4.1. Therapeutic indications

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

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

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

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 as monotherapy is 800 mg administered intravenously over 60 minutes every 2 weeks.

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

The recommended dose of Bavencio in combination with axitinib is 800 mg administered intravenously over 60 minutes every 2 weeks and axitinib 5 mg orally taken twice daily (12 hours apart) 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 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-mediated 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

For Bavencio in combination with axitinib, see below

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

Pancreatitis

Suspected pancreatitis

Withhold

Confirmed pancreatitis

Permanently discontinue

Myocarditis

Suspected myocarditis

Withhold

Confirmed myocarditis

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

Skin reactions

Grade 3 rash

Withhold until adverse reactions recover to Grade 0‑1

Grade 4 or recurrent Grade 3 rash or confirmed Stevens–Johnson syndrome (SJS) or Toxic epidermal necrolysis (TEN)

Permanently discontinue

Other immune-mediated adverse reactions (including other clinically important immune‑mediated adverse reactions listed under 'Other immune-mediated adverse reactions' (see section 4.4))

For any of the following:

• Grade 2 or Grade 3 clinical signs or symptoms of an immune-mediated 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-mediated 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)

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 equivalent followed by a taper should be considered. Rechallenge with Bavencio or axitinib or sequential rechallenge with both Bavencio and axitinib after recovery should be considered. Dose reduction according 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 or total bilirubin ≥ 3 times ULN, both Bavencio and axitinib should be permanently discontinued and corticosteroid 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 product information for recommended dose modifications for axitinib.

Special populations

Elderly

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

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.

Paediatric population

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

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 infusion or with sodium chloride 4.5 mg/mL (0.45%) solution for infusion. 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

Traceability

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

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 patients treated with avelumab as monotherapy, 24.6% (513/2 082) of patients experienced infusion-related reactions. Of these, 97.7% (501/513) had a first infusion‑related reaction during the first 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 with temporary or permanent discontinuation of avelumab, administration of corticosteroids and/or supportive care.

For suspected immune-mediated 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-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 suggest that the risk of immune-mediated adverse reactions following immune‑checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre‑existing AID. In addition, flares of 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 been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for signs and symptoms of immune-mediated pneumonitis and causes other than immune-mediated 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/ body weight (bw)/day prednisone or equivalent, followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 immune-mediated pneumonitis until resolution, and permanently 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 been reported in patients receiving avelumab (see section 4.8).

Patients should be monitored for changes in liver function and symptoms of immune-mediated hepatitis 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/day prednisone or equivalent, followed by a corticosteroid taper).

Avelumab should be withheld for Grade 2 immune-mediated hepatitis until resolution and permanently 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 other than 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 a corticosteroid taper).

Avelumab should be withheld for Grade 2 or Grade 3 immune-mediated colitis until resolution, and permanently 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 have been 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. In symptomatic patients, obtain gastroenterology consultation and laboratory investigations (including imaging) to ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered for immune-mediated pancreatitis (initial dose of 1 to 2 mg/kg bw/day prednisone or equivalent followed by a corticosteroid taper).

Avelumab should be withheld in the event of suspected immune-mediated pancreatitis. Avelumab should 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 have been 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. In symptomatic patients, obtain cardiologic consultation and laboratory investigations to ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered for immune-mediated myocarditis (initial dose of 1 to 2 mg/kg bw/day prednisone or equivalent followed by a corticosteroid taper). If no improvement within 24 hours on corticosteroids, additional immunosuppression (e.g., mycophenolate, infliximab, anti-thymocyte globulin) should be considered.

Avelumab should be withheld in the event of suspected immune-mediated myocarditis. Avelumab should 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 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/ bw/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-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 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-mediated adverse reactions

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

For suspected immune-mediated 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-mediated adverse reaction returns to Grade 1 or less following corticosteroid taper. Avelumab should be permanently 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 with higher than expected frequencies of Grade 3 and Grade 4 ALT and AST elevation compared to avelumab alone (see section 4.8).

