adrenal insufficiency,
Hypophysitis/Hypopituitaris m, Type 1 diabetes mellitus
Adrenal insufficiency, Type
1 diabetes mellitus,
Hypophysitis/Hypopituitaris m, Thyroiditism
Rare
Diabetes insipidus
Eye disorders
Uncommon
Uveitis
Rare
Uveitis
Uveitis
Metabolism and nutrition disorders
Very common
Decreased appetite
Decreased appetiteh
Nervous System Disorders
Very common
Neuropathy peripheraln
Neuropathy peripheral,
Dizzinessi, Headachei,
Dysgeusiai,o
Uncommon
Myasthenia gravis,
Encephalitisc,p
Myasthenia gravis
Rare
Meningitis
Encephalitisp, Guillain-
Barré syndrome
Not known
Guillain-Barré syndrome,
Myelitis transverseq
Vascular disorders
Common
Venous thromboembolic eventsi,r
Rare
Deep vein thrombosiss
Cardiac disorders
Uncommon
Myocarditis
Acute myocardial infarctiont,u, Myocarditisc
Respiratory, thoracic and mediastinal disorders
Very common Cough/Productive Cough
Cough/Productive Cough
Cough/Productive cough,
Dyspnoeai,v
Common
Pneumonitisc,w, Dysphonia Pneumonitisc,w, Dysphonia Pneumonitis, Dysphonia
Uncommon
Interstitial lung disease
Interstitial lung diseasec,
Pulmonary embolisms
Interstitial lung disease
Gastrointestinal disorders

IMFINZI as monotherapy IMFINZI in combination with chemotherapy
Platinum-based chemotherapy + IMFINZI
+ olaparib*
Very common Diarrhoea, Abdominal painx Diarrhoea, Abdominal painx,
Constipation, Nausea,
Vomiting
Diarrhoea, Abdominal painx,
Constipationh, Nauseah,
Vomitingh, Stomatitish
Common
Stomatitisy, Colitisz
Dyspepsiai, Colitisz
Uncommon
Colitisc,z, Pancreatitisaa
Pancreatitisaa, Pancreatic exocrine insufficiency
Rare
Coeliac diseaseq,
Pancreatic exocrine insufficiency
Coeliac diseaseq
Hepatobiliary disorders
Very common
Aspartate aminotransferase increased or Alanine aminotransferase increasedbb
Aspartate aminotransferase increased or Alanine aminotransferase increased
Common
Hepatitisc,cc, Aspartate aminotransferase increased or Alanine aminotransferase increasedc,bb Hepatitisc,cc Uncommon Hepatitiscc Skin and subcutaneous tissue disorders Very common Rashdd, Pruritus Rashdd, Alopecia, Pruritus Rashdd, Alopeciah, Pruritus Common Night sweats Dermatitis Dermatitisee Uncommon Dermatitis, Psoriasis, Pemphigoidff Pemphigoidff, Night sweats, Psoriasis Night sweats Musculoskeletal and connective tissue disorders Very common Arthralgia Arthralgia Arthralgiah, Myalgia Common Myalgia Myalgia Uncommon Myositisgg, Immune- mediated arthritishh Immune-mediated arthritishh, Myositisgg Myositis Rare Polymyositisii, Polymyalgia rheumatica Polymyalgia rheumaticajj Polymyalgia rheumaticajj Renal and urinary disorders Very common Blood creatinine increased Common Blood creatinine increased, Dysuria Blood creatinine increased, Dysuria Dysuria Uncommon Nephritiskk, Cystitis noninfective Cystitis noninfective, Nephritiskk Cystitis noninfectiveh General disorders and administration site conditions Very common Pyrexia Pyrexia, Fatiguell Pyrexia, Fatigueh, Peripheral oedemamm Common Peripheral oedemamm Peripheral oedemamm Injury, poisoning and procedural complications Common Infusion-related reactionnn Infusion-related reactionnn Infusion-related reaction 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.
* overall study of treatment with up to six 21-day cycles with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib.
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, pneumonia klebsiella, and pneumonia legionella.

