Leaflet BAVENCIO 20mg / ml concentrate for solution for infusion

Bavencio 20 mg/mL concentrate for solution for infusion

Each mL of concentrate contains 20 mg of avelumab.

One vial of 10 mL contains 200 mg of avelumab.

Avelumab is a human monoclonal IgG1 antibody directed against the immunomodulatory cell surfaceligand protein PD-L1 and produced in Chinese hamster ovary cells by recombinant DNA technology.

This medicinal product contains 5 mg of polysorbate 20 per vial.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless to slightly yellow solution. The solution pH is in the range of 5.0 - 5.6 and theosmolality is between 285 and 350 mOsm/kg.

Bavencio is indicated as monotherapy for the treatment of adult patients with metastatic Merkel cellcarcinoma (MCC).

Bavencio is indicated as monotherapy for the first-line maintenance treatment of adult patients withlocally advanced or metastatic urothelial carcinoma (UC) who are progression-free followingplatinum-based chemotherapy.

Bavencio in combination with axitinib is indicated for the first-line treatment of adult patients withadvanced renal cell carcinoma (RCC) (see section 5.1).

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

The recommended dose of Bavencio as monotherapy is 800 mg administered intravenously over60 minutes every 2 weeks.

Administration of Bavencio should continue according to the recommended schedule until diseaseprogression or unacceptable toxicity.

The recommended dose of Bavencio in combination with axitinib is 800 mg administeredintravenously over 60 minutes every 2 weeks, and axitinib 5 mg orally taken twice daily (12 hoursapart) with or without food until disease progression or unacceptable toxicity.

For information on the posology of axitinib, please refer to the axitinib product information.

Premedication

Patients have to be premedicated with an antihistamine and with paracetamol prior to the first4 infusions of Bavencio. If the fourth infusion is completed without an infusion-related reaction,premedication for subsequent doses should be administered at the discretion of the physician.

Treatment modifications

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be requiredbased on individual safety and tolerability; see Table 1.

Detailed guidelines for the management of immune-mediated adverse reactions are described insection 4.4.

Table 1: Guidelines for withholding or discontinuation of Bavencio

Treatment-related adverse Severity* Treatment modificationreaction

Infusion-related reactions Grade 1 infusion-related reaction Reduce infusion rate by 50%

Grade 2 infusion-related reaction Withhold until adversereactions recover to

Grade 0-1; restart infusionwith a 50% slower rate

Grade 3 or Grade 4 infusion-related Permanently discontinuereaction

Pneumonitis Grade 2 pneumonitis Withhold until adversereactions recover to

Grade 0-1

Grade 3 or Grade 4 pneumonitis or Permanently discontinuerecurrent Grade 2 pneumonitis

Hepatitis Aspartate aminotransferase (AST) or Withhold until adversealanine aminotransferase (ALT) greater reactions recover to

For Bavencio in than 3 and up to 5 times upper limit of Grade 0-1combination with axitinib, normal (ULN) or total bilirubin greatersee below than 1.5 and up to 3 times ULN

AST or ALT greater than 5 times ULN or Permanently discontinuetotal bilirubin greater than 3 times ULN

Colitis Grade 2 or Grade 3 colitis or diarrhoea Withhold until adversereactions recover to

Grade 0-1

Grade 4 colitis or diarrhoea or recurrent Permanently discontinue

Grade 3 colitis

Pancreatitis Suspected pancreatitis Withhold

Confirmed pancreatitis Permanently discontinue

Myocarditis Suspected myocarditis Withhold

Confirmed myocarditis Permanently discontinue

Endocrinopathies Grade 3 or Grade 4 endocrinopathies Withhold until adverse(hypothyroidism, reactions recover tohyperthyroidism, adrenal Grade 0-1insufficiency,hyperglycaemia)

Treatment-related adverse Severity* Treatment modificationreaction

Nephritis and renal Serum creatinine more than 1.5 and up to Withhold until adversedysfunction 6 times ULN reactions recover to

Grade 0-1

Serum creatinine more than 6 times ULN Permanently discontinue

Skin reactions Grade 3 rash Withhold until adversereactions recover to

Grade 0-1

Grade 4 or recurrent Grade 3 rash or Permanently discontinueconfirmed Stevens-Johnson syndrome(SJS) or Toxic epidermal necrolysis (TEN)

Other immune-mediated For any of the following: Withhold until adverseadverse reactions (including * Grade 2 or Grade 3 clinical signs or reactions recover toother clinically important symptoms of an immune-mediated Grade 0-1immune-mediated adverse adverse reaction not described abovereactions listed under 'Other For any of the following: Permanently discontinueimmune-mediated adverse * Life threatening or Grade 4 adversereactions' (see section 4.4)) reaction (excluding endocrinopathiescontrolled with hormone replacementtherapy)

* Recurrent Grade 3 immune-mediatedadverse reaction

* Requirement for 10 mg per day orgreater prednisone or equivalent formore than 12 weeks

* Persistent Grade 2 or Grade 3immune-mediate adverse reactionslasting 12 weeks or longer

* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events

Version 4.0 (NCI-CTCAE v4.03)

Treatment modifications when Bavencio is used in combination with axitinib

If ALT or AST ≥ 3 times ULN but < 5 times ULN or total bilirubin ≥ 1.5 times ULN but < 3 times

ULN, both Bavencio and axitinib should be withheld until these adverse reactions recover to

Grades 0-1. If persistent (greater than 5 days), corticosteroid therapy with prednisone or equivalentfollowed by a taper should be considered. Rechallenge with Bavencio or axitinib or sequentialrechallenge with both Bavencio and axitinib after recovery should be considered. Dose reductionaccording to the axitinib product information should be considered if rechallenging with axitinib.

If ALT or AST ≥ 5 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN ortotal bilirubin ≥ 3 times ULN, both Bavencio and axitinib should be permanently discontinued andcorticosteroid therapy should be considered.

Dose modification advice for axitinib when used with Bavencio

When Bavencio is administered in combination with axitinib, please refer to the axitinib productinformation for recommended dose modifications for axitinib.

No dose adjustment is needed for elderly patients (≥ 65 years) (see sections 5.1 and 5.2).

No dose adjustment is needed for patients with mild or moderate renal impairment (see section 5.2).

There are insufficient data in patients with severe renal impairment for dosing recommendations.

No dose adjustment is needed for patients with mild hepatic impairment (see section 5.2). There areinsufficient data in patients with moderate or severe hepatic impairment for dosing recommendations.

The safety and efficacy of Bavencio in children and adolescents below 18 years of age have not beenestablished. Currently available data of Bavencio are described in section 5.1 but no recommendationon a posology can be made.

Bavencio is for intravenous infusion only. It must not be administered as an intravenous push or bolusinjection.

Bavencio has to be diluted with either sodium chloride 9 mg/mL (0.9%) solution for infusion or withsodium chloride 4.5 mg/mL (0.45%) solution for infusion. It is administered over 60 minutes as anintravenous infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometre in-line oradd-on filter.

For instructions on the preparation and administration of the medicinal product, see section 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.

Infusion-related reactions, which might be severe, have been reported in patients receiving avelumab(see section 4.8).

Patients should be monitored for signs and symptoms of infusion-related reactions including pyrexia,chills, flushing, hypotension, dyspnoea, wheezing, back pain, abdominal pain, and urticaria.

For Grade 3 or Grade 4 infusion-related reactions, the infusion should be stopped and avelumabshould be permanently discontinued (see section 4.2).

For Grade 1 infusion-related reactions, the infusion rate should be slowed by 50% for the currentinfusion. For patients with Grade 2 infusion-related reactions, the infusion should be temporarydiscontinued until Grade 1 or resolved, then the infusion will restart with a 50% slower infusion rate(see section 4.2).

In case of recurrence of Grade 1 or Grade 2 infusion-related reaction, the patient may continue toreceive avelumab under close monitoring, after appropriate infusion rate modification andpremedication with paracetamol and antihistamine (see section 4.2).

In patients treated with avelumab as monotherapy, 24.6% (513/2 082) of patients experiencedinfusion-related reactions. Of these, 97.7% (501/513) had a first infusion-related reaction during thefirst 4 infusions of which 2.7% (14/513) were Grade ≥ 3. In the remaining 2.3% (12/513) of patients,infusion-related reactions occurred after the first 4 infusions and 91.7% (11/12) were of Grade 1 or

Grade 2.

Immune-mediated adverse reactions

Most immune-mediated adverse reactions with avelumab were reversible and managed withtemporary or permanent discontinuation of avelumab, administration of corticosteroids and/orsupportive care.

