Avelumab, a fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent.1 The drug is an IgG1 lambda immunoglobulin.1
Avelumab is used for the treatment of metastatic Merkel cell carcinoma in patients who are ≥12 years of a 1, 3 avelumab has been designated an orphan drug by FDA for the treatment of this cancer.12
The use of avelumab for Merkel cell carcinoma is based principally on the results of an open-label, multicenter, noncomparative, phase 2 study (JAVELIN Merkel 200).1, 3 The trial had 2 parts: Part A included patients with metastatic Merkel cell carcinoma with disease progression on or after treatment with chemotherapy for distant metastatic disease and Part B included patients with metastatic Merkel cell carcinoma who were treatment naïve.1 Patients received avelumab 10 mg/kg administered as an IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred.1 The primary measure of efficacy was confirmed overall response rate as assessed by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST).1
Part A enrolled 88 adults with metastatic Merkel cell carcinoma that had progressed during or following cytotoxic chemotherapy for metastatic disease.1, 3 In Part A of the study, the median age of patients was 73 years; 92% were White, 74% were male, 53% had visceral metastases, 65% had received one prior chemotherapy regimen for metastatic disease, and 35% had received 2 or more prior therapies.1, 3 All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1, 3 Most patients (66%) were programmed-death ligand-1 (PD-L1)-positive (defined as PD-L1 expression of any intensity in at least 1% of tumor cells) and 18% had negative PD-L1 expression as detected by an immunohistochemistry assay.1, 3 Among 77 patients with evaluable tumor samples, Merkel cell polyomavirus was detected in 52% of patients.1 At a median follow-up of 40.8 months, the objective response rate was 33%; complete response was achieved in 11.4% of patients.13 The median duration of response was 40.5 months (range: 2.8‒41.5 months) and median overall survival was 12.6 months.13
Part B enrolled 116 treatment-naïve adults with metastatic Merkel cell carcinoma.1, 14 In Part B, the median age of patients was 74 years; 65% were White, and 70% were male.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Eighteen percent of patients were PD-L1-positive, and Merkel cell polyomavirus was detected in 60% of patients.1 At a median follow-up of 21.2 months, the objective response rate was 39.7%; complete response was achieved in 16.4% of patients.14 The median duration of response was 18.2 months (range: 1.2‒28.3 months) and median overall survival was 20.3 months.14 At a median follow-up of 54.3 months, the median overall survival remained at 20.3 months.15
Merkel cell carcinoma is a rare and aggressive skin cancer, with 5-year survival rates ranging from 64% for patients without metastases to 17% to 29% for patients with distant metastases.333 Surgical excision of the primary lesion (wide local excision), regional lymph node dissection, and adjuvant radiation therapy are commonly employed to treat localized Merkel cell carcinoma.333 lmmunotherapy has emerged as a first-line treatment option in patients with inoperable stage III and IV Merkel cell carcinoma.333 In such patients, European experts recommend first-line treatment via enrollment in a clinical trial (preferred) or immunotherapy (i.e., avelumab, pembrolizumab, retifanlimab, or nivolumab) plus best supportive care (alternative).333 Second-line treatment includes enrollment in a clinical trial (preferred) or palliative radiotherapy and/or chemotherapy plus best supportive care (alternative).333
Avelumab is used for first-line maintenance treatment in patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.1, 16
Avelumab also is used for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing chemotherapy or within 12 months of platinum-containing chemotherapy in the neoadjuvant or adjuvant setting.1, 11
First-line Maintenance Treatment of Urothelial Carcinoma
The current indication for avelumab for the first-line treatment of locally advanced or metastatic urothelial carcinoma is based principally on the results from an open-label, randomized, phase 3 study (JAVELIN Bladder 100).1, 16 JAVELIN Bladder 100 included 700 adult patients with unresectable, locally advanced or metastatic urothelial carcinoma that did not progress with first-line platinum-containing chemotherapy (4-6 cycles of gemcitabine plus cisplatin or carboplatin).1, 16 The primary measure of efficacy was overall survival, which was measured in all randomized patients and in those with PD-L1-positive tumors.1, 16 In this study, the median age of patients was 69 years; 67% were White, 55% had visceral metastases prior to chemotherapy, 77% were male, and 51% had PD-L1-positive tumors.1 Fifty-six percent of patients received prior treatment with gemcitabine plus cisplatin, 38% previously received gemcitabine plus carboplatin, and 6% of patients received both regimens previously.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 Patients were randomized (stratified by best response to chemotherapy and site of metastasis at the time first-line chemotherapy was initiated) to receive avelumab 10 mg/kg administered as an IV infusion every 2 weeks plus best supportive care or best supportive care alone; treatment was initiated within 4-10 weeks after the last dose of chemotherapy and continued until disease progression or unacceptable toxicity occurred.1 Patients with a contraindication to or previous exposure to immune checkpoint inhibitors and those who received adjuvant or neoadjuvant systemic therapy in the preceding 12 months were excluded.16