c including fatal outcome.
d includes gingivitis, oral infection, periodontitis, pulpitis dental, tooth abscess and tooth infection.
e includes leukopenia and white blood cell count decreased.
f includes neutropenia and neutrophil count decreased.
g includes thrombocytopenia and platelet count decreased.
h adverse reaction only applies to chemotherapy ADRs in the DUO-E study.
i adverse reaction only applies to olaparib ADRs in the DUO-E study.
j includes drug hypersensitivity and hypersensitivity.
k includes autoimmune hypothyroidism, hypothyroidism, immune-mediated hypothyroidism, blood thyroid stimulating hormone increased.
l includes hyperthyroidism, Grave’s disease, immune-mediated hyperthyroidism and blood thyroid stimulating hormone decreased.
m includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis, and thyroiditis subacute.
n includes neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.
o includes dysgeusia and taste disorder.
p includes encephalitis, encephalitis autoimmune, immune-mediated encephalitis and noninfective encephalitis.
q events were reported from post-marketing data.
r includes deep vein thrombosis, embolism, embolism venous, pelvic venous thrombosis, superficial vein thrombosis and thrombosis.
s adverse reaction only applies to oxaliplatin ADRs in the MATTERHORN study.
t adverse reaction only applies to 5-FU ADRs in the MATTERHORN study.
u includes acute coronary syndrome, acute myocardial infarction, myocardial infarction, myocardial ischaemia, and coronary artery disease.
v includes dyspnoea and dyspnoea exertional.
w includes pneumonitis and immune-mediated lung disease.
x includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
y includes stomatitis and mucosal inflammation.
z includes colitis, enteritis, enterocolitis, immune-mediated enterocolitis and proctitis.
aa includes pancreatitis, pancreatitis acute, pancreatitis necrotising and immune-mediated pancreatitis.
bb includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.
cc includes hepatitis, autoimmune hepatitis, hepatitis toxic, hepatitis acute, hepatotoxicity, immune-mediated hepatitis, and hepatic cytolysis.
dd includes rash erythematous, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema and rash.
ee includes dermatitis and immune-mediated dermatitis.
ff includes pemphigoid, dermatitis bullous and pemphigus. Reported frequency from completed and ongoingstudies is uncommon.
gg includes myositis and rhabdomyolysis.
hh includes autoimmune arthritis, immune-mediate arthritis, polyarthritis, and rheumatoid arthritis.
ii polymyositis (fatal) was observed in a patient treated with IMFINZI from an ongoing sponsored clinical study outside of the pooled dataset.
jj not observed in the IMFINZI+Chemotherapy pool or the platinum-based chemotherapy+IMFINZI+olaparib dataset, but observed in other AstraZeneca-sponsored clinical studies.
kk includes autoimmune nephritis, tubulointerstitial nephritis, nephritis, glomerulonephritis, glomerulonephritis membranous, and immune-mediated nephritis.
ll includes fatigue and asthenia.
mm includes oedema peripheral and peripheral swelling.
nn includes infusion-related reaction and urticaria with onset on the day of dosing or 1 day after dosing.

Table 4. Adverse drug reactions in patients treated with IMFINZI in combination with tremelimumab IMFINZI in combination with tremelimumab 75 mg and platinum- based chemotherapy IMFINZI in combination with tremelimumab 300 mg Infections and infestations Very common Upper respiratory tract infectionsa, Pneumoniab Common Influenza, Oral candidiasis Upper respiratory tract infectionsa, Pneumoniab, Influenza, Dental and oral soft tissue infectionsc Uncommon Dental and oral soft tissue infectionsc Oral candidiasis Blood and lymphatic system disorders Very Common Anaemiad, Neutropeniad,e, Thrombocytopeniad,f, Leukopeniad,g Common Febrile neutropeniad, Pancytopeniad Uncommon Immune thrombocytopenia Not known Immune thrombocytopeniah Endocrine disorders Very common Hypothyroidismi Hypothyroidismi Common Hyperthyroidismj, Adrenal insufficiency, Hypopituitarism/ Hypophysitis, Thyroiditisk Hyperthyroidismj, Thyroiditisk, Adrenal insufficiency Uncommon Diabetes insipidus, Type 1 diabetes mellitus Hypopituitarism/Hypophysitis Not known Diabetes insipidush, Type 1 diabetes mellitush Eye disorders Uncommon Uveitis Rare Uveitish Metabolism and nutrition disorders Very common Decreased appetited Nervous system disorders Common Neuropathy peripherald,l Uncommon Encephalitism, Myasthenia gravis, Meningitis Not known Myasthenia gravisn, Guillain-Barre syndromen, Meningitisn, Transverse myelitiso Guillain-Barré syndromeh, Encephalitish, Transverse myelitiso Cardiac disorders Uncommon Myocarditisp Myocarditis Respiratory, thoracic, and mediastinal disorders Very common Cough/Productive Cough Cough/Productive cough Common Pneumonitisq, Dysphonia Pneumonitisq Uncommon Interstitial lung disease Dysphonia, Intersitial lung disease Gastrointestinal disorders Very common Nausead, Diarrhoea, Constipationd, Vomitingd Diarrhoea, Abdominal painr Common Stomatitisd,s, Amylase increased, Abdominal painr, Lipase increased, Colitist, Pancreatitisu Lipase increased, Amylase increased, Colitist, Pancreatitisu Rare Coeliac diseasen Coeliac diseaseh Not known Intestinal perforationn, Large intestine perforationn Intestinal perforationh, Large intestinal perforationh

