YERVOY 5mg / ml perfusive solution concentrate medication leaflet

YERVOY 5 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 5 mg ipilimumab.

One 10 ml vial contains 50 mg of ipilimumab.

One 40 ml vial contains 200 mg of ipilimumab.

Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody (IgG1κ) produced in Chinese hamsterovary cells by recombinant DNA technology.

Each ml of concentrate contains 0.1 mmol sodium, which is 2.30 mg sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few) particulatesand has a pH of 7.0 and an osmolarity of 260-300 mOsm/kg.

YERVOY as monotherapy or in combination with nivolumab is indicated for the treatment ofadvanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older(see section 4.4).

Relative to nivolumab monotherapy, an increase in progression-free survival (PFS) and overallsurvival (OS) for the combination of nivolumab with ipilimumab is established only in patients withlow tumour PD-L1 expression (see sections 4.4 and 5.1).

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients withintermediate/poor-risk advanced renal cell carcinoma (see section 5.1).

YERVOY in combination with nivolumab and 2 cycles of platinum-based chemotherapy is indicatedfor the first-line treatment of metastatic non-small cell lung cancer in adults whose tumours have nosensitising EGFR mutation or ALK translocation.

Malignant pleural mesothelioma (MPM)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients withunresectable malignant pleural mesothelioma.

Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC)

YERVOY in combination with nivolumab is indicated for the treatment of adult patients withmismatch repair deficient or microsatellite instability-high colorectal cancer in the following settings:

- first-line treatment of unresectable or metastatic colorectal cancer;

- treatment of metastatic colorectal cancer after prior fluoropyrimidine-based combinationchemotherapy (see section 5.1).

Oesophageal squamous cell carcinoma (OSCC)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients withunresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma with tumour cell

PD-L1 expression ≥ 1%.

Hepatocellular carcinoma (HCC)

YERVOY in combination with nivolumab is indicated for the first-line treatment of adult patients withunresectable or advanced hepatocellular carcinoma.

Treatment must be initiated and supervised by specialist physicians experienced in the treatment ofcancer.

If specified in the indication, patient selection for treatment with YERVOY based on the tumourexpression of PD-L1 should be confirmed by a validated test (see sections 4.1, pct. 4.4, and 5.1).

MSI/MMR testing

If specified in the indication, patient selection for treatment with YERVOY based on MSI-H/dMMRtumour status should be assessed by a CE-marked IVD with the corresponding intended purpose. If the

CE-marked IVD is not available, an alternative validated test should be used (see sections 4.1, pct. 4.4, and5.1).

YERVOY as monotherapy

Adults and adolescents 12 years of age and older

The recommended induction regimen of YERVOY is 3 mg/kg administered intravenously overa 30-minute period every 3 weeks for a total of 4 doses. Patients should receive the entire inductionregimen (4 doses) as tolerated, regardless of the appearance of new lesions or growth of existinglesions. Assessments of tumour response should be conducted only after completion of inductiontherapy.

YERVOY in combination with nivolumab

In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommendeddose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumabmonotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every4 weeks (see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first doseof nivolumab should be administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mgevery 2 weeks; or 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mgevery 4 weeks.

In adolescents 12 years of age and older and weighing less than 50 kg, the recommended dose is3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administered intravenously every3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumabmonotherapy is administered intravenously at either 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks(see sections 5.1 and 5.2), as presented in Table 1. For the monotherapy phase, the first dose ofnivolumab should be administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg/kgevery 2 weeks; or 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg/kgevery 4 weeks.

Table 1: Recommended doses and infusion times for intravenous administration ofipilimumab in combination with nivolumab

Combination phase, every3 weeks for 4 dosing cycles Monotherapy phase

Adults and adolescents (12 years of age and older weighingat least 50 kg):240 mg every 2 weeks over 30 minutes or

Adults and adolescents 480 mg every 4 weeks over 60 minutes

Nivolumab 12 years of age and older:

1 mg/kg over 30 minutes Adolescents (12 years of age and older and weighing lessthan 50 kg):3 mg/kg every 2 weeks over 30 minutes or6 mg/kg every 4 weeks over 60 minutes

Adults and adolescents

Ipilimumab 12 years of age and older: -3 mg/kg over 30 minutes

The recommended dose is 1 mg/kg ipilimumab in combination with 3 mg/kg nivolumab administeredintravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in whichnivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mgevery 4 weeks, as presented in Table 2. For the monotherapy phase, the first dose of nivolumab shouldbe administered; 3 weeks after the last dose of the combination of ipilimumab and nivolumab if using 240 mgevery 2 weeks; or 6 weeks after the last dose of the combination of ipilimumab and nivolumab if using 480 mgevery 4 weeks.

Table 2: Recommended doses and infusion times for intravenous administration ofipilimumab in combination with nivolumab for RCC

Combination phase, every3 weeks for 4 dosing cycles Monotherapy phase

Nivolumab 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 60 minutes

Ipilimumab 1 mg/kg over 30 minutes -dMMR or MSI-H colorectal cancer

The recommended dose for first-line treatment of dMMR or MSI-H CRC is 1 mg/kg ipilimumab incombination with 240 mg of nivolumab administered intravenously every 3 weeks for a maximum of4 doses, followed by nivolumab monotherapy is administered intravenously at either 240 mg every2 weeks or at 480 mg every 4 weeks, as presented in Table 3. For the monotherapy phase, the firstdose of nivolumab should be administered 3 weeks after the last dose of the combination of nivolumaband ipilimumab. Treatment with nivolumab is recommended until disease progression, unacceptabletoxicity, or up to 24 months in patients without disease progression.

The recommended dose in patients who received prior fluoropyrimidine-based combinationchemotherapy for dMMR or MSI-H CRC is 1 mg/kg ipilimumab in combination with 3 mg/kgnivolumab administered intravenously every 3 weeks for the first 4 doses, followed by nivolumabmonotherapy administered intravenously 240 mg every 2 weeks, as presented in Table 3. For themonotherapy phase, the first dose of nivolumab should be administered 3 weeks after the last dose ofthe combination of ipilimumab and nivolumab.

Table 3: Recommended doses and infusion times for intravenous administration ofipilimumab in combination with nivolumab for dMMR or MSI-H CRC

Combination phase,every 3 weeks for Monotherapy phase4 dosing cycles

First-line 240 mg over 30 minutes 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 30 minutes

Nivolumab After priorfluoropyrimidine-basedcombination 3 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minuteschemotherapy

Ipilimumab 1 mg/kg over 30 minutes -

Malignant pleural mesothelioma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every3 weeks. Treatment is continued for up to 24 months in patients without disease progression.

Oesophageal squamous cell carcinoma

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every6 weeks in combination with either 3 mg/kg nivolumab every 2 weeks or 360 mg nivolumab every3 weeks administered intravenously over 30 minutes. Treatment is recommended until diseaseprogression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Hepatocellular carcinoma

The recommended dose is 3 mg/kg ipilimumab in combination with 1 mg/kg nivolumab administeredintravenously every 3 weeks for up to 4 doses. This is then followed by a second phase in whichnivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mgevery 4 weeks (see sections 5.1 and 5.2), as presented in Table 4. Treatment is recommended untildisease progression, unacceptable toxicity, or up to 24 months. For the monotherapy phase, the firstdose of nivolumab should be administered: 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mgevery 2 weeks or 480 mg every 4 weeks.

Table 4: Recommended doses and infusion times for intravenous administration ofipilimumab in combination with nivolumab for HCC

Combination phase, every3 weeks for 4 dosing cycles Monotherapy phase

Nivolumab 1 mg/kg over 30 minutes 240 mg every 2 weeks over 30 minutes or480 mg every 4 weeks over 30 minutes

Ipilimumab 3 mg/kg over 30 minutes -

YERVOY in combination with nivolumab and chemotherapy

The recommended dose is 1 mg/kg ipilimumab administered intravenously over 30 minutes every6 weeks in combination with 360 mg nivolumab administered intravenously over 30 minutes every3 weeks, and platinum-based chemotherapy administered every 3 weeks. After completion of 2 cyclesof chemotherapy, treatment is continued with 1 mg/kg ipilimumab every 6 weeks in combination with360 mg nivolumab administered intravenously every 3 weeks. Treatment is recommended untildisease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Treatment with YERVOY in combination with nivolumab, should be continued as long as clinicalbenefit is observed or until treatment is no longer tolerated by the patient (and up to maximumduration of therapy if specified for an indication).

Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the firstfew months followed by tumour shrinkage) have been observed. It is recommended to continuetreatment with YERVOY in combination with nivolumab for clinically stable patients with initialevidence of disease progression until disease progression is confirmed.

Liver function tests (LFTs) and thyroid function tests should be evaluated at baseline and before eachdose of YERVOY. In addition, any signs or symptoms of immune-related adverse reactions, includingdiarrhoea and colitis, must be assessed during treatment with YERVOY (see Tables 5A, 5B, andsection 4.4).

Children younger than 12 years of age

The safety and efficacy of ipilimumab in children younger than 12 years of age has not beenestablished.

Permanent discontinuation of treatment or withholding of doses

Management of immune-related adverse reactions may require withholding of a dose or permanentdiscontinuation of YERVOY therapy and institution of systemic high-dose corticosteroid. In somecases, addition of other immunosuppressive therapy may be considered (see section 4.4).

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be requiredbased on individual safety and tolerability.

Guidelines for permanent discontinuation or withholding of doses are described in Tables 5A and 5Bfor YERVOY as monotherapy, and in Table 5C for YERVOY in combination with nivolumab oradministration of the second phase of treatment (nivolumab monotherapy) following combinationtreatment. Detailed guidelines for the management of immune-related adverse reactions are describedin section 4.4.

Table 5A: When to permanently discontinue YERVOY as monotherapy

Permanently discontinue YERVOY in patients with the following adverse reactions. Management of theseadverse reactions may also require systemic high-dose corticosteroid therapy if demonstrated or suspectedto be immune-related (see section 4.4 for detailed management guidelines).

Adverse reactions NCI-CTCAE v4 Gradea

Gastrointestinal:

Severe symptoms (abdominal pain, severe diarrhoea or significant  Grade 3 or 4 diarrhoea or colitischange in the number of stools, blood in stool, gastrointestinalhaemorrhage, gastrointestinal perforation)

Hepatic:

Severe elevations in aspartate aminotransferase (AST), alanine  Grade 3 or 4 elevation in AST,aminotransferase (ALT), or total bilirubin or symptoms of ALT, or total bilirubinhepatotoxicity

Skin:

Life threatening skin rash (including Stevens-Johnson syndrome or  Grade 4 rash or Grade 3 pruritustoxic epidermal necrolysis) or severe widespread pruritus interferingwith activities of daily living or requiring medical intervention

Neurologic:  Grade 3 or 4 motor or sensory

New onset or worsening severe motor or sensory neuropathy neuropathy

Other organ systemsb:  ≥ Grade 3 immune-relatedc(e.g. nephritis, pneumonitis, pancreatitis, non-infectious myocarditis, reactionsdiabetes)  ≥ Grade 2 for immune-related eyedisorders NOT responding to topicalimmunosuppressive therapy Grade 4 diabetesa Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events.

Version 4.0 (NCI-CTCAE v4).

b Any other adverse reactions that are demonstrated or suspected to be immune-related should be graded according to

CTCAE. Decision whether to discontinue YERVOY should be based on severity.

c Patients with severe (Grade 3 or 4) endocrinopathy controlled with hormone replacement therapy may remain ontherapy.

Table 5B: When to withhold dose of YERVOY as monotherapy

Withhold YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4for detailed management guidelines.

Adverse reactions Action

Gastrointestinal: 1. Withhold dose until an adverse

Moderate diarrhoea or colitis that either is not controlled with medical reaction resolves to Grade 1 ormanagement or that persists (5-7 days) or recurs Grade 0 (or returns to baseline).2. If resolution occurs, resume

Hepatic: therapy.d

Grade 2 elevation in AST, ALT, or total bilirubin 3. If resolution has not occurred,continue to withhold doses until

Skin: resolution then resume

Moderate to severe (Grade 3)b skin rash or (Grade 2) treatment.dwidespread/intense pruritus regardless of etiology 4. Discontinue YERVOY ifresolution to Grade 1 or Grade 0

Endocrine: or return to baseline does not

Severe adverse reactions in the endocrine glands, such as occur.hypophysitis and thyroiditis that are not adequately controlled withhormone replacement therapy or high-dose immunosuppressivetherapy

Grade 3 diabetes

Withhold YERVOY dosea in patients with the following immune-related adverse reactions. See section 4.4for detailed management guidelines.

Adverse reactions Action

Neurological:

Moderate (Grade 2)b unexplained motor neuropathy, muscleweakness, or sensory neuropathy (lasting more than 4 days)

Other moderate adverse reactionsca No dose reduction of YERVOY is recommended.b Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events.

Version 4.0 (NCI-CTCAE v4).c Any other organ system adverse reactions that are considered immune-related should be graded according to CTCAE.

Decision whether to withhold a dose should be based on severity.d Until administration of all 4 doses or 16 weeks from first dose, whichever occurs earlier.

Table 5C: Recommended treatment modifications for YERVOY in combination withnivolumab or administration of the second phase of treatment (nivolumabmonotherapy) following combination treatment

Immune-related Severity Treatment modificationadverse reaction

Grade 2 pneumonitis Withhold dose(s) until symptomsresolve, radiographic abnormalities

Immune-related improve, and management withpneumonitis corticosteroids is complete

Grade 3 or 4 pneumonitis Permanently discontinue treatment

Grade 2 diarrhoea or colitis Withhold dose(s) until symptomsresolve and management with

Immune-related colitis corticosteroids, if needed, is complete

Grade 3 or 4 diarrhoea or colitis Permanently discontinue treatment

Grade 2 elevation in aspartate Withhold dose(s) until laboratoryaminotransferase (AST), alanine values return to baseline and

Immune-related aminotransferase (ALT), or total management with corticosteroids, ifhepatitis without HCC bilirubin needed, is complete

Grade 3 or 4 elevation in AST, ALT, or Permanently discontinue treatmenttotal bilirubin

If AST/ALT is within normal limits at Withhold dose(s) until laboratorybaseline and increases to > 3 and values return to baseline and≤ 10 times ULN management with corticosteroids, ifor needed, is complete

Baseline AST/ALT is > 1 and ≤ 3 times

ULN and increases to > 5 and≤ 10 times ULN

Immune-related orhepatitis with HCC Baseline AST/ALT is > 3 and ≤ 5 times

ULN and increases to > 8 and≤ 10 times ULN

Permanently discontinue treatment

AST/ALT increases to > 10 times ULNor

Total bilirubin increases to > 3 times

ULN

Grade 2 or 3 creatinine elevation Withhold dose(s) until creatinine

Immune-related returns to baseline and managementnephritis and renal with corticosteroids is completedysfunction

Grade 4 creatinine elevation Permanently discontinue treatment

Immune-related Severity Treatment modificationadverse reaction

Symptomatic Grade 2 or 3 Withhold dose(s) until symptomshypothyroidism, hyperthyroidism, resolve and management withhypophysitis, corticosteroids (if needed for symptoms

Grade 2 adrenal insufficiency of acute inflammation) is complete.

Grade 3 diabetes Treatment should be continued in thepresence of hormone replacement

Immune-related therapya as long as no symptoms areendocrinopathies present

Grade 4 hypothyroidism

Grade 4 hyperthyroidism

Grade 4 hypophysitis Permanently discontinue treatment

Grade 3 or 4 adrenal insufficiency

Grade 4 diabetes

Grade 3 rash Withhold dose(s) until symptomsresolve and management with

Immune-related skin corticosteroids is completeadverse reactions Grade 4 rash Permanently discontinue treatment

Stevens-Johnson syndrome (SJS) or Permanently discontinue treatment (seetoxic epidermal necrolysis (TEN) section 4.4)

Grade 2 myocarditis Withhold dose(s) until symptoms

Immune-related resolve and management withmyocarditis corticosteroids is completeb

Grade 3 or 4 myocarditis Permanently discontinue treatment

Grade 3 (first occurrence) Withhold dose(s)

Grade 4 or recurrent Grade 3; persistent

Other immune-related Grade 2 or 3 despite treatmentadverse reactions modification; inability to reduce Permanently discontinue treatmentcorticosteroid dose to 10 mg prednisoneor equivalent per day

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events

Version 4.0 (NCI-CTCAE v4).a Recommendation for the use of hormone replacement therapy is provided in section 4.4.b The safety of re-initiating ipilimumab in combination with nivolumab therapy in patients previously experiencingimmune-related myocarditis is not known.

YERVOY in combination with nivolumab should be permanently discontinued for:

* Grade 4 or recurrent Grade 3 adverse reactions;

* Persistent Grade 2 or 3 adverse reactions despite management.

When YERVOY is administered in combination with nivolumab, if either agent is withheld, the otheragent should also be withheld. If dosing is resumed after a delay, either the combination treatment ornivolumab monotherapy could be resumed based on the evaluation of the individual patient.

The safety and efficacy of YERVOY as monotherapy in children younger than 12 years of age havenot been established. Very limited data are available. YERVOY should not be used in childrenyounger than 12 years of age.

The safety and efficacy of YERVOY in combination with nivolumab in children younger than18 years of age have not been established, except in adolescents 12 years of age and older withmelanoma. Currently available data are described in sections 4.2, pct. 4.8, 5.1 and 5.2.

No overall differences in safety or efficacy were reported between elderly (≥ 65 years) and youngerpatients (< 65 years). Data from first-line RCC patients 75 years of age or older are too limited to drawconclusions on this population (see section 5.1). No specific dose adjustment is necessary in thispopulation (see section 5.1).

The safety and efficacy of YERVOY have not been studied in patients with renal impairment. Basedon population pharmacokinetic results, no specific dose adjustment is necessary in patients with mildto moderate renal dysfunction (see section 5.2).

The safety and efficacy of YERVOY have not been studied in patients with hepatic impairment. Basedon the population pharmacokinetic results, no specific dose adjustment is necessary in patients withmild hepatic impairment (see section 5.2). YERVOY must be administered with caution in patientswith transaminase levels ≥ 5 x ULN or bilirubin levels > 3 x ULN at baseline (see section 5.1).

YERVOY is for intravenous use. The recommended infusion period is 30 minutes.

YERVOY can be used for intravenous administration without dilution or may be diluted in sodiumchloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection toconcentrations between 1 and 4 mg/ml.

YERVOY must not be administered as an intravenous push or bolus injection.

When administered in combination with nivolumab or in combination with nivolumab andchemotherapy, nivolumab should be given first followed by YERVOY and then by chemotherapy (ifapplicable) on the same day. Use separate infusion bags and filters for each infusion.

For instructions on the preparation and handling of the medicinal product before administration, seesection 6.6.

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

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

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robustmethodology is used.

Assessment of MSI/MMR status

When assessing the MSI-H and dMMR status of the tumour, it is important that a well-validated androbust methodology is used.

Ipilimumab in combination with nivolumab

When ipilimumab is administered in combination, refer to the Summary of Product Characteristics ofthe other combination therapy components prior to initiation of treatment. For additional informationon warnings and precautions associated with nivolumab treatment, please refer to the nivolumab

SmPC. Most immune-related adverse reactions improved or resolved with appropriate management,including initiation of corticosteroids and treatment modifications (see section 4.2). Immune-relatedadverse reactions have occurred at higher frequencies when nivolumab was administered incombination with ipilimumab compared with nivolumab as monotherapy.

Cardiac and pulmonary adverse events including pulmonary embolism have also been reported withcombination therapy. Patients should be monitored for cardiac and pulmonary adverse reactionscontinuously, as well as for clinical signs, symptoms, and laboratory abnormalities indicative ofelectrolyte disturbances and dehydration prior to and periodically during treatment. Ipilimumab incombination with nivolumab should be discontinued for life-threatening or recurrent severe cardiacand pulmonary adverse reactions (see section 4.2).

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adversereaction with ipilimumab in combination with nivolumab may occur at any time during or afterdiscontinuation of therapy.

Immune-related reactions

Ipilimumab is associated with inflammatory adverse reactions resulting from increased or excessiveimmune activity (immune-related adverse reactions), likely to be related to its mechanism of action.

Immune-related adverse reactions, which can be severe or life-threatening, may involve thegastrointestinal, liver, skin, nervous, endocrine, or other organ systems. While most immune-relatedadverse reactions occurred during the induction period, onset months after the last dose of ipilimumabhas also been reported. Unless an alternate etiology has been identified, diarrhoea, increased stoolfrequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatoryand ipilimumab-related. Early diagnosis and appropriate management are essential to minimiselife-threatening complications.

Systemic high-dose corticosteroid with or without additional immunosuppressive therapy may berequired for management of severe immune-related adverse reactions.

Ipilimumab specific management guidelines for immune-related adverse reactions are described belowfor use as monotherapy and in combination with nivolumab.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirmaetiology or exclude other causes. Based on the severity of the adverse reaction, ipilimumab, oripilimumab in combination with nivolumab should be withheld and corticosteroids administered. Ifimmunosuppression with corticosteroids is used to treat an adverse reaction that occurs as aconsequence of combination therapy, a taper of at least 1 month duration should be initiated uponimprovement. Rapid tapering may lead to worsening or recurrence of the adverse reaction.

Non-corticosteroid immunosuppressive therapy should be added if there is worsening or noimprovement despite corticosteroid use.

Ipilimumab in combination with nivolumab should not be resumed while the patient is receivingimmunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylacticantibiotics should be used to prevent opportunistic infections in patients receiving immunosuppressivetherapy.

Ipilimumab in combination with nivolumab must be permanently discontinued for any severeimmune-related adverse reaction that recurs and for any life-threatening immune-related adversereaction.

Immune-related gastrointestinal reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due togastrointestinal perforation have been reported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in a Phase 3 study of advanced(unresectable or metastatic) melanoma (MDX010-20, see section 5.1), the median time to onset ofsevere or fatal (Grade 3-5) immune-related gastrointestinal reactions was 8 weeks(range 5 to 13 weeks) from the start of treatment. With protocol-specified management guidelines,resolution (defined as improvement to mild [Grade 1] or less or to the severity at baseline) occurred inmost cases (90%), with a median time from onset to resolution of 4 weeks (range 0.6 to 22 weeks).