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

Avelumab should be withheld for Grade 2 hepatotoxicity until resolution and permanently discontinued for Grade 3 or Grade 4 hepatotoxicity. Corticosteroids should be considered for Grade ≥ 2 events (see section 4.2).

Patients excluded from clinical studies

Patients with the following conditions were excluded from clinical studies: 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.

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

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg dose, that is to say essentially “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 be taken 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 allergic reactions. 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 be provided with the Patient Card which instructs to carry the Card at all times.

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 machines until they are certain that avelumab does not adversely affect them.

4.8. Undesirable effects

Summary of the safety profile

Avelumab is associated with immune-mediated 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 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 were immune-mediated adverse reactions and infusion‑related reaction (see section 4.4).

Tabulated list of adverse reactions

The safety of avelumab as monotherapy has been evaluated in 2 082 patients with solid tumours including metastatic MCC or locally advanced or metastatic UC receiving 10 mg/kg every 2 weeks of avelumab 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: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data)). Within each 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

Blood and lymphatic system disorders

Very common

Anaemia

Common

Lymphopenia, thrombocytopenia

Uncommon

Eosinophilia§

Not known

Neutropenia*

Immune system disorders

Very common

Infusion-related reaction#

Uncommon

Hypersensitivity, drug hypersensitivity, sarcoidosis**

Rare

Anaphylactic reaction, Type I hypersensitivity

Endocrine disorders

Common

Hypothyroidism*, hyperthyroidism*

Uncommon

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

Rare

Adrenocortical insufficiency acute*, hypopituitarism*

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Hyponatraemia

Uncommon

Hyperglycaemia*

Rare

Diabetes mellitus*, Type 1 diabetes mellitus*

Nervous system disorders

Common

Headache, dizziness, neuropathy peripheral

Uncommon

Myasthenia gravis*†, myasthenic syndrome*†

Rare

Guillain‑Barré Syndrome*, Miller Fisher syndrome*

Eye disorders

Rare

Uveitis*

Cardiac disorders

Rare

Myocarditis*

Vascular disorders

Common

Hypertension

Uncommon

Hypotension, flushing

Respiratory, thoracic and mediastinal disorders

Very common

Cough, dyspnoea

Common

Pneumonitis*

Rare

Interstitial lung disease*

Gastrointestinal disorders

Very common

Nausea, diarrhoea, constipation, vomiting, abdominal pain

Common

Dry mouth

Uncommon

Ileus, colitis*

Rare

Pancreatitis*, autoimmune colitis*, enterocolitis*, autoimmune pancreatitis*, enteritis*, proctitis*

Not known

Gastritis*

Hepatobiliary disorders

Uncommon

Autoimmune hepatitis*

Rare

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

Not known

Sclerosing cholangitis*

Skin and subcutaneous tissue disorders

Common

Pruritus*, rash*, dry skin, rash maculo‑papular*

Uncommon

Eczema, dermatitis, rash pruritic*, psoriasis*, erythema*, rash erythematous*, rash generalised*, rash macular*, rash papular*

Rare

Erythema multiforme*, purpura*, vitiligo*, pruritus generalised*, dermatitis exfoliative*, pemphigoid*, dermatitis psoriasiform*, drug eruption*, lichen planus*

Musculoskeletal and connective tissue disorders

Very common

Back pain, arthralgia

Common

Myalgia

Uncommon

Myositis*, rheumatoid arthritis*

Rare

Arthritis*, polyarthritis*, oligoarthritis*, Sjogren's syndrome*

Not known

Polymyalgia rheumatica*

Renal and urinary disorders

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*

Investigations

Very common

Weight decreased

Common

Blood creatinine increased, blood alkaline phosphatase increased, lipase increased, 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 thyroid stimulating hormone increased*

* Immune-mediated adverse reaction based on medical review

** Sarcoidosis was observed in clinical studies in patients receiving avelumab in combination with platinum‑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 pooled analysis

Renal cell carcinoma

Summary of the safety profile

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 clinical studies.