For suspected immune-mediated adverse reactions, adequate evaluation should be performed toconfirm aetiology or exclude other causes. Based on the severity of the adverse reaction, avelumabshould be withheld and corticosteroids administered. If corticosteroids are used to treat an adversereaction, a taper of at least 1 month duration should be initiated upon improvement.

In patients, whose immune-mediated adverse reactions could not be controlled with corticosteroid use,administration of other systemic immunosuppressants may be considered.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggestthat the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapymay be increased as compared with the risk in patients without pre-existing AID. In addition, flaresof the underlying AID were frequent, but the majority were mild and manageable.

Immune-mediated pneumonitis

Immune-mediated pneumonitis occurred in patients treated with avelumab. One fatal case has beenreported in patients receiving avelumab (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated pneumonitis and causesother than immune-mediated pneumonitis should be ruled out. Suspected pneumonitis should beconfirmed with radiographic imaging.

Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 to 2 mg/kg body weight(bw)/day prednisone or equivalent, followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 immune-mediated pneumonitis until resolution, andpermanently discontinued for Grade 3, Grade 4 or recurrent Grade 2 immune-mediated pneumonitis(see section 4.2).

Immune-mediated hepatitis

Immune-mediated hepatitis occurred in patients treated with avelumab. Two fatal cases have beenreported in patients receiving avelumab (see section 4.8).

Patients should be monitored for changes in liver function and symptoms of immune-mediatedhepatitis and causes other than immune-mediated hepatitis should be ruled out.

Corticosteroids should be administered for Grade ≥ 2 events (initial dose 1 to 2 mg/kg bw/dayprednisone or equivalent, followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 immune-mediated hepatitis until resolution andpermanently discontinued for Grade 3 or Grade 4 immune-mediated hepatitis (see section 4.2).

Immune-mediated colitis

Immune-mediated colitis has been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated colitis and causes otherthan immune-mediated colitis should be ruled out. Corticosteroids should be administered for

Grade ≥ 2 events (initial dose of 1 to 2 mg/kg bw/day prednisone or equivalent followed by acorticosteroid taper).

Avelumab should be withheld for Grade 2 or Grade 3 immune-mediated colitis until resolution, andpermanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated colitis (see section 4.2).

Immune-mediated pancreatitis

Immune-mediated pancreatitis has been reported in patients receiving avelumab. Two fatal cases havebeen reported in patients receiving avelumab in combination with axitinib (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated pancreatitis. Insymptomatic patients, obtain gastroenterology consultation and laboratory investigations (includingimaging) to ensure the initiation of appropriate measures at an early stage. Corticosteroids should beadministered for immune-mediated pancreatitis (initial dose of 1 to 2 mg/kg bw/day prednisone orequivalent followed by a corticosteroid taper).

Avelumab should be withheld in the event of suspected immune-mediated pancreatitis. Avelumabshould be permanently discontinued if immune-mediated pancreatitis is confirmed (see section 4.2).

Immune-mediated myocarditis

Immune-mediated myocarditis has been reported in patients receiving avelumab. Two fatal cases havebeen reported in patients receiving avelumab in combination with axitinib (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated myocarditis. Insymptomatic patients, obtain cardiologic consultation and laboratory investigations to ensure theinitiation of appropriate measures at an early stage. Corticosteroids should be administered forimmune-mediated myocarditis (initial dose of 1 to 2 mg/kg bw/day prednisone or equivalent followedby a corticosteroid taper). If no improvement within 24 hours on corticosteroids, additionalimmunosuppression (e.g., mycophenolate, infliximab, anti-thymocyte globulin) should be considered.

Avelumab should be withheld in the event of suspected immune-mediated myocarditis. Avelumabshould be permanently discontinued if immune-mediated myocarditis is confirmed (see section 4.2).

Immune-mediated endocrinopathies

Immune-mediated thyroid disorders, immune-mediated adrenal insufficiency, and Type 1 diabetesmellitus have been reported in patients receiving avelumab (see section 4.8). Patients should bemonitored for clinical signs and symptoms of endocrinopathies. Avelumab should be withheld for

Grade 3 or Grade 4 endocrinopathies until resolution (see section 4.2).

Thyroid disorders (hypothyroidism/hyperthyroidism)

Thyroid disorders can occur at any time during treatment (see section 4.8).

Patients should be monitored for changes in thyroid function (at the start of treatment, periodicallyduring treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms ofthyroid disorders. Hypothyroidism should be managed with replacement therapy and hyperthyroidismwith anti-thyroid medicinal product, as needed.

Avelumab should be withheld for Grade 3 or Grade 4 thyroid disorders (see section 4.2).

Patients should be monitored for signs and symptoms of adrenal insufficiency during and aftertreatment. Corticosteroids should be administered (1 to 2 mg/kg bw/day prednisone intravenously ororal equivalent) for Grade ≥ 3 adrenal insufficiency followed by a taper until a dose of less than orequal to 10 mg/day has been reached.

Avelumab should be withheld for Grade 3 or Grade 4 symptomatic adrenal insufficiency (seesection 4.2).

Type 1 diabetes mellitus

Avelumab can cause Type 1 diabetes mellitus, including diabetic ketoacidosis (see section 4.8).

Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Initiatetreatment with insulin for Type 1 diabetes mellitus. Avelumab should be withheld andanti-hyperglycaemics in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatmentwith avelumab should be resumed when metabolic control is achieved on insulin replacement therapy.

Immune-mediated nephritis and renal dysfunction

Avelumab can cause immune-mediated nephritis (see section 4.8).

Patients should be monitored for elevated serum creatinine prior to and periodically during treatment.

Corticosteroids (initial dose of 1 to 2 mg/kg bw/day prednisone or equivalent followed by acorticosteroid taper) should be administered for Grade ≥ 2 nephritis. Avelumab should be withheld for

Grade 2 or Grade 3 nephritis until resolution to ≤ Grade 1 and permanently discontinued for Grade 4nephritis.

Other immune-mediated adverse reactions

Other clinically important immune-mediated adverse reactions were reported in clinical studies orfrom post-marketing use of avelumab: myositis, hypopituitarism, uveitis, myasthenia gravis,myasthenic syndrome, cystitis noninfective, sarcoidosis, Guillain-Barré syndrome, sclerosingcholangitis, arthritis, polymyalgia rheumatica, Sjogren’s syndrome, and gastritis (see section 4.8).

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm aetiology orto rule out other causes. Based on the severity of the adverse reaction, avelumab should be withheldand corticosteroids to be administered. Avelumab should be resumed when the immune-mediatedadverse reaction returns to Grade 1 or less following corticosteroid taper. Avelumab should bepermanently discontinued for any Grade 3 immune-mediated adverse reaction that recurs and for

Grade 4 immune-mediated adverse reaction (see section 4.2).

Hepatotoxicity (in combination with axitinib)

Hepatotoxicity occurred in patients treated with avelumab in combination with axitinib withhigher-than-expected frequencies of Grade 3 and Grade 4 ALT and AST elevation compared toavelumab alone (see section 4.8).

Patients should be more frequently monitored for changes in liver function and symptoms as comparedto when avelumab is used as monotherapy.

Avelumab should be withheld for Grade 2 hepatotoxicity until resolution and permanentlydiscontinued for Grade 3 or Grade 4 hepatotoxicity. Corticosteroids should be considered for

Grade ≥ 2 events (see section 4.2).

Patients with the following conditions were excluded from clinical studies: active central nervoussystem (CNS) metastasis; active or a history of autoimmune disease; a history of other malignancieswithin the last 5 years; organ transplant; conditions requiring therapeutic immune suppression or activeinfection with HIV, or hepatitis B or C.

Avelumab should be used with caution in these populations after careful consideration of the potentialbenefit/risk on an individual basis.

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg dose, that is to sayessentially ‘sodium-free’. Bavencio has to be diluted with either sodium chloride 9 mg/mL (0.9%)solution for infusion or with sodium chloride 4.5 mg/mL (0.45%) solution for infusion. This should betaken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate content

This medicinal product contains 5 mg of polysorbate 20 per vial. Polysorbates may cause allergicreactions. This should be taken into consideration for treating patients with Bavencio.

Patient Card

The prescriber must discuss the risks of Bavencio therapy with the patient. The patient will beprovided with the Patient Card which instructs to carry the Card at all times.

No interaction studies have been conducted with avelumab.

Avelumab is primarily metabolised through catabolic pathways, therefore, it is not expected thatavelumab will have pharmacokinetic drug-drug interactions with other medicinal products.

Women of childbearing potential should be advised to avoid becoming pregnant while receivingavelumab and should use effective contraception during treatment with avelumab and for at least1 month after the last dose of avelumab.

There are no or limited data from the use of avelumab in pregnant women.