At a median follow-up of >19 months in each group, median overall survival was substantially longer with avelumab compared to best supportive care alone (21.4 versus 14.3 months, respectively).1, 16 At a median follow-up of 38 months for the avelumab group and 39.6 months for the control group, median overall survival continued to be substantially longer with avelumab compared to placebo (23.8 versus 15 months, respectively).1, 17
Previously Treated Urothelial Carcinoma
The current indication for avelumab in the treatment of locally advanced or metastatic urothelial carcinoma is based principally on the results for a cohort of patients with urothelial carcinoma in an open-label, multicenter, noncomparative, phase 1 study (JAVELIN Solid Tumor); the cohort of patients with urothelial carcinoma included 242 adults with locally advanced or metastatic urothelial carcinoma that had progressed during or following platinum-containing chemotherapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.1, 5, 11 The primary measure of efficacy was confirmed objective response rate as assessed by an independent review committee according to RECIST.1, 5, 11 In this study, the median age of patients in the urothelial carcinoma cohort was 68 years; 80% were White, 83% had visceral metastases, 72% were male, and 44% had nonbladder urothelial carcinoma (23% had upper urinary tract disease).1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 In the cohort of patients with urothelial carcinoma, 47, 32, or 20% of patients received prior treatment with cisplatin-, carboplatin-, or both cisplatin- and carboplatin-based regimens, respectively; 4% of patients had disease progression following platinum-containing therapy in the neoadjuvant or adjuvant setting only.1 Patients received avelumab 10 mg/kg administered as an IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred.1, 11 Patients with a history of autoimmune disease (except for type 1 diabetes mellitus, vitiligo, psoriasis, or thyroid disease not requiring immunosuppressive therapy); those with active CNS metastasis or a history of CNS metastasis; those with HIV, HBV, or HCV infection; those with a history of allogeneic stem-cell or solid organ transplant; those diagnosed with other malignancies within the past 5 years; and those with conditions requiring therapy with immunosuppressive agents were excluded from the study.1, 5, 11 Patients were eligible for enrollment in the study regardless of their PD-L1 status.1
At a minimum follow-up of 13 weeks or 6 months, the overall response rate for patients in the urothelial carcinoma cohort of this study was 13.3 or 16.1%, respectively; complete responses were achieved in 4 or 5.6%, respectively, of patients.1 At a minimum follow-up of 13 weeks or 6 months, the median duration of response was not estimable.1 The median time to response was 2 months (range: 1.3-11 months).1 Among patients with evaluable data on PD-L1 expression, there were no clear differences in objective response rates based on PD-L1 expression.1 At a median follow-up of 31.9 months, the objective response rate for patients in the urothelial carcinoma cohort of this study was 16.5%; complete responses were achieved in 4.1% of patients.18 The median duration of response was 20.5 months, and median overall survival was 7 months.18
The European Association of Urology released updated guidelines on the treatment of muscle-invasive and metastatic bladder cancer in 2026.334 In patients with metastatic disease who are eligible for combination therapy (e.g., ECOG performance status of 0 to 2, estimated glomerular filtration rate >30 mL/minute [>50 mL/min for cisplatin], with adequate organ function), the EAU recommends first-line treatment with enfortumab vedotin plus pembrolizumab.334 If there are contraindications to enfortumab vedotin or it is unavailable, patients should be offered platinum-containing combination chemotherapy (cisplatin or carboplatin plus gemcitabine) followed by maintenance treatment with avelumab or cisplatin/gemcitabine plus nivolumab.334 In patients who are not eligible for enfortumab vedotin or checkpoint inhibitor therapy, platinum-containing chemotherapy plus gemcitabine is recommended.334 In patients who are ineligible for combination therapy, single-agent treatment with atezolizumab or pembrolizumab is recommended when PD-L1 positive and best supportive care is recommended for all other patients.334 Selection of later-line therapy options is variable and depends on which agents the patient received for first-line treatment.334
