Long-term follow-up subgroup analyses from JAVELIN Bladder 100 confirm avelumab first-line maintenance activity regardless of the first-line chemotherapy regimen

Long-term follow-up from the JAVELIN Bladder 100 trial confirms that avelumab first-line maintenance provides similar overall survival (OS) and progression-free survival (PFS) benefits in patients with advanced urothelial carcinoma who are progression-free following either standard-of-care first-line cisplatin- or carboplatin-based chemotherapy, with an acceptable safety profile. The median OS measured from start of chemotherapy further supports the use of avelumab first-line maintenance as standard of care in this setting.

To date, international guidelines recommend the use of first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab first-line maintenance for eligible patients with advanced urothelial carcinoma (aUC) without disease progression.^1-3 These guidelines are based on the results of the randomised, phase III JAVELIN Bladder 100 trial. In this trial, patients with aUC that had not progressed with first-line platinum-based chemotherapy who received first-line maintenance with avelumab plus best supportive care (BSC) demonstrated a significantly longer overall survival (OS) and progression-free survival (PFS) from start of maintenance (randomisation) vs. BSC alone.^4,5 With long-term follow-up, median OS was 23.8 vs. 15.0 months, respectively and the median investigator-assessed PFS was 5.5 vs. 2.1 months, respectively.⁵ At ASCO GU 2023, Dr. Sridhar reported post-hoc analyses of long-term outcomes from start of maintenance (≥2 years of follow-up in all patients) by first-line chemotherapy regimen and OS from start of first-line chemotherapy.⁶

Study design

Eligible patients had unresectable locally advanced or metastatic UC that had not progressed after 4 to 6 cycles of first-line gemcitabine in combination with either cisplatin or carboplatin.  Following a treatment-free interval of 4-10 weeks after the end of first-line chemotherapy, patients were randomised (1:1) to the avelumab first-line maintenance + BSC arm (N= 350) or the BSC alone arm (N= 350).^4,5

Exploratory analyses presented at ASCO GU 2023 included an analysis of outcomes from start of maintenance in subgroups defined by first-line chemotherapy regimen (cisplatin- or carboplatin-based chemotherapy). Patients who switched first-line platinum regimens are not included because of the small number of patients in this subgroup. A second exploratory analysis included OS from start of first-line chemotherapy (calculated from the date of first chemotherapy dose provided by the treating investigator) in the overall population and by first-line chemotherapy regimen.⁶

Results

At data cut-off, median follow-up from randomisation was 38.0 months in the avelumab + BSC arm and 39.6 months in the BSC alone arm. Across both study arms, patients who received carboplatin + gemcitabine were older, more likely to have an ECOG performance status ≥1 and a creatinine clearance below 60 ml/min as compared to patients who had received cisplatin plus gemcitabine. This is consistent with standard criteria defining cisplatin ineligibility.⁷ In both patient subgroups, the most common reason for treatment discontinuation was found to be disease progression.⁶

OS and PFS from start of maintenance (randomisation)

Overall survival from start of maintenance (randomisation) was longer in the avelumab + BSC arm than in the BSC alone arm in both the cisplatin + gemcitabine (cisplatin-subgroup) and carboplatin + gemcitabine (carboplatin-subgroup) subgroups. In the cisplatin-subgroup, median OS was 25.1 months for avelumab + BSC and was 17.5 months for BSC alone (HR[95%CI]: 0.79[0.611-1.020]). Corresponding values for carboplatin plus gemcitabine were 20.8 and 13.0 months (HR[95%CI]: 0.69[0.516-0.925]). In both subgroups, investigator-assessed PFS from start of maintenance was also longer in the avelumab + BSC arm vs. the BSC alone arm. In the cisplatin-subgroup, median investigator-assessed PFS was 5.7 months in the avelumab + BSC arm and 2.0 months in the BSC alone arm (HR[95%CI]: 0.56[0.446-0.713]). In the carboplatin-subgroup, median investigator-assessed PFS was 3.7 months in the avelumab + BSC arm and 2.0 months in the BSC alone arm (HR[95%CI]: 0.48[0.362-0.640]).⁶

OS from start of first-line chemotherapy

In the overall population, median OS measured from the start of first-line chemotherapy was 29.7 months in the avelumab + BSC arm and 20.5 months in the BSC alone arm (HR[95%CI]: 0.77[0.636-0.921]). OS measured from the start of first-line chemotherapy was also longer with avelumab + BSC vs. BSC alone, irrespective of the first-line chemotherapy regimen received.⁶ In the cisplatin- and carboplatin- subgroups, median OS from the start of first-line chemotherapy was 31.0 vs. 23.0 months and 25.8 vs. 17.6 months, respectively.