Animal reproduction studies have not been conducted with avelumab. However, in murine models ofpregnancy, blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and toresult in an increased foetal loss (see section 5.3). These results indicate a potential risk, based on itsmechanism of action, that administration of avelumab during pregnancy could cause foetal harm,including increased rates of abortion or stillbirth.

Human IgG1 immunoglobulins are known to cross the placental barrier. Therefore, avelumab has thepotential to be transmitted from the mother to the developing foetus. It is not recommended to useavelumab during pregnancy unless the clinical condition of the woman requires treatment withavelumab.

It is unknown whether avelumab is excreted in human milk. Since it is known that antibodies can besecreted in human milk, a risk to the newborns/infants cannot be excluded.

Breast-feeding women should be advised not to breast-feed during treatment and for at least 1 monthafter the last dose due to the potential for serious adverse reactions in breast-fed infants.

The effect of avelumab on male and female fertility is unknown.

Although studies to evaluate the effect of avelumab on fertility have not been conducted, there wereno notable effects in the female reproductive organs in monkeys based on 1-month and 3-monthrepeat-dose toxicity studies (see section 5.3).

Avelumab has negligible influence on the ability to drive and use machines. Fatigue has been reportedfollowing administration of avelumab (see section 4.8). Patients should be advised to use caution whendriving or operating machines until they are certain that avelumab does not adversely affect them.

Avelumab is associated with immune-mediated adverse reactions. Most of these, including severereactions, resolved following initiation of appropriate medical therapy or withdrawal of avelumab (see“Description of selected adverse reactions” below).

The most common adverse reactions with avelumab were fatigue (30.0%), nausea (23.6%), diarrhoea(18.5%), constipation (18.1%), decreased appetite (17.6%), infusion-related reactions (15.9%),vomiting (15.6%), and weight decreased (14.5%).

The most common Grade ≥ 3 adverse reactions were anaemia (5.6%), hypertension (3.9%),hyponatraemia (3.6%), dyspnoea (3.5%), and abdominal pain (2.6%). Serious adverse reactions wereimmune-mediated adverse reactions and infusion-related reaction (see section 4.4).

The safety of avelumab as monotherapy has been evaluated in 2 082 patients with solid tumoursincluding metastatic MCC or locally advanced or metastatic UC receiving 10 mg/kg every 2 weeks ofavelumab in clinical studies or reported from post-marketing use of avelumab (see Table 2).

These reactions are presented by system organ class and frequency. Frequencies are defined as: verycommon (≥ 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 the available data). Withineach frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Adverse reactions in patients treated with avelumab as monotherapy

Frequency Adverse reactions

Very common Anaemia

Common Lymphopenia, thrombocytopenia

Uncommon Eosinophilia§

Not known Neutropenia*

Frequency Adverse reactions

Very common Infusion-related reaction#

Uncommon Hypersensitivity, drug hypersensitivity, sarcoidosis**

Rare Anaphylactic reaction, Type I hypersensitivity

Common Hypothyroidism*, hyperthyroidism*

Uncommon Adrenal insufficiency*, autoimmune thyroiditis*, thyroiditis*,autoimmune hypothyroidism*

Rare Adrenocortical insufficiency acute*, hypopituitarism*

Very common Decreased appetite

Common Hyponatraemia

Uncommon Hyperglycaemia*

Rare Diabetes mellitus*, Type 1 diabetes mellitus*

Common Headache, dizziness, neuropathy peripheral

Uncommon Myasthenia gravis*†, myasthenic syndrome*†

Rare Guillain-Barré Syndrome*, Miller Fisher syndrome*

Rare Uveitis*

Rare Myocarditis*

Common Hypertension

Uncommon Hypotension, flushing

Very common Cough, dyspnoea

Common Pneumonitis*

Rare Interstitial lung disease*

Very common Nausea, diarrhoea, constipation, vomiting, abdominal pain

Common Dry mouth

Uncommon Ileus, colitis*

Rare Pancreatitis*, autoimmune colitis*, enterocolitis*, autoimmunepancreatitis*, enteritis*, proctitis*

Not known Gastritis*

Uncommon Autoimmune hepatitis*

Rare Acute hepatic failure*, hepatic failure*, hepatitis*, hepatotoxicity*

Not known Sclerosing cholangitis*

Common Pruritus*, rash*, dry skin, rash maculo-papular*

Uncommon Eczema, dermatitis, rash pruritic*, psoriasis*, erythema*, rasherythematous*, rash generalised*, rash macular*, rash papular*

Rare Erythema multiforme*, purpura*, vitiligo*, pruritus generalised*,dermatitis exfoliative*, pemphigoid*, dermatitis psoriasiform*, drugeruption*, lichen planus*

Very common Back pain, arthralgia

Common Myalgia

Uncommon Myositis*, rheumatoid arthritis*

Rare Arthritis*, polyarthritis*, oligoarthritis*, Sjogren’s syndrome*

Not known Polymyalgia rheumatica*

Frequency Adverse reactions

Uncommon Renal failure*, nephritis*

Rare Tubulo-interstitial nephritis*, cystitis noninfective*

General disorders and administrative site conditions

Very common Fatigue, pyrexia, oedema peripheral

Common Asthenia, chills, influenza like illness

Rare Systemic inflammatory response syndrome*

Very common Weight decreased

Common Blood creatinine increased, blood alkaline phosphatase increased, lipaseincreased, gamma-glutamyltransferase increased, amylase increased

Uncommon Alanine aminotransferase (ALT) increased*, aspartate aminotransferase(AST) increased*, blood creatine phosphokinase increased*

Rare Transaminases increased*, thyroxine free decreased*, blood thyroidstimulating hormone increased*

* Immune-mediated adverse reaction based on medical review

** Sarcoidosis was observed in clinical studies in patients receiving avelumab in combination withplatinum-based chemotherapy§ Reaction only observed from study EMR 100070-003 (Part B) after the data cut-off of the pooled analysis,hence frequency estimated# Including cytokine release syndrome with frequency uncommon† Adverse reactions occurred in estimated 4 000 patients exposed to avelumab monotherapy beyond the pooledanalysis

The safety of avelumab in combination with axitinib has been evaluated in 489 patients with advanced

RCC receiving 10 mg/kg avelumab every 2 weeks and axitinib 5 mg orally twice daily in two clinicalstudies.

In this patient population, the most common adverse reactions were diarrhoea (62.8%), hypertension(49.3%), fatigue (42.9%), nausea (33.5%), dysphonia (32.7%), decreased appetite (26.0%),hypothyroidism (25.2%), cough (23.7%), headache (21.3%), dyspnoea (20.9%), and arthralgia(20.9%).

Adverse reactions reported for 489 patients with advanced RCC treated in two clinical studies orreported from post-marketing use of avelumab in combination with axitinib are presented in Table 3.

These reactions are presented by system organ class and frequency. Frequencies are defined as: verycommon (≥ 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 the available data). Withineach frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions in patients treated with avelumab in combination with axitinib

Frequency Adverse reactions

Uncommon Rash pustular*

Common Anaemia, thrombocytopenia

Uncommon Lymphopenia, eosinophilia

Not known Neutropenia*

Frequency Adverse reactions

Very common Infusion-related reaction#

Common Hypersensitivity

Very common Hypothyroidism*

Common Hyperthyroidism*, adrenal insufficiency*, thyroiditis*

Uncommon Autoimmune thyroiditis*, hypophysitis*

Very common Decreased appetite

Common Hyperglycaemia*

Uncommon Diabetes mellitus*, Type 1 diabetes mellitus*

Very common Headache, dizziness

Common Neuropathy peripheral

Uncommon Myasthenia gravis*, myasthenic syndrome*

Uncommon Myocarditis*

Very common Hypertension

Common Hypotension, flushing

Very common Dysphonia, cough, dyspnoea

Common Pneumonitis*

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

Common Dry mouth, colitis*

Uncommon Autoimmune colitis*, autoimmune pancreatitis*, enterocolitis*, ileus,pancreatitis necrotizing*

Not known Gastritis*

Common Hepatic function abnormal*

Uncommon Hepatitis*, hepatotoxicity*, immune-mediated hepatitis*, liver disorder*

Not known Sclerosing cholangitis*

Very common Rash*, pruritus*

Common Rash pruritic*, rash maculo-papular*, pruritus generalized*, dermatitisacneiform, erythema*, rash macular*, rash papular*, rash erythematous*,dermatitis*, eczema, rash generalized*

Uncommon Drug eruption*, erythema multiforme*, psoriasis*

Very common Arthralgia, back pain, myalgia

Uncommon Arthritis*

Not known Polymyalgia rheumatica*, Sjogren’s syndrome*

Common Acute kidney injury*

General disorders and administrative site conditions

Very common Fatigue, chills, asthenia, pyrexia

Common Oedema peripheral, influenza like illness

Frequency Adverse reactions

Very common Weight decreased, alanine aminotransferase (ALT) increased*, aspartateaminotransferase (AST) increased*

Common Blood creatinine increased, amylase increased, lipase increased,gamma-glutamyltransferase increased, blood alkaline phosphataseincreased, blood creatine phosphokinase increased*, blood thyroidstimulating hormone decreased*, transaminases increased*

Uncommon Liver function test increased*

* Immune-mediated adverse reaction based on medical review# Including cytokine release syndrome with frequency not known

Data for immune-mediated adverse reactions for avelumab as a monotherapy are based on2 082 patients including 1 650 patients in the phase I study EMR100070-001 in solid tumours,88 patients in study EMR100070-003 in MCC, and 344 patients in study B9991001 in UC, and foravelumab in combination with axitinib are based on 489 patients in studies B9991002 and B9991003in RCC (see section 5.1).