Patients must be monitored for gastrointestinal signs and symptoms that may be indicative ofimmune-related colitis or gastrointestinal perforation. Clinical presentation may include diarrhoea,increased frequency of bowel movements, abdominal pain, or haematochezia, with or without fever. Inclinical trials, immune-related colitis was associated with evidence of mucosal inflammation, with orwithout ulcerations, and lymphocytic and neutrophilic infiltration. Post-marketing cases ofcytomegalovirus (CMV) infection/reactivation have been reported in patients withcorticosteroid-refractory immune-related colitis. Stool infections work-up should be performed uponpresentation of diarrhoea or colitis to exclude infectious or other alternate etiologies.

Management recommendations for diarrhoea or colitis are based on severity of symptoms (per

NCI-CTCAE v4 severity grading classification). Patients with mild to moderate (Grade 1 or 2)diarrhoea (an increase of up to 6 stools per day) or suspected mild to moderate colitis (e.g. abdominalpain or blood in stools) may remain on ipilimumab. Symptomatic treatment (e.g. loperamide, fluidreplacement) and close monitoring are advised. If mild to moderate symptoms recur or persistfor 5-7 days, the scheduled dose of ipilimumab should be withheld and corticosteroid therapy (e.g.prednisone 1 mg/kg orally once daily or equivalent) should be initiated. If resolution to Grades 0-1 orreturn to baseline occurs, ipilimumab may be resumed (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) diarrhoea orcolitis (see section 4.2), and systemic high-dose intravenous corticosteroid therapy should be initiatedimmediately. (In clinical trials, methylprednisolone 2 mg/kg/day has been used). Once diarrhoea andother symptoms are controlled, the initiation of corticosteroid taper should be based on clinicaljudgment. In clinical trials, rapid tapering (over periods < 1 month) resulted in recurrence of diarrhoeaor colitis in some patients. Patients must be evaluated for evidence of gastrointestinal perforation orperitonitis.

The experience from clinical trials on the management of corticosteroid-refractory diarrhoea or colitisis limited. Addition of an alternative immunosuppressive agent to the corticosteroid regimen should beconsidered in corticosteroid-refractory immune-related colitis if other causes are excluded (including

Cytomegalovirus (CMV) infection/reactivation evaluated with viral PCR on biopsy, and other viral,bacterial and parasitic etiology). In clinical trials, a single dose of infliximab 5 mg/kg was addedunless contraindicated. Infliximab must not be used if gastrointestinal perforation or sepsis issuspected (see the Summary of Product Characteristics for infliximab).

Ipilimumab in combination with nivolumab

Severe diarrhoea or colitis has been observed with ipilimumab in combination with nivolumab (seesection 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such asabdominal pain and mucus or blood in stool. Infectious and disease-related aetiologies should be ruledout.

For Grade 4 diarrhoea or colitis, ipilimumab in combination with nivolumab must be permanentlydiscontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisoloneequivalents.

Grade 3 diarrhoea or colitis observed with ipilimumab in combination with nivolumab requirespermanent discontinuation of treatment and initiation of corticosteroids at a dose of 1 to 2 mg/kg/daymethylprednisolone equivalents.

For Grade 2 diarrhoea or colitis, ipilimumab in combination with nivolumab should be withheld.

Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/daymethylprednisolone equivalents. Upon improvement, ipilimumab in combination with nivolumab maybe resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despiteinitiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/daymethylprednisolone equivalents and ipilimumab in combination with nivolumab must be permanentlydiscontinued.

Ipilimumab in combination with nivolumab

Severe pneumonitis or interstitial lung disease, including fatal cases, has been observed withipilimumab in combination with nivolumab (see section 4.8). Patients should be monitored for signsand symptoms of pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchyfiltrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, ipilimumab in combination with nivolumab must be permanentlydiscontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisoloneequivalents.

For Grade 2 (symptomatic) pneumonitis, ipilimumab in combination with nivolumab should bewithheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Uponimprovement, ipilimumab in combination with nivolumab may be resumed after corticosteroid taper.

If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose shouldbe increased to 2 to 4 mg/kg/day methylprednisolone equivalents and ipilimumab in combination withnivolumab must be permanently discontinued.

Immune-related hepatotoxicity

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has beenreported in clinical trials (see section 4.8).

In patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset of moderateto severe or fatal (Grade 2-5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the startof treatment. With protocol-specified management guidelines, time to resolution rangedfrom 0.7 to 2 weeks.

Hepatic transaminase and bilirubin must be evaluated before each dose of ipilimumab, as earlylaboratory changes may be indicative of emerging immune-related hepatitis (see section 4.2).

Elevations in LFTs may develop in the absence of clinical symptoms. Increases in AST and ALT ortotal bilirubin should be evaluated to exclude other causes of hepatic injury, including infections,tumour progression, or concomitant medication and monitored until resolution. Liver biopsies frompatients who had immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils,lymphocytes, and macrophages).

For patients with Grade 2 transaminase or total bilirubin elevation, the scheduled dose of ipilimumabshould be withheld, and LFTs must be monitored until resolution. Upon improvement, ipilimumabmay be resumed (see section 4.2).

For patients with Grade 3 or 4 transaminase or total bilirubin elevation, treatment must be permanentlydiscontinued (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g.

methylprednisolone 2 mg/kg daily or equivalent) should be initiated immediately. In such patients,

LFTs must be monitored until normalization. Once symptoms have resolved and LFTs show sustainedimprovement or return to baseline, the initiation of corticosteroid taper should be based on clinicaljudgment. Tapering should occur over a period of at least 1 month. Elevations in LFTs during tapermay be managed with an increase in the dose of corticosteroid and a slower taper.

For patients with significant LFT elevations that are refractory to corticosteroid therapy, addition of analternative immunosuppressive agent to the corticosteroid regimen may be considered. In clinicaltrials, mycophenolate mofetil was used in patients without response to corticosteroid therapy, or whohad an LFT elevation during corticosteroid tapering that was not responsive to an increase in the doseof corticosteroids (see the Summary of Product Characteristics for mycophenolate mofetil).

Ipilimumab in combination with nivolumab

Severe hepatitis has been observed with ipilimumab in combination with nivolumab (see section 4.8).

Patients should be monitored for signs and symptoms of hepatitis such as transaminase and totalbilirubin elevations. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 transaminase or total bilirubin elevation, ipilimumab in combination with nivolumabmust be permanently discontinued, and corticosteroids should be initiated at a doseof 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 transaminase or total bilirubin elevation, ipilimumab in combination with nivolumabshould be withheld. Persistent elevations in these laboratory values should be managed withcorticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement,ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed. Ifworsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose shouldbe increased to 1 to 2 mg/kg/day methylprednisolone equivalents and ipilimumab in combination withnivolumab must be permanently discontinued.

Caution should be used when considering the use of ipilimumab or ipilimumab in combination withnivolumab in a patient who has previously experienced a severe or life-threatening skin adversereaction on a prior cancer immune stimulatory therapy).

Ipilimumab as monotherapy

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Rare casesof toxic epidermal necrolysis (TEN) (including Steven Johnson Syndrome) have been observed, somewith fatal outcome. Rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)have also been reported in clinical trials and during post-marketing use (see section 4.8).

DRESS presents as a rash with eosinophilia associated with one or more of the following features:fever, lymphadenopathy, facial oedema, and internal organ involvement (hepatic, renal, pulmonary).

DRESS may be characterised by a long latency (two to eight weeks) between medicinal productexposure and disease onset.

Ipilimumab-induced rash and pruritus were predominantly mild or moderate (Grade 1 or 2) andresponsive to symptomatic therapy. In patients who received ipilimumab 3 mg/kg monotherapy in

MDX010-20, the median time to onset of moderate to severe or fatal (Grade 2-5) skin adversereactions was 3 weeks (range 0.9-16 weeks) from start of treatment. With protocol-specifiedmanagement guidelines, resolution occurred in most cases (87%), with a median time from onset toresolution of 5 weeks (range 0.6 to 29 weeks).

Ipilimumab-induced rash and pruritus should be managed based on severity. Patients with a mild tomoderate (Grade 1 or 2) rash may remain on ipilimumab therapy with symptomatic treatment (e.g.antihistamines). For mild to moderate rash or mild pruritus that persists for 1 to 2 weeks and does notimprove with topical corticosteroids, oral corticosteroid therapy should be initiated (e.g.prednisone 1 mg/kg once daily or equivalent).

For patients with a severe (Grade 3) rash, the scheduled dose of ipilimumab should be withheld. Ifinitial symptoms improve to mild (Grade 1) or resolve, ipilimumab therapy may be resumed (seesection 4.2).

Ipilimumab must be permanently discontinued in patients with a very severe (Grade 4) rash or severe(Grade 3) pruritus (see section 4.2), and systemic high-dose intravenous corticosteroid therapy (e.g.methylprednisolone 2 mg/kg/day) should be initiated immediately. Once rash or pruritus is controlled,initiation of corticosteroid taper should be based on clinical judgment. Tapering should occur over aperiod of at least 1 month.

Ipilimumab in combination with nivolumab

Severe rash has been observed with ipilimumab in combination with nivolumab (see section 4.8).

Ipilimumab in combination with nivolumab should be withheld for Grade 3 rash and discontinued for

Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of1 to 2 mg/kg/day methylprednisolone equivalents.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed. If symptoms orsigns of SJS or TEN appear, treatment with ipilimumab in combination with nivolumab should bediscontinued and the patient referred to a specialised unit for assessment and treatment. If the patienthas developed SJS or TEN with the use of ipilimumab in combination with nivolumab, permanentdiscontinuation of treatment is recommended (see section 4.2).

Immune-related neurological reactions

Ipilimumab as monotherapy

Ipilimumab is associated with serious immune-related neurological adverse reactions. Fatal

Guillain-Barré syndrome has been reported in clinical trials. Myasthenia gravis-like symptoms havealso been reported (see section 4.8). Patients may present with muscle weakness. Sensory neuropathymay also occur.

Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting > 4 days must beevaluated, and non-inflammatory causes such as disease progression, infections, metabolic syndromesand concomitant medication should be excluded. For patients with moderate (Grade 2) neuropathy(motor with or without sensory) likely related to ipilimumab, the scheduled dose should be withheld.

If neurologic symptoms resolve to baseline, the patient may resume ipilimumab (see section 4.2).

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) sensoryneuropathy suspected to be related to ipilimumab (see section 4.2). Patients must be treated accordingto institutional guidelines for management of sensory neuropathy, and intravenous corticosteroids (e.g.methylprednisolone 2 mg/kg/day) should be initiated immediately.

Progressive signs of motor neuropathy must be considered immune-related and managed accordingly.

Ipilimumab must be permanently discontinued in patients with severe (Grade 3 or 4) motor neuropathyregardless of causality (see section 4.2).

Ipilimumab in combination with nivolumab

Severe nephritis and renal dysfunction have been observed with ipilimumab in combination withnivolumab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renaldysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-relatedaetiologies should be ruled out.

For Grade 4 serum creatinine elevation, ipilimumab in combination with nivolumab must bepermanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/daymethylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, ipilimumab in combination with nivolumab should bewithheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisoloneequivalents. Upon improvement, ipilimumab in combination with nivolumab may be resumed aftercorticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids,corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, andipilimumab in combination with nivolumab must be permanently discontinued.

Immune-related endocrinopathy

Ipilimumab as monotherapy

Ipilimumab can cause inflammation of the endocrine system organs, manifesting as hypophysitis,hypopituitarism, adrenal insufficiency, hypothyroidism, Type 1 diabetes mellitus and diabeticketoacidosis (see sections 4.2 and 4.8), and patients may present with nonspecific symptoms, whichmay resemble other causes such as brain metastasis or underlying disease. The most common clinicalpresentation includes headache and fatigue. Symptoms may also include visual field defects,behavioural changes, electrolyte disturbances, and hypotension. Adrenal crisis as a cause of thepatient’s symptoms must be excluded. Clinical experience with ipilimumab associated endocrinopathyis limited.

For patients who received ipilimumab 3 mg/kg monotherapy in MDX010-20, time to onset ofmoderate to very severe (Grade 2-4) immune-related endocrinopathy ranged from 7 tonearly 20 weeks from the start of treatment. Immune-related endocrinopathy observed in clinical trialswas generally controlled with immunosuppressive therapy and hormone replacement therapy.

If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediateadministration of intravenous corticosteroids with mineralocorticoid activity is recommended, and thepatient must be evaluated for presence of sepsis or infections. If there are signs of adrenalinsufficiency but the patient is not in adrenal crisis, further investigations should be consideredincluding laboratory and imaging assessment. Evaluation of laboratory results to assess endocrinefunction may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratorytests of endocrine function are abnormal, a short course of high-dose corticosteroid therapy (e.g.dexamethasone 4 mg every 6 hrs or equivalent) is recommended to treat the inflammation of theaffected gland, and the scheduled dose of ipilimumab should be withheld (see section 4.2). It iscurrently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriatehormone replacement should also be initiated. Long-term hormone replacement therapy may benecessary.

For symptomatic diabetes, ipilimumab should be withheld, and insulin replacement should be initiatedas needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement isutilised. Ipilimumab must be permanently discontinued for life-threatening diabetes.

Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident,treatment with ipilimumab may be resumed and initiation of corticosteroid taper should be based onclinical judgment. Tapering should occur over a period of at least 1 month.

Ipilimumab in combination with nivolumab

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (includingsecondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), diabetes mellitus,and diabetic ketoacidosis have been observed with ipilimumab in combination with nivolumab (seesection 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies and forhyperglycaemia and changes in thyroid function (at the start of treatment, periodically duringtreatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache,mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecificsymptoms which may resemble other causes such as brain metastasis or underlying disease. Unless analternate aetiology has been identified, signs or symptoms of endocrinopathies should be consideredimmune-related.

For symptomatic hypothyroidism, ipilimumab in combination with nivolumab should be withheld, andthyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism,ipilimumab in combination with nivolumab should be withheld and antithyroid medication should beinitiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalentsshould also be considered if acute inflammation of the thyroid is suspected. Upon improvement,ipilimumab in combination with nivolumab may be resumed after corticosteroid taper, if needed.

Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised.

Ipilimumab in combination with nivolumab must be permanently discontinued for life-threateninghyperthyroidism or hypothyroidism.

For symptomatic Grade 2 adrenal insufficiency, ipilimumab in combination with nivolumab should bewithheld, and physiologic corticosteroid replacement should be initiated as needed. ipilimumab incombination with nivolumab must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Monitoring of adrenal function and hormone levels shouldcontinue to ensure appropriate corticosteroid replacement is utilised.

For symptomatic Grade 2 or 3 hypophysitis, ipilimumab in combination with nivolumab should bewithheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation ofthe pituitary gland is suspected. Upon improvement, ipilimumab in combination with nivolumab maybe resumed after corticosteroid taper, if needed. Ipilimumab in combination with nivolumab must bepermanently discontinued for life-threatening (Grade 4) hypophysitis. Monitoring of pituitary functionand hormone levels should continue to ensure appropriate hormone replacement is utilised.

For symptomatic diabetes, ipilimumab in combination with nivolumab should be withheld, and insulinreplacement should be initiated as needed. Monitoring of blood sugar should continue to ensureappropriate insulin replacement is utilised. Ipilimumab in combination with nivolumab must bepermanently discontinued for life-threatening diabetes.

Infusion reaction

Ipilimumab as monotherapy or in combination with nivolumab

Severe infusion reactions have been reported in clinical trials of ipilimumab or ipilimumab incombination with nivolumab (see section 4.8). In case of a severe or life-threatening infusion reaction,the ipilimumab or ipilimumab in combination with nivolumab infusion must be discontinued andappropriate medical therapy administered. Patients with mild or moderate infusion reaction mayreceive ipilimumab or ipilimumab in combination with nivolumab with close monitoring and use ofpremedication according to local treatment guidelines for prophylaxis of infusion reactions.

Ipilimumab as monotherapy

The following adverse reactions suspected to be immune-related have been reported in patients treatedwith ipilimumab 3 mg/kg monotherapy in MDX010-20: uveitis, eosinophilia, lipase elevation, andglomerulonephritis. In addition, iritis, haemolytic anaemia, amylase elevations, multi-organ failure,and pneumonitis have been reported in patients treated with ipilimumab 3 mg/kg + gp100 peptidevaccine in MDX010-20. Cases of Vogt-Koyanagi-Harada syndrome, serous retinal detachment, andcystitis noninfective have been reported post-marketing (see sections 4.2 and 4.8).

If severe (Grade 3 or 4), these reactions may require immediate systemic high-dose corticosteroidtherapy and discontinuation of ipilimumab (see section 4.2). For ipilimumab-related uveitis, iritis,serous retinal detachment or episcleritis, topical corticosteroid eye drops should be considered asmedically indicated. Transient vision loss has been reported in patients with ipilimumab-related ocularinflammations.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated withipilimumab. Treatment with ipilimumab may increase the risk of rejection in solid organ transplantrecipients. The benefit of treatment with ipilimumab versus the risk of possible organ rejection shouldbe considered in these patients.

Ipilimumab as monotherapy or in combination with a PD-1 or PD-L1 inhibitor

Haemophagocytic lymphohistiocytosis (HLH) has been observed with ipilimumab as monotherapyand ipilimumab in combination with a PD-1 or PD-L1 inhibitor (including with nivolumab). Cautionshould be taken when ipilimumab is administered as monotherapy or in combination with a PD-1 or

PD-L1 inhibitor. If HLH is confirmed, administration of ipilimumab or ipilimumab in combinationwith a PD-1 or PD-L1 inhibitor should be discontinued and treatment for HLH initiated.

Ipilimumab in combination with nivolumab

The following immune-related adverse reactions were reported in less than 1% of patients treated withipilimumab in combination with nivolumab in clinical trials across doses and tumour types:pancreatitis, uveitis, demyelination, autoimmune neuropathy (including facial and abducens nerveparesis), Guillain-Barré syndrome, myasthenia gravis, myasthenic syndrome, aseptic meningitis,encephalitis, gastritis, sarcoidosis, duodenitis, myositis, myocarditis, rhabdomyolysis, and myelitis.

Cases of Vogt-Koyanagi-Harada syndrome, serous retinal detachment, and cystitis noninfective havebeen reported post-marketing (see sections 4.2 and 4.8). Transient vision loss has been reported inpatients with ipilimumab-related ocular inflammations.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirmaetiology or exclude other causes. Based on the severity of the adverse reaction, ipilimumab incombination with nivolumab should be withheld and corticosteroids administered. Upon improvement,ipilimumab in combination with nivolumab may be resumed after corticosteroid taper. Ipilimumab incombination with nivolumab must be permanently discontinued for any severe immune-relatedadverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, havebeen reported with ipilimumab in combination with nivolumab. If a patient develops signs andsymptoms of myotoxicity, close monitoring should be implemented, and the patient referred to aspecialist for assessment and treatment without delay. Based on the severity of myotoxicity,ipilimumab in combination with nivolumab should be withheld or discontinued (see section 4.2), andappropriate treatment instituted.

The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac orcardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected,prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to currentclinical guidelines should be initiated. Once a diagnosis of myocarditis is established, ipilimumab incombination with nivolumab should be withheld or permanently discontinued (see section 4.2).

Disease specific precautions

Patients with ocular melanoma, primary CNS melanoma and active brain metastases were not includedin the MDX010-20 trial (see section 5.1).

Patients with ocular melanoma were not included in the CA184-169 clinical trial. However, patientswith brain metastases were included in this study, if they were free of neurologic symptoms related tometastatic brain lesions and if they did not require or receive systemic corticosteroid therapy in the10 days prior to beginning ipilimumab therapy (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with ipilimumab were notincluded in the paediatric trial CA184070 (see section 5.1).

Patients with ocular melanoma, active brain metastases and prior therapy with CTLA-4, PD-1, PD-L1,or CD137 targeted agents were not included in the paediatric trial CA184178 (see section 5.1).

Patients with a baseline performance score ≥ 2, active brain metastases or autoimmune disease, andpatients who had been receiving systemic immunosuppressants prior to study entry were excludedfrom the clinical trials of ipilimumab in combination with nivolumab. Patients with ocular/uvealmelanoma were excluded from clinical trials of melanoma. In the absence of data, nivolumab shouldbe used with caution in these populations after careful consideration of the potential benefit/risk on anindividual basis.

Relative to nivolumab monotherapy, an increase in PFS for the combination of ipilimumab withnivolumab is established only in patients with low tumour PD-L1 expression. The improvement in OSwas similar between ipilimumab with nivolumab and nivolumab monotherapy in patients with hightumour PD-L1 expression (PD-L1 ≥ 1%). Before initiating treatment with the combination, physiciansare advised to carefully evaluate the individual patient and tumour characteristics, taking intoconsideration the observed benefits and the toxicity of the combination relative to nivolumabmonotherapy (see sections 4.8 and 5.1).

Use of ipilimumab in combination with nivolumab in melanoma patients with rapidly progressingdisease.

Physicians should consider the delayed onset of ipilimumab in combination with nivolumab effectbefore initiating treatment in patients with rapidly progressing disease (see section 5.1).

Patients with any history of concurrent brain metastases, active autoimmune disease, or medicalconditions requiring systemic immunosuppression were excluded from the clinical trials ofipilimumab in combination with nivolumab (see sections 4.5 and 5.1). In the absence of data,ipilimumab in combination with nivolumab should be used with caution in these populations aftercareful consideration of the potential benefit/risk on an individual basis.

Patients with active autoimmune disease, symptomatic interstitial lung disease, medical conditionsrequiring systemic immunosuppression, active (untreated) brain metastasis, who received priorsystemic treatment for advanced disease, or who had sensitising EGFR mutations or ALKtranslocations were excluded from the pivotal trial in first-line treatment of NSCLC (see sections 4.5and 5.1). Limited data are available in elderly patients (≥ 75 years) (see section 5.1). In these patients,ipilimumab in combination with nivolumab and chemotherapy should be used with caution aftercareful consideration of the potential benefit/risk on an individual basis.

