Bavencio Adverse Reactions

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" as follows).
Summary of the safety profile: The safety of avelumab as monotherapy has been evaluated in 1,738 patients with solid tumours including metastatic MCC receiving 10 mg/kg every 2 weeks of avelumab in clinical studies. In this patient population, the most common adverse reactions with avelumab were fatigue (32.4%), nausea (25.1%), diarrhoea (18.9%), decreased appetite (18.4%), constipation (18.4%), infusion-related reactions (17.1%), weight decreased (16.6%), and vomiting (16.2%).
The most common Grade ≥ 3 adverse reactions were anaemia (6.0%), dyspnoea (3.9%), and abdominal pain (3.0%). Serious adverse reactions were immune-related adverse reactions and infusion-related reaction (see Precautions).
Tabulated list of adverse reactions: Adverse reactions reported for avelumab as monotherapy in patients with metastatic MCC, or locally advanced or metastatic UC are presented in Table 7. In all studies, avelumab was administered at 10 mg/kg every 2 weeks.
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. (See Table 7.)

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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 8.
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. (See Table 8.)

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Description of selected adverse reactions: Data for immune-mediated adverse reactions for avelumab as a monotherapy are based on 1,650 patients in the phase I study EMR100070-001 in solid tumours and 88 patients in study EMR100070-003, and for avelumab in combination with axitinib are based on 489 patients in study B9991002 and B9991003 who received avelumab (see Pharmacology: Pharmacodynamics under Actions).
The management guidelines for these adverse reactions are described in Precautions.
Immune-mediated pneumonitis: In patients treated with avelumab as monotherapy,1.3% (28/2082) 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, and6 (0.3%) patients with Grade 3 immune-related 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 weeks (range: 4 days to more than 4, 9 months).
Avelumab was discontinued in 0.4% (9/2082) 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% (21/2082) 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% (13/2082) of patients due to immune-related hepatitis. All 21 patients with immune-related hepatitis 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-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% (31/2082) 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% (11/2082) 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-related pancreatitis: In patients treated with avelumab as monotherapy, immune-related 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-related myocarditis: 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.
Immune-mediated endocrinopathies: Thyroid disorders: In patients treated with avelumab as monotherapy, 6.7% (140/2082) 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 3 (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% (4/2082) 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% (8/1,738) of patients developed immune-mediated adrenal insufficiency. Of these patients, there was 1 (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% (2/2082) of patients due to immune-mediated adrenal insufficiency. All 11 patients with immune-related adrenal insufficiency were treated with corticosteroids, 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-medited 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% (5/2082) 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% (2/2082) 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% (7/2082) 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% (4/2082) 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.
Immunogenicity: In ADA positive patients, there may be an increased risk for infusion-related reactions (about 40% and 25% in ADA ever-positive and ADA never-positive patients, respectively). For study B9991001 in the UC population, out of the 344 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks plus BSC, and that had a valid ADA result at any time, 66 (19.2%) patients tested ADA positive with 4 patients positive at baseline. Among the 326 patients with at least one valid post-baseline ADA result without positive baseline ADA, 62 (19.0%) had treatment-induced ADA. Of these 62 treatment-emergent ADA positive patients, 60 had treatment-induced nAb. Based on data available, including the low incidence of immunogenicity, the impact of ADA on pharmacokinetics, efficacy and safety is uncertain, the impact of neutralizing antibodies (nAb) is unknown.
For study B999102 and study B999103 in the RCC population, out of the 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. The new ADA method with improved sensitivity was used in the RCC population. Overall, there was no evidence of altered pharmacokinetic profile, increased incidence of infusion reactions or effects on efficacy with anti-avelumab antibody development.