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

Immune-mediated pneumonitis

In patients treated with avelumab as monotherapy, 1.3% (28/2 082) of patients developedimmune-mediated pneumonitis. Of these patients, there was 1 (less than 0.1%) patient with a fataloutcome, 1 (less than 0.1%) patient with Grade 4, and 6 (0.3%) patients with Grade 3immune-mediated pneumonitis.

The median time to onset of immune-mediated pneumonitis was 2.5 months (range: 3 days to13.8 months). The median duration was 8.1 weeks (range: 4 days to more than 4.9 months).

Avelumab was discontinued in 0.4% (9/2 082) of patients due to immune-mediated pneumonitis. All28 patients with immune-mediated pneumonitis were treated with corticosteroids and 21 (75%) of the28 patients were treated with high-dose corticosteroids for a median of 9 days (range: 1 day to2.3 months). Immune-mediated pneumonitis resolved in 18 (64.3%) of the 28 patients at the time ofdata cut-off.

In patients treated with avelumab in combination with axitinib, 0.6% (3/489) of patients developedimmune-mediated pneumonitis. Of these patients, none experienced immune-mediated pneumonitis

Grade ≥ 3.

The median time to onset of immune-mediated pneumonitis was 3.7 months (range: 2.7 months to8.6 months). The median duration was 2.6 months (range: 3.3 weeks to more than 7.9 months).

Immune-mediated pneumonitis did not lead to discontinuation of avelumab in any patient. All3 patients with immune-mediated pneumonitis were treated with high-dose corticosteroids for amedian of 3.3 months (range: 3 weeks to 22.3 months). Immune-mediated pneumonitis resolved in 2(66.7%) of the 3 patients at the time of data cut-off.

Immune-mediated hepatitis

In patients treated with avelumab as monotherapy, 1.0% (21/2 082) of patients developedimmune-mediated hepatitis. Of these patients, there were 2 (0.1%) patients with a fatal outcome, and16 (0.8%) patients with Grade 3 immune-mediated hepatitis.

The median time to onset of immune-mediated hepatitis was 3.3 months (range: 9 days to14.8 months). The median duration was 2.5 months (range: 1 day to more than 7.4 months).

Avelumab was discontinued in 0.6% (13/2 082) of patients due to immune-mediated hepatitis. All21 patients with immune-mediated hepatitis were treated with corticosteroids and 20 (95.2%) of the21 patients received high-dose corticosteroids for a median of 17 days (range: 1 day to 4.1 months).

Immune-mediated hepatitis resolved in 12 (57.1%) of the 21 patients at the time of data cut-off.

In patients treated with avelumab in combination with axitinib, 6.3% (31/489) of patients developedimmune-mediated hepatitis. Of these patients, there were 18 (3.7%) patients with Grade 3 and 3(0.6%) patients with Grade 4 immune-mediated hepatitis.

The median time to onset of immune-mediated hepatitis was 2.3 months (range: 2.1 weeks to14.5 months). The median duration was 2.1 weeks (range: 2 days to 8.9 months).

Avelumab was discontinued in 4.7% (23/489) of patients due to immune-mediated hepatitis. All31 patients with immune-mediated hepatitis were treated for hepatitis including 30 (96.8%) patientstreated with corticosteroids and 1 patient with a non-steroidal immunosuppressant. Twenty-eight(90.3%) of the 31 patients received high dose corticosteroids for a median of 2.4 weeks (range: 1 dayto 10.2 months). Immune-mediated hepatitis resolved in 27 (87.1%) of the 31 patients at the time ofdata cut-off.

Immune-mediated colitis

In patients treated with avelumab as monotherapy, 1.5% (31/2 082) of patients developedimmune-mediated colitis. Of these patients, there were 10 (0.5%) patients with Grade 3immune-mediated colitis.

The median time to onset of immune-mediated colitis was 2.0 months (range: 2 days to 11.5 months).

The median duration was 5.9 weeks (range: 1 day to more than 14 months).

Avelumab was discontinued in 0.5% (11/2 082) of patients due to immune-mediated colitis. All31 patients with immune-mediated colitis were treated with corticosteroids and 19 (61.3%) of the31 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months).

Immune-mediated colitis resolved in 22 (71%) of 31 patients at the time of data cut-off.

In patients treated with avelumab in combination with axitinib, 2.7% (13/489) of patients developedimmune-mediated colitis. Of these patients, there were 9 (1.8%) patients with Grade 3immune-mediated colitis.

The median time to onset of immune-mediated colitis was 5.1 months (range: 2.3 weeks to14 months). The median duration was 1.6 weeks (range: 1 day to more than 9 months).

Avelumab was discontinued in 0.4% (2/489) of patients due to immune-mediated colitis. All13 patients with immune-mediated colitis were treated with corticosteroids and 12 (92.3%) of the13 patients received high-dose corticosteroids for a median of 2.3 weeks (range: 5 days to 4.6 months).

Immune-mediated colitis resolved in 10 (76.9%) of 13 patients at the time of data cut-off.

Immune-mediated pancreatitis

In patients treated with avelumab as monotherapy, immune-mediated pancreatitis occurred in less than1% (1/4 000) of patients across clinical studies in multiple tumour types and in 0.6% (3/489) ofpatients receiving avelumab in combination with axitinib including 2 (0.4%) patients with fataloutcome.

Immune-mediated myocarditis

In patients treated with avelumab as monotherapy, immune-mediated myocarditis occurred in less than1% (5/4 000) of patients across clinical studies in multiple tumour types and in 0.6% (3/489) ofpatients receiving avelumab in combination with axitinib including 2 (0.4%) patients with fataloutcome.

Immune-mediated endocrinopathies

Thyroid disorders

In patients treated with avelumab as monotherapy, 6.7% (140/2 082) of patients developedimmune-mediated thyroid disorders, including 127 (6.1%) patients with hypothyroidism, 23 (1.1%)with hyperthyroidism, and 7 (0.3%) with thyroiditis. Of these patients, there were 4 (0.2%) patientswith Grade 3 immune-mediated thyroid disorders.

The median time to onset of thyroid disorders was 2.8 months (range: 2 weeks to 12.8 months). Themedian duration was not estimable (range: 3 days to more than 27.6 months).

Avelumab was discontinued in 0.2% (4/2 082) of patients due to immune-mediated thyroid disorders.

Thyroid disorders resolved in 14 (10%) of the 140 patients at the time of data cut-off.

In patients treated with avelumab in combination with axitinib, 24.7% (121/489) of patients developedimmune-mediated thyroid disorders, including 111 (22.7%) patients with hypothyroidism, 17 (3.5%)with hyperthyroidism, and 7 (1.4%) with thyroiditis. Of these patients, there were 2 (0.4%) patientswith Grade 3 immune-mediated thyroid disorders.

The median time to onset of thyroid disorders was 2.8 months (range: 3.6 weeks to 19.3 months). Themedian duration was not estimable (range: 8 days to more than 23.9 months).

Avelumab was discontinued in 0.2% (1/489) of patients due to immune-mediated thyroid disorders.

Thyroid disorders resolved in 15 (12.4%) of the 121 patients at the time of data cut-off.

In patients treated with avelumab as monotherapy, 0.5% (11/2 082) of patients developedimmune-mediated adrenal insufficiency. Of these patients, there was 1 (less than 0.1%) patient with

Grade 3 immune-mediated adrenal insufficiency.

The median time to onset of immune-mediated adrenal insufficiency was 3.3 months (range: 1 day to7.6 months). The median duration was not estimable (range: 2 days to more than 10.4 months).