Malignant pleural mesothelioma

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lungdisease, active autoimmune disease, medical conditions requiring systemic immunosuppression, andbrain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolutionwithin 3 months prior to inclusion in the study) were excluded from the pivotal trial in first-linetreatment of MPM (see sections 4.5 and 5.1). In the absence of data, ipilimumab in combination withnivolumab should be used with caution in these populations after careful consideration of the potentialbenefit/risk on an individual basis.

dMMR or MSI-H colorectal cancer

Patients with a baseline performance score ≥ 2, active brain metastases or leptomeningeal metastases,active autoimmune disease, or medical conditions requiring systemic immunosuppression wereexcluded from the clinical trial in dMMR or MSI-H metastatic CRC (see sections 4.5 and 5.1). In theabsence of data, ipilimumab in combination with nivolumab should be used with caution in thesepopulations after careful consideration of the potential benefit/risk on an individual basis.

Oesophageal squamous cell carcinoma

Patients with a baseline performance score ≥ 2, any history of concurrent brain metastases, activeautoimmune disease, medical conditions requiring systemic immunosuppression, or at high risk ofbleeding or fistula due to apparent invasion of tumour to organs adjacent to the oesophageal tumourwere excluded from the clinical trial in OSCC (see sections 4.5 and 5.1). In the absence of data,ipilimumab in combination with nivolumab should be used with caution in these populations aftercareful consideration of the potential benefit/risk on an individual basis.

In the first-line OSCC trial, a higher number of deaths within 4 months was observed with ipilimumabin combination with nivolumab compared to chemotherapy. Physicians should consider the delayedonset of effect of ipilimumab in combination with nivolumab before initiating treatment in patientswith poorer prognostic features and/or aggressive disease (see section 5.1).

Hepatocellular carcinoma

Patients who had baseline ECOG performance score ≥ 2, prior liver transplant, Child-Pugh C liverdisease, a history of concurrent brain metastases, a history of hepatic encephalopathy (within12 months of randomization), clinically significant ascites, infection with HIV, or active co infectionwith hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV), activeautoimmune disease, or medical conditions requiring systemic immunosuppression were excludedfrom the clinical study in HCC (see sections 4.5 and 5.1). Limited data are available in HCC patientswith Child-Pugh B. In the absence of data, ipilimumab in combination with nivolumab followed bynivolumab should be used with caution in these populations after careful consideration of the potentialbenefit/risk on an individual basis.

In HCC, a higher number of deaths within 6 months was observed with ipilimumab in combinationwith nivolumab compared to lenvatinib or sorafenib. A higher risk of death may be associated withpoor prognostic features. Physicians should consider this risk before initiating treatment withipilimumab in combination with nivolumab in patients with poor prognostic features.

Patients with autoimmune disease

Patients with a history of autoimmune disease (other than vitiligo and adequately controlled endocrinedeficiencies such as hypothyroidism), including those who require systemic immunosuppressivetherapy for pre-existing active autoimmune disease or for organ transplantation graft maintenance,were not evaluated in clinical trials. Ipilimumab is a T-cell potentiator that enables the immuneresponse (see section 5.1) and may interfere with immunosuppressive therapy, resulting in anexacerbation of the underlying disease or increased risk of graft rejection. Ipilimumab should beavoided in patients with severe active autoimmune disease where further immune activation ispotentially imminently life threatening. In other patients with a history of autoimmune disease,ipilimumab should be used with caution after careful consideration of the potential risk-benefit on anindividual basis.

Patients on controlled sodium diet

This medicinal product contains 23 mg sodium per 10 ml vial and 92 mg sodium per 40 ml vial,respectively equivalent to 1.15% and 4.60% of the WHO recommended maximum daily intake of 2 gsodium for an adult. To be taken into consideration when treating patients on a controlled sodium diet.

Concurrent administration with vemurafenib

In a Phase 1 trial, asymptomatic grade 3 increases in transaminases (ALT/AST > 5 × ULN) andbilirubin (total bilirubin > 3 × ULN) were reported with concurrent administration of ipilimumab(3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, theconcurrent administration of ipilimumab and vemurafenib is not recommended.

Sequential administration with vemurafenib

In a Phase 2 trial, the sequential treatment with vemurafenib followed by 10 mg/kg ipilimumab inpatients with BRAF-mutated metastatic melanoma showed a higher incidence of Grade 3+ skinadverse reactions than with ipilimumab alone. Caution should be used when ipilimumab isadministered following prior vemurafenib.

Limited, but no long-term, safety data is available on the use of ipilimumab in adolescents 12 years ofage and older.

Only very limited data are available in children younger than 12 years of age. Therefore, ipilimumabshould not be used in children younger than 12 years of age.

Before initiating treatment with ipilimumab monotherapy in adolescents of 12 years and older,physicians are advised to carefully evaluate the individual patient, taking into consideration the limitedavailable data, the observed benefits and the toxicity of ipilimumab monotherapy in the paediatricpopulation (see sections 4.8 and 5.1).

Ipilimumab is a human monoclonal antibody that is not metabolised by cytochrome P450 enzymes(CYPs) or other drug metabolizing enzymes.

A drug-interaction study in adults of ipilimumab administered alone and in combination withchemotherapy (dacarbazine or paclitaxel/carboplatin) was conducted evaluating interaction with CYPisozymes (particularly CYP1A2, CYP2E1, CYP2C8, and CYP3A4) in patients with treatment-naiveadvanced melanoma. No clinically relevant pharmacokinetic drug-drug interaction was observedbetween ipilimumab and paclitaxel/carboplatin, dacarbazine or its metabolite,5-aminoimidazole-4-carboxamide (AIC).

Other forms of interaction

The use of systemic corticosteroids at baseline, before starting ipilimumab, should be avoided becauseof their potential interference with the pharmacodynamic activity and efficacy of ipilimumab.

However, systemic corticosteroids or other immunosuppressants can be used after starting ipilimumabto treat immune-related adverse reactions. The use of systemic corticosteroids after startingipilimumab treatment does not appear to impair the efficacy of ipilimumab.

Anticoagulants

The use of anticoagulants is known to increase the risk of gastrointestinal haemorrhage. Sincegastrointestinal haemorrhage is an adverse reaction with ipilimumab (see section 4.8), patients whorequire concomitant anticoagulant therapy should be monitored closely.

There are no data on the use of ipilimumab in pregnant women. Animal reproduction studies haveshown reproductive toxicity (see section 5.3). Human IgG1 crosses the placental barrier. The potentialrisk of treatment to the developing foetus is unknown. YERVOY is not recommended duringpregnancy or in women of childbearing potential not using effective contraception, unless the clinicalbenefit outweighs the potential risk.

Ipilimumab has been shown to be present at very low levels in milk from cynomolgus monkeys treatedduring pregnancy. It is unknown whether ipilimumab is secreted in human milk. Secretion of IgGs inhuman milk is generally limited and IgGs have a low oral bioavailability. Significant systemicexposure of the infant is not expected and no effects on the breast-fed newborn/infant are anticipated.

However, because of the potential for adverse reactions in nursing infants, a decision must be madewhether to discontinue breast-feeding or to discontinue from YERVOY therapy taking into accountthe benefit of breast-feeding for the child and the benefit of YERVOY therapy for the woman.

Studies to evaluate the effect of ipilimumab on fertility have not been performed. Thus, the effect ofipilimumab on male and female fertility is unknown.

YERVOY has minor influence on the ability to drive and use machines.

Because of potential adverse reactions such as fatigue (see section 4.8), patients should be advised touse caution when driving or operating machinery until they are certain that ipilimumab does notadversely affect them.

Ipilimumab as monotherapy (see section 4.2)

a. Summary of safety profile

Ipilimumab has been administered to approximately 10 000 patients in a clinical programmeevaluating its use with various doses and tumour types. Unless otherwise specified, the data belowreflect exposure to ipilimumab at 3 mg/kg in clinical trials of melanoma. In the Phase 3 study

MDX010-20, (see section 5.1), patients received a median of 4 doses (range 1-4).

Ipilimumab is most commonly associated with adverse reactions resulting from increased or excessiveimmune activity. Most of these, including severe reactions, resolved following initiation of appropriatemedical therapy or withdrawal of ipilimumab (see section 4.4 for management of immune-relatedadverse reactions).

In patients who received 3 mg/kg ipilimumab monotherapy in MDX010-20, the most frequentlyreported adverse reactions (≥ 10% of patients) were diarrhoea, rash, pruritus, fatigue, nausea,vomiting, decreased appetite, and abdominal pain. The majority were mild to moderate (Grade 1 or 2).

Ipilimumab therapy was discontinued for adverse reactions in 10% of patients.

Adverse reactions reported in patients with advanced melanoma who were treated withipilimumab 3 mg/kg in clinical trials (n = 767) and from post-marketing surveillance are presented in

Table 6.

These reactions are presented by system organ class and by frequency. Frequencies are 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 availablepost-marketing data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness. Rates of immune-related adverse reactions in HLA-A2*0201 positive patientswho received ipilimumab in MDX010-20 were similar to those observed in the overall clinicalprogramme.

The safety profile of ipilimumab 3 mg/kg in chemotherapy-naive patients pooled across Phase 2 and3 clinical trials (N = 75; treated), in treatment-naive patients in two retrospective observational studies(N = 273 and N = 157), and in CA184-169 (N = 362) was similar to that in previously-treatedadvanced melanoma.

The safety data for patients with unresectable or metastatic melanoma, treated with ipilimumab(3 mg/kg, with a minimum of 3 year follow-up) and enrolled in multi-national, prospective,observational study CA184143 (N = 1151) were similar to what has been reported in ipilimumabclinical trials for advanced melanoma.

Table 6: Adverse reactions in patients with advanced melanoma treated with ipilimumab3 mg/kga

Common sepsisb, urinary tract infection, respiratory tract infection

Uncommon septic shockb, pneumonia

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common tumour pain

Uncommon paraneoplastic syndrome

Common anaemia, lymphopaenia, thrombocytopaenia, neutropaenia

Uncommon haemolytic anaemiab, eosinophilia

Not known haemophagocytic lymphohistiocytosise

Uncommon hypersensitivity

Very rare anaphylactic reaction

Not known solid organ transplant rejectione

Common hypopituitarism (including hypophysitis)c, hypothyroidismc

Uncommon adrenal insufficiencyc, secondary adrenocortical insufficiencyd, hyperthyroidismc,hypogonadism

Rare autoimmune thyroiditisd, thyroiditisd

Very common decreased appetite

Common dehydration, hypokalaemia, weight decreased, hyponatremia

Uncommon alkalosis, hypophosphatemia, tumour lysis syndrome, hypocalcaemiad

Rare type 1 diabetes mellitus (including diabetic ketoacidosis)h

Common confusional state, depression

Uncommon mental status changes, decreased libido

Common peripheral sensory neuropathy, dizziness, headache, lethargy, cranial neuropathy, brainoedema, peripheral neuropathy

Uncommon Guillain-Barré syndromeb,c, meningitis (aseptic), autoimmune central neuropathy(encephalitis)d, syncope, ataxia, tremor, myoclonus, dysarthria

Rare myasthenia gravisd

Not known myelitis

Common blurred vision, eye pain

Uncommon uveitisc, vitreous haemorrhage, iritisc, eye oedemad, blepharitisd, reduced visual acuity,foreign body sensation in eyes, conjunctivitis

Rare Vogt-Koyanagi-Harada syndromee, serous retinal detachment

Common arrhythmia, atrial fibrillation

Common hypotension, flushing, hot flush

Uncommon vasculitis, angiopathyb, peripheral ischaemia, orthostatic hypotension

Rare temporal arteritisd

Common dyspnoea, cough, allergic rhinitis

Uncommon respiratory failure, acute respiratory distress syndromeb, lung infiltration, pulmonary oedema,pneumonitis

Very common diarrhoeac, vomiting, nausea, constipation, abdominal pain

Common gastrointestinal haemorrhage, colitisb,c, gastroesophageal reflux disease, mucosalinflammationd, gastroenteritis, stomatitis

Uncommon gastrointestinal perforationb,c, large intestine perforationb,c, intestinal perforationb,c,peritonitisb, diverticulitis, pancreatitis, enterocolitis, gastric ulcer, large intestinal ulcer,oesophagitis, ileusd, proctitisd

Rare pancreatic exocrine insufficiency; coeliac disease

Common abnormal hepatic function

Uncommon hepatic failureb,c, hepatitis, hepatomegaly, jaundice

Very common rashc, pruritusc

Common dermatitis, erythema, vitiligo, urticaria, eczemad, alopecia, night sweats, dry skin

Uncommon toxic epidermal necrolysisb,c, leukocytoclastic vasculitis, skin exfoliation, hair colourchangesd

Rare erythema multiformed, psoriasisd, Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS)d

Not known pemphigoid

Very common musculoskeletal painf

Common arthralgia, myalgia, muscle spasms, arthritis

Uncommon polymyalgia rheumatica, myositisd, muscular weaknessd

Rare polymyositisd

Common renal failureb

Uncommon glomerulonephritisc, autoimmune nephritisd, renal tubular acidosis, haematuriad, cystitisnoninfectiveg, proteinuriad

Uncommon amenorrhea

Very common fatigue, injection site reaction, pyrexia, oedema, pain

Common chills, asthenia, influenza-like illnessd

Uncommon multi-organ failureb,c, systemic inflammatory response syndromed, infusion related reaction

Common increased alanine aminotransferasec, increased aspartate aminotransferasec, increased bloodalkaline phosphatased, increased blood bilirubin, increased lipasec,

Uncommon increased gamma-glutamyltransferased, increased blood creatinine, increased blood thyroidstimulating hormone, decreased blood cortisol, decreased blood corticotrophin, increasedblood amylasec, positive antinuclear antibodyd, decreased blood testosterone

Rare decreased blood thyroid stimulating hormoned, decreased thyroxined, abnormal bloodprolactind

Adverse reaction frequencies presented in Table 6 may not be fully attributable to ipilimumab, but may contain contributionsfrom the underlying disease.a Frequencies are based on pooled data from 9 clinical trials investigating the ipilimumab 3 mg/kg dose in melanoma.b Including fatal outcome.c Additional information about these potentially inflammatory adverse reactions is provided in “Description of selectedadverse reactions” and section 4.4. Data presented in those sections primarily reflect experience from a Phase 3 study,

MDX010-20.

d Data outside the 9 completed clinical trials in melanoma were included in frequency determinations.e Post-marketing event (also see section 4.4).f Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain,musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.g Reported in clinical studies and in the post-marketing setting.h Type 1 diabetes mellitus that may be associated with diabetic ketoacidosis

Additional adverse reactions not listed in Table 6 have been reported in patients who received otherdoses (either < or > 3 mg/kg) of ipilimumab in clinical trials of melanoma. These additional reactionsoccurred at a frequency of < 1% unless otherwise noted: meningism, myocarditis, pericardial effusion,cardiomyopathy, autoimmune hepatitis, erythema nodosum, autoimmune pancreatitis,hyperpituitarism, hypoparathyroidism, infectious peritonitis, episcleritis, scleritis, Raynaud’sphenomenon, palmar-plantar erythrodysaesthesia syndrome, cytokine release syndrome, sarcoidosis,decreased blood gonadotrophin, leukopenia, polycythaemia, lymphocytosis, ocular myositis, andneurosensory hypoacusis.

The overall safety profile of ipilimumab 3 mg/kg in clinical trial CA184-169 (N = 362) was consistentwith that established for ipilimumab in patients treated for advanced melanoma.

Ipilimumab in combination with nivolumab (with or without chemotherapy) (see section 4.2)

When ipilimumab is administered in combination, refer to the SmPC for the other therapeutic agent(s)prior to initiation of treatment. For additional information on the safety profile of the other therapeuticagents used in combination with ipilimumab, please refer to the respective SmPC.

In the pooled dataset of ipilimumab administered in combination with nivolumab (with or withoutchemotherapy) across tumour types (n = 2626) with minimum follow-up ranging from 6 to 47 months,the most frequent adverse reactions (≥ 10%) were fatigue (47%), diarrhoea (35%), rash (37%), nausea(27%), pruritus (29%), musculoskeletal pain (26%), pyrexia (23%), decreased appetite (22%), cough(21%), abdominal pain (18%), vomiting (18%), constipation (18%), arthralgia (18%), dyspnoea(17%), hypothyroidism (16%), headache (15%), upper respiratory tract infection (13%), oedema(13%) and dizziness (10%). The incidence of Grade 3-5 adverse reactions was 66% for ipilimumab incombination with nivolumab (with or without chemotherapy), with 1.0% fatal adverse reactionsattributed to study drug. Among patients treated with ipilimumab 3 mg/kg in combination withnivolumab 1 mg/kg for melanoma, fatigue (62%), rash (57%), diarrhoea (52%), nausea (42%), pruritus(40%), pyrexia (36%), and headache (26%) were reported at an incidence rate ≥ 10% higher than therates reported in the pooled dataset of ipilimumab in combination with nivolumab (with or withoutchemotherapy) incidence rate. Among patients treated with ipilimumab 1 mg/kg in combination withnivolumab 360 mg and chemotherapy for NSCLC, anaemia (32%) and neutropaenia (15%) werereported at an incidence rate ≥ 10% higher than the rates reported in the pooled dataset of ipilimumabin combination with nivolumab (with or without chemotherapy) incidence rate.

b. Tabulated summary of adverse reactions

Adverse reactions reported in the pooled dataset for patients treated with ipilimumab in combinationwith nivolumab (with or without chemotherapy) (n = 2626) and from post-marketing are presented in

Table 7. These reactions are presented by system organ class and by frequency. Frequencies aredefined 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 availablepost-marketing data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Table 7: Adverse reactions with ipilimumab in combination with other therapeutic agents

Combination with nivolumab (with or without chemotherapy)

Very upper respiratory tract infectioncommon

Common pneumonia, bronchitis, conjunctivitis

Rare aseptic meningitis

Very anaemiab,i, thrombocytopaeniab, leucopoeniab, lymphopaeniab, neutropaeniabcommon

Common eosinophilia

Uncommon febrile neutropaenia

Not known haemophagocytic lymphohistiocytosis

Common infusion-related reaction (including cytokine release syndrome), hypersensitivity

Rare sarcoidosis

Not known solid organ transplant rejectionf

Very hypothyroidismcommon

Common hyperthyroidism, thyroiditis, adrenal insufficiency, hypophysitis, hypopituitarism, diabetesmellitus

Uncommon diabetic ketoacidosis

Rare hypoparathyroidism

Very decreased appetite, hyperglycaemiab, hypoglycaemiabcommon

Common dehydration, hypoalbuminaemia, hypophosphataemia, weight decreased

Uncommon metabolic acidosis

Not known tumour lysis syndromeg

Very headachecommon

Common dizziness, peripheral neuropathy

Uncommon polyneuropathy, peroneal nerve palsy, autoimmune neuropathy (including facial and abducensnerve paresis), encephalitis, myasthenia gravis

Rare Guillain-Barré syndrome, neuritis, myelitis (including transverse myelitis)

Common blurred vision, dry eye

Uncommon uveitis, episcleritis

Rare Vogt-Koyanagi-Harada syndrome, serous retinal detachment

Combination with nivolumab (with or without chemotherapy)

Common tachycardia, atrial fibrillation

Uncommon myocarditisa, arrhythmia (including ventricular arrhythmia)a, bradycardia

Not known pericardial disordersh

Common hypertension

Very cough, dyspnoeacommon

Common pneumonitisa, pulmonary embolisma, pleural effusion

Very diarrhoea, vomiting, nausea, abdominal pain, constipationcommon

Common colitisa, pancreatitis, stomatitis, gastritis, dry mouth

Uncommon duodenitis

Rare Intestinal perforationa, pancreatic exocrine insufficiency, coeliac disease

Common hepatitis

Very rashc, prurituscommon

Common alopecia, vitiligo, urticaria, dry skin, erythema

Uncommon Stevens-Johnson syndrome, erythema multiforme, psoriasis, other lichen disordersj

Rare toxic epidermal necrolysisa,d, lichen sclerosus

Very musculoskeletal paine, arthralgiacommon

Common muscle spasms, muscular weakness, arthritis

Uncommon polymyalgia rheumatica, myopathy, myositis (including polymyositis)a

Rare spondyloarthropathy, Sjogren’s syndrome, rhabdomyolysisa

Common renal failure (including acute kidney injury)a

Uncommon tubulointerstitial nephritis, nephritis

Rare cystitis noninfective

Very fatigue, pyrexia, oedema (including peripheral oedema)common

Common chest pain, pain, chills

Very increased alkaline phosphataseb, increased ASTb, increased ALTb, increased total bilirubinb,common increased creatinineb, increased amylaseb, increased lipaseb, hyponatraemiab, hyperkalaemiab,hypokalaemiab, hypercalcaemiab, hypocalcaemiab

Common hypernatraemiab, hypermagnesaemiab, increased thyroid stimulating hormone, increased gamma-glutamyltransferase

Adverse reaction frequencies presented in Table 7 may not be fully attributable to ipilimumab alone or in combination withother therapeutic agents, but may contain contributions from the underlying disease or from medicinal product used incombination.a Fatal cases have been reported in completed or ongoing clinical studiesb Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline inlaboratory measurements. See “Description of selected adverse reactions; laboratory abnormalities” below.c Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rashmacular, rash morbilliform, rash papular, rash pustular, rash papulosquamous, rash vesicular, rash generalised,exfoliative rash, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitisexfoliative, dermatitis psoriasiform, drug eruption, nodular rash, and pemphigoid.

d Reported also in studies outside the pooled dataset. The frequency is based on the programme-wide exposure.e Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain,musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, and spinal pain.f Post-marketing event (also see section 4.4).g Reported in clinical studies and in the post-marketing setting.h Pericardial disorders is a composite term which includes pericarditis, pericardial effusion, cardiac tamponade, and

Dressler’s syndrome.i Anaemia is a composite term which includes, among other causes, haemolytic anaemia and autoimmune anaemia,haemoglobin decreased, iron deficiency anaemia, and red blood cell count decreased.j Lichen disorders is a composite term which includes lichen keratosis and lichen planus.