IMFINZI in combination with tremelimumab 75 mg and platinum- based chemotherapy
IMFINZI in combination with tremelimumab 300 mg
Hepatobiliary disorders
Very common
Aspartate aminotransferase increased/Alanine aminotransferase increasedv
Aspartate aminotransferase increased/Alanine aminotransferase increasedv
Common
Hepatitisw
Hepatitisw
Skin and subcutaneous tissue disorders
Very common
Alopeciad, Rashx, Pruritus
Rashx, Pruritus
Common
Dermatitisy, Night sweats,
Uncommon
Dermatitis, Night sweats, Pemphigoid Pemphigoid
Musculoskeletal and connective tissue disorders
Very common
Arthralgia
Common
Myalgia
Myalgia
Uncommon
Myositisz, Polymyositisz, Immune- mediated arthritisn
Myositisz, Polymyositisz, Immune-mediated arthritis, Polymyalgia rheumatica
Not known
Polymyalgia rheumatican
Renal and urinary disorders
Common
Blood creatinine increased, Dysuria
Blood creatinine increased, Dysuria
Uncommon
Nephritis, Cystitis noninfective
Nephritisaa
Not known
Cystitis noninfectiveh
General disorders and administration site conditions
Very common
Fatigued, Pyrexia
Pyrexia, Oedema peripheralbb
Common
Oedema peripheralbb
Injury, poisoning and procedural complications
Common
Infusion-related reactioncc
Infusion-related reactioncc a Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.
b Includes pneumocystis jirovecii pneumonia, pneumonia and pneumonia bacterial.
c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.
d Adverse reaction only applies to chemotherapy ADRs in the POSEIDON study.
e Includes neutropenia and neutrophil count decreased.
f Includes platelet count decreased and thrombocytopenia.
g Includes leukopenia and white blood cell count decreased.
h 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.
i Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.
j Includes blood thyroid stimulating hormone decreased and hyperthyroidism.
k Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.
l Includes neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.
m Includes encephalitis and encephalitis autoimmune.
n Adverse reaction was not observed in the POSEIDON study but was reported in patients treated with IMFINZI or IMFINZI+tremelimumab in clinical studies outside of the POSEIDON dataset.
o Reported in studies outside of the POSEIDON study and HCC pool.
p Includes autoimmune myocarditis.
q Includes immune-mediated pneumonitis and pneumonitis.
r Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
s Includes mucosal inflammation and stomatitis.
t Includes colitis, enteritis and enterocolitis.
u Includes autoimmune pancreatitis, pancreatitis and pancreatitis acute.
v Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.

w Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity, hepatitis acute and immune- mediated hepatitis.
x Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular, rash pruritic and rash pustular.
y Includes dermatitis and immune-mediated dermatitis.
z Includes rhabdomyolysis, myositis, and polymyositis.
aa Includes autoimmune nephritis and immune-mediated nephritis.
bb Includes oedema peripheral and peripheral swelling.
cc 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 4 642 patients which includes the PACIFIC, HIMALAYA and ADRIATIC studies 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 1 500 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 are also based on 2 280 patients who received IMFINZI 20 mg/kg every 4 weeks in combination with tremelimumab 1 mg/kg or IMFINZI 1 500 mg in combination with tremelimumab 75 mg every 4 weeks. Details for the significant adverse reactions for IMFINZI when given in combination with tremelimumab and platinum-based chemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI in combination with tremelimumab.