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%).

Tabulated list of adverse reactions

Adverse reactions reported for 489 patients with advanced RCC treated in two clinical studies or reported 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: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each 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

Infections and infestations

Uncommon

Rash pustular*

Blood and lymphatic system disorders

Common

Anaemia, thrombocytopenia

Uncommon

Lymphopenia, eosinophilia

Not known

Neutropenia*

Immune system disorders

Very common

Infusion‑related reaction#

Common

Hypersensitivity

Endocrine disorders

Very common

Hypothyroidism*

Common

Hyperthyroidism*, adrenal insufficiency*, thyroiditis*

Uncommon

Autoimmune thyroiditis*, hypophysitis*

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Hyperglycaemia*

Uncommon

Diabetes mellitus*, Type 1 diabetes mellitus*

Nervous system disorders

Very common

Headache, dizziness

Common

Neuropathy peripheral

Uncommon

Myasthenia gravis*, myasthenic syndrome*

Cardiac disorders

Uncommon

Myocarditis*

Vascular disorders

Very common

Hypertension

Common

Hypotension, flushing

Respiratory, thoracic and mediastinal disorders

Very common

Dysphonia, cough, dyspnoea

Common

Pneumonitis*

Gastrointestinal disorders

Very common

Diarrhoea, nausea, constipation, vomiting, abdominal pain

Common

Dry mouth, colitis*

Uncommon

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

Not known

Gastritis*

Hepatobiliary disorders

Common

Hepatic function abnormal*

Uncommon

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

Not known

Sclerosing cholangitis*

Skin and subcutaneous tissue disorders

Very common

Rash*, pruritus*

Common

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

Uncommon

Drug eruption*, erythema multiforme*, psoriasis*

Musculoskeletal and connective tissue disorders

Very common

Arthralgia, back pain, myalgia

Uncommon

Arthritis*

Not known

Polymyalgia rheumatica*, Sjogren's syndrome*

Renal and urinary disorders

Common

Acute kidney injury*

General disorders and administrative site conditions

Very common

Fatigue, chills, asthenia, pyrexia

Common

Oedema peripheral, influenza like illness

Investigations

Very common

Weight decreased, alanine aminotransferase (ALT) increased*, aspartate aminotransferase (AST) increased*

Common

Blood creatinine increased, amylase increased, lipase increased, gamma‑glutamyltransferase increased, blood alkaline phosphatase increased, blood creatine phosphokinase increased*, blood thyroid stimulating 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

Description of selected adverse reactions

Data for immune-mediated adverse reactions for avelumab as a monotherapy are based on 2 082 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 for avelumab in combination with axitinib are based on 489 patients in studies B9991002 and B9991003 in 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 developed immune-mediated pneumonitis. Of these patients, there was 1 (less than 0.1%) patient with a fatal outcome, 1 (less than 0.1%) patient with Grade 4, and 6 (0.3%) patients with Grade 3 immune-mediated pneumonitis.

The median time to onset of immune-mediated pneumonitis was 2.5 months (range: 3 days to 13.8 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. All 28 patients with immune-mediated pneumonitis were treated with corticosteroids and 21 (75%) of the 28 patients were treated with high‑dose corticosteroids for a median of 9 days (range: 1 day to 2.3 months). Immune-mediated pneumonitis resolved in 18 (64.3%) of the 28 patients at the time of data cut‑off.