Except where noted, data relating to ipilimumab monotherapy are based on patients who receivedeither ipilimumab 3 mg/kg monotherapy (n = 131) or ipilimumab 3 mg/kg in combination withgp100 (n = 380) in a Phase 3 study of advanced (unresectable or metastatic) melanoma (MDX010-20,see section 5.1).

Ipilimumab in combination is associated with immune-related adverse reactions. With appropriatemedical therapy, immune-related adverse reactions resolved in most cases. Permanent discontinuationof treatment generally was required in a greater proportion of patients receiving ipilimumab incombination with nivolumab than in those receiving nivolumab monotherapy. Table 8 presents thepercentage of patients with immune-related adverse reactions who were permanently discontinuedfrom treatment. Additionally, for patients who experienced an event, Table 8 presents the percentageof patients who required high-dose corticosteroids (at least 40 mg daily prednisone equivalents). Themanagement guidelines for these adverse reactions are described in section 4.4.

Table 8: Immune-related adverse reactions leading to permanent discontinuation orrequiring high-dose corticosteroids

Ipilimumab in combination with nivolumab (with or without chemotherapy)%

Immune-related adverse reaction leading to permanent discontinuation

Pneumonitis 2.1

Colitis 6

Hepatitis 5

Nephritis and renal 1.1dysfunction

Endocrinopathies 2.2

Skin 1.0

Hypersensitivity/Infusion 0.3reaction

Immune-related adverse reaction requiring high-dose corticosteroidsa,b

Pneumonitis 59

Colitis 32

Hepatitis 39

Nephritis and renal 27dysfunction

Endocrinopathies 18

Skin 8

Hypersensitivity/Infusion 18reactiona at least 40 mg daily prednisone equivalentsb frequency is based on the number of patients who experienced the immune-related adverse reaction

Immune-related gastrointestinal reactions

Ipilimumab is associated with serious immune-related gastrointestinal reactions. Fatalities due togastrointestinal perforation have been reported in < 1% of patients who received ipilimumab 3 mg/kgin combination with gp100.

In the ipilimumab 3 mg/kg monotherapy group, diarrhoea and colitis of any severity were reportedin 27% and 8%, respectively. The frequency of severe (Grade 3 or 4) diarrhoea and severe(Grade 3 or 4) colitis was 5% each. The median time to onset of severe or fatal (Grade 3 to 5)immune-related gastrointestinal reactions was 8 weeks (range 5 to 13 weeks) from the start oftreatment. With protocol-specified management guidelines, resolution (defined as improvement tomild [Grade 1] or less or to the severity at baseline) occurred in most cases (90%), with a median timefrom onset to resolution of 4 weeks (range 0.6 to 22 weeks). In clinical trials, immune-related colitiswas associated with evidence of mucosal inflammation, with or without ulcerations, and lymphocyticand neutrophilic infiltration.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of diarrhoea or colitis was 26.0% (682/2626). Grade 2, Grade 3, and Grade 4 cases werereported in 8.1% (212/2626), 6.4% (167/2626), and 0.2% (4/2626), of patients, respectively. Twopatients (< 0.1%) had a fatal outcome. Median time to onset was 1.4 months (range: 0.0-48.9).

Resolution occurred in 618 patients (91%) with a median time to resolution of 2.9 weeks(range: 0.1-170.0+). Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab1 mg/kg for melanoma, the incidence of diarrhoea or colitis was 46.7%, including Grade 2 (13.6%),

Grade 3 (15.8%), and Grade 4 (0.4%).

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of pneumonitis including interstitial lung disease, was 6.0% (157/2626). Grade 2,

Grade 3, and Grade 4 cases were reported in 3.0% (78/2626), 1.0% (27/2626), and 0.3% (8/2626) ofpatients, respectively. Four patients (0.2%) had a fatal outcome. Median time to onset was 2.7 months(range: 0.1-56.8). Resolution occurred in 129 patients (82.2%) with a median time to resolution of6.1 weeks (range: 0.1+-149.3+).

Immune-related hepatotoxicity

Ipilimumab is associated with serious immune-related hepatotoxicity. Fatal hepatic failure has beenreported in < 1% of patients who received ipilimumab 3 mg/kg monotherapy.

Increases in AST and ALT of any severity were reported in 1% and 2% of patients, respectively.

There were no reports of severe (Grade 3 or 4) AST or ALT elevation. Time to onset of moderate tosevere or fatal (Grade 2 to 5) immune-related hepatotoxicity ranged from 3 to 9 weeks from the startof treatment. With protocol-specified management guidelines, time to resolution rangedfrom 0.7 to 2 weeks. In clinical trials, liver biopsies from patients who had immune-relatedhepatotoxicity showed evidence of acute inflammation (neutrophils, lymphocytes, and macrophages).

In patients receiving ipilimumab at a higher than recommended dose in combination with dacarbazine,immune-related hepatotoxicity occurred more frequently than in patients receivingipilimumab 3 mg/kg monotherapy.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of liver function test abnormalities was 21.2% (556/2626). Grade 2, Grade 3, and

Grade 4 cases were reported in 5.0% (132/2626), 8.3% (218/2626), and 1.3% (34/2626) of patients,respectively. Seven patients (0.3%) had a fatal outcome. Median time to onset was 1.5 months(range: 0.0-36.6). Resolution occurred in 482 patients (87.0%) with a median time to resolution of5.9 weeks (range: 0.1-175.9+). Among patients treated with ipilimumab 3 mg/kg in combination withnivolumab 1 mg/kg for melanoma, the incidence of liver function test abnormalities was 30.1%,including Grade 2 (6.9%), Grade 3 (15.8%), and Grade 4 (1.8%). Among patients treated withipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg for HCC, the incidence of liver functiontest abnormalities was 34.3% including Grade 2 (8.4%), Grade 3 (14.2%), and Grade 4 (2.7%).

Ipilimumab is associated with serious skin adverse reactions that may be immune-related. Fatal toxicepidermal necrolysis (including SJS) has been reported in < 1% of patients who received ipilimumabin combination with gp100 (see section 5.1). Drug Reaction with Eosinophilia and Systemic

Symptoms (DRESS) has been rarely reported with Ipilimumab in clinical studies and during post-marketing use. Incidental cases of pemphigoid have been reported during post-marketing use.

In the ipilimumab 3 mg/kg monotherapy group, rash and pruritus of any severity were each reportedin 26% of patients. Ipilimumab-induced rash and pruritus were predominantly mild (Grade 1) ormoderate (Grade 2) and responsive to symptomatic therapy. The median time to onset of moderate tosevere or fatal (Grade 2 to 5) skin adverse reactions was 3 weeks from start of treatment(range 0.9 to 16 weeks). With protocol-specified management guidelines, resolution occurred in mostcases (87%), with a median time from onset to resolution of 5 weeks (range 0.6 to 29 weeks).

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of rash was 46.1% (1210/2626). Grade 2, Grade 3, and Grade 4 cases were reported in14.3% (375/2626), pct. 4.6% (120/2626), and 0.1% (3/2626) of patients, respectively. Median time toonset was 0.7 months (range: 0.0-33.8). Resolution occurred in 843 patients (70%) with a median timeto resolution of 12.1 weeks (range: 0.1-268.7+). Among patients treated with ipilimumab 3 mg/kg incombination with nivolumab 1 mg/kg for melanoma, the incidence of rash was 65.2%, including

Grade 2 (20.3%) and Grade 3 (7.8%).

Immune-related neurological reactions

Ipilimumab is associated with serious immune-related neurological reactions. Fatal Guillain-Barrésyndrome has been reported in < 1% of patients who received ipilimumab 3 mg/kg in combinationwith gp100. Myasthenia gravis-like symptoms have also been reported in < 1% of patients whoreceived higher doses of ipilimumab in clinical trials.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of nephritis or renal dysfunction was 5.4% (141/2626). Grade 2, Grade 3, and Grade 4cases were reported in 2.0% (52/2626), 0.8% (21/2626), and 0.4% (11/2626) of patients, respectively.

Two patients (< 0.1%) had a fatal outcome. Median time to onset was 2.6 months (range: 0.0-34.8).

Resolution occurred in 110 patients (78.0%) with a median time to resolution of 5.9 weeks(range: 0.1-172.1+).

Immune-related endocrinopathy

In the ipilimumab 3 mg/kg monotherapy group, hypopituitarism of any severity was reported in 4% ofpatients. Adrenal insufficiency, hyperthyroidism, and hypothyroidism of any severity were eachreported in 2% of patients. The frequency of severe (Grade 3 or 4) hypopituitarism was reported in 3%of patients. Time to onset of moderate to very severe (Grade 2 to 4) immune-related endocrinopathyranged from 7 to nearly 20 weeks from the start of treatment. Immune-related endocrinopathyobserved in clinical trials was generally controlled with hormone replacement therapy.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of thyroid disorders was 23.2% (608/2626). Grade 2 and Grade 3 thyroid disorders werereported in 12.7% (333/2626) and 1.0% (27/2626) of patients, respectively.

Grade 2 and Grade 3 hypophysitis (including lymphocytic hypophysitis) occurred in 1.9% (49/2626)and 1.5% (40/2626) of patients, respectively. Grade 2 and Grade 3 hypopituitarism occurred in 0.6%(16/2626) and 0.5% (13/2626) of patients, respectively. Grade 2, Grade 3, and Grade 4 adrenalinsufficiency (including secondary adrenocortical insufficiency, adrenocortical insufficiency acute,blood corticotrophin decreased and immune-mediated adrenal insufficiency) occurred in 2.7%(72/2626), 1.6% (43/2626) and 0.2% (4/2626) of patients, respectively. Grade 1, Grade 2, Grade 3,and Grade 4 diabetes mellitus (including Type 1 diabetes mellitus, and diabetic ketoacidosis) occurredin < 0.1% (1/2626), 0.3% (8/2626), 0.3% (7/2626), and 0.2% (6/2626) of patients, respectively.

Median time to onset of these endocrinopathies was 2.1 months (range: 0.0-28.1). Resolution occurredin 297 patients (40.0%). Time to resolution ranged from 0.3 to 257.1+ weeks.

Infusion reactions

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the incidence of hypersensitivity/infusion reactions was 4.5% (118/2626). Grade 1, Grade 2, Grade 3,and Grade 4 cases were reported in 1.9% (49/2626), 2.4% (62/2626), 0.2% (6/2626), and < 0.1%(1/2626) of patients, respectively. Among patients with MPM treated with ipilimumab 1 mg/kg incombination with nivolumab 3 mg/kg, the incidence of hypersensitivity/infusion reactions was 12%.

Less than 2% of patients with advanced melanoma who received ipilimumab in Phase 2 and 3 clinicaltrials developed antibodies against ipilimumab. None had any infusion-related or peri-infusionalhypersensitivity or anaphylactic reactions. Neutralising antibodies against ipilimumab were notdetected. Overall, no apparent association was observed between antibody development and adversereactions.

Of the patients who were treated with ipilimumab in combination with nivolumab and evaluable forthe presence of anti-ipilimumab antibodies, the incidence of anti-ipilimumab antibodies rangedfrom 6.3 to 13.7%. Neutralising antibodies against ipilimumab ranged from 0 to 0.4%. Of the patientswho were treated with ipilimumab in combination with nivolumab and chemotherapy and evaluablefor the presence of anti-ipilimumab antibodies or neutralising antibodies against ipilimumab, theincidence of anti-ipilimumab antibodies was 7.5% and neutralising antibodies against ipilimumabwas 1.6%. Of patients evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% with nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks,24.9% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks, 37.8% withnivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks, and 33.8% with nivolumab 360 mg every3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy. The incidence ofneutralising antibodies against nivolumab was 0.8% with nivolumab 3 mg/kg and ipilimumab 1 mg/kgevery 3 weeks, 1.5% with nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks,4.6% with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks and 2.6% with nivolumab360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy.

When administered in combination with nivolumab, the CL of ipilimumab was unchanged in thepresence of anti-ipilimumab antibodies and there was no evidence of altered toxicity profile.

In patients treated with ipilimumab in combination with nivolumab (with or without chemotherapy),the proportion of patients who experienced a worsening from baseline to a Grade 3 or 4 laboratoryabnormality was as follows: 4.8% for anaemia, 1.8% for thrombocytopaenia, 2.2% for leucopoenia,6.9% for lymphopaenia, 3.3% for neutropaenia, 2.7% for increased alkaline phosphatase, 9.8% forincreased AST, 9.3% for increased ALT, 2.3% for increased total bilirubin, 1.8% for increasedcreatinine, 1.4% for hypoalbuminaemia, 7.1% for hyperglycaemia, 0.7% for hypoglycaemia, 7.8% forincreased amylase, 16.3% for increased lipase, 0.8% for hypocalcaemia, 0.2% for hypernatraemia,0.8% for hypercalcaemia, 2.0% for hyperkalaemia, 0.8% for hypermagnesaemia, 0.4% forhypomagnesaemia, 3.0% for hypokalaemia, and 8.7% for hyponatraemia.

Among patients treated with ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg formelanoma, a higher proportion of patients experienced a worsening from baseline to a Grade 3 or 4increased ALT (15.3%).

Ipilimumab as monotherapy

No new adverse drug reactions were reported in adolescents 12 years of age and older.

In study CA184070, no immune-related adverse reactions (irAR) ≥ Grade 3 were reported for thesingle patient 12 years of age and older who was treated with ipilimumab 3 mg/kg. Two (25.0%) of8 patients treated with 5 mg/kg and 1 (11.1%) of 9 patients treated with 10 mg/kg reported

Grade 3-4 events. None of the events were fatal. The types of irARs were consistent with the adultexperience, with the most commonly reported irARs across all groups in the categories ofgastrointestinal (0 [3 mg/kg], 62.5% [5 mg/kg], and 44.4% [10 mg/kg]), hepatic function (0 [3 mg/kg],75.0% [5 mg/kg], 33.3% [10 mg/kg]), and skin (0 [3 mg/kg], 25.0% [5 mg/kg], 33.3% [10 mg/kg])events. No new or unexpected irARs were observed in this study. No differences in the spectrum ofirARs reported in adults and the paediatric population were evident.

In study CA184178, no new or unexpected irARs were observed, and the observed irARs were similarin frequency, intensity and organ site to what has been reported in adult studies. Two patients in the10 mg/kg group experienced a Grade 1 and Grade 3 on-study endocrine irAR of hyperglycemia. Noother endocrine abnormalities were reported.

A summary of adverse events in adolescents 12 years of age and older, as well as adults, is presentedin Table 9.

Table 9: Summary of adverse events after up to four doses of 3, 5 and 10 mg/kg, alltreated patients

Number of patients (%)

Age ≥ 12 to 21 years Age 12 to < 18 years Adults

Advanced melanoma and non-melanoma solid tumours Advanced melanoma Advanced melanoma

CA184004/

CA184004/ 007/008/022

CA184070 CA184178 022 pooled pooled3 mg/kg 5 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kgn = 1 n = 8 n = 9 n = 4 n = 8 n = 111 n = 325

All deaths, n (%) 1 (100.0) 4 (50.0) 2 (22.2) 2 (50.0) 3 (37.5) 26 (23.4) 71 (21.8)

Treatment-related deaths,n (%) 0 0 0 0 0 2 (1.8) 6 (1.8)

SAEs, n (%) 1 (100.0) 7 ( 87.5) 4 ( 44.4) 1 (25.0) 6 (75.0) 50 (45.0) 168 (51.7)

SAEs, drug-related, n (%) 1 (100.0) 5 ( 62.5) 4 ( 44.4) 1 (25.0) 5 (62.5) 19 (17.1) 95 (29.2)

AEs leading to study drugdiscontinuation, n (%) 0 3 ( 37.5) 2 ( 22.2) 1 (25.0) 5 (62.5) 12 (10.8) 88 (27.1)

Drug-related AEs leadingto study drug 0 3 ( 37.5) 2 ( 22.2) 1 (25.0) 5 (62.5) 9 (8.1) 61 (18.8)discontinuation, n (%)irAEs, n (%) 1 (100.0) 7 ( 87.5) 7 ( 77.8) 2 (50.0) 4 (50.0) 68 (61.3) 234 (72.0)

AE, n (%) 1 (100.0) 8 (100.0) 9 (100.0) 4 (100.0) 8 (100.0) 108 (97.3) 315 (96.9)

Drug-related AEs, n (%) 1 (100.0) 7 ( 87.5) 9 (100.0) 2 (50.0) 7 (87.5) 88 (79.3) 274 (84.3)

MedDRA v.17.0 for CA184070, v.19.0 for CA184178, and V.12.1 for adult safety pool. NA = not assessed

For adults, deaths reported in this table are within 70 days of the last dose, regardless of relationship. Deaths forpaediatric patients are those with on-study events within 30 days of the last dose, except for “all deaths,” which were>30 days after the last dose. In CA184178, deaths were reported at least 90 days of the last dose.

Attribution to ipilimumab reported as possible, probable, definite, or missing for CA184178 and adult safety pool,and related or missing for CA184070.

Abbreviations: SAEs = serious adverse events; AEs = adverse events; irAEs = immune-related adverse events

Ipilimumab in combination with nivolumab

The safety of ipilimumab (1 mg/kg every 3 weeks) in combination with nivolumab (1 mg/kg or3 mg/kg for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks) wasevaluated in 33 paediatric patients aged ≥ 1 year to < 18 years (including 20 patients 12 to < 18 years)with recurrent or refractory solid or haematological tumours, including advanced melanoma, inclinical study CA209070. The safety profile in paediatric patients was generally similar to that seen inadults treated with ipilimumab in combination with nivolumab. No new safety signals were observed.

The most common adverse reactions (reported in at least 20% of paediatric patients) for ipilimumab incombination with nivolumab were fatigue (33.3%) and rash maculo-papular (21.2%). The majority ofadverse reactions reported for ipilimumab in combination with nivolumab were of Grades 1 or 2 inseverity. Ten patients (30%) had one or more Grades 3 to 4 adverse reactions.

No new safety signals were observed in clinical study CA209908 of 74 paediatric patients withhigh-grade primary central nervous system (CNS) malignancies (see section 5.1) relative to dataavailable in adult studies across indications.

In MPM patients, there was a higher rate of serious adverse reactions and discontinuation rate due toadverse reactions in patients 75 years of age or older (68% and 35%, respectively) relative to allpatients who received ipilimumab in combination with nivolumab (54% and 28%, respectively). Datafrom dMMR or MSI-H CRC patients 75 years of age or older are limited (see section 5.1). In HCCpatients, there were higher rates of serious adverse reactions and discontinuation due to adversereactions in patients aged 75 years or older (67% and 35%, respectively) relative to all patients whoreceived ipilimumab with nivolumab (53% and 27%, respectively).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The maximum tolerated dose of ipilimumab has not been determined. In clinical trials, patientsreceived up to 20 mg/kg without apparent toxic effects.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions,and appropriate symptomatic treatment instituted.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX04.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key regulator of T-cell activity. Ipilimumab isa CTLA-4 immune checkpoint inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4pathway, increasing the number of reactive T-effector cells which mobilize to mount a direct T-cellimmune attack against tumour cells. CTLA-4 blockade can also reduce T-regulatory cell function,which may contribute to an anti-tumour immune response. Ipilimumab may selectively deplete

T-regulatory cells at the tumour site, leading to an increase in the intratumoural T-effector/

T-regulatory cell ratio which drives tumour cell death.

In patients with melanoma who received ipilimumab, the mean peripheral blood absolute lymphocytecounts (ALC) increased throughout the induction dosing period. In Phase 2 studies, this increase wasdose-dependent. In MDX010-20 (see section 5.1), ipilimumab at 3 mg/kg with or withoutgp100 increased ALC throughout the induction dosing period, but no meaningful change in ALC wasobserved in the control group of patients who received an investigational gp100 peptide vaccine alone.

In peripheral blood of patients with melanoma, a mean increase in the percent of activated HLA-DR+

CD4+ and CD8+ T cells was observed after treatment with ipilimumab, consistent with its mechanismof action. A mean increase in the percent of central memory (CCR7+ CD45RA-) CD4+ and CD8+ Tcells and a smaller, but significant, mean increase in the percent of effector memory(CCR7- CD45RA-) CD8+ T cells also was observed after treatment with ipilimumab.

Ipilimumab in combination with nivolumab

For additional information on clinical efficacy and safety associated with the dosing recommendationsof nivolumab when administered as monotherapy following combination therapy with ipilimumab,please refer to the nivolumab SmPC.

Based on modelling of dose/exposure efficacy and safety relationships, there are no clinicallysignificant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significantdifferences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks inadvanced melanoma and RCC.

Clinical trials with ipilimumab monotherapy

Overall survival (OS) advantage of ipilimumab at the recommended dose of 3 mg/kg in patients withpreviously-treated advanced (unresectable or metastatic) melanoma was demonstrated in a

Phase 3 study (MDX010-20). Patients with ocular melanoma, primary CNS melanoma, active brainmetastases, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C were not included inthe MDX010-20 clinical trial. Clinical trials excluded patients with ECOG performance status > 1 andmucosal melanoma. Patients without liver metastasis who had a baseline AST > 2.5 x ULN, patientswith liver metastasis who had a baseline AST > 5 x ULN, and patients with a baseline totalbilirubin ≥ 3 x ULN were also excluded.

For patients with a history of autoimmune disease, see also section 4.4.

MDX010-20

A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) melanomawho had previously been treated with regimens containing one or more of the following: IL-2,dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomised in a 3:1:1 ratio toreceive ipilimumab 3 mg/kg + an investigational gp100 peptide vaccine (gp100), ipilimumab 3 mg/kgmonotherapy, or gp100 alone. All patients were HLA-A2*0201 type; this HLA type supports theimmune presentation of gp100. Patients were enrolled regardless of their baseline BRAF mutationstatus. Patients received ipilimumab every 3 weeks for 4 doses as tolerated (induction therapy).

