Adverse reactions : תופעות לוואי

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 (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*
Frequency               Adverse reactions
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-mediated 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

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 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

Frequency               Adverse reactions
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
*
Immune-mediated adverse reaction based on medical review

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 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.

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 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.

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.

Immunogenicity
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 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 Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/