Avelumab is used in combination with axitinib for the first-line treatment of advanced renal cell carcinoma.1, 19
The current indication for avelumab in combination with axitinib for the treatment of advanced renal cell carcinoma is based principally on the results of an open-label, randomized, controlled trial (JAVELIN Renal 101) in 886 patients who had not received treatment for advanced renal cell carcinoma.1, 19 The primary measures of efficacy were progression-free survival (assessed by a blinded independent review committee according to RECIST), and overall survival in patients with PD-L1-positive tumors.1, 19 In this study, the median age of patients enrolled was 61 years; 75% were male, 75% were White, and 63% had PD-L1-positive tumors.1 All patients enrolled in the study had an ECOG performance status of 0 or 1.1 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group status was favorable, intermediate, and poor in 21, 62, and 16% of patients, respectively.1 Patients were randomized (stratified by ECOG performance status score and geographic region) to receive avelumab in combination with axitinib or sunitinib monotherapy.1, 19 Treatment was continued until disease progression or unacceptable toxicity occurred.1 Patients randomized to axitinib received a dosage of 5 mg orally twice daily in combination with avelumab 10 mg/kg IV every 2 weeks; the dosage of axitinib was increased to 7 mg twice daily, followed by an increase to 10 mg twice daily if the initial 5-mg dosage was tolerated without Grade 2 or greater axitinib-related adverse events for 2 consecutive weeks.1, 19 Patients randomized to sunitinib received a dosage of 50 mg orally once daily for 4 consecutive weeks followed by 2 weeks without therapy.1, 19 Patients with autoimmune disease, active CNS metastases, and current or prior use of glucocorticoids or other immunosuppressants within 7 days prior to randomization were excluded.1, 19 Patients were eligible for enrollment in the study regardless of their PD-L1 status.1
At the time of data analysis, median progression-free survival in the overall population was 13.8 months with avelumab plus axitinib and 8.4 months with sunitinib.1, 19 Median progression-free survival was also substantially higher with avelumab plus axitinib compared to sunitinib in patients with PD-L1-positive tumors (13.8 versus 7.2 months, respectively).19 Objective response rates were also substantially higher with avelumab plus axitinib compared to sunitinib in both the overall population (51.4 versus 25.7%, respectively; complete responses in 3.4 versus 1.8%, respectively) and the PD-L1-positive population (55.2 versus 25.5%, respectively; complete responses in 4.4 versus 2.1%, respectively).19 These findings were sustained at the final analysis (minimum follow-up of 68 months).20 The final analysis for overall survival was not statistically different between groups in either population.1, 20
Prognosis is generally poor in patients with metastatic renal cell carcinoma, including those who have undergone complete tumor resection.110 First-line therapy with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors has been shown to provide benefits in patients with advanced renal cell carcinoma; however, relapsed or refractory renal cell carcinoma eventually develops in most patients.111 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have become a standard for the treatment of advanced renal cell carcinoma.110
The American Society of Clinical Oncology (ASCO) recommends that all patients with metastatic renal cell carcinoma who require systemic therapy in the first-line setting undergo risk stratification.112 Patients with intermediate- or poor-risk disease should be offered combination treatment with 2 immune checkpoint inhibitors (i.e., ipilimumab and nivolumab) or an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor (e.g., nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib, avelumab plus axitinib, pembrolizumab plus lenvatinib).112 Treatment selection should be based on adverse events, comorbid conditions, provider experience, and treatment cost.112 Patients with favorable-risk disease who require systemic therapy may be offered an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor.112
Avelumab is administered by IV infusion.1
Avelumab is available as a 20 mg/mL, preservative-free, injection concentrate in single-use vials containing 200 mg of the drug.1 Further dilution is required prior to administration.1
Store avelumab injection vial protected from light at 2-8°C.1 Do not shake or freeze.1
Avelumab is administered as an IV infusion through an IV line containing an in-line, sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 micron).1
Do not co-administer other drugs through the same IV line.1