Patients with apparent tumour burden increase before completion of the induction period werecontinued on induction therapy as tolerated if they had adequate performance status. Assessment oftumour response to ipilimumab was conducted at approximately Week 12, after completion ofinduction therapy.

Additional treatment with ipilimumab (re-treatment) was offered to those who developed PD afterinitial clinical response (PR or CR) or after SD (per the modified WHO criteria) > 3 months from thefirst tumour assessment. The primary endpoint was OS in the ipilimumab+ gp100 group vs. thegp100 group. Key secondary endpoints were OS in the ipilimumab+ gp100 group vs. the ipilimumabmonotherapy group and in the ipilimumab monotherapy group vs. the gp100 group.

A total of 676 patients were randomised: 137 to the ipilimumab monotherapy group, 403 to theipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 dosesduring induction. Thirty-two patients received re-treatment: 8 in the ipilimumab monotherapygroup, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of follow-up rangedup to 55 months. Baseline characteristics were well balanced across groups. The median agewas 57 years. The majority (71-73%) of patients had M1c stage disease and 37-40% of patients had anelevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients had a history of previouslytreated brain metastases.

The ipilimumab-containing regimens demonstrated a statistically significant advantage over thegp100 control group in OS. The hazard ratio (HR) for comparison of OS between ipilimumabmonotherapy and gp100 was 0.66 (95% CI: 0.51, 0.87; p = 0.0026).

By subgroup analysis, the observed OS benefit was consistent within most of the subgroups of patients(M [metastases]-stage, prior interleukin-2, baseline LDH, age, sex, and the type and number of priortherapy). However, for women above 50 years of age, the data supporting an OS benefit of ipilimumabtreatment were limited. As the subgroups analysis includes only small numbers of patients, nodefinitive conclusions can be drawn from these data.

Median and estimated rates of OS at 1 year and 2 years are presented in Table 10.

Table 10: Overall survival in MDX010-20

Ipilimumab 3 mg/kg gp100an = 137 n = 13610 months 6 months

Median Months (95% CI)(8.0, 13.8) (5.5, 8.7)

OS at 1 year % (95% CI) 46% (37.0, 54.1) 25% (18.1, 32.9)

OS at 2 years % (95% CI) 24% (16.0, 31.5) 14% (8.0, 20.0)a gp100 peptide vaccine is an experimental control.

In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for patientswith SD and those with PD, respectively. At the time of this analysis, medians were not reached forpatients with CR or PR.

For patients who required re-treatment, the BORR was 38% (3/8 patients) in the ipilimumabmonotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as

CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of patientsin these analyses, no definitive conclusion regarding the efficacy of ipilimumab re-treatment can bedrawn.

The development or maintenance of clinical activity following ipilimumab treatment was similar withor without the use of systemic corticosteroids.

CA184-169

A Phase 3, double-blind study enrolled patients with previously treated or untreated unresectable

Stage III or Stage IV melanoma. A total of 727 patients were randomised, 362 to receive ipilimumab3 mg/kg and 365 to receive ipilimumab 10 mg/kg every 3 weeks for 4 doses. In the ipilimumab10 mg/kg group, the median OS (95% CI) was 16 months (11.63, 17.84) and in the ipilimumab3 mg/kg group the median OS (95% CI) was 12 months (9.86, 13.27). Overall survival comparedbetween Ipilimumab 10 mg/kg and 3 mg/kg groups showed HR = 0.84 (95% CI: 0.70, 0.99;

P-value = 0.04). No statistically significant difference in progression free survival (PFS) was observedbetween the 10 mg/kg and the 3 mg/kg groups. (HR 0.89 with a 95% CI of 0.76, 1.04 and log-rank test

P-value = 0.1548). BORR was similar in the 10 mg/kg and 3 mg/kg groups. BORR in the 10 mg/kggroup was 15.3% (95% CI: 11.8, 19.5) and in the 3 mg/kg group was 12.2% (95% CI: 9.0, 16.0).

Ipilimumab 10 mg/kg was associated with higher rates of adverse events compared with the 3 mg/kgdose. The frequencies of serious adverse reactions in the 10 mg/kg and 3 mg/kg groups were 37% and18%, with the 3 most common serious adverse reactions being diarrhoea (10.7% vs 5.5%), colitis(8.0% vs 3.0%), and hypophysitis (4.4% vs 1.9%). Adverse events leading to discontinuation in the10 mg/kg and 3 mg/kg groups occurred in 31% and 19% of patients, with AEs leading to death in4 and 2 patients, respectively.

At the recommended dose of 3 mg/kg median OS was similar in the subgroup of females ≥ 50 years ofage compared to the overall population (11.40 vs 11.53 months). Median OS in the subgroup withbrain metastases at baseline was 5.67 months at the recommended dose of 3 mg/kg.

Other studies with ipilimumab monotherapy

CA184332 and CA184338

OS of ipilimumab 3 mg/kg monotherapy in chemotherapy-naive patients pooled across Phase 2and 3 clinical trials (N = 78; randomised) and in treatment-naive patients in two retrospectiveobservational studies (N = 273 and N = 157) were generally consistent. In the two observationalstudies, 12.1% and 33.1% of the patients had brain metastases at the time of advanced melanomadiagnosis. Median OS and estimated 1-year, 2-year, 3-year and 4-year survival rates are presented in

Table 11. The estimated 1-year, 2-year and 3-year survival rates for chemotherapy-naive patients(N = 78) pooled across Phase 2 and 3 clinical trials were 54.1% (95% CI: 42.5 - 65.6), 31.6%(95% CI: 20.7 - 42.9) and 23.7% (95% CI: 14.3 - 34.4) respectively.

Table 11: Overall survival in observational studies

CA184338 CA184332n = 273 n = 157

Median OS (95% CI) 14 months 10 months(12.8-18.7) (7.0-12.8)

OS at 1 year % (95% CI) 59% (52.5-64.3) 44% (35.5, 51.4)

OS at 2 years % (95% CI) 39% (33.1-44.8) 26% (18.9-33.3)

OS at 3 years % (95% CI) 31% (25.5-36.7) 22% (15.5-29.2)

OS at 4 years % (95% CI) 26% (20.4-31.3) 22% (15.5-29.2)

Patients with brain metastases in study CA184332 had a median OS of 7 months (95%

CI: 5.06 - 12.81) and patients without brain metastases had a median OS of 14.1 months (95%

CI: 9.96-Not estimated).

Patients with brain metastases in study CA184338 had a median OS of 6.3 months (95%

CI: 3.2 - 12.0) and patients without brain metastases had a median OS of 17.7 months (95%

CI: 13.6 - 12.1).

Long term survival benefit of treatment with ipilimumab (at 3 mg/kg) is demonstrated through apooled analysis of OS data from clinical trials in patients with previously treated and treatment naiveadvanced melanoma (N = 965). The Kaplan-Meier OS curve revealed a plateau beginning aroundyear 3 (OS rate = 21% [95% CI: 17-24]) that extended up to 10 years in some patients (see Figure 1).

Figure 1: Overall survival with ipilimumab 3 mg/kg in pooled analysis3.0 mg/kg

Time (months)

No. at Risk3.0 mg/kg 965 429 127 73 41 29 28 12 8 4 0

Clinical trials with ipilimumab in combination with nivolumab

Randomised phase 3 study of ipilimumab in combination with nivolumab or nivolumab asmonotherapy vs. ipilimumab as monotherapy (CA209067)

The safety and efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg nivolumab3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable ormetastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). Thedifferences between the two nivolumab-containing groups were evaluated descriptively. The studyincluded adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were tohave ECOG performance status score of 0 or 1. Patients who had not received prior systemicanticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant orneoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patientswith active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastaseswere excluded from the study.

A total of 945 patients were randomised to receive ipilimumab in combination with nivolumab(n = 314), nivolumab monotherapy (n = 316), or ipilimumab monotherapy (n = 315). Patients in thecombination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm receivednivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg andnivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every2 weeks. Randomisation was stratified by PD-L1 expression (≥ 5% vs. < 5% tumour cell membraneexpression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) stagingsystem. Treatment was continued as long as clinical benefit was observed or until treatment was nolonger tolerated. Tumour assessments were conducted 12 weeks after randomisation then every6 weeks for the first year, and every 12 weeks thereafter. The primary outcome measures wereprogression-free survival and OS. ORR and the duration of response were also assessed.

Overall Survival (proportion)

Baseline characteristics were balanced across the three treatment groups. The median age was 61 years(range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance statusscore was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58%had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy.

Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1≥ 5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and36% of patients had a baseline LDH level greater than ULN at study entry. Among patients withquantifiable tumour PD-L1 expression, the distribution of patients was balanced across the threetreatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDxassay.

At primary analysis (minimum follow-up 9 months) the median PFS was 6.9 months in the nivolumabgroup as compared with 2.9 months in the ipilimumab group (HR = 0.57, 99.5% CI: 0.43, 0.76;p < 0.0001). The median PFS was 11.5 months in the ipilimumab in combination with nivolumabgroup, as compared with 2.9 months in the ipilimumab group (HR = 0.42, 99.5% CI: 0.31, 0.57;p < 0.0001).

PFS results from descriptive analysis (with minimum follow up of 90 months) are shown in Figure 2(all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour

PD-L1 1% cut off).

Figure 2: Progression-free survival (CA209067)

Progression-free survival per investigator (months)

Number of subjects at risk

Nivolumab + ipilimumab314 175 138 126 112 103 99 93 87 84 78 76 70 66 57 33 1 -

Nivolumab316 151 120 106 97 84 78 73 69 66 62 57 54 50 44 21 0 -

Ipilimumab315 78 46 34 31 28 21 18 16 15 12 11 10 9 9 7 1 -

- - -- - - Nivolumab+ipilimumab (events: 189/314), median and 95% CI: 11.50 (8.90, 20.04).

PFS rate at 12 months and 95% CI: 49% (44, 55), PFS rate at 60 months and 95% CI: 36% (32, 42), PFS rate at 90 monthsand 95% CI: 33% (27, 39) Nivolumab (events: 208/316), median and 95% CI: 6.93 (5.13, 10.18).

PFS rate at 12 months and 95% CI: 42% (36, 47), PFS rate at 60 months and 95% CI: 29% (24, 35), PFS rate at 90 monthsand 95% CI: 27% (22, 33)

- - -- - - Ipilimumab (events: 261/315), median and 95% CI: 2.86 (2.79, 3.09).

PFS rate at 12 months and 95% CI: 18% (14, 23), PFS rate at 60 months and 95% CI: 8% (5, 12), PFS rate at 90 months and95% CI: 7% (4, 11)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.35, 0.51);

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.53 (0.44, 0.64);

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.79 (0.65, 0.97)

Probability of progression-free survival

Figure 3: Progression-free survival by PD-L1 expression: 5% cut off (CA209067)

PD-L1 expression < 5%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab210 113 87 78 71 64 60 56 54 52 50 49 45 43 39 22 0 -

Nivolumab208 91 73 66 60 51 49 46 42 40 38 33 31 29 27 12 0 -

Ipilimumab202 45 26 19 18 16 14 13 11 10 7 6 5 4 4 3 0 -

- - -- - - Nivolumab+ipilimumab (events: 127/210), median and 95% CI: 11.17 (7.98, 17.51) Nivolumab (events: 139/208), median and 95% CI: 5.39 (2.96, 7.13)

- - -- - - Ipilimumab (events: 171/202), median and 95% CI: 2.79 (2.76, 3.02)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.33, 0.53)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.54 (0.43, 0.68)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.77 (0.61, 0.98)

PD-L1 expression ≥ 5%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab68 45 37 35 30 29 29 27 24 23 20 19 17 15 13 8 1 -

Nivolumab80 52 41 36 33 29 26 24 24 23 21 21 20 18 14 7 0 -

Ipilimumab75 21 14 10 10 9 5 5 5 5 5 5 5 5 5 4 1 -

- - -- - - Nivolumab+ipilimumab (events: 36/68), median and 95% CI: 22.11 (9.72, 82.07) Nivolumab (events: 48/80), median and 95% CI: 22.34 (9.46, 39.13)

- - -- - - Ipilimumab (events: 60/75), median and 95% CI: 3.94 (2.79, 4.21)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.38 (0.25, 0.58)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.43 (0.29, 0.64)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.89 (0.58, 1.35)

Probability of progression-free survival Probability of progression-free survival

Figure 4: Progression-free survival by PD-L1 expression: 1% cut off (CA209067)

PD-L1 expression < 1%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab123 65 51 46 41 38 36 33 31 29 29 28 25 24 21 13 0 -

Nivolumab117 44 35 33 30 26 24 21 19 17 15 11 11 9 9 5 0 -

Ipilimumab113 20 12 9 9 7 5 5 3 3 3 2 1 0 0 0 0 -

- - -- - - Nivolumab+ipilimumab (events: 76/123), median and 95% CI: 11.17 (6.93, 22.18) Nivolumab (events: 85/117), median and 95% CI: 2.83 (2.76, 5.62)

- - -- - - Ipilimumab (events: 94/113), median and 95% CI: 2.73 (2.66, 2.83)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.39 (0.28, 0.53)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.59 (0.44, 0.79)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.66 (0.48, 0.90)

PD-L1 expression ≥ 1%

Progression-free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab155 93 73 67 60 55 53 50 47 46 41 40 37 34 31 17 1 -

Nivolumab171 99 79 69 63 54 51 49 47 46 44 43 40 38 32 14 0 -

Ipilimumab164 46 28 20 19 18 14 13 13 12 9 9 9 9 9 7 1 -

- - -- - - Nivolumab+ipilimumab (events: 90/155), median and 95% CI: 16.13 (8.90, 45.08) Nivolumab (events: 102/171), median and 95% CI: 16.20 (8.11, 27.60)

- - -- - - Ipilimumab (events: 137/164), median and 95% CI: 3.48 (2.83, 4.17)

Nivolumab+ipilimumab vs. ipilimumab - hazard ratio and 95% CI: 0.42 (0.32, 0.55)

Nivolumab vs. ipilimumab - hazard ratio and 95% CI: 0.45 (0.35, 0.59)

Nivolumab+ipilimumab vs. nivolumab - hazard ratio and 95% CI: 0.92 (0.69, 1.22)

Probability of progression-free survival

Probability of progression-free survival

The final (primary) OS analysis occurred when all patients had a minimum follow-up of 28 months.

At 28 months, median OS was not reached in the nivolumab group as compared with 19.98 months inthe ipilimumab group (HR = 0.63, 98% CI: 0.48, 0.81; p-value: < 0.0001). Median OS was notreached in the ipilimumab in combination with nivolumab group as compared with the ipilimumabgroup (HR = 0.55, 98% CI: 0.42, 0.72; p-value: < 0.0001).

OS results at an additional descriptive analysis undertaken at a minimum follow-up of 90 monthsshow outcomes consistent with the original primary analysis. OS results from this follow-up analysisare shown in Figure 5 (all randomised), Figure 6 and 7 (at the tumour PD-L1 5% and 1% cut off).

The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemictherapy was received by 36.0%, 49.1%, and 66.3% of patients in the combination, nivolumabmonotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 19.1%, 34.2%, and 48.3%of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively.

Figure 5 Overall survival (CA209067) - Minimum follow-up of 90 months

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab314 265 227 210 199 187 179 169 163 158 156 153 147 144 141 129 7 -

Nivolumab316 266 231 201 181 171 158 145 141 137 134 130 126 123 120 107 4 -

Ipilimumab315 253 203 163 135 113 100 94 87 81 75 68 64 63 63 57 5 -

- - -- - - Nivolumab+ipilimumab (events: 162/314), median and 95% CI: 72.08 (38.18, N.A.)

OS rate and 95% CI at 12 months: 73% (68, 78), 24 months: 64% (59, 69), 36 months: 58% (52, 63), 60 months: 52% (46,57), and 90 months: 48% (42, 53) Nivolumab (events: 182/316), median and 95% CI: 36.93 months (28.25, 58.71)

OS rate and 95% CI at 12 months: 74% (69, 79), 24 months: 59% (53, 64), 36 months: 52% (46, 57), 60 months: 44% (39,50), and 90 months: 42% (36, 47)

- - -- - - Ipilimumab (events: 235/315), median and 95% CI: 19.94 months (16.85, 24.61)

OS rate and 95% CI at 12 months: 67% (61, 72), 24 months: 45% (39, 50), 36 months: 34% (29, 39), 60 months: 26% (22,31), and 90 months: 22% (18, 27)

Nivolumab+ipilimumab vs ipilimumab - HR (95% CI): 0.53 (0.44, 0.65)

Nivolumab vs ipilimumab - HR (95% CI): 0.63 (0.52, 0.77)

Nivolumab+ipilimumab vs nivolumab - HR (95% CI): 0.84 (0.68, 1.04)

Probability of overall survival

Figure 6: Overall survival by PD-L1 expression: 5% cut off (CA209067) - Minimumfollow-up of 90 months

PD-L1 expression < 5%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab210 178 146 139 130 123 116 109 106 104 102 100 98 96 96 88 6 -

Nivolumab208 169 144 123 112 108 102 92 90 88 86 84 83 80 79 70 3 -

Ipilimumab202 158 124 99 80 69 59 57 55 50 46 41 39 38 38 33 0 -

- - -- - - Nivolumab+ipilimumab (events: 109/210), median and 95% CI: 65.94 (32.72, N.A.) Nivolumab (events: 121/208), median and 95% CI: 35.94 months (23.06, 60.91)

- - -- - - Ipilimumab (events: 157/202), median and 95% CI: 18.40 months (13.70, 22.51)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.51 (0.40, 0.66)

Nivolumab vs. ipilimumab - HR (95% CI): 0.62 (0.49, 0.79)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.83 (0.64, 1.07)

PD-L1 expression ≥ 5%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab68 56 52 45 45 43 43 41 40 37 37 36 33 32 30 27 1 -

Nivolumab80 76 69 61 57 53 47 44 43 41 41 40 38 38 36 33 1 -

Ipilimumab75 66 60 46 40 34 32 29 25 24 22 20 19 19 19 18 4 -

- - -- - - Nivolumab+ipilimumab (events: 33/68), median and 95% CI: N.A. (39.06, N.A.) Nivolumab (events: 41/80), median and 95% CI: 64.28 months (33.64, N.A.)

- - -- - - Ipilimumab (events: 51/75), median and 95% CI: 28.88 months (18.10, 44.16)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.61 (0.39, 0.94)

Nivolumab vs. ipilimumab - HR (95% CI): 0.61 (0.41, 0.93)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.99 (0.63, 1.57)

Probability of overall survival Probability of overall survival

Figure 7: Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimumfollow-up of 90 months

PD-L1 expression < 1%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab123 102 82 79 74 70 65 63 62 62 62 60 59 57 56 50 5 -

Nivolumab117 86 73 62 57 53 49 43 43 42 41 41 40 38 37 33 2 -

Ipilimumab113 87 71 57 44 36 33 32 31 28 27 22 22 22 22 18 0 -

- - -- - - Nivolumab+ipilimumab (events: 66/123), median and 95% CI: 61.44 (26.45, N.A.) Nivolumab (events: 76/117), median and 95% CI: 23.46 months (13.01, 36.53)

- - -- - - Ipilimumab (events: 87/113), median and 95% CI: 18.56 months (13.67, 23.20)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.55 (0.40, 0.76)

Nivolumab vs. ipilimumab - HR (95% CI): 0.77 (0.57, 1.05)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 0.71 (0.51, 0.99)

PD-L1 expression ≥ 1%

Overall survival (months)

Number of subjects at risk

Nivolumab+ipilimumab155 132 116 105 101 96 94 87 84 79 79 77 74 72 70 65 2 -

Nivolumab171 159 140 122 112 108 100 93 90 87 86 83 81 80 78 70 2 -

Ipilimumab164 137 113 88 76 67 58 54 49 46 41 39 36 35 35 33 4 -

- - -- - - Nivolumab+ipilimumab (events: 76/155), median and 95% CI: 82.30 (39.06, N.A.) Nivolumab (events: 86/171), median and 95% CI: 85.09 months (39.00, N.A.)

- - -- - - Ipilimumab (events: 121/164), median and 95% CI: 21.49 months (16.85, 29.08)

Nivolumab+ipilimumab vs. ipilimumab - HR (95% CI): 0.52 (0.39, 0.70)

Nivolumab vs. ipilimumab - HR (95% CI): 0.52 (0.39, 0.69)

Nivolumab+ipilimumab vs. nivolumab - HR (95% CI): 1.01 (0.74, 1.37)

Probability of overall survival Probability of overall survival

Minimum follow-up for the analysis of ORR was 90 months. Responses are summarised in

Table 12.

Table 12: Objective response (CA209067)nivolumab +ipilimumab nivolumab ipilimumab(n = 314) (n = 316) (n = 315)

Objective response 183 (58%) 142 (45%) 60 (19%)(95% CI) (52.6, 63.8) (39.4, 50.6) (14.9, 23.8)

Odds ratio (vs. 6.35 3.5ipilimumab)(95% CI) (4.38, 9.22) (2.49, 5.16)

Complete response (CR) 71 (23%) 59 (19%) 19 (6%)

Partial response (PR) 112 (36%) 83 (26%) 41 (13%)

Stable disease (SD) 38 (12%) 29 (9%) 69 (22%)

Duration of response

N.A. 90.8 19.3

Median (range), months (69.1-N.A.) (45.7-N.A.) (8.8-47.4)

Proportion ≥12 months in 68% 73% 44%duration

Proportion ≥24 months in 58% 63% 30%duration

ORR (95% CI) by tumour PD-L1 expression56% (48.7, 62.5) 43% (36, 49.8) 18% (12.8, 23.8)<5% n = 210 n = 208 n = 20272% (59.9, 82.3) 59% (47.2, 69.6) 21% (12.7, 32.3)≥5% n = 68 n = 80 n = 7554% (44.4, 62.7) 36% (27.2, 45.3) 18% (11.2, 26.0)<1% n = 123 n = 117 n = 11365% (56.4, 72) 55% (47.2, 62.6) 20% (13.7, 26.4)≥1% n = 155 n = 171 n = 164

Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORRcompared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and

OS results at 28 months of follow-up were consistently demonstrated across subgroups of patientsincluding baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases,and baseline LDH level. This observation was maintained with the OS results with a minimum follow-up of 90 months.

