This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Bavencio 20 mg/mL concentrate for solution for infusion

2. Qualitative and quantitative composition

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 surface ligand protein PD-L1 and produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless to slightly yellow solution. The solution pH is in the range of 5.0 - 5.6 and the osmolality is between 270 and 330 mOsm/kg.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

Posology

The recommended dose of Bavencio is 10 mg/kg body weight administered intravenously over 60 minutes every 2 weeks.

Administration of Bavencio should continue according to the recommended schedule until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than two weeks, and no need for salvage therapy, could continue treatment.

Premedication

Patients have to be premedicated with an antihistamine and with paracetamol prior to the first 4 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 required based on individual safety and tolerability; see Table 1.

Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 1: Guidelines for withholding or discontinuation of Bavencio

Treatment-related adverse reaction

Severity*

Treatment modification

Infusion-related reactions

Grade 1 infusion-related reaction

Reduce infusion rate by 50%

Grade 2 infusion-related reaction

Withhold until adverse reactions recover to Grade 0-1; restart infusion with a 50% slower rate

Grade 3 or Grade 4 infusion-related reaction

Permanently discontinue

Pneumonitis

Grade 2 pneumonitis

Withhold until adverse reactions recover to Grade 0-1

Grade 3 or Grade 4 pneumonitis or recurrent Grade 2 pneumonitis

Permanently discontinue

Hepatitis

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN

Withhold until adverse reactions recover to Grade 0-1

AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN

Permanently discontinue

Colitis

Grade 2 or Grade 3 colitis or diarrhoea

Withhold until adverse reactions recover to Grade 0-1

Grade 4 colitis or diarrhoea or recurrent Grade 3 colitis

Permanently discontinue

Endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, hyperglycaemia)

Grade 3 or Grade 4 endocrinopathies

Withhold until adverse reactions recover to Grade 0-1

Nephritis and renal dysfunction

Serum creatinine more than 1.5 and up to 6 times ULN

Withhold until adverse reactions recover to Grade 0-1

Serum creatinine more than 6 times ULN

Permanently discontinue

Other immune-related adverse reactions (including myocarditis myositis, hypopituitarism, uveitis, Guillain-Barré syndrome)

For any of the following:

• Grade 2 or Grade 3 clinical signs or symptoms of an immune-related adverse reaction not described above.

Withhold until adverse reactions recover to Grade 0-1

For any of the following:

• Life threatening or Grade 4 adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy)

• Recurrent Grade 3 immune-related adverse reaction

• Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks

• Persistent Grade 2 or Grade 3 immune-mediate adverse reactions lasting 12 weeks or longer

Permanently discontinue

* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.03)

Special populations

Elderly

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

Paediatric population

The safety and efficacy of Bavencio in children and adolescents below 18 years of age have not been established.

Renal impairment

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.

Hepatic impairment

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

Method of administration

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

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

For instructions on the preparation and administration of the medicinal product, see section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Infusion-related reactions

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 avelumab should be permanently discontinued (see section 4.2).

For Grade 1 infusion-related reactions, the infusion rate should be slowed by 50% for the current infusion. For patients with Grade 2 infusion-related reactions, the infusion should be temporary discontinued 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 to receive avelumab under close monitoring, after appropriate infusion rate modification and premedication with paracetamol and antihistamine (see section 4.2).

In clinical trials, 98.6% (433/439) of patients with infusion-related reactions had a first infusion-related reaction during the first 4 infusions of which 2.7% (12/439) were Grade ≥ 3. In the remaining 1.4% (6/439) of patients, infusion-related reactions occurred after the first 4 infusions and all were of Grade 1 or Grade 2.

Immune-related adverse reactions

Most immune-related adverse reactions with avelumab were reversible and managed with temporary or permanent discontinuation of avelumab, administration of corticosteroids and/or supportive care.

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

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

Immune-related pneumonitis

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

Patients should be monitored for signs and symptoms of immune-related pneumonitis and causes other than immune-related pneumonitis should be ruled out. Suspected pneumonitis should be confirmed with radiographic imaging.