Visually inspect vial for particulate matter and discoloration.1 Avelumab is a clear, colorless to slightly yellow solution.1 Discard vial if the solution is cloudy, discolored, or contains particulate matter.1 Withdraw the required volume of drug from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% or 0.45% Sodium Chloride Injection.1 Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing.1 Inspect the solution to ensure it is clear, colorless, and free of visible particles.1 Discard any partially used or empty vials.1
Store diluted avelumab solution protected from light at room temperature (25°C) for no more than 4 hours from the time of dilution or under refrigeration (2-8°C) for no more than 24 hours from the time of dilution.1 If refrigerated, allow the diluted solution to come to room temperature prior to administration.1
Infuse final diluted avelumab solution IV over 60 minutes.1
The recommended adult dosage of avelumab for the treatment of metastatic Merkel cell carcinoma (MCC) is 800 mg given by IV infusion over 60 minutes once every 2 weeks until disease progression or unacceptable toxicity.1
Locally Advanced or Metastatic Urothelial Carcinoma
The recommended adult dosage of avelumab for the treatment of urothelial carcinoma (UC) is 800 mg given by IV infusion over 60 minutes once every 2 weeks until disease progression or unacceptable toxicity.1
The recommended adult dosage of avelumab for the treatment of renal cell carcinoma (RCC) is 800 mg given by IV infusion over 60 minutes once every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.1 Consult axitinib's prescribing information for details on axitinib dose escalation.1
The recommended dosage of avelumab for the treatment of metastatic Merkel cell carcinoma in pediatric patients 12 years of age and older is 800 mg given by IV infusion over 60 minutes once every 2 weeks until disease progression or unacceptable toxicity.1
Dosage Modification for Toxicity
Permanently discontinue avelumab in patients experiencing any life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.1
Withhold in patients experiencing any severe (grade 3) immune-mediated adverse reaction.1
Adverse Reaction | Severitya | Dosage Modification |
|---|---|---|
Immune-mediated Adverse Reactions | ||
Pneumonitis | Grade 2 | Withholdb |
Pneumonitis | Grade 3 or 4 | Permanently discontinue |
Colitis | Grade 2 or 3 | Withholdb |
Colitis | Grade 4 | Permanently discontinue |
Hepatitis with no tumor involvement of the liver | AST or ALT increases to more than 3 and up to 8 x ULN OR Total bilirubin increases to more than 1.5 and up to 3 x ULN | Withholdb |
Hepatitis with no tumor involvement of the liver | AST or ALT increases to more than 8 x ULN OR Total bilirubin increases to more than 3 x ULN | Permanently discontinue |
Hepatitis with tumor involvement of the liverc | Baseline AST or ALT is more than 1 and up to 3 x ULN and increases to more than 5 and up to 10 x ULN OR Baseline AST or ALT is more than 3 and up to 5 x ULN and increases to more than 8 and up to 10 x ULN | Withholdb |
Hepatitis with tumor involvement of the liverc | AST or ALT increases to more than 10 x ULN OR Total bilirubin increases to more than 3 x ULN | Permanently discontinue |
Endocrinopathies | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
Nephritis with renal dysfunction | Grade 2 or 3 increased blood creatinine | Withholdb |
Nephritis with renal dysfunction | Grade 4 increased blood creatinine | Permanently discontinue |
Exfoliative dermatologic conditions | Suspected SJS, TEN, or DRESS | Withholdb |
Exfoliative dermatologic conditions | Confirmed SJS, TEN, or DRESS | Permanently discontinue |
Myocarditis | Grade 2, 3, or 4 | Permanently discontinue |
Neurological toxicities | Grade 2 | Withholdb |
Neurological toxicities | Grade 3 or 4 | Permanently discontinue |
Other Adverse Reactions | ||
Infusion-related reactions | Grade 1 or 2 | Interrupt or slow the rate of infusion |
Infusion-related reactions | Grade 3 or 4 | Permanently discontinue |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DRESS, drug rash with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrosis; ULN, upper limit of normal.
aBased on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03
bResume in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg/day or less (or equivalent) within 12 weeks of initiating corticosteroids.
cIf AST and ALT ≤ ULN at baseline, withhold or permanently discontinue avelumab based on recommendations for hepatitis where there is no tumor involvement of the liver.
Adverse Reaction | Severitya | Dosage Modification |
|---|---|---|
Liver enzyme elevations | AST or ALT at least 3 x ULN but <10 x ULN without concurrent total bilirubin at least 2 x ULN | Withhold both agents until adverse reactions recover to grades 0-1b Consider rechallenge with avelumab or axitinib or sequential rechallenge with both after recoveryc |
Liver enzyme elevations | AST or ALT at least 10 x ULN or >3 x ULN with concurrent total bilirubin at least 2 x ULN | Permanently discontinue both agentsb |
aBased on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03
bConsider corticosteroid therapy
cDose reduction according to axitinib Full Prescribing Information should be considered if rechallenging with axitinib.