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 1 500 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=4 642 multiple tumour types), immune-mediated pneumonitis occurred in 147 (3.2%) patients, including Grade 3 in 37 (0.8%) patients, Grade 4 in 2 (< 0.1%) patients and Grade 5 in 10 (0.2%) patients. The median time to onset was 56 days (range: 1-1 308 days). One hundred and fourteen of the 147 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 4 patients also received other immunosuppressants including infliximab and cyclosporine. IMFINZI was discontinued in 60 patients. Resolution occurred in 85 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 study treatment (10.7%), than in the other patients in the combined safety database (1.0%).

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 and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the IMFINZI treated group vs. 6 in placebo.

In the ADRIATIC Study, in patients with LS-SCLC (n=262 in the IMFINZI arm, and n=265 in the placebo arm), immune-mediated pneumonitis occurred in 31 (11.8%) patients in the IMFINZI-treated group and 8 (3.0%) patients in the placebo group, including Grade 3 in 5 (1.9%) patients on IMFINZI vs. 1 (0.4%) patient on placebo and Grade 5 (fatal) in 1 (0.4%) patient on IMFINZI. The median time to onset in the IMFINZI-treated group was 55 days (range: 1-375 days) vs. 65.5 days (range:
24-124 days) in the placebo group. In the IMFINZI-treated group all patients received systemic corticosteroids, including 25 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received infliximab. In the placebo group all patients received systemic corticosteroids, including 7 patients who received high-dose corticosteroid treatment. Resolution occurred for 18 patients in the IMFINZI treated group vs. 3 in placebo.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated pneumonitis occurred in 86 (3.8%) patients, including Grade 3 in 30 (1.3%) patients, Grade 4 in 1 (< 0.1%) patient, and Grade 5 (fatal) in 7 (0.3%) patients. The median time to onset was 57 days (range: 8 - 912 days). All patients received systemic corticosteroids and 79 of the 86 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients also received other immunosuppressants. Treatment was discontinued in 39 patients. Resolution occurred in 51 patients.

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.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm) immune-mediated pneumonitis occurred in 5 2.1%) patients, including Grade 3 in 3 (1.3%) patients. The median time to onset was 85 days (range: 65-321 days). Five patients received systemic corticosteroids, including 4 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 5 patients.

Immune-mediated hepatitis
In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in 120 (2.6%) patients, including Grade 3 in 70 (1.5%) patients, Grade 4 in 9 (0.2%) patients and Grade 5 (fatal) in 6 (0.1%) patients. The median time to onset was 36 days (range: 1-644 days). Ninety-four of the 120 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants including mycophenolate treatment.
IMFINZI was discontinued in 30 patients. Resolution occurred in 56 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hepatitis occurred in 80 (3.5%) patients, including Grade 3 in 48 (2.1%) patients, Grade 4 in 8 (0.4%) patients and Grade 5 (fatal) in 2 (< 0.1%) patients. The median time to onset was 36 days (range: 1 - 533 days). All patients received systemic corticosteroids and 68 of the 80 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients also received other immunosuppressants. Treatment was discontinued in 27 patients.
Resolution occurred in 47 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 79 (1.7%) patients, including Grade 3 in 15 (0.3%) patients and Grade 4 in 2 (< 0.1%) patients. The median time to onset was 72 days (range: 1-920 days). Fifty-five of the 79 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Five patients also received other immunosuppressants including infliximab treatment and mycophenolate.
IMFINZI was discontinued in 15 patients. Resolution occurred in 54 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated colitis or diarrhoea occurred in 167 (7.3%) patients, including Grade 3 in 76 (3.3%) patients and Grade 4 in 3 (0.1%) patients. The median time to onset was 57 days range: 3-906 days).
All patients received systemic corticosteroids and 151 of the 167 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty-two patients also received other immunosuppressants. Treatment was discontinued in 54 patients. Resolution occurred in 141 patients.

Intestinal perforation and large intestine perforation were uncommonly reported in patients receiving IMFINZI in combination with tremelimumab.