Avelumab was discontinued in 0.1% (2/2 082) of patients due to immune-mediated adrenalinsufficiency. All 11 patients with immune-mediated adrenal insufficiency were treated withcorticosteroids, and 5 (45.5%) of the 11 patients received high-dose systemic corticosteroids (≥ 40 mgprednisone or equivalent) for a median of 2 days (range: 1 day to 24 days). Adrenal insufficiencyresolved in 3 (27.3%) of patients at the time of data cut-off.

In patients treated with avelumab in combination with axitinib, 1.8% (9/489) of patients developedimmune-mediated adrenal insufficiency. Of these patients, there were 2 (0.4%) patients with Grade 3immune-mediated adrenal insufficiency.

The median time to onset of immune-mediated adrenal insufficiency was 5.5 months (range:3.6 weeks to 8.7 months). The median duration was 2.8 months (range: 3 days to more than15.5 months).

Immune-mediated adrenal insufficiency did not lead to discontinuation of avelumab in any patient.

Eight (88.9%) patients with immune-mediated adrenal insufficiency were treated with corticosteroidsand 2 (25%) of the 8 patients received high-dose corticosteroids (≥ 40 mg prednisone or equivalent)for a median of 8 days (range: 5 days to 11 days). Adrenal insufficiency resolved in 4 (44.4%) of the9 patients at the time of data cut-off.

Type 1 diabetes mellitus

In patients treated with avelumab as monotherapy, Type 1 diabetes mellitus without an alternativeaetiology occurred in 0.2% (5/2 082) of patients. All 5 patients experienced Grade 3 Type 1 diabetesmellitus.

The median time to onset of Type 1 diabetes mellitus was 3.3 months (range: 1 day to 18.7 months).

The median duration was not estimable (range: 14 days to more than 4.8 months).

Avelumab was discontinued in 0.1% (2/2 082) of patients due to Type 1 diabetes mellitus. Type 1diabetes mellitus resolved in 2 (40%) patients at the time of data cut-off.

In patients treated with avelumab in combination with axitinib, Type 1 diabetes mellitus without analternative aetiology occurred in 1.0% (5/489) of patients. Of these patients, there was 1 (0.2%) patientwith Grade 3 Type 1 diabetes mellitus.

The median time to onset of Type 1 diabetes mellitus was 1.9 months (range: 1.1 months to7.3 months).

Avelumab was discontinued in 0.2% (1/489) of patients due to Type 1 diabetes mellitus. All 5 patientswith Type 1 diabetes mellitus were treated with insulin. Type 1 diabetes mellitus did not resolve in anyof the patients at the time of data cut-off.

Immune-mediated nephritis and renal dysfunction

In patients treated with avelumab as monotherapy, immune-mediated nephritis occurred in 0.3%(7/2 082) of patients. There was 1 (less than 0.1%) patient with Grade 3 immune-mediated nephritis.

The median time to onset of immune-mediated nephritis was 2.4 months (range: 7.1 weeks to21.9 months). The median duration was 6.1 months (range: 9 days to 6.1 months).

Avelumab was discontinued in 0.2% (4/2 082) of patients due to immune-mediated nephritis. All7 patients with immune-mediated nephritis were treated with corticosteroids. 6 (85.7%) of those7 patients with immune-mediated nephritis were treated with high-dose corticosteroids for a median of2.5 weeks (range: 6 days to 2.8 months). Immune-mediated nephritis resolved in 4 (57.1%) patients atthe time of data cut-off.

In patients treated with avelumab in combination with axitinib, immune-mediated nephritis occurredin 0.4% (2/489) of patients. Of these patients, there were 2 (0.4%) patients with Grade 3immune-mediated nephritis.

The median time to onset of immune-mediated nephritis was 1.2 months (range: 2.9 weeks to1.8 months). The median duration was 1.3 weeks (range: more than 4 days to 1.3 weeks).

Immune-mediated nephritis did not lead to discontinuation of avelumab in any patient. All 2 patientswith immune-mediated nephritis were treated with high-dose corticosteroids for a median of 1.1 weeks(range: 3 days to 1.9 weeks). Immune-mediated nephritis resolved in 1 (50%) of the 2 patients at thetime of data cut-off.

Hepatotoxicity (in combination with axitinib)

In patients treated with avelumab in combination with axitinib, Grades 3 and Grade 4 increased ALTand increased AST were reported in 9% and 7% of patients, respectively.

In patients with ALT ≥ 3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%.

Among the 73 patients who were rechallenged with either avelumab (59%) or axitinib (85%)monotherapy or with both (55%), 66% had no recurrence of ALT ≥ 3 times ULN.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immunecheckpoint inhibitors which might also occur during treatment with avelumab: pancreatic exocrineinsufficiency, coeliac disease.

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.

Three patients were reported to be overdosed with 5% to 10% above the recommended dose ofavelumab. The patients had no symptoms, did not require any treatment for the overdose, andcontinued on avelumab therapy.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions.

The treatment is directed to the management of symptoms.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, PD-1/PDL-1 (Programmedcell death protein 1/death ligand 1) inhibitors, ATC code: L01FF04.

Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmeddeath ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and theprogrammed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 oncytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses. Avelumab has alsoshown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependentcell-mediated cytotoxicity (ADCC).

Merkel cell carcinoma (study EMR100070-003)

The efficacy and safety of avelumab was investigated in the single arm, multi-centre study

EMR100070-003 with two parts. Part A was conducted in patients with histologically confirmedmetastatic MCC, whose disease had progressed on or after chemotherapy administered for distantmetastatic disease, with a life expectancy of more than 3 months. Part B included patients withhistologically confirmed metastatic MCC who were treatment-naïve to systemic therapy in themetastatic setting.

Patients with active or a history of central nervous system (CNS) metastasis; active or a history ofautoimmune disease; a history of other malignancies within the last 5 years; organ transplant;conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or Cwere excluded.

Patients received avelumab at a dose of 10 mg/kg every 2 weeks until disease progression orunacceptable toxicity. Patients with radiological disease progression not associated with significantclinical deterioration, defined as no new or worsening symptoms, no change in performance status forgreater than two weeks, and no need for salvage therapy could continue treatment.

Tumour response assessments were performed every 6 weeks, as assessed by an Independent Endpoint

Review Committee (IERC) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Study 003 Part A - previously-treated patients

The major efficacy outcome measure was confirmed best overall response (BOR); secondary efficacyoutcome measures included duration of response (DOR), progression-free survival (PFS), and overallsurvival (OS).

An efficacy analysis was conducted in all 88 patients after a minimum follow-up of 36 months. Patientsreceived a median of 7 doses of avelumab (range: 1 dose to 95 doses), and the median duration oftreatment was 17 weeks (range: 2 weeks to 208 weeks).

Of the 88 patients, 65 (74%) were male, the median age was 73 years (range 33 years to 88 years),81 (92%) patients were Caucasian, and 49 (56%) patients and 39 (44%) patients with an Eastern

Cooperative Oncology Group (ECOG) performance status 0 and 1, respectively.

Overall, 52 (59%) patients were reported to have had 1 prior anti-cancer therapy for MCC, 26 (30%)with 2 prior therapies, and 10 (11%) with 3 or more prior therapies. Forty-seven (53%) of the patientshad visceral metastases.

Table 4 summarises efficacy endpoints in patients receiving avelumab at the recommended dose forstudy EMR100070-003, Part A with a minimum follow-up of 36 months. Overall survival wasevaluated in an analysis with a minimum follow-up of 44 months. The median OS was 12.6 months(95% CI 7.5, 17.1).

Table 4: Response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC instudy EMR100070-003 (Part A)*

Efficacy endpoints (Part A) Results(per RECIST v1.1, IERC) (N=88)

Objective response rate (ORR)

Response rate, CR+PR** n (%) 29 (33.0%)(95% CI) (23.3, 43.8)

Confirmed best overall response (BOR)

Complete response (CR)** n (%) 10 (11.4%)

Partial response (PR)** n (%) 19 (21.6%)

Duration of response (DOR)a

Median, months 40.5(95% CI) (18, not estimable)

Minimum, maximum (months) 2.8, 41.5+≥ 6 months by K-M, (95% CI) 93% (75, 98)≥ 12 months by K-M, (95% CI) 71% (51, 85)≥ 24 months by K-M, (95% CI) 67% (47, 82)≥ 36 months by K-M, (95% CI) 52% (26, 73)

Progression-free survival (PFS)

Median PFS, months 2.7(95% CI) (1.4, 6.9)6-month PFS rate by K-M, (95% CI) 40% (29, 50)12-month PFS rate by K-M, (95% CI) 29% (19, 39)24-month PFS rate by K-M, (95% CI) 26% (17, 36)36-month PFS rate by K-M, (95% CI) 21% (12, 32)

CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC:

Independent Endpoint Review Committee; K-M: Kaplan-Meier; +denotes a censored value

* Efficacy data with a minimum follow-up of 36 months (cut-off date 14 September 2018)

** CR or PR was confirmed at a subsequent tumour assessmenta Based on number of patients with confirmed response (CR or PR)

The median time to response was 6 weeks (range: 6 weeks to 36 weeks) after the first dose ofavelumab. Twenty-two out of 29 (76%) patients with response were reported to have responded within7 weeks after the first dose of avelumab.