Dosage modifications are recommended if hepatic impairment occurs due to treatment.1 For patients with pre-existing hepatic impairment, the manufacturer makes no recommendations for dosage adjustment.1
Dosage modifications are recommended if renal impairment occurs due to treatment.1 For patients with pre-existing renal impairment, the manufacturer makes no recommendations for dosage adjustment.1
The manufacturer makes no special dosage recommendations for geriatric patients.1
Severe and Fatal Immune-mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue.1 Immune-mediated adverse reactions can occur at any time after starting treatment with a programmed cell death protein (PD)-1/programmed cell death ligand 1 (PD-L1) blocking antibody.1 While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.1
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies.1 Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions.1 Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.1 In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.1
Withhold or permanently discontinue avelumab depending on severity.1 In general, if interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg per day prednisone or equivalent) until improvement to grade 1 or less.1 Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.1 Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.1
Avelumab can cause immune-mediated pneumonitis.1 Immune-mediated pneumonitis occurred in 1.1% (21/1854) of patients, including fatal (0.1%), grade 4 (0.1%), grade 3 (0.3%) and grade 2 (0.6%) adverse reactions.1 Pneumonitis led to permanent discontinuation in 0.3% and withholding of avelumab in 0.3% of patients.1
Systemic corticosteroids were required in all (21/21) patients with pneumonitis.1 Pneumonitis resolved in 57% (12/21) of patients.1 Of the 5 patients in whom avelumab was withheld for pneumonitis, 5 reinitiated treatment after symptom improvement; of these, none had recurrence of pneumonitis.1
With other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.1
Avelumab can cause immune-mediated colitis.1 The primary component of the immune-mediated colitis consists of diarrhea.1 Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis.1 In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.1
Immune-mediated colitis occurred in 1.5% (27/1854) of patients receiving avelumab, including grade 3 (0.4%) and grade 2 (0.8%) adverse reactions.1 Colitis led to permanent discontinuation in 0.5% and withholding of avelumab in 0.4% of patients.1 Systemic corticosteroids were required in all (27/27) patients with colitis.1 Colitis resolved in 70% (19/27) of patients.1 Of the 8 patients in whom avelumab was withheld for colitis, 5 reinitiated treatment after symptom improvement; of these, 40% had recurrence of colitis.1
Hepatotoxicity and Immune-mediated Hepatitis
Avelumab monotherapy can cause immune-mediated hepatitis.1 Immune-mediated hepatitis occurred in 1.1% (20/1854) of patients receiving avelumab, including fatal (0.1%), grade 3 (0.8%), and grade 2 (0.2%) adverse reactions.1 Hepatitis led to permanent discontinuation in 0.6% and withholding of avelumab in 0.2% of patients.1
Systemic corticosteroids were required in all (20/20) patients with hepatitis.1 Hepatitis resolved in 60% (12/20) of patients.1 Of the 4 patients in whom avelumab was withheld for hepatitis, 4 reinitiated treatment after symptom improvement; of these, 25% had recurrence.1
Avelumab in combination with axitinib can cause hepatotoxicity with higher-than expected frequencies of grade 3 and 4 ALT and AST elevation compared to avelumab alone.1 Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy.1 For elevated liver enzymes, interrupt avelumab and axitinib and consider administering corticosteroids as needed.1
In patients treated with avelumab in combination with axitinib in the advanced renal cell carcinoma (RCC) trials, increased ALT and AST were reported in 9% (grade 3) and 7% (grade 4) of patients.1 In patients with ALT ≥3 times the upper limit of normal (ULN) (grades 2-4), ALT resolved to grades 0-1 in 92%.1 Among the 73 patients who were rechallenged with either avelumab or axitinib administered as a single agent or with both drugs, recurrence of ALT ≥3 times ULN was observed in 0 patients receiving avelumab, 6 patients receiving axitinib, and 15 patients receiving the combination.1 Recovery to grade 0-1 occurred in 88% of these patients.1
Immune-mediated hepatitis was reported in 7% of patients, including 4.9% with grade 3 or 4 immune-mediated hepatitis.1 Hepatotoxicity led to permanent discontinuation in 6.5% of patients, and immune-mediated hepatitis led to permanent discontinuation of either avelumab or axitinib in 5.3% of patients.1 Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant.1 Resolution of hepatitis occurred in 31 of the 35 patients at the time of data cut-off.1
Immune-mediated Endocrinopathies
Adrenal Insufficiency: Avelumab can cause primary or secondary adrenal insufficiency.1 For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated.1 Withhold avelumab depending on severity.1
Immune-mediated adrenal insufficiency occurred in 0.6% (11/1854) of patients receiving avelumab, including grade 3 (0.1%) and grade 2 (0.4%) adverse reactions.1 Adrenal insufficiency led to permanent discontinuation in 0.1% and withholding of avelumab in 0.1% of patients.1