In patients treated with avelumab in combination with axitinib, 0.6% (3/489) of patients developed immune-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 to 8.6 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. All 3 patients with immune-mediated pneumonitis were treated with high‑dose corticosteroids for a median 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 developed immune-mediated hepatitis. Of these patients, there were 2 (0.1%) patients with a fatal outcome, and 16 (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 to 14.8 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. All 21 patients with immune-mediated hepatitis were treated with corticosteroids and 20 (95.2%) of the 21 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 developed immune-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 to 14.5 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. All 31 patients with immune-mediated hepatitis were treated for hepatitis including 30 (96.8%) patients treated 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 day to 10.2 months). Immune-mediated hepatitis resolved in 27 (87.1%) of the 31 patients at the time of data cut‑off.

Immune-mediated colitis

In patients treated with avelumab as monotherapy, 1.5% (31/2 082) of patients developed immune-mediated colitis. Of these patients, there were 10 (0.5%) patients with Grade 3 immune-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. All 31 patients with immune-mediated colitis were treated with corticosteroids and 19 (61.3%) of the 31 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 developed immune-mediated colitis. Of these patients, there were 9 (1.8%) patients with Grade 3 immune-mediated colitis.

The median time to onset of immune-mediated colitis was 5.1 months (range: 2.3 weeks to 14 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. All 13 patients with immune-mediated colitis were treated with corticosteroids and 12 (92.3%) of the 13 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 than 1% (1/4 000) of patients across clinical studies in multiple tumour types and in 0.6% (3/489) of patients receiving avelumab in combination with axitinib including 2 (0.4%) patients with fatal outcome.

Immune-mediated myocarditis

In patients treated with avelumab as monotherapy, immune-mediated myocarditis occurred in less than 1% (5/4 000) of patients across clinical studies in multiple tumour types and in 0.6% (3/489) of patients receiving avelumab in combination with axitinib including 2 (0.4%) patients with fatal outcome.

Immune-mediated endocrinopathies

Thyroid disorders

In patients treated with avelumab as monotherapy, 6.7% (140/2 082) of patients developed immune-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%) patients with 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). The median 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 developed immune-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%) patients with 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). The median 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.

Adrenal insufficiency

In patients treated with avelumab as monotherapy, 0.5% (11/2 082) of patients developed immune-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 to 7.6 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 adrenal insufficiency. All 11 patients with immune-mediated adrenal insufficiency were treated with corticosteroids, and 5 (45.5%) of the 11 patients received high‑dose systemic corticosteroids (≥ 40 mg prednisone or equivalent) for a median of 2 days (range: 1 day to 24 days). Adrenal insufficiency resolved 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 developed immune-mediated adrenal insufficiency. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-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 than 15.5 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 corticosteroids and 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 the 9 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 alternative aetiology occurred in 0.2% (5/2 082) of patients. All 5 patients experienced Grade 3 Type 1 diabetes mellitus.

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 1 diabetes 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 an alternative aetiology occurred in 1.0% (5/489) of patients. Of these patients, there was 1 (0.2%) patient with Grade 3 Type 1 diabetes mellitus.

The median time to onset of Type 1 diabetes mellitus was 1.9 months (range: 1.1 months to 7.3 months).

Avelumab was discontinued in 0.2% (1/489) of patients due to Type 1 diabetes mellitus. All 5 patients with Type 1 diabetes mellitus were treated with insulin. Type 1 diabetes mellitus did not resolve in any of 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 to 21.9 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. All 7 patients with immune-mediated nephritis were treated with corticosteroids. 6 (85.7%) of those 7 patients with immune-mediated nephritis were treated with high‑dose corticosteroids for a median of 2.5 weeks (range: 6 days to 2.8 months). Immune-mediated nephritis resolved in 4 (57.1%) patients at the time of data cut‑off.

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

The median time to onset of immune-mediated nephritis was 1.2 months (range: 2.9 weeks to 1.8 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 patients with 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 the time of data cut‑off.

Hepatotoxicity (in combination with axitinib)

In patients treated with avelumab in combination with axitinib, Grades 3 and Grade 4 increased ALT and 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 immune checkpoint inhibitors which might also occur during treatment with avelumab: pancreatic exocrine insufficiency, coeliac disease.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store

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.