The Kaplan-Meier estimates of PFS of the 88 patients (Part A) with metastatic MCC is presented in

Figure 1.

Figure 1: Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC(Part A, minimum follow-up of 36 months)

Product-Limit Survival Estimate (N=88)1.0 | |0.90.80.70.60.50.4 |0.3 | | || | | | | ||0.2 | | |||0.1 |0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Progression Free Survival by IERC (months)# At Risk88 43 32 30 27 24 21 20 20 20 20 17 15 14 10 10 10 8 5 2 2 2 1 0

Tumour samples were evaluated for PD-L1 tumour cell expression, and for Merkel cell polyomavirus(MCV) using an investigational immunohistochemistry (IHC) assay. Table 5 summarises the objectiveresponse rates by the PD-L1 expression and MCV status of patients with metastatic MCC in study

EMR100070-003 (Part A).

Table 5: Objective response rates by PD-L1 expression and MCV tumour status in patients withmetastatic MCC in study EMR100070-003 (Part A)

Avelumab

ORR (95% CI)*

PD-L1 expression at cut-off of ≥ 1% N=74a

Positive (n=58) 36.2% (24.0, 49.9)

Negative (n=16) 18.8% (4.0, 45.6)

IHC-MCV tumour status N=77b

Positive (n=46) 28.3% (16.0, 43.5)

Negative (n=31) 35.5% (19.2, 54.6)

IHC: Immunohistochemistry; MCV: Merkel cell polyomavirus; ORR: objective response rate

* ORR (cut-off date 14 September 2018)a Based on data from patients evaluable for PD-L1b Based on data from patients evaluable for MCV by immunohistochemistry (IHC)

Study 003 Part B - patients who have not received systemic therapy in the metastatic setting

The major efficacy outcome measure was durable response, defined as objective response (completeresponse (CR) or partial response (PR)) with a duration of at least 6 months; secondary outcomemeasures included BOR, DOR, PFS, and OS.

The primary analysis for Part B included 116 patients who received at least one dose of avelumab witha minimum follow-up of 15 months at the time of the data cut-off (cut-off date 02 May 2019).

Kaplan-Meier Estimate

Of the 116 patients, 81 (70%) were male, the median age was 74 years (range: 41 to 93 years), 75(65%) were white, and 72 (62%) and 44 (38%) had an ECOG performance status of 0 and 1respectively.

Table 6 summarises the primary analysis of efficacy endpoints including an estimate of the 24-monthrates by Kaplan-Meier for DOR, and PFS in patients receiving avelumab at the recommended dose forstudy EMR100070-003, Part B.

Table 6: Primary analysis of response to avelumab 10 mg/kg every 2 weeks in patients withmetastatic MCC in study EMR100070-003 (Part B)*

Efficacy endpoints (Part B) Results(per RECIST v1.1, IERC) (N=116)

Durable response≥ 6 months 30.2%(95% CI) (22.0, 39.4)

Objective response rate (ORR)

Response rate, CR+PR** n (%) 46 (39.7%)(95% CI) (30.7, 49.2)

Confirmed best overall response (BOR)

Complete response (CR)** n (%) 19 (16.4%)

Partial response (PR)** n (%) 27 (23.3%)

Duration of response (DOR)a

Median, months 18.2(95% CI) (11.3, not estimable)

Minimum, maximum (months) 1.2, 28.3≥ 3 months by K-M, (95% CI) 89% (75, 95)≥ 6 months by K-M, (95% CI) 78% (63, 87)≥ 12 months by K-M, (95% CI) 66% (50, 78)≥ 18 months by K-M, (95% CI) 52% (34, 67)≥ 24 months by K-M, (95% CI) 45% (25, 63)

Progression-free survival (PFS)

Median PFS, months 4.1(95% CI) (1.4, 6.1)3-month PFS rate by K-M, (95% CI) 51% (42, 60)6-month PFS rate by K-M, (95% CI) 41% (32, 50)12-month PFS rate by K-M, (95% CI) 31% (23, 40)24-month PFS rate by K-M, (95% CI) 20% (12, 30)

CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC:

Independent Endpoint Review Committee; K-M: Kaplan-Meier

* Efficacy data with a minimum follow-up of 15 months (cut-off date 02 May 2019)

** CR or PR was confirmed at a subsequent tumour assessmenta Based on number of patients with confirmed response (CR or PR)

Figure 2 presents the Kaplan-Meier estimates for PFS from the primary analysis with 116 patientsenrolled into Part B with a minimum follow-up of 15 months.

Figure 2: Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC(Part B, N=116)

Product-Limit Survival Estimate (N=116)1.0 |0.90.80.7 |0.6 ||0.50.4 | | ||| |0.3 || | | | | ||||| | |0.2 || | ||0.10.00 2 4 6 8 10 12 14 16 18 20 22 24

Progression Free Survival by IERC (months)# At Risk116 60 56 45 39 24 18 10 8 5 4 3 0

Tumour samples were evaluated for PD-L1 tumour cell expression, and for MCV using aninvestigational IHC assay. Table 7 summarises the objective response rates by PD-L1 expression and

MCV status of patients with metastatic MCC in study EMR100070-003 (Part B).

Table 7: Objective response rates by PD-L1 expression and MCV tumour status in patients withmetastatic MCC in study EMR100070-003 (Part B)

Avelumab

ORR (95% CI)*

PD-L1 expression at cut-off of ≥ 1% N=108a

Positive (n=21) 61.9% (38.4, 81.9)

Negative (n=87) 33.3% (23.6, 44.3)

IHC-MCV tumour status N=107b

Positive (n=70) 34.3% (23.3, 46.6)

Negative (n=37) 48.6% (31.9, 65.6)

IHC: Immunohistochemistry; MCV: Merkel cell polyomavirus; ORR: objective response rate

* ORR (cut-off date 02 May 2019)a Based on data from patients evaluable for PD-L1b Based on data from patients evaluable for MCV by IHC

Locally advanced or metastatic urothelial carcinoma (study B9991001)

The efficacy and safety of avelumab was demonstrated in study B9991001, a randomised, multi-centre,open-label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelialcarcinoma whose disease had not progressed with 4-6 cycles of first-line platinum-based inductionchemotherapy. Patients with autoimmune disease or a medical condition that requiredimmunosuppression were excluded.

Randomization was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) andsite of metastasis (visceral vs. non-visceral) at the time of initiating first-line induction chemotherapy.

Patients were randomised (1:1) to receive either avelumab 10 mg/kg intravenous infusion every2 weeks plus best supportive care (BSC) or BSC alone.

Kaplan-Meier Estimate

Administration of avelumab was permitted beyond Response Evaluation Criteria in Solid Tumours(RECIST) v1.1-defined progression of disease by Blinded Independent Central Review (BICR) if thepatient was clinically stable and considered to be deriving clinical benefit by the investigator.

Assessment of tumour status was performed at baseline, 8 weeks after randomization, then every8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documentedconfirmed disease progression based on BICR assessment per RECIST v1.1.

Demographic and baseline characteristics were generally well balanced between the avelumab plus

BSC and the BSC alone arm. Baseline characteristics were a median age of 69 years (range: 32 to 90),66% of patients were 65 years or older, 77% were male, 67% were White, and the ECOG PS was0 (61%) or 1 (39%) for both arms.

For first-line induction chemotherapy, 56% of patients received cisplatin plus gemcitabine, 38% ofpatients received carboplatin plus gemcitabine and 6% of patients received cisplatin plus gemcitabineand carboplatin plus gemcitabine (i.e. these patients received one or more cycles of each combination).

Best response to first-line induction chemotherapy was CR or PR (72%) or SD (28%). Sites ofmetastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty-one percent ofpatients had PD-L1-positive tumours. Six percent of patients in the avelumab plus BSC arm and 44% ofpatients in the BSC alone arm received another PD-1/PD-L1 checkpoint inhibitor after discontinuationof treatment.

The primary efficacy outcome measure was overall survival (OS) in all randomized patients and inpatients with PD-L1-positive tumours. Progression-free survival (PFS) based on BICR assessment per

RECIST v1.1 was an additional efficacy outcome measure. Efficacy outcomes were measured fromtime of randomisation after 4 to 6 cycles of platinum-based induction chemotherapy.