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 384 (8.3%) patients, including Grade 3 in 7 (0.2%) patients. The median time to onset was 90.5 days (range: 1-951 days). Of the 384 patients, 379 patients received hormone replacement therapy and 7 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism. One patient discontinued IMFINZI due to immune-mediated hypothyroidism. Resolution occurred in 79 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hypothyroidism occurred in 209 (9.2%) patients, including Grade 3 in 6 (0.3%) patients. The median time to onset was 85 days (range: 1-624 days). Thirteen patients received systemic corticosteroids and 8 of the 13 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment discontinued in 3 patients. Resolution occurred in 52 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 25 patients or immune-mediated thyroiditis in 2 patients.

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 76 (1.6%) patients. The median time to onset was 43 days (range: 1-253 days). Seventy- one of the 76 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), 15 patients received systemic corticosteroids and 8 of the 15 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 62 patients. Thirty-one patients experienced hypothyroidism following hyperthyroidism.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hyperthyroidism occurred in 62 (2.7%) patients, including Grade 3 in 5 (0.2%) patients. The median time to onset was 33 days (range: 4-176 days). Eighteen patients received systemic corticosteroids, and 11 of the 18 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Fifty-three patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 47 patients.

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 corticosteroids, 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 21 (0.5%) patients, including Grade 3 in 2 (< 0.1%) patients. The median time to onset was 57 days (range: 14-217 days). Of the 21 patients, 18 patients received hormone replacement therapy and 3 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated thyroiditis. Resolution occurred in 8 patients.
Five patients experienced hypothyroidism following thyroiditis.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated thyroiditis occurred in 15 (0.7%) patients, including Grade 3 in 1 (< 0.1%) patient.
The median time to onset was 57 days (range: 22-141 days). Five patients received systemic corticosteroids and 2 of the 5 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Thirteen patients required other therapy including, hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. No patients discontinued treatment due to immune-mediated thyroiditis. Resolution occurred in 5 patients.

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 24 (0.5%) patients, including Grade 3 in 8 (0.2%) patients. The median time to onset was

157.5 days (range: 20-547 days). All 24 patients received systemic corticosteroids; 8 of the 24 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 6 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in 16 (0.7%) patients and Grade 4 in 1 (< 0.1%) patient. The median time to onset was 105 days (range: 20-428 days). Thirty-two patients received systemic corticosteroids, and 10 of the 32 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
Treatment was discontinued in one patient. Resolution occurred in 11 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, immune-mediated type 1 diabetes mellitus occurred in 5 (0.1%) patients, including Grade 3 in 3 (0.1%) patients and Grade 4 in 1 (< 0.1%) patient. The time to onset was 43 days (range: 29-631 days). All five patients required insulin therapy. IMFINZI was permanently discontinued in one patient. One patient recovered and one patient recovered with sequelae.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated type 1 diabetes mellitus occurred in 6 (0.3%) patients, including Grade 3 in 1 (< 0.1%) patient and Grade 4 in 2 (< 0.1%) patients. The median time to onset was 58 days (range:
7-220 days). All patients required insulin. Treatment was discontinued for 1 patient. Resolution occurred in 1 patient.

Immune mediated hypophysitis/hypopituitarism
In the combined safety database with IMFINZI monotherapy, immune-mediated hypophysitis/hypopituitarism occurred in 6 (0.1%) patients, including Grade 3 in 5 (0.1%) patients.
The time to onset for the events was 85 days (range: 44-225 days). Three patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), three patients discontinued IMFINZI due to immune-mediated hypophysitis/hypopituitarism and resolution occurred in 1 patient.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hypophysitis/hypopituitarism occurred in 16 (0.7%) patients, including Grade 3 in 8 (0.4%) patients. The median time to onset for the events was 123 days (range: 63-388 days). All patients received systemic corticosteroids and 8 of the 16 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy. Treatment was discontinued in 2 patients. Resolution occurred in 7 patients.