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

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

Immune-related hepatitis

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

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

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

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

Immune-related colitis

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

Patients should be monitored for signs and symptoms of immune-related colitis and causes other than immune-related colitis should be ruled out. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper).

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

Immune-related endocrinopathies

Immune-related thyroid disorders, immune-related adrenal insufficiency, and Type 1 diabetes mellitus have been reported in patients receiving avelumab (see section 4.8). Patients should be monitored 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, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Hypothyroidism should be managed with replacement therapy and hyperthyroidism with anti-thyroid medicinal product, as needed.

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

Adrenal insufficiency

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

Avelumab should be withheld for Grade 3 or Grade 4 symptomatic adrenal insufficiency (see section 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. Initiate treatment with insulin for Type 1 diabetes mellitus. Avelumab should be withheld and anti-hyperglycaemics in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatment with avelumab should be resumed when metabolic control is achieved on insulin replacement therapy.

Immune-related nephritis and renal dysfunction

Avelumab can cause immune-related 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/day prednisone or equivalent followed by a corticosteroid 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 4 nephritis.

Other immune-related adverse reactions

Other clinically important immune-related adverse reactions were reported in less than 1% of patients: myocarditis including fatal cases, myositis, hypopituitarism, uveitis, and Guillain-Barré syndrome (see section 4.8).

For suspected immune-related adverse reactions, ensure adequate evaluation to confirm aetiology or to rule out other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids to be administered. Avelumab should be resumed when the immune-related adverse reaction returns to Grade 1 or less following corticosteroid taper. Avelumab should be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for Grade 4 immune-related adverse reaction (see section 4.2).

Patients excluded from clinical studies

Patients with the following conditions were excluded from clinical trials: active central nervous system (CNS) metastasis; active or a history of autoimmune 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 C.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been conducted with avelumab.

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential should be advised to avoid becoming pregnant while receiving avelumab and should use effective contraception during treatment with avelumab and for at least 1 month after the last dose of avelumab.

Pregnancy

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 of pregnancy, blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss (see section 5.3). These results indicate a potential risk, based on its mechanism 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 the potential to be transmitted from the mother to the developing foetus. It is not recommended to use avelumab during pregnancy unless the clinical condition of the woman requires treatment with avelumab.

Breast-feeding

It is unknown whether avelumab is excreted in human milk. Since it is known that antibodies can be secreted 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 month after the last dose due to the potential for serious adverse reactions in breast-fed infants.

Fertility

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 were no notable effects in the female reproductive organs in monkeys based on 1-month and 3-month repeat-dose toxicity studies (see section 5.3).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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

The safety of avelumab has been evaluated in 1,738 patients with solid tumours including metastatic MCC receiving 10 mg/kg every 2 weeks of avelumab in clinical studies. In this patient population, the most common adverse reactions with avelumab were fatigue (32.4%), nausea (25.1%), diarrhoea (18.9%), decreased appetite (18.4%), constipation (18.4%), infusion-related reactions (17.1%), weight decreased (16.6%), and vomiting (16.2%).

The most common Grade ≥ 3 adverse reactions were anaemia (6.0%), dyspnoea (3.9%), and abdominal pain (3.0%). Serious adverse reactions were immune-related adverse reactions and infusion-related reaction (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions reported for 88 patients with metastatic MCC treated with avelumab 10 mg/kg and adverse reactions reported for 1,650 patients in a phase I study in other solid tumours are presented in Table 2.

These reactions are presented by system organ class and 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Adverse reactions in patients treated with avelumab in clinical study EMR100070-003 and adverse reactions from a phase I study (EMR100070-001) in other solid tumours

Frequency

Adverse drug reactions

Blood and lymphatic system disorders

Very common

Anaemia

Common

Lymphopenia

Uncommon

Thrombocytopenia, eosinophilia§

Immune system disorders

Uncommon

Drug hypersensitivity, hypersensitivity anaphylactic reaction, Type I hypersensitivity