Systemic corticosteroids were required in all (11/11) patients with adrenal insufficiency.1 Adrenal insufficiency resolved in 18% (2/11) of patients.1 Of the 2 patients in whom avelumab was withheld for adrenal insufficiency, none reinitiated treatment.1
Hypophysitis: Avelumab can cause immune-mediated hypophysitis.1 Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects.1 Hypophysitis can cause hypopituitarism.1 Initiate hormone replacement, as clinically indicated.1 Withhold or permanently discontinue avelumab depending on severity.1
Immune-mediated pituitary disorders occurred in 0.1% (1/1854) of patients receiving avelumab, which was a grade 2 (0.1%) adverse reaction.1 Hypopituitarism did not lead to withholding of avelumab in this patient and systemic corticosteroids were not required.1
Thyroid Disorders: Avelumab can cause immune-mediated thyroid disorders.1 Thyroiditis can present with or without endocrinopathy.1 Hypothyroidism can follow hyperthyroidism.1 Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated.1 Withhold or permanently discontinue avelumab depending on severity.1
Thyroiditis occurred in 0.2% (4/1854) of patients receiving avelumab, including grade 2 (0.1%) adverse reactions.1 Thyroiditis did not lead to permanent discontinuation or withholding of avelumab in any patients.1 No patients with thyroiditis required systemic corticosteroids.1 Thyroiditis did not resolve in any patient.1
Hyperthyroidism occurred in 0.4% (8/1854) of patients receiving avelumab, including grade 2 (0.3%) adverse reactions.1 Hyperthyroidism did not lead to permanent discontinuation of avelumab in any patient and led to withholding of avelumab in 0.1% of patients.1 Systemic corticosteroids were required in 25% (2/8) of patients with hyperthyroidism.1 Hyperthyroidism resolved in 88% (7/8) of patients.1 Of the 2 patients in whom avelumab was withheld for hyperthyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hyperthyroidism.1
Hypothyroidism occurred in 5% (97/1854) of patients receiving avelumab, including grade 3 (0.2%) and grade 2 (3.6%) adverse reactions.1 Hypothyroidism led to permanent discontinuation in 0.1% and withholding of avelumab in 0.4% of patients.1 Systemic corticosteroids were required in 6% (6/97) of patients with hypothyroidism.1 Hypothyroidism resolved in 6% (6/97) of patients.1 Of the 8 patients in whom avelumab was withheld for hypothyroidism, none reinitiated treatment.1
Diabetes: Type I diabetes mellitus, which can present with diabetic ketoacidosis, can occur.1 Monitor patients for hyperglycemia or other signs and symptoms of diabetes.1 Initiate treatment with insulin as clinically indicated.1 Withhold avelumab depending on severity.1
Immune-mediated type I diabetes mellitus occurred in 0.2% (3/1854) of patients receiving avelumab, including grade 3 (0.2%) adverse reactions.1 Type I diabetes mellitus led to permanent discontinuation of avelumab in 0.1% of patients.1 Type I diabetes mellitus did not lead to withholding of avelumab in any patient.1 Systemic corticosteroids were not required in any patient with type I diabetes mellitus.1 Type I diabetes mellitus did not resolve in any patient and all patients required ongoing insulin treatment.1
Immune-Mediated Nephritis with Renal Dysfunction
Avelumab can cause immune-mediated nephritis.1 Immune-mediated nephritis with renal dysfunction occurred in 0.1% (2/1854) of patients receiving avelumab, including grade 3 (0.1%) and grade 2 (0.1%) adverse reactions.1 Nephritis with renal dysfunction led to permanent discontinuation of avelumab in 0.1% of patients and did not lead to withholding of avelumab in any patient.1 Systemic corticosteroids were required in 100% of patients with nephritis with renal dysfunction.1 Nephritis with renal dysfunction resolved in 50% of the patients.1
Immune-mediated Dermatologic Adverse Reactions
Avelumab can cause immune-mediated rash or dermatitis.1 Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies.1 Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.1 Withhold or permanently discontinue avelumab depending on severity.1 Immune-mediated dermatologic adverse reactions occurred in 6% (108/1854) of patients receiving avelumab, including grade 3 (0.1%) and grade 2 (1.9%) adverse reactions.1 Dermatologic adverse reactions led to permanent discontinuation in 0.3% of patients and withholding of avelumab in 0.4% of patients.1 Systemic corticosteroids were required in 25% (27/108) of patients with dermatologic adverse reactions.1 One patient required the addition of tacrolimus to high-dose corticosteroids.1
Dermatologic adverse reactions resolved in 46% (50/108) of patients.1 Of the 8 patients in whom avelumab was withheld for dermatologic adverse reactions, 4 reinitiated treatment after symptom improvement; of these, none had recurrence of dermatologic adverse reactions.1
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% in patients who received avelumab or were reported with the use of other PD-1/PD-L1 blocking antibodies.1 Severe or fatal cases have been reported for some of these adverse reactions.1
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis.1
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.1
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.1
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities.1 Some cases can be associated with retinal detachment.1 Various grades of visual impairment, including blindness, can occur.1 If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.1