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 17 (0.4%) patients, including Grade 3 in 4 (0.1%) patients and Grade 4 in 1 (< 0.1%) patient. The median time to onset was 84 days (range: 4-393 days). Twelve 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 7 patients. Resolution occurred in 8 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated nephritis occurred in 9 (0.4%) patients, including Grade 3 in 1 (< 0.1%) patient. The median time to onset was 79 days (range: 39-183 days). All patients received systemic corticosteroids and 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 3 patients. Resolution occurred in 5 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 74 (1.6%) patients, including Grade 3 in 20 (0.4%) patients. The median time to onset was 56 days (range: 4-600 days). Thirty-seven of the 74 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 5 patients. Resolution occurred in 46 patients.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated rash or dermatitis (including pemphigoid) occurred in 112 (4.9%) patients, including Grade 3 in 17 (0.7%) patients. The median time to onset was 35 days (range: 1-778 days).
All patients received systemic corticosteroids, and 57 of the 112 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 10 patients. Resolution occurred in 65 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.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm) immune-mediated rash occurred in 8 (3.4%) patients, including Grade 3 in 2 (0.8%) patients. The median time to onset was 155 days (range: 2-308 days). All patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 8 patients.

Infusion-related reactions
In the combined safety database with IMFINZI monotherapy, infusion-related reactions occurred in 70 (1.5%) patients, including Grade 3 in 6 (0.1%) patients. There were no Grade 4 or 5 events.

In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), infusion-related reactions occurred in 45 (2.0%) patients, including Grade 3 in 2 (< 0.1%) patients.
There were no Grade 4 or 5 events.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), infusion-related reactions occurred in 13 (5.5%) patients, including Grade 3 in 1 (0.4%) patient. There were no Grade 4 or 5 events.

Pure Red Cell Aplasia
Pure Red Cell Aplasia (PRCA) has been reported when IMFINZI has been used in combination with olaparib. In a clinical study of patients with endometrial cancer treated with IMFINZI in combination with olaparib, the incidence of PRCA was 1.6%. All events were CTCAE Grade 3 or 4. Events were manageable following discontinuation of both IMFINZI and olaparib. The majority of events were managed with blood transfusion and immunosuppression and recovered; there were no fatal events.
For management see section 4.4.

Laboratory abnormalities
In patients treated with IMFINZI monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.7% for alanine aminotransferase increased, 5.7% for aspartate aminotransferase increased, 0.9% for blood creatinine increased, 4.8% for amylase increased and 8.2% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 20% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 18.2%.

In patients treated with IMFINZI 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: 4.2% for alanine aminotransferase increased, 3.4% for aspartate aminotransferase increased, 4.0% for blood creatinine increased, 6.0% for amylase increased, 12.1% for lipase increased, and 2.3% for bilirubin increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 22.8% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 22.6%.

In patients treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 6.2% for alanine aminotransferase increased, 5.2% for aspartate aminotransferase increased, 4.0% for blood creatinine increased, 9.4% for amylase increased and 13.6% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 24.8% and a TSH shift from baseline that was ≥ LLN to < LLN was 32.9%.

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%.

In patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.8% for alanine aminotransferase increased, 3.4% for aspartate aminotransferase increased and 1.7% for blood creatinine increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 28.6% and a TSH shift from baseline that was ≥ LLN to < LLN was 20.1%.

Immunogenicity
Immunogenicity of IMFINZI as monotherapy is based on pooled data in 3 069 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). Eighty-four patients (2.7%) tested positive for treatment emergent ADAs. Neutralising antibodies (nAb) against durvalumab were detected in 0.5% (16/3 069) of patients. The presence of ADAs did not have a clinically relevant effect on pharmacokinetics or safety. There are insufficient number of patients to determine ADA impact on efficacy.

Across multiple phase III studies, in patients treated with IMFINZI in combination with other therapeutic agents, 0% to 10.1% 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
No overall differences in safety were reported between elderly (≥ 65 years) and younger patients.

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

In first line metastatic NSCLC patients in the POSEIDON study, some differences in safety were reported between elderly (≥ 65 years) and younger patients. The safety data from patients 75 years of age or older are limited to a total of 74 patients. There was a higher frequency of serious adverse reactions and discontinuation rate of any study treatment due to adverse reactions in 35 patients aged 75 years of age or older treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy (45.7% and 28.6%, respectively) relative to 39 patients aged 75 years of age or older who received platinum-based chemotherapy only (35.9% and 20.5%, respectively).

In resectable NSCLC patients in the AEGEAN study, some differences in safety were reported between elderly (≥ 65 years) and younger patients. The safety data from patients 75 years of age or older are limited to 86 patients in both treatment arms. There was a higher frequency of serious adverse reactions in patients aged 75 years or older who received IMFINZI in combination with chemotherapy relative to patients who received chemotherapy only (26.5% vs. 10.8%, respectively).
There was a higher frequency of discontinuation of any study treatment due to adverse reactions in patients aged 75 years or older who received IMFINZI in combination with chemotherapy relative to patients who received chemotherapy only (16.3% vs. 8.1%, respectively).