Endocrine disorders

Common

Hypothyroidism*

Uncommon

Adrenal insufficiency*, hyperthyroidism*, thyroiditis*, autoimmune thyroiditis*, adrenocortical insufficiency acute*, autoimmune hypothyroidism*, hypopituitarism*

Metabolism and nutrition disorders

Very common

Decreased appetite

Uncommon

Diabetes mellitus*, Type 1 diabetes mellitus*

Nervous system disorders

Common

Headache, dizziness, neuropathy peripheral

Uncommon

Guillain-Barré Syndrome*

Eye disorders

Uncommon

Uveitis*

Cardiac disorders

Rare

Myocarditis*

Vascular disorders

Common

Hypertension, hypotension

Uncommon

Flushing

Respiratory, thoracic and mediastinal disorders

Very common

Cough, dyspnoea

Common

Pneumonitis*

Gastrointestinal disorders

Very common

Nausea, diarrhoea, constipation, vomiting, abdominal pain

Common

Dry mouth

Uncommon

Colitis*, autoimmune colitis*, enterocolitis*, ileus

Hepatobiliary disorders

Uncommon

Autoimmune hepatitis*, acute hepatic failure*, hepatic failure*, hepatitis*

Skin and subcutaneous tissue disorders

Common

Rash*, pruritus*, rash maculo-papular*, dry skin

Uncommon

Rash pruritic*, erythema*, rash generalised*, psoriasis*, rash erythematous*, rash macular*, rash papular*, dermatitis exfoliative*, erythema multiforme*, pemphigoid*, pruritus generalised*, eczema, dermatitis

Musculoskeletal and connective tissue disorders

Very common

Back pain, arthralgia

Common

Myalgia

Uncommon

Myositis*

Renal and urinary disorders

Uncommon

Tubulointerstitial nephritis*

General disorders and administrative site conditions

Very common

Fatigue, pyrexia, oedema peripheral

Common

Asthenia, chills, influenza like illness

Uncommon

Systemic inflammatory response syndrome*

Investigations

Very common

Weight decreased

Common

Gamma-glutamyltransferase increased, blood alkaline phosphatase increased, amylase increased, lipase increased, blood creatinine increased

Uncommon

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

Injury, poisoning and procedural complications

Very common

Infusion related reaction

* Immune-related adverse reaction based on medical review

§ Reaction only observed from study EMR 100070-003 (part B) after the data cut-off of the pooled analysis, hence frequency estimated

Description of selected adverse reactions

Data for the following immune-related adverse reactions are based on 1,650 patients in the phase I study EMR100070-001 in other solid tumours and 88 patients in study EMR100070-003 who received avelumab (see section 5.1).

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

Immune-related pneumonitis

Across clinical studies, 1.2% (21/1,738) of patients developed immune-related pneumonitis. Of these patients there was 1 (0.1%) patient with a fatal outcome, 1 (0.1%) patient with Grade 4, and 5 (0.3%) patients with Grade 3 immune-related pneumonitis.

The median time to onset of immune-related pneumonitis was 2.5 months (range: 3 days to 11 months). The median duration was 7 weeks (range: 4 days to more than 4 months).

Avelumab was discontinued in 0.3% (6/1,738) of patients due to immune-related pneumonitis. All 21 patients with immune-related pneumonitis were treated with corticosteroids and 17 (81%) of the 21 patients were treated with high-dose corticosteroids for a median of 8 days (range: 1 day to 2.3 months). Immune-related pneumonitis resolved in 12 (57%) of the 21 patients at the time of data cut-off.

Immune-related hepatitis

Across clinical studies, 0.9% (16/1,738) of patients developed immune-related hepatitis. Of these patients, there were 2 (0.1%) patients with a fatal outcome, and 11 (0.6%) patients with Grade 3 immune-related hepatitis.

The median time to onset of immune-related hepatitis was 3.2 months (range: 1 week to 15 months). The median duration was 2.5 months (range: 1 day to more than 7.4 months).