The PD-L1 status of the tumour was assessed using the Ventana PD-L1 (SP263) assay.

PD-L1-positivity was defined as ≥ 25% of tumour cells stained for PD-L1; or ≥ 25% of immune cellsstained for PD-L1 if > 1% of the tumour area contained immune cells; or 100% of immune cellsstained for PD-L1 if = 1% of the tumour area contained immune cells.

At the pre-specified interim analysis (cut-off date 21 October 2019), study B9991001 met its primaryendpoint for OS in both coprimary populations: in all randomized patients with a median OS of21.4 months (95% CI: 18.9, 26.1; HR 0.69, 95% CI: 0.556, 0.863) in the avelumab plus BSC arm andwith a median OS of 14.3 months (95% CI: 12.9, 17.8) in the BSC alone arm. For patients with

PD-L1-positive tumours the median OS was not reached (95% CI: 20.3, not reached; HR 0.56, 95%,

CI: 0.404, 0.787) in the avelumab plus BSC arm and the median OS in the BSC alone arm was17.1 months (95% CI: 13.5, 23.7). Updated OS results with a data cut-off date of 19 January 2020 and

PFS data with a cut-off date of 21 October 2019 are presented in Table 8 and in Figure 3 and Figure 4below.

Table 8: Efficacy results by PD-L1 expression in study B9991001

Efficacy endpoints Avelumab BSC Avelumab BSC Avelumab BSCplus BSC plus BSC plus BSC(N=350) (N=350) (N=189) (N=169) (N=139) (N=131)

All randomized patients PD-L1-positive tumours PD-L1-negative tumoursc

Overall survival (OS)a

Events (%) 156 (44.6) 190 (54.3) 68 (36.0) 85 (50.3) 80 (57.6) 80 (61.1)

Median in months 22.1 14.6 NE 17.5 18.9 13.4(95% CI) (19.0, 26.1) (12.8, 17.8) (20.6, NE) (13.5, 31.6) (13.3, 22.1) (10.4, 17.3)

Hazard ratio 0.70 0.60 0.83(95% CI) (0.564, 0.862) (0.439, 0.833) (0.603, 1.131)2-sided p-valued 0.0008 0.0019 -

Progression-free survival (PFS)b, e, f

Events (%) 225 (64.3) 260 (74.3) 109 (57.7) 130 (76.9) 103 (74.1) 99 (75.6)

Median in months 3.7 2.0 5.7 2.1 3.0 1.9(95% CI) (3.5, 5.5) (1.9, 2.7) (3.7, 7.4) (1.9, 3.5) (2.0, 3.7) (1.9, 2.1)

Hazard ratio 0.62 0.56 0.63(95% CI) (0.519, 0.751) (0.431, 0.728) (0.474, 0.847)2-sided p-valued < 0.0001 < 0.0001 -

CI: Confidence interval; K-M: Kaplan-Meier, NE: not estimable

Note: 72 patients (22 patients on avelumab plus BSC arm and 50 patients on BSC alone arm) had a tumour withan unknown PD-L1 statusa OS cutoff date 19 January 2020b PFS cut-off date 21 October 2019c PD-L1-negative population analyses were exploratory and no formal test was performedd p-value based on stratified log-ranke Based on BICR assessment per RECIST v1.1f PFS censoring reasons follow the hierarchy in sequential order: no adequate baseline assessment, start of newanti-cancer therapy, event after 2 or more missing assessments, withdrawal of consent, lost to follow-up, noadequate post-baseline tumour assessment, ongoing without an event

Figure 3: Kaplan-Meier estimates for overall survival (OS) by PD-L1 expression (cut-off date19 January 2020) - Full analysis set(A): All randomized patients(B): Patients by PD-L1 expression

Figure 4: Kaplan-Meier estimates for progression-free survival (PFS) by PD-L1 expressionbased on BICR assessment (RECIST v1.1) (cut-off date 21 October 2019) - Full analysis set(A): All randomized patients(B): Patients by PD-L1 expression

Renal cell carcinoma (study B9991003)

The efficacy and safety of avelumab in combination with axitinib was demonstrated in study

B9991003, a randomised, multi-centre, open-label study of avelumab in combination with axitinib in886 patients with untreated advanced or metastatic RCC with a clear-cell component.

Patients were included irrespective of prognostic risk groups or tumour PD-L1 expression and had tohave at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumours(RECIST) version 1.1 that was not been previously irradiated. Patients with prior systemic therapydirected at advanced or metastatic RCC; prior systemic immunotherapy treatment with IL-2, IFN-α,anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies, or active brain metastasis; active autoimmunedisease that might deteriorate when receiving an immunostimulatory agents; a history of othermalignancies within the last 5 years; organ transplant were ineligible.

Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG)

Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest ofthe world). Patients were randomised (1:1) to one of the following treatment arms:

* Avelumab 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mgtwice daily orally (N=442). Patients who tolerated axitinib 5 mg twice daily without Grade 2 orgreater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and thensubsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice dailyand subsequently to 2 mg twice daily to manage toxicity.

* Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) untilradiographic or clinical progression or unacceptable toxicity.

Treatment with avelumab and axitinib continued until RECIST v1.1-defined progression of disease by

Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration ofavelumab and axitinib was permitted beyond RECIST-defined disease progression based oninvestigator’s assessment of the patient’s benefit-risk and clinical condition, including performancestatus, clinical symptoms, adverse events and laboratory data. The majority (n=160, 71.4%) of thepatients with progressive disease continued treatment with both medicinal products after progression.

Assessment of tumour status was performed at baseline, after randomisation at 6 weeks, then every6 weeks thereafter up to 18 months after randomisation, and every 12 weeks thereafter untildocumented confirmed disease progression by BICR.

The primary efficacy endpoints were progression-free survival (PFS), as assessed by BICR using

RECIST v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC whohave PD-L1-positive tumours (PD-L1 expression level ≥ 1%). The key secondary endpoints were PFSbased on BICR assessment per RECIST v1.1 and OS irrespective of PD-L1 expression. PD-L1 statuswas determined by immunohistochemistry. Additional secondary endpoints included objectiveresponse (OR), time to response (TTR) and duration of response (DOR).

Study population characteristics: median age of 61 years (range: 27.0 to 88.0), 38% of patients were65 years or older, 75% were male, 75% were White, and the ECOG performance score was 0 (63%) or1 (37%).

Patient distribution by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)risk groups was 21% favourable, 62% intermediate, and 16% poor. Patient distribution by Memorial

Sloan-Kettering Cancer Center (MSKCC) risk groups was 22% favourable, 65% intermediate, and11% poor.

Efficacy results are presented in Table 9 and Figure 5 based on a data cut-off date of 28 January 2019.

With a median OS follow-up of 19 months, OS data were immature with 27% deaths. The observedhazard ratio (HR) for OS was 0.80 (95% CI: 0.616, 1.027) for avelumab in combination with axitinibcompared to sunitinib.

Table 9: Efficacy results from study B9991003 in patients irrespective of PD-L1 expression

Efficacy endpoints Avelumab plus axitinib Sunitinib(Based on BICR assessment) (N=442) (N=444)

Progression-free survival (PFS)

Events (%) 229 (52) 258 (58)

Median in months (95% CI) 13.3 (11.1, 15.3) 8.0 (6.7, 9.8)

Hazard ratio (95% CI) 0.69 (0.574, 0.825)p-value* < 0.000112-month PFS rate by K-M, (95% CI)** 52.4% (47.4, 57.2) 39.2% (34.1, 44.2)18-month PFS rate by K-M, (95% CI)** 43.9% (38.8, 49.0) 29.3% (24.2, 34.6)

Confirmed objective response rate (ORR)

Objective response rate (ORR) n (%) 232 (52.5) 121 (27.3)(95% CI) 47.7, 57.2 23.2, 31.6

Complete response (CR) n (%) 17 (3.8) 9 (2.0)

Partial response (PR) n (%) 215 (48.6) 112 (25.2)

Time to response (TTR)

Median, months (range) 2.7 (1.2, 20.7) 4.0 (1.2, 18.0)

Duration of response (DOR)

Median, months (95% CI) 18.5 (17.8, NE) NE (16.4, NE)

BICR: Blinded Independent Central Review; CI: Confidence interval; K-M: Kaplan-Meier; NE: Not estimable

* 1-sided p-value based on stratified log-rank

** CIs are derived using the log-log transformation with back transformation to untransformed scale

Figure 5: Kaplan-Meier estimates for progression-free survival based on BICR assessment inpatients irrespective of PD-L1 expression

Improvement of PFS was observed across pre-specified subgroups.