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 Appendix V.

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, IMFINZI in combination with tremelimumab, IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib, or in combination with chemotherapy (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 study treatment, 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%). In the AEGEAN study, in patients who have received post-operative radiotherapy (PORT), pneumonitis and radiation pneumonitis occurred in 10 (33.3%) patients in the IMFINZI-treated group and 3 (11.1%) patients in the placebo group, including 2 patients with maximum Grade 3 (6.7%) in the IMFINZI-treated group.

In the ADRIATIC Study, in patients who had completed chemoradiation within 1 to 42 days prior to initiation of study treatment, pneumonitis or radiation pneumonitis occurred in 100 (38.2%) patients in the IMFINZI-treated group and 80 (30.2%) in the placebo group, including Grade 3 (3.1% vs. 2.3%), and Grade 5 (0.4% vs. 0.0).

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, or in combination with chemotherapy (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, or in combination with chemotherapy (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, or in combination with chemotherapy 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, or in combination with chemotherapy (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 a 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, or in combination with chemotherapy (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, or in combination with chemotherapy (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 a 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, or in combination with chemotherapy (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 a 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, or in combination with chemotherapy (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 a 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 or IMFINZI in combination with tremelimumab, or in combination with chemotherapy (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.

Immune-mediated pancreatitis
Immune-mediated pancreatitis occurred in patients receiving IMFINZI in combination with tremelimumab and chemotherapy, or in combination with chemotherapy (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated pancreatitis and managed as recommended in section 4.2.

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, or in combination with chemotherapy: myasthenia gravis, myelitis transverse, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, immune-mediated arthritis, uveitis, cystitis noninfective and polymyalgia rheumatica (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, or in combination with chemotherapy (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 institutional 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.

Treatment-specific precaution (IMFINZI in combination with olaparib in endometrial cancer) Haematological toxicity

Pure red cell aplasia (PRCA) (see section 4.8) was reported when olaparib maintenance treatment was used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum- based chemotherapy. If PRCA is confirmed, treatment with IMFINZI and olaparib should be discontinued.

Autoimmune haemolytic anemia (AIHA) was reported when olaparib maintenance treatment was used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy. If AIHA is confirmed, treatment with IMFINZI and olaparib should be discontinued.

Metastatic NSCLC
Limited data are available in elderly patients (≥ 75 years) treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy (see sections 4.8 and 5.1). Careful consideration of the potential benefit/risk of this regimen on an individual basis is recommended.

Patients excluded from clinical studies
Patients with the following were excluded from clinical studies: 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 interactions of durvalumab in combination with other therapeutic agents were compared with durvalumab in the CASPIAN, POSEIDON, HIMALAYA, and DUO-E studies; no clinically meaningful PK drug-drug interactions were identified.

Women of childbearing potential/Contraception
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.

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 PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, 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, 1 120 mg every 3 weeks or 1 500 mg every 4 weeks were evaluated in NSCLC, ES-SCLC and endometrial cancer 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, 1 120 mg every 3 weeks or 1 500 mg every 4 weeks.

Resectable NSCLC – AEGEAN Study
AEGEAN was a randomised, double-blind, placebo-controlled, multicentre, Phase III study designed to evaluate the efficacy of IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, then continued as IMFINZI monotherapy after surgery, in patients with resectable NSCLC.

The following selection criteria define patients with high risk of recurrence who are included in the therapeutic indication and are reflective of a patient population with Stage IIA to select Stage IIIB as per the AJCC/UICC, 8th edition staging system:
- any patient with a tumour size ≥ 4 cm;
- any patient with N1 or N2 disease (regardless of primary tumour size), including multi-station N2 disease;

The pharmacokinetics (PK) of durvalumab was assessed for IMFINZI as a single agent, in combination with chemotherapy, in combination with tremelimumab and platinum-based chemotherapy, in combination with tremelimumab and in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib.

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, in combination with chemotherapy, in combination with tremelimumab and platinum-based chemotherapy, in combination with tremelimumab and in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib. 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.

Renal impairment