Among 131 patients who discontinued the combination due to adverse reaction after 28 months offollow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median

OS was not reached.

Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumabregardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab andipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 12)after 90 months of follow-up, with a best overall response of complete response correlating to animproved survival rate.

After 90 months of follow-up, median durations of response for patients with tumour PD-L1expression level ≥ 5% were 78.19 months (range: 18.07-N.A.) in the combination arm, 77.21 months(range: 26.25-N.A.) in the nivolumab monotherapy arm and 31.28 months (range: 6.08-N.A.) in theipilimumab arm. At tumour PD-L1 expression < 5%, median durations of response were not reached(range: 61.93-N.A.) in the combination arm, were 90.84 months (range: 50.43-N.A.) in the nivolumabmonotherapy arm and 19.25 months (range: 5.32-47.44) in the ipilimumab monotherapy arm.

No clear cut off for PD-L1 expression can reliably be established when considering the relevantendpoints of tumour response and PFS and OS. Results from exploratory multivariate analysesidentified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH,

BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome.

Efficacy by BRAF status:

After 90 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patientsrandomised to ipilimumab in combination with nivolumab had a median PFS of 16.76 months(95% CI: 8.28, 32.0) and 11.17 months (95% CI: 7.0, 19.32), while those in the nivolumabmonotherapy arm had a median PFS of 5.62 months (95% CI: 2.79, 9.46) and 8.18 months(95% CI: 5.13, 19.55), respectively. BRAF[V600] mutation-positive and BRAF wild-type patientsrandomised to ipilimumab monotherapy had a median PFS of 3.09 months (95% CI: 2.79, 5.19) and2.83 months (95% CI: 2.76, 3.06), respectively.

After 90 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patientsrandomised to ipilimumab in combination with nivolumab had an ORR of 67.0% (95% CI: 57.0, 75.9;n = 103) and 54.0% (95% CI: 47.1, 60.9; n = 211), while those in the nivolumab monotherapy arm hadan ORR of 37.87% (95% CI: 28.2, 48.1; n = 98) and 48.2% (95% CI: 41.4, 55.0; n = 218),respectively. BRAF[V600] mutation-positive and BRAF wild-type patients randomised to ipilimumabmonotherapy had an ORR of 23.0% (95% CI: 15.2, 32.5; n = 100) and 17.2% (95% CI: 12.4, 22.9;n = 215).

After 90 months of follow-up, in BRAF [V600] mutation-positive patients median OS was not reachedin the combination arm and 45.5 months in the nivolumab monotherapy arm. Median OS for BRAF[V600] mutation-positive patients in the ipilimumab monotherapy arm was 24.6 months. In BRAFwild-type patients median OS was 39.06 months in the combination arm, 34.37 months in thenivolumab monotherapy arm, and 18.5 months in the ipilimumab monotherapy arm. The OS HRs foripilimumab in combination with nivolumab vs. nivolumab monotherapy were 0.66(95% CI: 0.44, 0.98) for BRAF[V600] mutation-positive patients and 0.95 (95% CI: 0.74, 1.22) for

BRAF wild-type patients.

Randomised phase 2 study of ipilimumab in combination with nivolumab and ipilimumab (CA209069)

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination ofnivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable ormetastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis inpatients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was61% (95% CI: 48.9, 72.4) in the combination arm (n = 72) versus 11% (95% CI: 3.0, 25.4) for theipilimumab arm (n = 37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61%(95% CI: 49, 71), respectively, for the combination (n = 73) and 53% (95% CI: 36, 68) and 44%(95% CI: 28, 60), respectively, for ipilimumab (n = 37).

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. sunitinib (CA209214)

The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg for thetreatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study(CA209214). The study included patients (18 years or older) with previously untreated, advanced ormetastatic renal cell carcinoma with a clear-cell component. The primary efficacy population includedthose intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the

International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time ofinitial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status < 80%,haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dl, plateletcount greater than the upper limit of normal, and absolute neutrophil count greater than the upper limitof normal). This study included patients regardless of their tumour PD-L1 status. Patients with

Karnofsky performance status < 70% and patients with any history of or concurrent brain metastases,active autoimmune disease, or medical conditions requiring systemic immunosuppression wereexcluded from the study. Patients were stratified by IMDC prognostic score and region.

A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk

RCC and received either ipilimumab 1 mg/kg (n = 425) administered intravenously over 30 minutes incombination with nivolumab administered intravenously over 60 minutes every 3 weeks for 4 dosesfollowed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n = 422) 50 mg daily,administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued aslong as clinical benefit was observed or until treatment was no longer tolerated. The first tumourassessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter forthe first year and then every 12 weeks until progression or treatment discontinuation, whicheveroccurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-definedprogression was permitted if the patient had a clinical benefit and was tolerating study drug asdetermined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS asdetermined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.

Baseline characteristics were generally balanced between the two groups. The median age was61 years (range: 21-85) with 38% ≥ 65 years of age and 8% ≥ 75 years of age. The majority of patientswere male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was0.4 years in both the ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg and sunitinibgroups. The median duration of treatment was 7.9 months (range: 1 day-21.4+ months) in ipilimumabwith nivolumab- treated patients and was 7.8 months (range: 1 days-20.2+ months) in sunitinib-treatedpatients. Ipilimumab with nivolumab was continued beyond progression in 29% of patients.

Efficacy results for the intermediate/poor risk patients are shown in Table 13 (primary analysis with aminimum follow-up of 17.5 months and with a minimum follow-up of 60 months) and in Figure 8(minimum follow-up of 60 months).

OS results at an additional descriptive analysis undertaken at a minimum follow-up of 60 monthsshow outcomes consistent with the original primary analysis.

Table 13: Efficacy results in intermediate/poor risk patients (CA209214)nivolumab + ipilimumab sunitinib(n = 425) (n = 422)

Primary analysisminimum follow-up: 17.5 months

Overall survival

Events 140 (33%) 188 (45%)

Hazard ratioa 0.6399.8% CI (0.44, 0.89)p-valueb, c < 0.0001

Median (95% CI) NE (28.2, NE) 25.9 (22.1, NE)

Rate (95% CI)

At 6 months 89.5 (86.1, 92.1) 86.2 (82.4, 89.1)

At 12 months 80.1 (75.9, 83.6) 72.1 (67.4, 76.2)nivolumab + ipilimumab sunitinib(n = 425) (n = 422)

Progression-free survival

Events 228 (53.6%) 228 (54.0%)

Hazard ratioa 0.8299.1% CI (0.64, 1.05)p-valueb,h 0.0331

Median (95% CI) 11.6 (8.71, 15.51) 8.4 (7.03, 10.81)

Confirmed objective response 177 (41.6%) 112 (26.5%)(BICR)(95% CI) (36.9, 46.5) (22.4, 31.0)

Difference in ORR (95% CI)d 16.0 (9.8, 22.2)p-valuee,f < 0.0001

Complete response (CR) 40 (9.4%) 5 (1.2%)

Partial response (PR) 137 (32.2%) 107 (25.4%)

Stable disease (SD) 133 (31.3%) 188 (44.5%)

Median duration of responseg

Months (range) NE (1.4+-25.5+) 18.17 (1.3+-23.6+)

Median time to response

Months (range) 2.8 (0.9-11.3) 3.0 (0.6-15.0)

Updated analysis*minimum follow-up: 60 months

Overall survival

Events 242 (57%) 282 (67%)

Hazard ratioa 0.6895% CI (0.58, 0.81)

Median (95% CI) 46.95 (35.35, 57.43) 26.64 (22.08, 33.54)

Rate (95% CI)

At 24 months 66.3 (61.5, 70.6) 52.4 (47.4, 57.1)

At 36 months 54.6 (49.7, 59.3) 43.7 (38.7, 48.5)

At 48 months 49.9 (44.9, 54.6) 35.8 (31.1, 40.5)

At 60 months 43.0 (38.1, 47.7) 31.3 (26.8, 35.9)

Progression-free survival

Events 245 (57.6%) 253 (60.0%)

Hazard ratioa 0.7395% CI (0.61, 0.87)

Median (95% CI) 11.6 (8.44, 16.63) 8.3 (7.03, 10.41)

Confirmed objective response 179 (42.1%) 113 (26.8%)(BICR)(95% CI) (37.4, 47.0) (22.6, 31.3)

Difference in ORR (95% CI)d,e 16.2 (10.0, 22.5)

Complete response (CR) 48 (11.3%) 9 (2.1%)

Partial response (PR) 131 (30.8%) 104 (24.6%)

Stable disease (SD) 131 (30.8%) 187 (44.3%)nivolumab + ipilimumab sunitinib(n = 425) (n = 422)

Median duration of responseg

Months (range) NE (50.89-NE) 19.38 (15.38-25.10)

Median time to response

Months (range) 2.8 (0.9-35.0) 3.1 (0.6-23.6)a Based on a stratified proportional hazards model.b Based on a stratified log-rank test.c p-value is compared to alpha 0.002 in order to achieve statistical significance.d Strata adjusted difference.e Based on the stratified DerSimonian-Laird test.f p-value is compared to alpha 0.001 in order to achieve statistical significance.g Computed using Kaplan-Meier method.h p-value is compared to alpha 0.009 in order to achieve statistical significance.“+” denotes a censored observation.

NE = non-estimable

* Descriptive analysis based on data cut-off: 26-Feb-2021.

Figure 8: Kaplan-Meier curves of OS in intermediate/poor risk patients (CA209214)

Minimum follow-up of 60 months

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab425 372 332 306 270 241 220 207 196 181 163 79 2 0

Sunitinib422 353 291 237 206 184 169 151 137 125 112 58 3 0 Nivolumab + ipilimumab (events: 242/425), median and 95.0% CI: 46.95 (35.35, 57.43)

- - -- - - Sunitinib (events: 282/422), median and 95.0% CI: 26.64 (22.08, 33.54)

An updated descriptive OS analysis was performed when all patients had a minimum follow-up of24 months. At the time of this analysis, the hazard ratio was 0.66 (99.8% CI 0.48-0.91) with166/425 events in the combination arm and 209/422 events in the sunitinib arm. In intermediate/poor-risk patients, OS benefit was observed in the ipilimumab in combination with nivolumab arm vs.sunitinib regardless of tumour PD-L1 expression. Median OS for tumour PD-L1 expression ≥ 1% was

Probability of survivalnot reached for ipilimumab in combination with nivolumab, and was 19.61 months in the sunitinibarm (HR = 0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 expression < 1%, the median OS was34.7 months for the ipilimumab in combination with nivolumab and was 32.2 months in the sunitinibarm (HR = 0.70; 95% CI: 0.54, 0.92).

CA209214 also randomised 249 favourable risk patients as per IMDC criteria to ipilimumab plusnivolumab (n = 125) or to sunitinib (n = 124). These patients were not evaluated as part of the primaryefficacy population. At a minimum of 24 months follow-up, OS in favourable risk patients receivingipilimumab plus nivolumab compared to sunitinib had a hazard ratio of 1.13(95% CI: 0.64, 1.99; p = 0.6710). With 60 months minimum follow-up, the HR for OS was 0.94 (95%

CI: 0.65, 1.37).

There are no data on the use of ipilimumab in combination with nivolumab in patients with only a nonclear-cell histology in first-line RCC.

Patients ≥ 75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and thecombination of ipilimumab and nivolumab showed numerically less effect on OS (HR 0.97, 95%

CI: 0.48, 1.95) in this subgroup versus the overall population at a minimum follow-up of 17.5 months.

Because of the small size of this subgroup, no definitive conclusions can be drawn from these data.

First-line treatment of non-small cell lung cancer

Randomised phase 3 study of ipilimumab in combination with nivolumab and 2 cycles of platinum-based chemotherapy vs. 4 cycles of platinum-based chemotherapy (CA2099LA)

The safety and efficacy of ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 360 mgevery 3 weeks and 2 cycles of platinum-based chemotherapy were evaluated in a phase 3, randomised,open-label study (CA2099LA). The study included patients (18 years or older) with histologicallyconfirmed non-squamous or squamous Stage IV or recurrent NSCLC (per the 7th International

Association for the Study of Lung Cancer classification), ECOG performance status 0 or 1, and noprior anticancer therapy (including EGFR and ALK inhibitors). Patients were enrolled regardless oftheir tumour PD-L1 status.

Patients with sensitising EGFR mutations or ALK translocations, active (untreated) brain metastases,carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemicimmunosuppression were excluded from the study. Patients with treated brain metastases were eligibleif neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids,or on a stable or decreasing dose of < 10 mg daily prednisone equivalents. Randomisation wasstratified by histology (squamous vs non-squamous), tumour PD-L1 expression level (≥ 1% vs < 1%),and gender (male vs female).

A total of 719 patients were randomised to receive either ipilimumab in combination with nivolumaband platinum-based chemotherapy (n = 361) or platinum-based chemotherapy (n = 358). Patients inthe ipilimumab in combination with nivolumab and platinum-based chemotherapy arm receivedipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks in combination withnivolumab 360 mg administered intravenously over 30 minutes every 3 weeks and platinum-basedchemotherapy administered every 3 weeks for 2 cycles. Patients in the chemotherapy arm receivedplatinum-based chemotherapy administered every 3 weeks for 4 cycles; non-squamous patients couldreceive optional pemetrexed maintenance therapy.

Platinum-based chemotherapy consisted of carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2; orcisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6)and paclitaxel 200 mg/m2 for squamous NSCLC.

Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

Treatment could continue beyond disease progression if the patient was clinically stable and wasconsidered to be deriving clinical benefit by the investigator. Patients who discontinued combinationtherapy because of an adverse event attributed to ipilimumab were permitted to continue nivolumabmonotherapy. Tumour assessments were performed every 6 weeks after first dose of study treatmentfor the first 12 months, then every 12 weeks until disease progression or study treatment wasdiscontinued.

CA2099LA baseline characteristics were generally balanced across all treatment groups. The medianage was 65 years (range: 26-86) with 51% ≥ 65 years of age and 10% ≥ 75 years of age. The majorityof patients were white (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or1 (68%), 57% of patients with PD-L1 ≥ 1% and 37% with PD-L1 < 1%, 31% had squamous and 69%had non-squamous histology, 17% had brain metastases, and 86% were former/current smokers. Nopatients received prior immunotherapy.

CA2099LA primary efficacy outcome measure was OS. Additional efficacy endpoints were PFS,

ORR, and duration of response as assessed by BICR.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR for patientsrandomised to ipilimumab in combination with nivolumab and platinum-based chemotherapy ascompared to platinum-based chemotherapy alone at the prespecified interim analysis when 351 eventswere observed (87% of the planned number of events for final analysis). Minimum follow-up for OSwas 8.1 months.

Efficacy results are shown in Figure 9 (updated OS analysis with a minimum follow-up of12.7 months) and Table 14 (primary analysis with a minimum follow-up of 8.1 months).

An updated efficacy analysis was performed when all patients had a minimum follow-up of12.7 months (see Figure 9). At the time of this analysis, the hazard ratio for OS was 0.66 (95% CI:0.55, 0.80) and the hazard ratio for PFS was 0.68 (95% CI: 0.57, 0.82).

Figure 9: Kaplan-Meier plot of OS (CA2099LA)

Overall Survival (Months)

Number of subjects at risk

Nivolumab + ipilimumab + chemotherapy361 326 292 250 227 153 86 33 10 1 0

Chemotherapy358 319 260 208 166 116 67 26 11 0 0 Nivolumab + ipilimumab + chemotherapy (events: 190/361), median and 95% CI: 15.64 (13.93, 19.98)

- - -- - - Chemotherapy (events: 242/358), median and 95% CI: 10.91 (9.46, 12.55)

Table 14: Efficacy results (CA2099LA)ipilimumab + nivolumab +chemotherapy chemotherapy(n = 361) (n = 358)

Overall Survival

Events 156 (43.2%) 195 (54.5%)

Hazard ratio 0.69(96.71% CI)a (0.55, 0.87)

Stratified log-rank p-valueb 0.0006

Median (months) 14.1 10.7(95% CI) (13.24, 16.16) (9.46, 12.45)

Rate (95% CI) at 6 months 80.9 (76.4,84.6) 72.3 (67.4,76.7)

Progression-free Survival

Events 232 (64.3%) 249 (69.6%)

Hazard ratio 0.70(97.48% CI)a (0.57, 0.86)

Stratified log-rank p-valuec 0.0001

Median (months)d 6.83 4.96(95% CI) (5.55, 7.66) (4.27, 5.55)

Rate (95% CI) at 6 months 51.7 (46.2, 56.8) 35.9 (30.5, 41.3)

Probabilty of Survivalipilimumab + nivolumab +chemotherapy chemotherapy(n = 361) (n = 358)

Overall Response Ratee 136 (37.7%) 90 (25.1%)(95% CI) (32.7, 42.9) (20.7, 30.0)

Stratified CMH test p-valuef 0.0003

Complete response (CR) 7 (1.9%) 3 (0.8%)

Partial response (PR) 129 (35.7%) 87 (24.3%)

Duration of Response

Median (months) 10.02 5.09(95% CI)d (8.21, 13.01) (4.34, 7.00)% with duration ≥ 6 monthsg 74 41a Based on a stratified Cox proportional hazard model.b p-value is compared with the allocated alpha of 0.0329 for this interim analysis.c p-value is compared with the allocated alpha of 0.0252 for this interim analysis.d Kaplan-Meier estimate.e Proportion with complete or partial response; CI based on the Clopper and Pearson Method.f p-value is compared with the allocated alpha of 0.025 for this interim analysis.g Based on Kaplan-Meier estimates of duration of response.

CMH = Cochran-Mantel-Haenszel

Subsequent systemic therapy was received by 28.8% and 41.1% of patients in the combination andchemotherapy arms, respectively. Subsequent immunotherapy (including anti-PD-1, anti-PD-L1, andanti-CTLA4) was received by 3.9% and 27.9% of patients in the combination and chemotherapy arms,respectively.

In study CA2099LA, subgroup descriptive analysis relative to chemotherapy, OS benefit was shownin patients treated with ipilimumab in combination with nivolumab and chemotherapy with squamoushistology (HR [95% CI] 0.65 [0.46, 0.93], n = 227) and in patients with non-squamous histology (HR[95% CI] 0.72 [0.55, 0.93], n = 492).

Table 15 summarises efficacy results of OS, PFS, and ORR by tumour PD-L1 expression in pre-specified subgroup analyses.

Table 15: Efficacy results by tumour PD-L1 expression (CA2099LA)ipilimumab ipilimumab ipilimumab ipilimumab+ + + +nivolumab chemo- chemo- chemo- chemo-+ chemo- therapy nivolumab therapy nivolumab nivolumab+ chemo- + chemo- therapy + chemo- therapytherapy therapy therapy therapy

PD-L1 < 1% PD-L1 ≥ 1% PD-L1 ≥ 1% to 49% PD-L1 ≥ 50%(n = 264) (n = 406) (n = 233) (n = 173)

OS Hazard

Ratio 0.65 0.67 0.69 0.64(95% CI)a (0.46, 0.92) (0.51, 0.89) (0.48, 0.98) (0.41, 1.02)

PFS Hazard

Ratio 0.77 0.67 0.71 0.59(95% CI)a (0.57, 1.03) (0.53, 0.85) (0.52, 0.97) (0.40, 0.86)

ORR % 31.1 20.9 41.9 27.6 37.8 24.5 48.7 30.9a Hazard ratio based on unstratified Cox proportional hazards model.

A total of 70 NSCLC patients aged ≥ 75 years were enrolled in study CA2099LA (37 patients in theipilimumab in combination with nivolumab and chemotherapy arm and 33 patients in thechemotherapy arm). A HR of 1.36 (95% CI: 0.74, 2.52) in OS and a HR of 1.12 (95% CI: 0.64, 1.96)in PFS was observed for ipilimumab in combination with nivolumab and chemotherapy vs.chemotherapy within this study subgroup. ORR was 27.0% in the ipilimumab in combination withnivolumab and chemotherapy arm and 15.2% in the chemotherapy arm. Forty-three percent of patientsaged ≥ 75 years discontinued treatment with ipilimumab in combination with nivolumab andchemotherapy. Efficacy and safety data of ipilimumab in combination with nivolumab andchemotherapy are limited in this patient population.

In a subgroup analysis, a reduced survival benefit for ipilimumab in combination with nivolumab andchemotherapy compared to chemotherapy was observed in patients who were never smokers.

However, due to the small numbers of patients, no definitive conclusions can be drawn from thesedata.

Malignant pleural mesothelioma

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. chemotherapy(CA209743)

The safety and efficacy of ipilimumab 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kgevery 2 weeks were evaluated in a phase 3, randomised, open-label study (CA209743). The studyincluded patients (18 years or older) with histologically confirmed and previously untreated malignantpleural mesothelioma of epithelioid or non-epithelioid histology, ECOG performance status 0 or 1,and no palliative radiotherapy within 14 days of first study therapy. Patients were enrolled regardlessof their tumour PD-L1 status.

Patients with primitive peritoneal, pericardial, testis, or tunica vaginalis mesothelioma, interstitial lungdisease, active autoimmune disease, medical conditions requiring systemic immunosuppression, andbrain metastasis (unless surgically resected or treated with stereotaxic radiotherapy and no evolutionwithin 3 months prior to inclusion in the study) were excluded from the trial. Randomisation wasstratified by histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and gender (male vs.female).

A total of 605 patients were randomised to receive either ipilimumab in combination with nivolumab(n = 303) or chemotherapy (n = 302). Patients in the ipilimumab in combination with nivolumab armreceived ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks in combinationwith nivolumab 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks for up to 2 years.

Patients in the chemotherapy arm received chemotherapy for up to 6 cycles (each cycle was 21 days).