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica.1
Endocrine: Hypoparathyroidism.1
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.1
Avelumab can cause severe or life-threatening infusion-related reactions.1 Premedicate with antihistamine and acetaminophen prior to the first 4 infusions.1 Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria.1 Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions.1 Stop the infusion and permanently discontinue avelumab for severe (grade 3) or life-threatening (grade 4) infusion-related reactions.1
Infusion-related reactions occurred in 26% of patients treated with avelumab, including 3 (0.2%) grade 4 and 10 (0.5%) grade 3 infusion-related reactions.1 Ninety-three percent of patients received premedication with antihistamine and acetaminophen.1 Eleven (85%) of the 13 patients with grade ≥3 reactions were treated with IV corticosteroids.1 Fifteen percent of patients had infusion-related reactions that occurred after the avelumab infusion was completed.1
Complications of Allogeneic Hematopoietic and Stem Cell Transplant
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody.1 Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause).1 These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.1
Follow patients closely for evidence of transplant-related complications and intervene promptly.1 Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after allogeneic HSCT.1
Major Adverse Cardiovascular Events (MACE)
Avelumab in combination with axitinib can cause severe and fatal cardiovascular events.1 Consider baseline and periodic evaluations of left ventricular ejection fraction.1 Monitor for signs and symptoms of cardiovascular events.1 Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia.1 Discontinue avelumab and axitinib for grade 3-4 cardiovascular events.1
MACE occurred in 7% of patients with advanced RCC treated with avelumab in combination with axitinib compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101.1 These events included death due to cardiac events (1.4%), grade 3-4 myocardial infarction (2.8%), and grade 3-4 congestive heart failure (1.8%).1 Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).1
Fetal/Neonatal Morbidity and Mortality
Avelumab can cause fetal harm when administered to a pregnant woman.1 Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death.1 If this drug is used during pregnancy, or if the patient becomes pregnant while taking avelumab, inform the patient of the potential risk to a fetus.1 Advise females of childbearing potential to use effective contraception during treatment with avelumab and for at least one month after the last dose.1
There is a potential for immunogenicity with avelumab therapy.1 The incidence of anti-drug antibodies (ADA) in patients receiving avelumab in clinical trials ranged from 8.2% to 19%; between 71% and 97% were neutralizing antibodies.1 The effect of ADA on efficacy and safety of avelumab is not known.1 In patients with advanced UC or advanced RCC who tested positive for antibodies, avelumab clearance was about 15% higher than in patients who tested negative.1
Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman.1 There are no available data on the use of avelumab in pregnant women or data from animal reproduction studies.1 Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death.1 Human IgG1 immunoglobulins (IgG1) are known to cross the placenta.1 Therefore, avelumab has the potential to be transmitted from the mother to the developing fetus.1 If avelumab is used during pregnancy, or if the patient becomes pregnant while taking the drug, advise the patient of the potential risk to a fetus.1
There is no information regarding the presence of avelumab in human milk, the effect on the breast-fed infant, or the effects on milk production.1 Advise a lactating woman not to breast-feed during treatment and for at least 1 month after the last dose of avelumab due to the potential for serious adverse reactions in breast-fed infants.1
Females and Males of Reproductive Potential
Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman.1 Advise females of reproductive potential to use effective contraception during treatment with avelumab and for at least 1 month after the last dose.1
Safety and efficacy of avelumab have not been established in pediatric patients younger than 12 years of age.1
Safety and efficacy of avelumab for the treatment of Merkel cell carcinoma in patients 12 years of age and older are based on results from adult clinical trials and extrapolated data.1 Additional population pharmacokinetic data demonstrated that age and body weight had no clinically meaningful effect on the steady-state exposure of avelumab, that drug exposure for monoclonal antibodies is generally similar between adults and pediatric patients 12 years of age and older, and that the course of Merkel cell carcinoma is sufficiently similar in adult and pediatric patients to allow extrapolation of data from adults to pediatric patients.1
The proportion of patients ≥65 years of age was 78%, 63%, and 38% in clinical trials evaluating avelumab in patients with Merkel cell carcinoma, locally advanced or metastatic urothelial carcinoma, and advanced renal cell carcinoma, respectively.1 The proportion of patients ≥75 years of age was 43%, 24%, and 8% in clinical trials evaluating avelumab in patients with Merkel cell carcinoma, locally advanced or metastatic urothelial carcinoma, and advanced renal cell carcinoma, respectively.1 No overall differences in safety or efficacy were reported between elderly and younger patients.1