Avelumab was discontinued in 0.5% (9/1,738) of patients due to immune-related hepatitis. All 16 patients with immune-related hepatitis treated with corticosteroids and 15 (94%) of the 16 patients received high-dose corticosteroids for a median of 14 days (range: 1 day to 2.5 months). Immune-related hepatitis resolved in 9 (56%) of the 16 patients at the time of data cut-off.

Immune-related colitis

Across clinical studies, 1.5% (26/1,738) of patients developed immune-related colitis. Of these patients, there were 7 (0.4%) patients with Grade 3 immune-related colitis.

The median time to onset of immune-related colitis was 2.1 months (range: 2 days to 11 months). The median duration was 6 weeks (range: 1 day to more than 14 months).

Avelumab was discontinued in 0.5% (9/1,738) of patients due to immune-related colitis. All 26 patients with immune-related colitis were treated with corticosteroids and 15 (58%) of the 26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). Immune-related colitis resolved in 18 (70%) of 26 patients at the time of data cut-off.

Immune-related endocrinopathies

Thyroid disorders

Across clinical studies, 6% (98/1,738) of patients developed immune-related thyroid disorders, of which 90 (5%) patients with hypothyroidism, 7 (0.4%) with hyperthyroidism, and 4 (0.2%) with thyroiditis. Of these patients, there were 3 (0.2%) patients with Grade 3 immune-related thyroid disorders.

The median time to onset of thyroid disorders was 2.8 months (range: 2 weeks to 13 months). The median duration was not estimable (range: 1 day to more than 26 months).

Avelumab was discontinued in 0.1% (2/1,738) of patients due to immune-related thyroid disorders. Thyroid disorders resolved in 7 (7%) of the 98 patients at the time of data cut-off.

Adrenal insufficiency

Across clinical studies, 0.5% (8/1,738) of patients developed immune-related adrenal insufficiency. Of these patients, there was 1 (0.1%) patient with Grade 3.

The median time to onset of immune-related adrenal insufficiency was 2.5 months (range: 1 day to 8 months). The median duration was not estimable (range: 2 days to more than 6 months).

Avelumab was discontinued in 0.1% (2/1,738) of patients due to immune-related adrenal insufficiency. All 8 patients with immune-related adrenal insufficiency were treated with corticosteroids, 4 (50%) of the 8 patients received high-dose systemic corticosteroids (≥ 40 mg prednisone or equivalent) followed by a taper for a median of 1 day (range: 1 day to 24 days). Adrenal insufficiency resolved in 1 patient with corticoid treatment at the time of data cut-off.

Type 1 diabetes mellitus

Type 1 diabetes mellitus without an alternative aetiology occurred in 0.1% (2/1,738) of patients including two Grade 3 reactions that led to permanent discontinuation of avelumab.

Immune-related nephritis and renal dysfunction

Immune-related nephritis occurred in 0.1% (1/1,738) of patients receiving avelumab leading to permanent discontinuation of avelumab.

Immunogenicity

Of 1,738 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 1,627 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 96 (5.9%) tested positive. In ADA positive patients, there may be an increased risk for infusion-related reactions (about 40% and 25% in ADA ever-positive and ADA never-positive patients, respectively). Based on data available, including the low incidence of immunogenicity, the impact of ADA on pharmacokinetics, efficacy and safety is uncertain, while the impact of neutralizing antibodies (nAb) is unknown.

Reporting of suspected adverse reactions

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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, monoclonal antibodies, ATC code: not yet assigned.

Mechanism of action

Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the programmed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 on cytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses.

Avelumab has also shown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC).

Clinical efficacy and safety

Merkel cell carcinoma (study EMR100070-003)

The efficacy and safety of avelumab was investigated in the study EMR100070-003 with two parts. Part A was a single-arm, multi-centre study conducted in patients with histologically confirmed metastatic MCC, whose disease had progressed on or after chemotherapy administered for distant metastatic disease, with a life expectancy of more than 3 months. Part B included patients with histologically confirmed metastatic MCC who were treatment-naïve to systemic therapy in the metastatic setting.

Patients with active or a history of central nervous system (CNS) metastasis; active or a history of autoimmune 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 C were excluded.

Patients received avelumab at a dose of 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater 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.