Chemotherapy consisted of cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 or carboplatin 5 AUC andpemetrexed 500 mg/m2.

Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

Treatment could continue beyond disease progression if the patient was clinically stable and wasconsidered to be deriving clinical benefit by the investigator. Patients who discontinued combinationtherapy because of an adverse reaction attributed to ipilimumab were permitted to continue nivolumabmonotherapy. Tumour assessments were performed every 6 weeks after first dose of study treatmentfor the first 12 months, then every 12 weeks until disease progression or study treatment wasdiscontinued.

CA209743 baseline characteristics were generally balanced across all treatment groups. The medianage was 69 years (range: 25-89) with 72% ≥ 65 years of age and 26% ≥ 75 years of age. The majorityof patients were white (85%) and male (77%). Baseline ECOG performance status was 0 (40%) or1 (60%), 80% of patients with PD-L1 ≥ 1% and 20% with PD-L1 < 1%, 75% had epithelioid and 25%had non-epithelioid histology.

CA209743 primary efficacy outcome measure was OS. Key secondary efficacy endpoints were PFS,

ORR, and duration of response as assessed by BICR utilising modified RECIST criteria for pleuralmesothelioma. Descriptive analyses for these secondary endpoints are presented in Table 16.

The study demonstrated a statistically significant improvement in OS for patients randomised toipilimumab in combination with nivolumab as compared to chemotherapy at the prespecified interimanalysis when 419 events were observed (89% of the planned number of events for final analysis).

Minimum follow-up for OS was 22 months.

Efficacy results are shown in Figure 10 and Table 16.

Figure 10: Kaplan-Meier curves of OS (CA209743)

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab303 273 251 226 200 173 143 124 101 65 30 11 2 0

Chemotherapy302 268 233 190 162 136 113 95 62 38 20 11 1 0 Nivolumab + ipilimumab (events: 200/303), median and 95% CI: 18.07 (16.82, 21.45)

- - -- - - Chemotherapy (events: 219/302), median and 95% CI: 14.09 (12.45, 16.23)

Table 16: Efficacy results (CA209743)ipilimumab + nivolumab chemotherapy(n = 303) (n = 302)

Overall survival

Events 200 (66%) 219 (73%)

Hazard ratio 0.74(96.6% CI)a (0.60, 0.91)

Stratified log-rank p-valueb 0.002

Median (months)c 18.1 14.1(95% CI) (16.8, 21.5) (12.5, 16.2)

Rate (95% CI) at 24 monthsc 41% (35.1, 46.5) 27% (21.9, 32.4)

Progression-free survival

Events 218 (72%) 209 (69%)

Hazard ratio 1.0(95% CI)a (0.82, 1.21)

Median (months)c 6.8 7.2(95% CI) (5.6, 7.4) (6.9, 8.1)

Overall response rate 40% 43%(95% CI) (34.1, 45.4) (37.1, 48.5)

Complete response (CR) 1.7% 0

Partial response (PR) 38% 43%

Probability of survivalipilimumab + nivolumab chemotherapy(n = 303) (n = 302)

Duration of response

Median (months)c 11.0 6.7(95% CI) (8.1, 16.5) (5.3, 7.1)a Stratified Cox proportional hazard model.b p-value is compared with the allocated alpha of 0.0345 for this interim analysis.c Kaplan-Meier estimate.

Subsequent systemic therapy was received by 44.2% and 40.7% of patients in the combination andchemotherapy arms, respectively. Subsequent immunotherapy (including anti-PD-1, anti-PD-L1, andanti-CTLA-4) was received by 3.3% and 20.2% of patients in the combination and chemotherapyarms, respectively.

Table 17 summarises efficacy results of OS, PFS, and ORR by histology in prespecified subgroupanalyses.

Table 17: Efficacy results by histology (CA209743)

Epithelioid Non-epithelioid(n = 471) (n = 134)ipilimumab chemotherapy ipilimumab chemotherapy+ (n = 235) + (n = 67)nivolumab nivolumab(n = 236) (n = 67)

Overall survival

Events 157 164 43 55

Hazard ratio 0.85 0.46(95% CI)a (0.68, 1.06) (0.31, 0.70)

Median (months) 18.73 16.23 16.89 8.80(95% CI) (17.05, 21.72) (14.09, 19.15) (11.83, 25.20) (7.62, 11.76)

Rate (95% CI) at 41.2 31.8 39.5 9.724 months (34.7, 47.6) (25.7, 38.1) (27.5, 51.2) (3.8, 18.9)

Progression-free survival

Hazard ratio 1.14 0.58(95% CI)a (0.92, 1.41) (0.38, 0.90)

Median (months) 6.18 7.66 8.31 5.59(95% CI) (5.49, 7.03) (7.03, 8.31) (3.84, 11.01) (5.13, 7.16)

Overall response rate 38.6% 47.2% 43.3% 26.9%(95% CI)b (32.3, 45.1) (40.7, 53.8) (31.2, 56.0) (16.8, 39.1)

Duration of response 8.44 6.83 24.02 4.21

Median (months)(95% CI)c (7.16, 14.59) (5.59, 7.13) (8.31, N.A.) (2.79, 7.03)a Hazard ratio based on unstratified Cox proportional hazards model.b Confidence interval based on the Clopper and Pearson methodc Median computed using Kaplan-Meier method

Table 18 summarises efficacy results of OS, PFS, and ORR by baseline tumour PD-L1 expression inprespecified subgroup analyses.

Table 18: Efficacy results by tumour PD-L1 expression (CA209743)

PD-L1 < 1% PD-L1 ≥ 1%(n = 135) (n = 451)ipilimumab chemotherapy ipilimumab chemotherapy+ (n = 78) + (n = 219)nivolumab nivolumab(n = 57) (n = 232)

Overall survival

Events 40 58 150 157

Hazard ratio 0.94 0.69(95% CI)a (0.62, 1.40) (0.55, 0.87)

Median (months) 17.3 16.5 18.0 13.3(95% CI)b (10.1, 24.3) (13.4, 20.5) (16.8, 21.5) (11.6, 15.4)

Rate (95% CI) at 38.7 24.6 40.8 28.324 months (25.9, 51.3) (15.5, 35.0) (34.3, 47.2) (22.1, 34.7)

Progression-free survival

Hazard ratio 1.79 0.81(95% CI)a (1.21, 2.64) (0.64, 1.01)

Median (months) 4.1 8.3 7.0 7.1(95% CI)b (2.7, 5.6) (7.0, 11.1) (5.8, 8.5) (6.2, 7.6)

Overall response rate 21.1% 38.5% 43.5% 44.3%(95% CI)c (11.4, 33.9) (27.7, 50.2) (37.1, 50.2) (37.6, 51.1)a Hazard ratio based on unstratified Cox proportional hazards model.b Median computed using Kaplan-Meier method.c Confidence interval based on the Clopper and Pearson method.

A total of 157 MPM patients aged ≥ 75 years were enrolled in study CA209743 (78 in the ipilimumabin combination with nivolumab arm and 79 in the chemotherapy arm). A

HR of 1.02 (95% CI: 0.70, 1.48) in OS was observed for ipilimumab in combination with nivolumabvs. chemotherapy within this study subgroup. A higher rate of serious adverse reactions anddiscontinuation rate due to adverse reactions in patients 75 years of age or older relative to all patientswho received ipilimumab in combination with nivolumab was shown (see section 4.8). However, dueto the exploratory nature of this subgroup analysis, no definitive conclusions can be drawn.

dMMR or MSI-H colorectal cancer

Open-label study of nivolumab in combination with ipilimumab versus chemotherapy in dMMR or

MSI-H CRC patients naive to treatment in the metastatic setting

The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 240 mg every 3 weeks,for a maximum of 4 doses, followed by nivolumab monotherapy 480 mg every 4 weeks in the first-line treatment of unresectable or metastatic CRC with known tumour MSI-H or dMMR status wasevaluated in a randomized, multi-arm, phase 3, open-label study (CA2098HW). Study treatment armsincluded nivolumab monotherapy, nivolumab in combination with ipilimumab, or investigator’schoice of chemotherapy. MSI-H or dMMR tumour status was determined in accordance with localstandard of practice using PCR, NGS or IHC, assays. Central assessment of MSI-H status using PCR(Idylla MSI) test and dMMR status using IHC (Omnis MMR) test was conducted retrospectively onpatient tumour specimens used for local MSI-H/dMMR status determination. Patients with confirmed

MSI-H/dMMR status by either central test comprised the primary efficacy population. Patients withbrain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroidsor immunosuppressants, or had been treated with checkpoint inhibitors were excluded from the study.

Randomization was stratified by tumour location (right vs left). Patients randomized to thechemotherapy arm could receive ipilimumab plus nivolumab combination upon progression assessedby BICR.

A total of 303 previously untreated patients, in the metastatic setting, were randomised to study,including 202 patients to nivolumab in combination with ipilimumab and 101 patients tochemotherapy. Among them 255 had centrally confirmed MSI-H/dMMR status, 171 in the ipilimumabin combination with nivolumab arm and 84 in the chemotherapy arm. Patients in the ipilimumab plusnivolumab arm received ipilimumab 1 mg/kg every 3 weeks in combination with nivolumab 240 mgevery 3 weeks, for a maximum of 4 doses, followed by nivolumab monotherapy 480 mg every4 weeks. Patients in the chemotherapy arm received: mFOLFOX6 (oxaliplatin, leucovorin, andfluorouracil) with or without either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin400 mg/m2, and fluorouracil 400 mg/m2 bolus followed by fluorouracil 2400 mg/m2 over 46 hoursevery 2 weeks. Bevacizumab 5 mg/kg or cetuximab 500 mg/m2 administered prior to mFOLFOX6every 2 weeks; or FOLFIRI (irinotecan, leucovorin, and fluorouracil) with or without eitherbevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2bolus and fluorouracil 2400 mg/m2 over 46 hours every 2 weeks. Bevacizumab 5 mg/kg or cetuximab500 mg/m2 administered prior to FOLFIRI every 2 weeks. Treatment continued until diseaseprogression, unacceptable toxicity, or for ipilimumab in combination with nivolumab up to 24 months.

Patients who discontinued combination therapy because of an adverse reaction attributed toipilimumab were permitted to continue nivolumab as a single agent. Tumour assessments per

RECIST v1.1 were conducted every 6 weeks for the first 24 weeks, then every 8 weeks thereafter untilweek 96, then every 16 weeks thereafter until week 146, and then every 24 weeks.

The baseline characteristics of all randomised previously untreated for metastatic disease patientswere: the median age was 63 years (range: 21 to 87), with 46% ≥ 65 years of age and 18% ≥ 75 yearsof age; 46% were male and 86% were White. Baseline ECOG performance status was 0 (54%) and ≥ 1(46%); tumour location was right-sided or left-sided for 68% and 32% of patients, respectively; and39 patients had confirmed Lynch syndrome among the 223 patients with a known status. The baselinecharacteristics of previously untreated for metastatic disease patients with centrally confirmed

MSI-H/dMMR were consistent with all randomised previously untreated patients. Among the101 patients randomised to receive chemotherapy, 88 received chemotherapy per the protocol,including oxaliplatin-containing regimens (58%) and irinotecan-containing regimens (42%).

Additionally, 66 patients received a targeted agent, either bevacizumab (64%) or cetuximab (11%).

A primary efficacy outcome measure of the study was BICR-assessed PFS per RECIST 1.1.

Additional efficacy measures included ORR assessed by BICR, OS, and duration of response.

The study met the primary endpoint, at the planned interim analysis, demonstrating a statisticallysignificant improvement in BICR assessed-PFS for patients with centrally confirmed MSI-H/dMMRrandomized to the ipilimumab and nivolumab arm compared with chemotherapy. The BICR-assessed

PFS results are presented in Table 19 and Figure 11. At the time of this interim analysis, the otherendpoints, including the data from nivolumab monotherapy arm, were not tested, due to testinghierarchy.

Table 19: Efficacy results first-line MSI-H/dMMR centrally confirmed CRC (CA2098HW)aipilimumab + nivolumab chemotherapy(n = 171) (n = 84)

Progression-free survival

Events 48 (28%) 52 (62%)

Hazard ratio 0.2195% CI (0.14, 0.32)p-valueb < 0.0001

Median (95% CI) (months) NR (38.4, NR) 5.9 (4.4, 7.8)a Median follow-up of 31.5 months (range: 6.1 to 48.4 months).b Based on stratified 2-sided log-rank test

Figure 11: Kaplan-Meier curve of PFS in first-line patients with MSI-H/dMMR centrallyconfirmed CRC (CA2098HW)

Progression free survival (months)

Number of subjects at risk

Nivolumab + ipilimumab171 144 132 122 108 95 92 77 64 53 42 37 22 10 9 1 0

Chemotherapy84 53 29 20 10 6 5 5 3 2 0 0 0 0 0 0 0 Nivolumab + ipilimumab (events: 48/171), median and 95% CI: N.A. (38.44, N.A.)

- - -- - - Chemotherapy (events: 52/84), median and 95% CI: 5.85 (4.37, 7.79)

Open-label study of nivolumab in combination with ipilimumab in dMMR or MSI-H CRC in patientswho received prior fluoropyrimidine-based combination chemotherapy

The safety and efficacy of ipilimumab 1 mg/kg in combination with nivolumab 3 mg/kg for thetreatment of dMMR or MSI-H metastatic CRC was evaluated in a Phase 2, multi-centre, open-label,single-arm study (CA209142).

The study included patients (18 years or older) with locally determined dMMR or MSI-H status, whohad disease progression during, after, or were intolerant to, prior therapy with fluoropyrimidine andoxaliplatin or irinotecan. Patients who had their most recent prior treatment in the adjuvant settingshould have progressed on or within 6 months of completion of adjuvant chemotherapy. Patients hadan ECOG performance status score of 0 or 1 and were enrolled regardless of their tumour PD-L1status. Patients with active brain metastases, active autoimmune disease, or medical conditionsrequiring systemic immunosuppression were excluded from the study.

A total of 119 patients were treated with ipilimumab 1 mg/kg administered intravenously over90 minutes in combination with nivolumab 3 mg/kg administered intravenously over 60 minutes every3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks. Treatment wascontinued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumourassessments according to RECIST version 1.1 were conducted every 6 weeks for the first 24 weeksand every 12 weeks thereafter. The primary outcome measure was investigator-assessed ORR.

Secondary outcome measures were BICR-assessed ORR and disease control rate. Analysis of ORRincluded duration of and time to response. Exploratory outcome measures included PFS and OS.

The median age was 58 years (range: 21-88) with 32% ≥ 65 years of age and 9% ≥ 75 years of age,59% were male and 92% were white. Baseline ECOG performance status was 0 (45%) or 1 (55%),25% of patients had BRAF mutations, 37% had KRAS mutations, and 12% were unknown. Of the

Probability of progression-free survival119 treated patients, 109 had received prior fluoropyrimidine based chemotherapy in the metastaticsetting and 9 in the adjuvant setting. Before study enrolment, of the 119 treated patients, 118 (99%)had received fluorouracil, 111 (93%) had received oxaliplatin, 87 (73%) had received irinotecan aspart of prior therapies; 82 (69%) had received prior treatment with fluoropyrimidine, oxaliplatin, andirinotecan. Twenty three percent, 36%, 24%, and 16% received 1, 2, 3, or 4 or more prior therapiesrespectively, and 29% of patients had received an EGFR inhibitor.

Efficacy results (minimum follow-up 46.9 months; median follow-up 51.1 months) are shown in

Table 20.

Table 20: Efficacy results (CA209142) in dMMR or MSI-H CRC patients*ipilimumab + nivolumab(n = 119)

Confirmed objective response, n (%) 77 (64.7)(95% CI) (55.4, 73.2)

Complete response (CR), n (%) 15 (12.6)

Partial response (PR), n (%) 62 (52.1)

Stable disease (SD), n (%) 25 (21.0)

Duration of response

Median (range) months NR (1.4, 58.0+)

Median time to response

Months (range) 2.8 (1.1, 37.1)

* per investigator assessment“+” denotes a censored observation.

NR = not reached

The BICR-assessed ORR was 61.3% (95% CI: 52.0, 70.1), including CR rate of 20.2% (95% CI: 13.4,28.5), PR rate of 41.2% (95% CI: 32.2, 50.6) and stable disease reported in 22.7%. BICR assessmentswere generally consistent with the investigator assessment. Confirmed responses were observedregardless of BRAF or KRAS mutation status, and tumour PD-L1 expression levels.

Of 119 patients 11 (9.2%) patients were ≥ 75 years. The investigator assessed ORR in patients≥ 75 years was 45.5% (95% CI: 16.7, 76.6).

Oesophageal squamous cell carcinoma

Randomised phase 3 study of ipilimumab in combination with nivolumab vs. chemotherapy as first-line treatment (CA209648)

The safety and efficacy of ipilimumab in combination with nivolumab were evaluated in arandomised, active-controlled, open-label phase 3 study (CA209648). The study included adultpatients (18 years or older) with previously untreated, unresectable advanced, recurrent or metastaticoesophageal squamous cell carcinoma (OSCC). Patients were enrolled regardless of their tumour

PD-L1 status, and tumour cell PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDxassay. Patients were required to have squamous cell carcinoma or adenosquamous cell carcinoma ofoesophagus, not amenable to chemoradiation and/or surgery. Prior adjuvant, neoadjuvant, ordefinitive, chemotherapy, radiotherapy or chemoradiotherapy was permitted if given as part ofcurative intent regimen prior to trial enrolment. Patients who had a baseline performance score ≥ 2,had brain metastases that were symptomatic, had active autoimmune disease, used systemiccorticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparentinvasion of tumour to organs adjacent to the oesophageal tumour were excluded from the study.

Randomisation was stratified by tumour cell PD-L1 status (≥ 1% vs. < 1% or indeterminate), region(East Asia vs. rest of Asia vs. rest of world), ECOG performance status (0 vs. 1), and number oforgans with metastases (≤1 vs. ≥2).

A total of 649 patients were randomised to receive either ipilimumab in combination with nivolumab(n = 325), or chemotherapy (n = 324), respectively. Of these, 315 patients had tumour cell PD-L1expression ≥ 1%,158 in the ipilimumab plus nivolumab arm and 157 in the chemotherapy arm.

Patients in the ipilimumab plus nivolumab arm received ipilimumab 1 mg/kg every 6 weeks incombination with nivolumab 3 mg/kg every 2 weeks. Patients in the chemotherapy arm receivedfluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2intravenously on day 1 (of a 4-week cycle). Treatment continued until disease progression,unacceptable toxicity, or up to 24 months. Patients who discontinued combination therapy because ofan adverse reaction attributed to ipilimumab were permitted to continue nivolumab as a single agent.

Baseline characteristics were generally balanced across treatment groups. In patients with tumour cell

PD-L1 expression ≥ 1%, the median age was 63 years (range: 26-85), 8.2% were ≥ 75 years of age,81.8% were male, 73.1% were Asian, and 23.3% were white. Patients had histological confirmation ofsquamous cell carcinoma (98.9%) or adenosquamous cell carcinoma (1.1%) in the oesophagus.

Baseline ECOG performance status was 0 (45.2%) or 1 (54.8%).

The primary efficacy outcome measures were PFS (by BICR) and OS assessed in patients with tumourcell PD-L1expression ≥ 1%. Secondary endpoints per the pre-specified hierarchical testing included

OS, PFS (by BICR), and ORR (by BICR) in all randomised patients. The tumour assessments per

RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeksthereafter.

At the primary pre-specified analysis, with a minimum follow-up of 13.1 months, the studydemonstrated a statistically significant improvement in OS in patients with tumour cell PD-L1expression ≥ 1%. Efficacy results are shown in Table 21.

Table 21: Efficacy results in patients with tumour cell PD-L1 ≥ 1% (CA209648)ipilimumab + nivolumab chemotherapya(n = 158) (n = 157)

Overall survival

Events 106 (67.1%) 121 (77.1%)

Hazard ratio (98.6% CI)b 0.64 (0.46, 0.90)p-valuec 0.0010

Median (95% CI) (months)d 13.70 (11.24, 17.02) 9.07 (7.69, 9.95)

Rate (95% CI) at 12 monthsd 57.1 (49.0, 64.4) 37.1 (29.2, 44.9)

Progression-free survivale

Events 123 (77.8%) 100 (63.7%)

Hazard ratio (98.5% CI)b 1.02 (0.73, 1.43)p-valuec 0.8958

Median (95% CI) (months)d 4.04 (2.40, 4.93) 4.44 (2.89, 5.82)

Rate (95% CI) at 12 monthsd 26.4 (19.5, 33.9) 10.5 (4.7, 18.8)

Overall response rate, n (%)e 56 (35.4) 31 (19.7)(95% CI) (28.0, 43.4) (13.8, 26.8)

Complete response 28 (17.7) 8 (5.1)

Partial response 28 (17.7) 23 (14.6)

Duration of responsee

Median (95% CI) (months)d 11.83 (7.10, 27.43) 5.68 (4.40, 8.67)

Range 1.4+, 34.5+ 1.4+, 31.8+a Fluorouracil and cisplatin.b Based on stratified Cox proportional hazard model.c Based on stratified 2-sided log-rank test.d Based on Kaplan-Meier estimates.e Assessed by BICR.

At an updated descriptive analysis with a minimum follow-up of 20 months, OS improvements wereconsistent with the primary analysis. Median OS was 13.70 months (95% CI: 11.24, 17.41) foripilimumab plus nivolumab vs. 9.07 months (95% CI: 7.69, 10.02) for chemotherapy (HR = 0.63;95% CI: 0.49, 0.82). Median PFS was 4.04 months (95% CI: 2.40, 4.93) for ipilimumab plusnivolumab vs. 4.44 months (95% CI: 2.89, 5.82) for chemotherapy (HR = 1.02; 95% CI: 0.77, 1.34).

The ORR was 35.4% (95% CI: 28.0, 43.4) for ipilimumab plus nivolumab vs. 19.7% (95% CI:13.8, 26.8) for chemotherapy.