Figure 6: Forest plot of progression-free survival based on BICR assessment in patientsirrespective of PD-L1 expression

Treatment emergent anti-drug antibodies (ADA) were detected in 8.5% of MCC patients (study

EMR107000-003, 8.9% for Part A and 8.2% for Part B), 19% of UC patients (study B9991001) and16% of RCC patients (study B9991003). The majority of the ADA were of neutralising character. Noevidence of ADA or neutralising antibodies (nAb) impact on pharmacokinetics, efficacy or safety wasobserved.

Study MS100070-0306 was a multi-centre, open-label, Phase I/II study to evaluate the dose, safetyand tolerability, antitumour activity, pharmacokinetic, and pharmacodynamics of avelumab inpaediatric patients from birth to less than 18 years of age with refractory or relapsed solid tumoursincluding central nervous system (CNS) tumours and lymphoma for which no standard therapy isavailable or for which the patient was not eligible for the existing therapy.

The study enrolled 21 paediatric patients with an age ranged from 3 to 17 years (11 patients ≤ 12 yearsand 10 patients > 12 years) receiving either 10 mg/kg (N=6) or 20 mg/kg (N=15) avelumabintravenously every 2 weeks until confirmed progression, death, or unacceptable toxicity.

The primary tumour categories were soft tissue/bone sarcoma (N=12), CNS malignancies (N=8), andgastro-intestinal (GI) carcinoma (N=1).

There was no complete response (CR) or partial response (PR) in this study as assessed according to

RECIST 1.1.

The European Medicines Agency has waived the obligation to submit the results of studies with

Bavencio in all subsets of the paediatric population for the treatment of Merkel cell carcinoma,urothelial carcinoma, and renal cell carcinoma (see section 4.2 for information on paediatric use).

Avelumab pharmacokinetics (PK) was assessed using a population PK approach for avelumab asmonotherapy and avelumab in combination with axitinib.

Based on a population PK analysis for avelumab as monotherapy and in combination with axitinib,there are no expected clinically meaningful differences in exposure of avelumab between settingsadministered every 2 weeks at 800 mg or 10 mg/kg.

Avelumab is expected to be distributed in the systemic circulation and to a lesser extent in theextracellular space. The volume of distribution at steady state was 4.72 L.

Consistent with a limited extravascular distribution, the volume of distribution of avelumab at steadystate is small. As expected for an antibody, avelumab does not bind to plasma proteins in a specificmanner.

Based on a population pharmacokinetic analysis from 1 629 patients, the value of total systemicclearance (CL) is 0.59 L/day. In the supplemental analysis, avelumab CL was found to decrease overtime: the largest mean maximal reduction (% coefficient of variation [CV%]) from baseline value withdifferent tumour types was approximately 32.1% (CV 36.2%).

Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles)of repeated dosing at 10 mg/kg every 2 weeks, and systemic accumulation was approximately1.25-fold.

The elimination half-life (t½) at the recommended dose is 6.1 days based on the population PKanalysis.

The exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kgevery 2 weeks.

When avelumab 10 mg/kg was administered in combination with axitinib 5 mg, the respectiveexposures of avelumab and axitinib were unchanged compared to the single agents. There was noevidence to suggest a clinically relevant change of avelumab clearance over time in patients withadvanced RCC.

A population pharmacokinetic analysis suggested no difference in the total systemic clearance ofavelumab based on age, gender, race, PD-L1 status, tumour burden, renal impairment and mild ormoderate hepatic impairment.

Total systemic clearance increases with body weight. Steady-state exposure was approximatelyuniform over a wide range of body weights (30 to 204 kg) for body weight normalised dosing.

No clinically important differences in the clearance of avelumab were found between patients withmild (glomerular filtration rate (GFR) 60 to 89 mL/min, Cockcroft-Gault Creatinine Clearance(CrCL); n=623), moderate (GFR 30 to 59 mL/min, n=320) and patients with normal (GFR≥ 90 mL/min, n=671) renal function.

Avelumab has not been studied in patients with severe renal impairment (GFR 15 to 29 mL/min).

No clinically important differences in the clearance of avelumab were found between patients withmild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin between 1 and 1.5 times ULN,n=217) and normal hepatic function (bilirubin and AST ≤ ULN, n=1 388) in a population PK analysis.

Hepatic impairment was defined by National Cancer Institute (NCI) criteria of hepatic dysfunction.

Avelumab has not been studied in patients with moderate hepatic impairment (bilirubin between 1.5and 3 times ULN) or severe hepatic impairment (bilirubin > 3 times ULN).

The pharmacokinetics of avelumab was evaluated in 21 children and adolescents from 3 years to17 years in study MS100070-0306 receiving either 10 mg/kg (N=6) or 20 mg/kg (N=15) avelumabintravenously every 2 weeks until confirmed progression, death, or unacceptable toxicity.

The paediatric PK parameters and the corresponding PK profiles for all patients were evaluatedaccording to dosing and stratified by body weight.

The exposure in paediatric patients receiving 20 mg/kg avelumab were similar or higher compared tothose in adults receiving 10 mg/kg or 800 mg avelumab. In paediatric patients receiving 10 mg/kgavelumab the exposure was lower compared to those in adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once aweek for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosingperiod. Perivascular mononuclear cell cuffing was observed in the brain and spinal cord of monkeystreated with avelumab at ≥ 20 mg/kg for 3 months. Although there was no clear dose-responserelationship, it cannot be excluded that this finding was related to avelumab treatment.

Animal reproduction studies have not been conducted with avelumab. The PD-1/PD-L1 pathway isthought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of

PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus andto result in an increase in foetal loss. These results indicate a potential risk that administration ofavelumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.

No studies have been conducted to assess the potential of avelumab for carcinogenicity orgenotoxicity.

Fertility studies have not been conducted with avelumab. In 1-month and 3-month repeat-dosetoxicology studies in monkeys, there were no notable effects in the female reproductive organs. Manyof the male monkeys used in these studies were sexually immature and thus no explicit conclusionsregarding effects on male reproductive organs can be made.

Mannitol (E421)

Glacial acetic acid

Polysorbate 20 (E432)

Sodium hydroxide

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years

From a microbiological point of view, once opened, the medicinal product should be diluted andinfused immediately.

Chemical and physical in-use stability of the diluted solution has been demonstrated as follows:

Infusion preparation Storage at 2°C to 8°C Storage at 20°C to 25°Cprotected from light and room light

Sodium chloride 9 mg/mL (0.9%) 96 hours 72 hourssolution for infusion

Sodium chloride 4.5 mg/mL (0.45%) 24 hours 24 hourssolution for infusion

From a microbiological point of view, unless the method of dilution precludes the risk of microbialcontamination, the diluted solution should be infused immediately. If not used immediately, in-usestorage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

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

10 mL of concentrate in a vial (Type I glass) with a halobutyl rubber stopper and an aluminium sealfitted with a removable plastic cap.

Pack size of 1 vial.

Bavencio is compatible with polyethylene, polypropylene, and ethylene vinyl acetate infusion bags,glass bottles, polyvinyl chloride infusion sets and in-line filters with polyethersulfone membranes withpore sizes of 0.2 micrometre.

An aseptic technique for the preparation of the solution for infusion should be used.

* The vial should be visually inspected for particulate matter and discoloration. Bavencio is aclear, colourless to slightly yellow solution. If the solution is cloudy, discoloured, or containsparticulate matters, the vial should be discarded.

* An infusion bag of appropriate size (preferably 250 mL) containing either sodium chloride9 mg/mL (0.9%) solution for infusion or with sodium chloride 4.5 mg/mL (0.45%) solution forinfusion should be used. The required volume of Bavencio should be withdrawn from the vial(s)and transferred to the infusion bag. Any partially used or empty vials have to be discarded.

* The diluted solution should be mixed by gently inverting the bag in order to avoid foaming orexcessive shearing of the solution.

* The solution should be inspected to ensure it is clear, colourless, and free of visible particles.

The diluted solution should be used immediately once prepared.

* Do not co-administer other medicinal products through the same intravenous line. Administerthe solution for infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometrein-line or add-on filter as described in section 4.2.

After administration of Bavencio, the line should be flushed with either sodium chloride 9 mg/mL(0.9%) solution for infusion or with sodium chloride 4.5 mg/mL (0.45%) solution for infusion.

Do not freeze or shake the diluted solution. If refrigerated, allow the diluted solution in the intravenousbags to come to room temperature (20°C to 25°C) prior to use.

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

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/17/1214/001

Date of first authorisation: 18 September 2017

Date of latest renewal: 12 March 2025

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

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