For Part A, the major efficacy outcome measure was confirmed best overall response (BOR); secondary efficacy outcome measures included duration of response (DOR), and progression-free survival (PFS).

For Part A, the efficacy analysis was conducted in all 88 patients after a minimum follow-up of 18 months Patients received a median of 7 doses of avelumab (range: 1 dose to 61 doses), and the median duration of treatment was 17 weeks (range: 2 weeks to 132 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 metastatic MCC, 26 (30%) with 2 prior therapies, and 10 (11%) with 3 or more prior therapies. Forty-seven (53%) of the patients had visceral metastases.

Table 3 summarises efficacy endpoints in patients receiving avelumab at the recommended dose for study EMR100070-003, Part A.

Table 3: Response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC in study EMR100070-003 (Part A)

Efficacy endpoints (Part A)

(per RECIST v1.1, IERC)

Results

(N=88)

Objective response rate (ORR)

Response rate, CR+PR* n (%)

(95% CI)

29 (33.0%)

(23.3, 43.8)

Confirmed best overall response (BOR)

Complete response (CR)* n (%)

Partial response (PR)* n (%)

10 (11.4%)

19 (21.6%)

Duration of response (DOR)a

Median, months

(95% CI)

Minimum, maximum

≥ 6 months by K-M, (95% CI)

≥ 12 months by K-M, (95% CI)

NR

(18, not estimable)

2.8, 24.9+

93% (75, 98)

71% (51, 85)

Progression-free survival (PFS)

Median PFS, months

(95% CI)

6-month PFS rate by K-M, (95% CI)

12-month PFS rate by K-M, (95% CI)

2.7

(1.4, 6.9)

40% (29, 50)

29% (19, 39)

CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: Independent Endpoint Review Committee; K-M: Kaplan-Meier; NR: Not reached; +denotes a censored value

* CR or PR was confirmed at a subsequent tumour assessment

a 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 of avelumab. Twenty-two out of 29 (76%) patients with response were reported to have responded within 7 weeks after the first dose of avelumab.

The Kaplan-Meier curve 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)

Tumour samples were evaluated for PD-L1 tumour cell expression, and for Merkel cell polyomavirus (MCV) using an investigational immunohistochemistry (IHC) assay. Table 4 summarises the PD-L1 expression and MCV status of patients with metastatic MCC in study EMR100070-003 (Part A).

Table 4: Objective response rates by PD-L1 expression and MCV status in patients with metastatic MCC in study EMR100070-003 (Part A)

Avelumab

ORR (95% CI)

PD-L1 expression at cut-off of 1%

Positive (n=58)

Negative (n=16)

N=74a

36.2% (24.0, 49.9)

18.8% (4.0, 45.6)

PD-L1 expression at cut-off of 5%

Positive (n=19)

Negative (n=55)

N=74a

57.9% (33.5, 79.7)

23.6% (13.2, 37.0)

IHC-MCV tumour status

Positive (n=46)

Negative (n=31)

N=77b

28.3% (16.0, 43.5)

35.5% (19.2, 54.6)

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

a Based on data from patients evaluable for PD-L1

b Based on data from patients evaluable for MCV by immunohistochemistry (IHC)

The clinical utility of PD-L1 as a predictive biomarker in MCC has not been established.

For Part B, the major efficacy outcome measure was durable response, defined as objective response (complete response (CR) or partial response (PR)) with a duration of at least 6 months; secondary outcome measures included BOR, DOR, PFS, and OS.

For Part B, an interim analysis of efficacy was conducted with 39 patients who received at least one dose. Of those, 30 (77%) were males, the median age was 75 years (range: 47 years to 88 years), 33 (85%) patients were Caucasian, and 31 (79%) patients and 8 (21%) patients had an ECOG performance status 0 and 1, respectively. Twenty-nine patients had at least 13 weeks of follow-up at the time of the data cut-off.

Table 5 summarises efficacy endpoints in patients receiving avelumab at the recommended dose for study EMR100070-003, Part B.