Long-term safety was similar in both the cisplatin- and carboplatin- subgroups, with no new safety concerns identified. Grade ≥3 treatment-related adverse events with avelumab plus BSC were reported in 16.5% of patients in the cisplatin-subgroup and in 22.5% of patients in the carboplatin-subgroup.⁶

Conclusion

With at least two years of follow-up since randomisation (or since start of maintenance) in all patients, long-term outcomes from JAVELIN Bladder 100 confirm that avelumab first-line maintenance provides similar OS and investigator-assessed PFS benefits in patients with advanced UC who are progression-free following either standard-of-care first-line cisplatin- or carboplatin-based chemotherapy, with an acceptable safety profile. In the overall population, median OS from start of first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab first-line maintenance was 29.7 months.⁶

References

1. NCCN Clinical Practice Guidelines: Bladder Cancer. V3.2022.
2. Cathomas R, et al. Eur Urol. 2022;81(1):95-103.
3. Powles T, et al. Ann Oncol. 2022;33:244-58.
4. Powles T, et al. N Engl J Med. 2020;383(13):1218-30.
5. Powles T, et al. J Clin Oncol; 2022;40(Suppl 6). Abstract 487.
6. Sridhar S, et al. Presented at ASCO GU 2023; Abstract 508.
7. Galsky MD, et al. J Clin Oncol. 2011;29(17):2432-8.

Article produced by ARIEZ International at the request of Pfizer/Merck based on the following article: “Sridhar S, et al. Presented at ASCO GU 2023; Abstract 508”

BE-AVEBL-00160 – 02/2023

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

SHORT SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT Bavencio 20 mg/mL concentrate for solution for infusion. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mL of concentrate contains 20 mg of avelumab. One vial of 10 mL contains 200 mg of avelumab. Avelumab is a human monoclonal IgG1 antibody directed against the immunomodulatory cell surface ligand protein PD-L1 and produced in Chinese hamster ovary cells by recombinant DNA technology. For the full list of excipients, see section 6.1. PHARMACEUTICAL FORM Concentrate for solution for infusion (sterile concentrate). Clear, colourless to slightly yellow solution. The solution pH is in the range of 5.0 ‑ 5.6 and the osmolality is between 285 and 350 mOsm/kg. 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). 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‑related adverse reactions are described in section 4.4.

Guidelines for withholding or discontinuation of Bavencio

* 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). 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. Renal impairment No dose adjustment is needed for patients with mild or moderate renal impairment (see section 5.2). There are insufficient data in patients with severe renal impairment for dosing recommendations. Hepatic impairment No dose adjustment is needed for patients with mild hepatic impairment (see section 5.2). There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations. Method of administration Bavencio is for intravenous infusion only. It must not be administered as an intravenous push or bolus injection.

Bavencio has to be diluted with either sodium chloride 9 mg/mL (0.9%) solution for injection or with sodium chloride 4.5 mg/mL (0.45%) solution for injection. It is administered over 60 minutes as an intravenous infusion using a sterile, non‑pyrogenic, low‑protein binding 0.2 micrometre in‑line or add‑on filter. For instructions on the preparation and administration of the medicinal product, see section 6.6. CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. UNDESIRABLE EFFECTS Summary of the safety profile 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). 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. Adverse reactions in patients treated with avelumab as monotherapy

Blood and lymphatic system disorders: Very common: Anaemia; Common: Lymphopenia, thrombocytopenia; Uncommon: Eosinophilia^§. Immune system disorders: Uncommon: Hypersensitivity, drug hypersensitivity; 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, dyspnea; 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 increase; Uncommon: Alanine aminotransferase (ALT) increased*, aspartate aminotransferase (AST) increased*, blood creatine phosphokinase increased*. Injury, poisoning and procedural complications: Very common: Infusion related reaction.

^* Immune‑related adverse reaction based on medical review

^† 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. Adverse reactions in patients treated with avelumab in combination with axitinib in clinical studies B9991002 and B9991003. 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

Description of selected adverse reactions: 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. Immune‑related pneumonitis 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. Immune‑related hepatitis 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. Immune‑related colitis 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. 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‑related endocrinopathies Thyroid disorders

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. Adrenal insufficiency 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. 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-related nephritis and renal dysfunction 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. 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.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Belgium Federal Agengy for Medicinal and Health Products Service Vigilance Postbus 97 B-1000 BRUSSEL Madou. Website: www.eenbijwerkingmelden.be or cww.notifieruneffetindesirable.be. e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.. Luxemburg Centre Régional de Pharmacovigilance de Nancy Bâtiment de Biologie Moléculaire et de Biopathologie (BBB) CHRU de Nancy – Hôpitaux de Brabois Rue du Morvan 54 511 VANDOEUVRE LES NANCY CEDEX. Tél: (+33) 3 83 65 60 85 / 87 - e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.  or Direction de la Santé Division de la Pharmacie et des Médicaments 20, rue de Bitbourg - L-1273 Luxembourg-Hamm Tél.: (+352) 2478 5592. e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.  Lien pour le formulaire : https://guichet.public.lu/fr/entreprises/sectoriel/sante/medecins/notification-effets-indesirables-medicaments.html. MARKETING AUTHORISATION HOLDER: Merck Europe B.V. Gustav Mahlerplein 102 1082 MA Amsterdam - The Netherlands. MARKETING AUTHORISATION NUMBER(S): EU/1/17/1214/00. LOCAL REPRESENTATIVE: Merck n.v./s.a., Ildefonse Vandammestraat 5/7B, 1560 Hoeilaart, Belgium. DELIVERY MODE: Medicinal product on medical prescription. DATE OF REVISION OF THE TEXT: 12/2022.