The Kaplan-Meier curves for OS with a minimum follow-up of 20 months are shown in Figure 12.

Figure 12: Kaplan-Meier curves of OS in patients with tumour cell PD-L1 ≥ 1% (CA209648)

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab158 136 116 98 89 72 63 55 43 31 20 16 10 9 4 2 0

Chemotherapy157 137 107 73 53 40 30 21 15 12 8 6 3 2 1 0 0 Nivolumab + ipilimumab (events: 119/158), median and 95% CI: 13.70 (11.24, 17.41)

- - -- - - Chemotherapy (events: 130/157), median and 95% CI: 9.07 (7.69, 10.02)

Based on data cut-off: 23-Aug-2021, minimum follow-up of 20 months

Hepatocellular carcinoma

The safety and efficacy of ipilimumab 3 mg/kg in combination with nivolumab 1 mg/kg every3 weeks, for a maximum of 4 doses, followed by nivolumab monotherapy 480 mg every 4 weeks inthe first-line treatment of unresectable or advanced hepatocellular carcinoma (HCC) were evaluated ina phase 3, randomised, active-controlled, open-label study (CA2099DW). The study included adultpatients (18 years or older) with histologically confirmed HCC, Child Pugh Class A, ECOGperformance status 0 or 1, and no prior systemic therapy for advanced disease.

Esophagogastroduodenoscopy was not mandated prior to enrolment. The study enrolled adults whosedisease was not amenable to or progressed after surgical and/or locoregional therapies. Priorneo-adjuvant or adjuvant systemic therapy was permitted. Patients with active autoimmune disease,brain or leptomeningeal metastases, prior liver transplant, a history of hepatic encephalopathy (within12 months of randomisation), clinically significant ascites, medical conditions requiring systemicimmunosuppression, infection with HIV, or active co infection with hepatitis B virus (HBV) and

Probability of survivalhepatitis C virus (HCV) or HBV and hepatitis D virus (HDV) were excluded from the study.

Randomisation was stratified by aetiology (HBV vs. HCV vs. non-viral), macrovascular invasionand/or extrahepatic spread (present or absent), and alpha-fetoprotein levels (≥ 400 or < 400 ng/ml).

A total of 668 patients were randomised to receive ipilimumab in combination with nivolumab(n = 335) or investigator’s choice (n = 333) of lenvatinib or sorafenib. In the investigator arm, 85%and 15% of treated patients received lenvatinib or sorafenib, respectively. Patients in the ipilimumabplus nivolumab arm received ipilimumab 3 mg/kg every 3 weeks in combination with nivolumab1 mg/kg every 3 weeks, for up to a maximum of 4 doses, followed by nivolumab monotherapy 480 mgevery 4 weeks. Patients in the investigators’ choice arm received either lenvatinib 8 mg orally daily (ifbody weight < 60 kg) or 12 mg orally daily (if body weight ≥ 60 kg), or sorafenib 400 mg orally twicedaily. Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

Patients who discontinued combination therapy because of an adverse reaction attributed toipilimumab were permitted to continue nivolumab as a single agent. Tumour assessments wereconducted at baseline, after randomisation at week 9 and week 16, then every 8 weeks up to 48 weeks,and then every 12 weeks thereafter until disease progression, treatment discontinuation, or initiation ofsubsequent therapy.

Baseline characteristics were generally balanced across treatment groups. The median age was66 years (range: 20 to 89), with 53% ≥ 65 years and 16% ≥ 75 years, 53% were White, 44% were

Asian, 2.2% were Black, and 82% were male. Baseline ECOG performance status was 0 (71%) or1 (29%). Thirty-four percent (34%) of patients had HBV infection, 28% had HCV infection, and 36%had no evidence of HBV or HCV infection. Nineteen percent (19%) of patients had alcoholic liverdisease and 11% had non-alcoholic fatty liver disease. The majority of patients had BCLC stage C(73%) disease at baseline, 19% had stage B, and 6% had stage A. Patients with Child-Pugh scores of5, 6, and ≥ 7 were 77%, 20%, and 3%, respectively. A total of 54% of patients had extrahepaticspread; 25% had macrovascular invasion; and 33% had AFP levels ≥ 400 µg/l.

The study demonstrated a statistically significant benefit in OS and ORR for patients randomised toipilimumab in combination with nivolumab compared to investigator’s choice of lenvatinib orsorafenib. Efficacy results are presented in Table 22 and Figure 13.

Table 22: Efficacy results in first-line HCC (CA2099DW)aipilimumab + nivolumab lenvatinib or sorafenib(n = 335) (n = 333)

Overall survival

Events 194 (58%) 228 (68%)

Median (months) 23.7 20.6(95% CI) (18.8, 29.4) (17.5, 22.5)

Hazard ratio (95% CI)b 0.79 (0.65, 0.96)p-valuec 0.0180

Overall Response Rate, n (%)d 121 (36.1) 44 (13.2)(95% CI) (31.0, 41.5) (9.8, 17.3)p-valuee <0.0001

Complete response (%) 23 (6.9) 6 (1.8)

Partial response (%) 98 (29.3) 38 (11.4)

Duration of Response (months)d

Median 30.4 12.9(95% CI) (21.2, N.A.) (10.2, 31.2)a Minimum follow-up of 26.8 months. Median follow up of 35.2 months.b Based on stratified Cox proportional hazard model.c Based on a 2-sided stratified log-rank test. Boundary for statistical significance: p-value ≤ 0.0257.d Assessed by BICR using RECIST 1.1.e Based on a 2-sided stratified Cochran-Mantel-Haenszel test. Boundary for statistical significance: p-value ≤ 0.025.

Figure 13: Kaplan-Meier curve of OS in first-line patients with HCC (CA2099DW)

Overall survival (months)

Number of subjects at risk

Nivolumab + ipilimumab335 300 264 239 220 206 179 162 150 137 104 71 42 24 11 8 0 0

Investigator’s choice333 310 280 245 216 194 164 144 116 106 76 44 34 20 4 3 1 0--+---- Nivolumab + ipilimumab (events: 194/335), median and 95% CI: 23.66 (18.33, 29.44)

- - -+- - - Lenvatinib or sorafenib (events: 228/333), median and 95% CI: 20.63 (17.48, 22.54)

Ipilimumab as monotherapy

Study CA184070 was a multi-centre, Phase 1, open-label, dose-escalation study of ipilimumab inpaediatric patients ≥ 1 year to ≤ 21 years of age with measurable/evaluable, untreatable, relapsed orrefractory solid malignant tumours without a curative option with standard therapy. The study enrolled13 patients < 12 of age and 20 patients ≥ 12 years of age. Ipilimumab was administered every 3 weeksfor 4 doses and then every 12 weeks thereafter in the absence of dose limiting toxicity (DLT) anddisease progression. The primary endpoints were safety and pharmacokinetics (PK). Of patients12 years of age and older with advanced melanoma, ipilimumab 5 mg/kg was administered to threepatients and ipilimumab 10 mg/kg was administered to two patients. Stable disease was achieved intwo patients at the ipilimumab 5 mg/kg dose, one with a duration of > 22 months.

Study CA184178 was a non-randomised, multicenter, open-label Phase 2 study, in adolescent patients12 to < 18 years of age with previously treated or untreated, unresectable Stage III or Stage IVmalignant melanoma. Ipilimumab was administered every 3 weeks for 4 doses. The primary efficacyendpoint was 1-year survival rate. Secondary efficacy endpoints of best overall response rate (BORR),stable disease (SD), disease control rate (DCR), and progression free survival (PFS) were based onmWHO criteria and determined by the investigator’s assessment. Overall survival (OS) was alsoevaluated. Tumour assessment was performed at Week 12. All patients were followed for at least1 year. Ipilimumab 3 mg/kg was administered to four patients and ipilimumab 10 mg/kg wasadministered to eight patients. Most patients were male (58%) and white (92%). Median age was15 years. Stable disease was achieved for 260 days in one patient on ipilimumab 3 mg/kg andapproximately 14 months in one patient on ipilimumab 10 mg/kg. Two patients treated with

Probability of overall survivalipilimumab 10 mg/kg experienced a partial response, one of which was a durable response for morethan 1 year. Additional efficacy results are presented in Table 23.

Table 23: Efficacy results in CA184178

Ipilimumab 3 mg/kg Ipilimumab 10 mg/kg

N = 4 N = 81-year OS (%) (95% CI) 75% (12.8, 96.1) 62.5% (22.9, 86.1)

BORR (%) (95% CI) 0% (0, 60.2) 25% (3.2, 65.1)

SD (n/N)a 1/4 1/8

DCR (%) (95% CI) 25% (0.6, 80.6) 37.5% (8.5, 75.5)

Median PFS (months) (95% CI) 2.6 (2.3, 8.5) 2.9 (0.7,NEa)

Median OS (months) (95% CI) 18.2 (8.9, 18.2) Not reached (5.2, NE)a NE = not estimable

Ipilimumab in combination with nivolumab

Study CA209070 was an open-label, single-arm, dose-confirmation and dose-expansion, phase 1/2study of nivolumab as a single agent and in combination with ipilimumab in paediatric and youngadult patients with recurrent or refractory solid or haematological tumours, including neuroblastoma,osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, advanced melanoma, cHL and non-Hodgkinlymphoma (NHL). Among the 126 treated patients, 97 were paediatric patients from 12 months to< 18 years of age. Of the 97 paediatric patients, 64 were treated with nivolumab monotherapy(3 mg/kg administered intravenously over 60 minutes every 2 weeks) and 33 were treated withipilimumab in combination with nivolumab (nivolumab 1 mg/kg or 3 mg/kg administeredintravenously over 60 minutes in combination with ipilimumab 1 mg/kg administered intravenouslyover 90 minutes every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapyevery 2 weeks). Patients received either nivolumab as monotherapy for a median of 2 doses(range: 1, 89) or ipilimumab in combination with nivolumab for a median of 2 doses (range: 1, 24).

The main primary outcome measures were safety, tolerability and antitumour activity as evaluated bydescriptive ORR and OS.

Among the 64 paediatric patients treated with nivolumab monotherapy, 60 were response-evaluablepatients (melanoma n = 1, solid tumours n = 47 and haematological tumours n = 12). In the48 response-evaluable paediatric patients with melanoma or solid tumours, no objective responseswere observed. In the 12 response-evaluable paediatric patients with haematological tumours, ORRwas 25.0% (95% CI: 5.5, 57.2), including 1 complete response in cHL and 2 partial responses, one incHL and another one in NHL. In the descriptive analyses for the 64 paediatric patients treated withnivolumab monotherapy, the median OS was 6.67 months (95% CI: 5.98, NA); 6.14 months(95% CI: 5.39, 24.67) for patients with melanoma or solid tumours, and not reached for patients withhaematological tumours.

Among the 30 response-evaluable paediatric patients treated with ipilimumab in combination withnivolumab (solid tumours other than melanoma only), no objective responses were observed. For the33 paediatric patients treated with ipilimumab in combination with nivolumab, the median OS was8.25 months (95% CI: 5.45, 16.95) in a descriptive analyses.

Study CA209908 was an open-label, sequential-arm, phase 1b/2 clinical study of nivolumabmonotherapy and ipilimumab in combination with nivolumab in paediatric and young adult patientswith high-grade primary CNS malignancies, including diffuse intrinsic pontine glioma (DIPG),high-grade glioma, medulloblastoma, ependymoma and other recurrent subtypes of high-grade CNSmalignancy (e.g., pineoblastoma, atypical teratoid/rhabdoid tumour, and embryonal CNS tumours). Ofthe 151 paediatric patients (from ≥ 6 months to < 18 years old) enrolled in the study, 77 were treatedwith nivolumab monotherapy (3 mg/kg every 2 weeks) and 74 were treated with ipilimumab 1 mg/kgin combination with nivolumab 3 mg/kg, every 3 weeks for 4 doses, followed by nivolumabmonotherapy 3 mg/kg every 2 weeks. The primary efficacy outcome measures were OS in the DIPGcohort and investigator-assessed PFS, based on RANO criteria, for all other tumour types. The median

OS in the DIPG cohort was 10.97 months (80% CI: 9.92, 12.16) in patients treated with nivolumabmonotherapy and 10.50 months (80% CI: 9.10, 12.32) in patients treated with ipilimumab incombination with nivolumab. For all other studied CNS paediatric tumour types, the median PFSranged from 1.23 to 2.35 months in patients treated with nivolumab monotherapy and from 1.45 to3.09 months in patients treated with ipilimumab in combination with nivolumab. There were noobjective responses observed in the study with the exception of one ependymoma patient treated withnivolumab monotherapy who had a partial response. Results for OS, PFS, and ORR observed in study

CA209908 do not suggest clinically meaningful improvement over what is expected in these patientpopulations.

The pharmacokinetics of ipilimumab was studied in 785 patients with advanced melanoma whoreceived induction doses ranging from 0.3 to 10 mg/kg administered once every 3 weeks for 4 doses.

Cmax, Cmin and AUC of ipilimumab were found to be dose proportional within the dose rangeexamined. Upon repeated dosing of ipilimumab administered every 3 weeks, CL was found to betime-invariant, and minimal systemic accumulation was observed as evident by an accumulationindex 1.5 fold or less. Ipilimumab steady-state was reached by the third dose. Based on populationpharmacokinetic analysis, the following mean (percent coefficient of variation) parameters ofipilimumab were obtained: terminal half-life of 15.4 days (34.4%); systemic CL of 16.8 ml/h (38.1%);and volume of distribution at steady-state of 7.47 l (10.1%). The mean (percent coefficient ofvariation) ipilimumab Cmin achieved at steady-state with a 3 mg/kg induction regimen was 19.4 µg/ml(74.6%).

Ipilimumab CL increased with increasing body weight and with increasing LDH at baseline; however,no dose adjustment is required for elevated LDH or body weight after administration on a mg/kg basis.

CL was not affected by age (range 23-88 years), gender, concomitant use of budesonide ordacarbazine, performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment,immunogenicity, and previous anticancer therapy. The effect of race was not examined as there wasinsufficient data in non-Caucasian ethnic groups. No controlled studies have been conducted toevaluate the pharmacokinetics of ipilimumab in the paediatric population or in patients with hepatic orrenal impairment.

Based on an exposure-response analysis in 497 patients with advanced melanoma, OS wasindependent of prior systemic anti-cancer therapy and increased with higher ipilimumab Cminssplasma concentrations.

YERVOY in combination with nivolumab: When ipilimumab 1 mg/kg was administered in combinationwith nivolumab 3 mg/kg, the CL of ipilimumab was decreased by 1.5% and the CL of nivolumab wasincreased by 1% which were not considered clinically relevant. When ipilimumab 3 mg/kg wasadministered in combination with nivolumab 1 mg/kg, the CL of ipilimumab was increased by 9% andthe CL of nivolumab was increased by 29%, which was not considered clinically relevant.

When administered in combination with nivolumab, the CL of ipilimumab increased by 5.7% in thepresence of anti-ipilimumab antibodies and the CL of nivolumab increased by 20% in the presence ofpresence of anti-nivolumab antibodies. These changes were not considered clinically relevant.

YERVOY in combination with nivolumab and chemotherapy: When ipilimumab 1 mg/kg every6 weeks was administered in combination with nivolumab 360 mg every 3 weeks and with 2 cycles ofchemotherapy, the CL of ipilimumab increased approximately 22% and the CL of nivolumabdecreased approximately 10%, which was not considered clinically relevant.

In the population pharmacokinetic analysis of data from clinical studies in patients with metastaticmelanoma, pre-existing mild and moderate renal impairment did not influence the CL of ipilimumab.

Clinical and pharmacokinetic data with pre-existing severe renal impairment are limited; the potentialneed for dose adjustment cannot be determined.

In the population pharmacokinetic analysis of data from clinical studies in patients with metastaticmelanoma, pre-existing mild hepatic impairment did not influence the CL of ipilimumab. Clinical andpharmacokinetic data with pre-existing moderate hepatic impairment are limited; the potential need fordose adjustment cannot be determined. No patients with pre-existing severe hepatic impairment wereidentified in clinical studies.

For ipilimumab monotherapy, based on a population PK analysis using available pooled data from565 patients from 4 phase 2 adult studies (N = 521) and 2 paediatric studies (N = 44), CL ofipilimumab increased with increasing baseline body weight. Age (2-87 years) had no clinicallyimportant effect on the CL of ipilimumab. The estimated geometric mean CL is 8.72 ml/h inadolescent patients aged ≥ 12 to < 18 years. Exposures in adolescents are comparable with those inadults receiving the same mg/kg dose. Based on the simulation in adults and paediatrics, comparableexposure is achieved in adults and paediatrics at the recommended dose of 3 mg/kg every 3 weeks.

For ipilimumab in combination with nivolumab, the exposures of ipilimumab and nivolumab inpaediatric patients 12 years of age and older are expected to be comparable to that in adult patients atthe recommended dose.

In intravenous repeat-dose toxicology studies in monkeys, ipilimumab was generally well tolerated.

Immune-mediated adverse reactions were observed infrequently (~3%) and included colitis (whichresulted in a single fatality), dermatitis, and infusion reaction (possibly due to acute cytokine releaseresulting from a rapid injection rate). A decrease in the weight of the thyroid and testes was seen inone study without accompanying histopathologic findings; the clinical relevance of this finding isunknown.

The effects of ipilimumab on prenatal and postnatal development were investigated in a study incynomolgus monkeys. Pregnant monkeys received ipilimumab every 3 weeks from the onset oforganogenesis in the first trimester through delivery, at exposure (AUC) levels either similar to orhigher than those associated with the clinical dose of 3 mg/kg of ipilimumab. No treatment-relatedadverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginningin the third trimester, both ipilimumab groups experienced higher incidences of abortion, stillbirth,premature delivery (with corresponding lower birth weight), and infant mortality relative to controlanimals; these findings were dose-dependent. Additionally, developmental external or visceralabnormalities were identified in the urogenital system of 2 infants exposed in utero to ipilimumab.

One female infant had unilateral renal agenesis of the left kidney and ureter, and one male infant hadan imperforate urethra with associated urinary obstruction and subcutaneous scrotal oedema. Therelationship of these malformations to treatment is unclear.

Studies to evaluate the mutagenic and carcinogenic potential of ipilimumab have not been performed.

Fertility studies have not been performed.

Tris hydrochloride (2-amino-2-hydroxymethyl-1,3-propanediol hydrochloride)

Sodium chloride

Mannitol (E421)

Pentetic acid (diethylenetriaminepentaacetic acid)

Polysorbate 80

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

Water for injections

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

Unopened vial3 years

From a microbiological point of view, once opened, the medicinal product should be infused or dilutedand infused immediately. The chemical and physical in-use stability of the undiluted or dilutedconcentrate (between 1 and 4 mg/ml) has been demonstrated for 24 hrs at 25°C and 2°C to 8°C. If notused immediately, the infusion solution (undiluted or diluted) may be stored for up to 24 hours in arefrigerator (2°C to 8°C) or at room temperature (20°C to 25°C).

Store in a refrigerator (2°C-8°C).

Do not freeze.

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

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

10 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal(aluminium). Pack size of 1.40 ml of concentrate in a vial (Type I glass) with a stopper (coated butyl rubber) and a flip-off seal(aluminium). Pack size of 1.

Not all pack sizes may be marketed.

Preparation should be performed by trained personnel in accordance with good practices rules,especially with respect to asepsis.

Calculating the dose:

Ipilimumab monotherapy or ipilimumab in combination with nivolumab:

The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the totaldose to be given. More than one vial of YERVOY concentrate may be needed to give the total dose forthe patient.

 Each 10 ml vial of YERVOY concentrate provides 50 mg of ipilimumab; each 40 ml vialprovides 200 mg of ipilimumab. The total ipilimumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg. The volume of YERVOY concentrate to prepare the dose (ml) = the total dose in mg, dividedby 5 (the YERVOY concentrate strength is 5 mg/ml).

Preparing the infusion:

Take care to ensure aseptic handling when you prepare the infusion.

YERVOY can be used for intravenous administration either: without dilution, after transfer to an infusion container using an appropriate sterile syringe;or after diluting to up to 5 times the original volume of concentrate (up to 4 parts of diluentto 1 part of concentrate). The final concentration should range from 1 to 4 mg/ml. To dilute the

YERVOY concentrate, you can use either: sodium chloride 9 mg/ml (0.9%) solution for injection; or 50 mg/ml (5%) glucose solution for injection

STEP 1 Allow the appropriate number of vials of YERVOY to stand at room temperature forapproximately 5 minutes. Inspect the YERVOY concentrate for particulate matter or discoloration. YERVOY concentrateis a clear to slightly opalescent, colourless to pale yellow liquid that may contain light (few)particulates. Do not use if unusual amount of particles and signs of discoloration are present.

 Withdraw the required volume of YERVOY concentrate using an appropriate sterile syringe.

STEP 2 Transfer the concentrate into a sterile, evacuated glass bottle or intravenous bag (PVC ornon-PVC). If applicable, dilute with the required volume of sodium chloride 9 mg/ml (0.9%) solution forinjection or 50 mg/ml (5%) glucose solution for injection. For ease of preparation, theconcentrate can also be transferred directly into a pre-filled bag containing the appropriatevolume of sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucosesolution for injection. Gently mix the infusion by manual rotation.

The YERVOY infusion must not be administered as an intravenous push or bolus injection.

Administer the YERVOY infusion intravenously over a period of 30 minutes.

The YERVOY infusion should not be infused at the same time in the same intravenous line with otheragents. Use a separate infusion line for the infusion.

Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore sizeof 0.2 μm to 1.2 μm).

The YERVOY infusion is compatible with: PVC infusion sets Polyethersulfone (0.2 μm to 1.2 μm) and nylon (0.2 μm) in-line filters

Flush the line with sodium chloride 9 mg/ml (0.9%) solution for injection or 50 mg/ml (5%) glucosesolution for injection at the end of the infusion.

Any unused medicinal product or waste material should be discarded in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/11/698/001-002

Date of first authorisation: 13 July 2011

Date of latest renewal: 21 April 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.