Table 5: Response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC in study EMR100070-003 (Part B)

Efficacy endpoints (Part B)

(per RECIST v1.1, IERC)

Results

Objective response rate (ORR)

Response rate, CR+PR* n (%)

(95% CI)

(N=29)

18 (62.1%)

(42.3, 79.3)

Confirmed best overall response (BOR)

Complete response (CR)* n (%)

Partial response (PR)* n (%)

(N=29)

4 (13.8%)

14 (48.3%)

Duration of response (DOR)a

Median, months

(95% CI)

Minimum, maximum

≥ 3 months by K-M, (95% CI)

(N=29)

NR

(4.0, not estimable)

1.2+, 8.3+

93% (61, 99)

Progression-free survival (PFS)

Median PFS, months

(95% CI)

3-month PFS rate by K-M, (95% CI)

(N=39)

9.1

(1.9, not estimable)

67% (48, 80)

CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: Independent Endpoint Review Committee; K-M: Kaplan-Meier; NR: Not reached; +denotes a censored value

* CR or PR was confirmed at a subsequent tumour assessment

a Based on number of patients with confirmed response (CR or PR)

Figure 2 presents the Kaplan-Meier curve for PFS for the 39 patients enrolled into Part B who received at least one dose of study drug prior to the data cut-off for the interim analysis.

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

Paediatric population

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 (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Distribution

Avelumab is expected to be distributed in the systemic circulation and to a lesser extent in the extracellular 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 steady state is small. As expected for an antibody, avelumab does not bind to plasma proteins in a specific manner.

Elimination

Based on a population pharmacokinetic analysis from 1,629 patients, the value of total systemic clearance (CL) is 0.59 L/day. In the supplemental analysis, avelumab CL was found to decrease over time: the largest mean maximal reduction (% coefficient of variation [CV%]) from baseline value with different 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 approximately 1.25-fold.

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

Linearity/non-linearity

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

Special populations

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

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

Renal impairment

No clinically important differences in the clearance of avelumab were found between patients with mild (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).

Hepatic impairment

No clinically important differences in the clearance of avelumab were found between patients with mild 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 1.5 and 3 times ULN) or severe hepatic impairment (bilirubin > 3 times ULN).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing period. Perivascular mononuclear cell cuffing was observed in the brain and spinal cord of monkeys treated with avelumab at ≥ 20 mg/kg for 3 months. Although there was no clear dose-response relationship, 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 is thought 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 and to result in an increase in foetal loss. These results indicate a potential risk that administration of avelumab 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 or genotoxicity.

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

6. Pharmaceutical particulars
6.1 List of excipients

Mannitol

Glacial acetic acid

Polysorbate 20

Sodium hydroxide

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened vial

2 years

After opening

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

After preparation of infusion

Chemical and physical in-use stability of the diluted solution has been demonstrated for 24 hours at 20°C to 25°C and room light. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the diluted solution should be infused immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user (see section 6.6).

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

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

6.5 Nature and contents of container

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

Pack size of 1 vial.

6.6 Special precautions for disposal and other handling

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 with pore sizes of 0.2 micrometre.

The diluted solution must not be stored longer than a total of 24 hours under refrigerated conditions (2°C to 8°C) or up to 8 hours at room temperature (20°C to 25°C). If refrigerated, allow the vials and/or intravenous bags to come to room temperature prior to use.

Handling instructions

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 a clear, colourless to slightly yellow solution. If the solution is cloudy, discoloured, or contains particulate matters, the vial should be discarded.

• An infusion bag of appropriate size (preferably 250 mL) containing either sodium chloride 9 mg/mL (0.9%) solution for injection or with sodium chloride 4.5 mg/mL (0.45%) solution for injection 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 or excessive 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. Administer the solution for infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometre in-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 injection or with sodium chloride 4.5 mg/mL (0.45%) solution for injection.

Do not freeze or shake the diluted solution.

Disposal

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

7. Marketing authorisation holder

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

8. Marketing authorisation number(s)

EU/1/17/1214/001

9. Date of first authorisation/renewal of the authorisation

18 September 2017

10. Date of revision of the text

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.