Avelumab has not been studied in patients with hepatic impairment.1 No clinically meaningful differences were observed in avelumab clearance based on mild or moderate hepatic impairment (bilirubin ≤3 x ULN).1
Avelumab has not been studied in patients with renal impairment.1 No clinically meaningful differences were observed in avelumab clearance based on mild to severe renal impairment (creatinine clearance: 89 to 15 mL/min).1
Adverse effects reported in 20% or more of patients receiving avelumab for Merkel cell carcinoma: fatigue, musculoskeletal pain, infusion-related reaction, rash, nausea, constipation, cough, and diarrhea.1
Adverse effects reported in 20% or more of patients receiving avelumab for maintenance treatment of urothelial carcinoma: fatigue, musculoskeletal pain, urinary tract infection, and rash.1
Adverse effects reported in 20% or more of previously treated patients receiving avelumab for urothelial carcinoma: fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.1
Adverse effects reported in 20% or more of patients receiving avelumab for renal cell carcinoma (in combination with axitinib): diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.1
No formal drug interaction studies have been performed to date.1
No clinically meaningful differences in avelumab exposure were observed when administered in combination with axitinib.1
Avelumab, a fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent.1 The drug is an IgG1 lambda immunoglobulin.1
The immune-checkpoint receptor PD-1 is expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells.6, 7, 8, 9 Overexpression of PD-1 ligands on the surface of tumor cells results in activation of PD-1 and B7.1 and suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production.1, 8, 9, 10 Avelumab blocks the interaction between PD-L1 and the receptors PD-1 and B7.1, resulting in restoration of immune responses, including activation of the antitumor immune response.1 In vitro, avelumab has been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC).1 The drug also has been shown to reduce tumor growth in syngeneic mouse tumor models.1
Avelumab exhibits dose-proportional systemic exposure over the dosage range of 10-20 mg/kg every 2 weeks.1 When avelumab is administered every 2 weeks, steady-state concentrations are reached by approximately 4-6 weeks, and systemic accumulation of the drug is 1.25-fold.1 Avelumab is eliminated by proteolytic degradation.1 The terminal half-life of avelumab is 6.1 days.1 No clinically meaningful differences in the clearance of avelumab have been observed based on age, body weight, sex, race, PD-L1 status, or tumor burden.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Avelumab is obtained through designated specialty pharmacies. Contact manufacturer for specific availability information.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV infusion only | 200 mg/10 mL (20 mg/mL) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. EMD Serono, Inc. Bavencio® (avelumab) injection for intravenous infusion prescribing information. Boston, MA; 2025 Jun.
3. Kaufman HL, Russell J, Hamid O et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol . 2016; 17:1374-1385. [PubMed 27592805]
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11. Apolo AB, Infante JR, Balmanoukian A et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol . 2017; :JCO2016716795. [PubMed 28375787]
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13. D'Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer. 2020;8(1):e000674.
14. D'Angelo SP, Lebbé C, Mortier L, et al. First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. J Immunother Cancer. 2021;9(7):e002646.
15. D'Angelo SP, Lebbé C, Mortier L, et al. First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from part B of the JAVELIN Merkel 200 study. ESMO Open. 2024;9(5):103461.
16. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230.
17. Powles T, Park SH, Caserta C, et al. Avelumab first-line maintenance for advanced urothelial carcinoma: results from the JAVELIN Bladder 100 trial after ≥2 years of follow-up. J Clin Oncol. 2023;41(19):3486-3492.
18. Apolo AB, Ellerton JA, Infante JR, et al. Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. J Immunother Cancer. 2020;8(2):e001246.
19. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115.
20. Choueiri TK, Penkov K, Uemura H, et al. Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN Renal 101 trial. Ann Oncol. 2025;36(4):387-392.
100. Institute of Safe Medicine Practices. ISMP List of High-Alert Medication in Acute Care Settings. 2024. [Web]
110. National Cancer Institute. Renal cell cancer treatment - health professional version. Revised May 13, 2025. Accessed 2026 May 19. [Web]
111. Motzer R, Alekseev B, Rha SY et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021; 384:1289-1300.
112. Rathmell WK, Rumble RB, Van Veldhuizen PJ, et al. Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline. J Clin Oncol. 2022;40(25):2957-2995.
333. Lugowska I, Becker JC, Ascierto PA, et al. Merkel-cell carcinoma: ESMO-EURACAN clinical practice guideline for diagnosis, treatment and follow-up. ESMO Open. 2024;9(5):102977.
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