Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Merck Europe B.V., Gustav Mahlerplein 102, 1082 MA Amsterdam, The Netherlands
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 number of 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 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.
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.
In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-related 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-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 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 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 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-related 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-related pancreatitis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper).
Avelumab should be withheld in the event of suspected immune-related pancreatitis. Avelumab should be permanently discontinued if immune-related pancreatitis is confirmed (see section 4.2).
Immune-related 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-related 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-related myocarditis (initial dose of 1 to 2 mg/kg/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-related myocarditis. Avelumab should be permanently discontinued if immune-related myocarditis is confirmed (see section 4.2).
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 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).
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).
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 antihyperglycaemics in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatment with avelumab should be resumed when metabolic control is achieved on insulin replacement therapy.
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 clinically important immune-related adverse reactions were reported in less than 1% of patients: myositis, hypopituitarism, uveitis, myasthenia gravis, myasthenic syndrome, cystitis noninfective, sarcoidosis, 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).
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 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.
Avelumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.
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.
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.
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.
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.
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).
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.
Avelumab is 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 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-related 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 tumours including metastatic MCC or locally advanced or metastatic UC receiving 10 mg/kg every 2 weeks of avelumab in clinical studies (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). 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§ |
| Immune system disorders | |
| 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* |
| Hepatobiliary disorders | |
| Uncommon | Autoimmune hepatitis* |
| Rare | Acute hepatic failure*, hepatic failure*, hepatitis*, hepatotoxicity* |
| 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* |
| 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* |
| Injury, poisoning and procedural complications | |
| Very common | Infusion related reaction |
* Immune-related adverse reaction based on medical review
** Sarcoidosis was observed in clinical trials in patients receiving avelumab in combination with platinum-based chemotherapy
† Adverse reactions occurred in estimated 4 000 patients exposed to avelumab monotherapy beyond the pooled analysis.
§ Reaction only observed from study EMR 100070-003 (Part B) after the data cut-off of the pooled analysis, hence frequency estimated
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%).
Adverse reactions reported for 489 patients with advanced RCC treated in two clinical studies with 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). 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 in clinical studies B9991002 and B9991003:
| Frequency | Adverse reactions |
|---|---|
| Infections and infestations | |
| Uncommon | Rash pustular |
| Blood and lymphatic system disorders | |
| Common | Anaemia, thrombocytopenia |
| Uncommon | Lymphopenia, eosinophilia |
| Immune system disorders | |
| 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 |
| Hepatobiliary disorders | |
| Common | Hepatic function abnormal |
| Uncommon | Hepatitis, hepatotoxicity, immune-mediated hepatitis, liver disorder |
| 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 |
| 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 |
| Injury, poisoning and procedural complications | |
| Very common | Infusion related reaction |
Data for immune-related 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.
In patients treated with avelumab as monotherapy, 1.3% (28/2 082) of patients developed immune-related 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-related pneumonitis.
The median time to onset of immune-related 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-related pneumonitis. All 28 patients with immune-related 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-related 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-related pneumonitis. Of these patients, none experienced immune-related pneumonitis Grade ≥3.
The median time to onset of immune-related 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-related pneumonitis did not lead to discontinuation of avelumab in any patient. All 3 patients with immune-related pneumonitis were treated with high-dose corticosteroids for a median of 3.3 months (range: 3 weeks to 22.3 months). Immune-related pneumonitis resolved in 2 (66.7%) of the 3 patients at the time of data cut-off.
In patients treated with avelumab as monotherapy, 1.0% (21/2 082) of patients developed immune-related hepatitis. Of these patients, there were 2 (0.1%) patients with a fatal outcome, and 16 (0.8%) patients with Grade 3 immune-related hepatitis.
The median time to onset of immune-related 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-related hepatitis. All 21 patients with immune-related 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-related 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-related hepatitis. Of these patients, there were 18 (3.7%) patients with Grade 3 and 3 (0.6%) patients with Grade 4 immune-related hepatitis.
The median time to onset of immune-related 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-related hepatitis. All 31 patients with immune-related 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-related hepatitis resolved in 27 (87.1%) of the 31 patients at the time of data cut-off.
In patients treated with avelumab as monotherapy, 1.5% (31/2 082) of patients developed immune-related colitis. Of these patients, there were 10 (0.5%) patients with Grade 3 immune-related colitis.
The median time to onset of immune-related 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-related colitis. All 31 patients with immune-related 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-related 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-related colitis. Of these patients, there were 9 (1.8%) patients with Grade 3 immune-related colitis.
The median time to onset of immune-related 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-related colitis. All 13 patients with immune-related 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-related colitis resolved in 10 (76.9%) of 13 patients at the time of data cut-off.
In patients treated with avelumab as monotherapy, immune-related pancreatitis occurred in less than 1% (¼ 000) of patients across clinical trials 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.
In patients treated with avelumab as monotherapy, immune-related myocarditis occurred in less than 1% (5/4 000) of patients across clinical trials 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.
In patients treated with avelumab as monotherapy, 6.7% (140/2 082) of patients developed immune-related 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-related 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-related 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-related 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-related 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-related 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 developed immune-related adrenal insufficiency. Of these patients, there was 1 (less than 0.1%) patient with Grade 3 immune-related adrenal insufficiency.
The median time to onset of immune-related 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-related adrenal insufficiency. All 11 patients with immune-related 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-related adrenal insufficiency. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-related adrenal insufficiency.
The median time to onset of immune-related 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-related adrenal insufficiency did not lead to discontinuation of avelumab in any patient. Eight (88.9%) patients with immune-related 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.
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.
In patients treated with avelumab as monotherapy, immune-related nephritis occurred in 0.3% (7/2 082) of patients. There was 1 (less than 0.1%) patient with Grade 3 immune-related nephritis.
The median time to onset of immune-related 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-related nephritis. All 7 patients with immune-related nephritis were treated with corticosteroids. 6 (85.7%) of those 7 patients with immune-related nephritis were treated with high-dose corticosteroids for a median of 2.5 weeks (range: 6 days to 2.8 months). Immune-related nephritis resolved in 4 (57.1%) patients at the time of data cut-off.
In patients treated with avelumab in combination with axitinib, immune-related nephritis occurred in 0.4% (2/489) of patients. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-related nephritis.
The median time to onset of immune-related 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-related nephritis did not lead to discontinuation of avelumab in any patient. All 2 patients with immune-related nephritis were treated with high-dose corticosteroids for a median of 1.1 weeks (range: 3 days to 1.9 weeks). Immune-related nephritis resolved in 1 (50%) of the 2 patients at the time of data cut-off.
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.
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.
For study EMR107000-003 in the MCC population, out of 204 patients (88 from Part A and 116 from Part B) with at least one valid anti-drug antibodies (ADA) result at any time point treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 189 (79 from Part A and 110 from Part B) were evaluable for treatment-emergent ADA and 16 (8.5%) (7 from Part A and 9 from Part B) tested positive.
For study B9991001 in the UC population, out of 344 patients with at least one valid ADA result at any time point treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks plus BSC, 325 were evaluable for treatment-emergent ADA and 62 (19.1%) tested positive.
For study B9991002 and study B9991003 in the RCC population, out of 480 patients with at least one valid ADA result at any time point treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily, 453 were evaluable for treatment-emergent ADA and 66 (14.6%) tested positive.
Overall, there was no evidence of altered pharmacokinetic profile, increased incidence of infusion reactions or effects on efficacy with anti-avelumab antibody development. The impact of neutralizing antibodies (nAb) is unknown.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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