Avelumab Intravenous

Merkel Cell Carcinoma

Avelumab is used for the treatment of metastatic Merkel cell carcinoma;^[1][3] avelumab has been designated an orphan drug by FDA for the treatment of this cancer.^[12] The accelerated approval of avelumab for this indication is based on objective response rate and duration of response.^[1] Continued approval for this indication may be contingent on verification and description of clinical benefit of avelumab in confirmatory studies.^[1]

The current indication for avelumab is based principally on the results of an open-label, multicenter, noncomparative phase 2 study (JAVELIN Merkel 200) in 88 adults with metastatic Merkel cell carcinoma that had progressed during or following cytotoxic chemotherapy for metastatic disease.^[1][3] The primary measure of efficacy was objective response rate as assessed by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST).^[1][3] In this study, the median age of patients was 73 years; 92% were Caucasian, 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 enrolled in the study had an ECOG performance status of 0 or 1.^[1][3] Most patients (66%) had positive programmed-death ligand-1 (PD-L1) expression (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] Patients received avelumab 10 mg/kg administered as an IV infusion every 2 weeks until disease progression or unacceptable toxicity occurred; however, patients with radiologic evidence of disease progression in the absence of substantial clinical deterioration (defined as new or worsening symptoms, change in performance status for more than 2 weeks, necessity of salvage therapy) could continue receiving avelumab therapy.^[1][3] Patients with a history of autoimmune disease; those with brain metastases or hematologic malignancies; those with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; those with a history of allogeneic stem-cell or solid organ transplant; those with conditions requiring therapy with immunosuppressive agents; those who had received any vaccine within 4 weeks prior to administration of avelumab; and those who had received prior therapy with other anti-programmed-death 1 (anti-PD-1), anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibodies were excluded from the study.^[1][3]

At a minimum follow-up of 12 months, the objective response rate was 33%; complete responses were achieved in 11.4% of patients.^[1] At the time of analysis, the median duration of response had not been reached; however, 45% of patients had durable responses of 12 months or more.^[1][3] After a median follow-up of 10.4 months, median progression-free and overall survival were 2.7 and 11.3 months, respectively.^[3] Objective responses were observed regardless of PD-L1 expression or presence of Merkel cell polyomavirus.^[1][3]

Urothelial Carcinoma

Avelumab is used for the treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.^[1][11] The accelerated approval of avelumab for this indication is based on objective response rate and duration of response.^[1] Continued approval for this indication may be contingent on verification and description of clinical benefit of avelumab in confirmatory studies.^[1]

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 therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.^[1][5][11] The primary measure of efficacy was 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 Caucasian, 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 had 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 brain metastases or a history of brain metastases; 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 objective 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 6 months, the median duration of response had not been reached.^[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]

General

Because infusion-related events may occur, the manufacturer recommends a premedication regimen (i.e., acetaminophen and an antihistamine) prior to the initial 4 infusions of avelumab.^[1] Premedication also may be administered as clinically indicated prior to subsequent infusions of the drug based on the occurrence and severity of previous infusion reactions.^[1] In the JAVELIN Solid Tumor study, patients received an antihistamine (e.g., diphenhydramine hydrochloride 25-50 mg) and IV acetaminophen 500-650 mg (or oral equivalent) 30-60 minutes prior to each infusion of avelumab.^[5][11]

Restricted Distribution Program

Avelumab can only be obtained through specialty distributors.^[4] Clinicians may consult the Bavencio^® website for specific availability information (https://www.bavencio.com).^[4]

Administration

Avelumab is administered by IV infusion over 60 minutes.^[1] Avelumab should be administered through a sterile, nonpyrogenic, low-protein-binding 0.2-µm inline filter.^[1]

Avelumab injection concentrate must be diluted prior to IV administration.^[1] Prior to dilution, the injection concentrate should be inspected visually for particulate matter and discoloration.^[1] The solution should be clear and colorless to pale yellow; the solution should not be used if it is cloudy or discolored or contains a precipitate.^[1] The appropriate dose (10 mg/kg) of avelumab injection concentrate (containing 20 mg/mL) should be withdrawn and injected into an infusion bag containing 250 mL of 0.45 or 0.9% sodium chloride injection.^[1] This diluted solution should be mixed by gentle inversion and should not be shaken.^[1] Diluted solutions of the drug should be clear, colorless, and free of visible particulate matter.^[1]

Diluted solutions of the drug are stable for up to 4 hours after dilution when stored at room temperature or up to 24 hours after dilution when stored under refrigeration (2-8°C), and should be protected from light; diluted solutions of the drug should be brought to room temperature prior to administration.^[1] Diluted solutions of the drug should not be frozen.^[1]

Any unused portion in the vial should be discarded since avelumab injection concentrate contains no preservative.^[1]

Avelumab should not be administered simultaneously through the same IV line with any other drug.^[1]

Dosage

Merkel Cell Carcinoma

For the treatment of metastatic Merkel cell carcinoma in adults and adolescents (12 years of age and older), the recommended dosage of avelumab is 10 mg/kg administered as a 60-minute IV infusion every 2 weeks.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs.^[1]

Urothelial Carcinoma

For the treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following therapy with platinum-containing chemotherapy or within 12 months of platinum-containing chemotherapy in the neoadjuvant or adjuvant setting, the recommended adult dosage of avelumab is 10 mg/kg administered as a 60-minute IV infusion every 2 weeks.^[1] Therapy should be continued until disease progression or unacceptable toxicity occurs.^[1]

Therapy Interruption for Toxicity

If immune-mediated adverse effects occur, temporary or permanent discontinuance of avelumab may be required based on the severity of the reaction.^[1]

Immune-mediated Pneumonitis

If grade 2 immune-mediated pneumonitis occurs, avelumab therapy should be interrupted.^[1] Once the toxicity has resolved to grade 0 or 1, avelumab may be restarted following completion of the corticosteroid taper.^[1] If pneumonitis recurs, avelumab therapy should be permanently discontinued.^[1] (See Immune-mediated Pneumonitis under Cautions: Warnings/Precautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, avelumab therapy should be permanently discontinued.^[1]

Immune-mediated Hepatic Effects

For serum aminotransferase (ALT or AST) elevations exceeding 3 times but not more than 5 times the upper limit of normal (ULN) or total bilirubin concentrations exceeding 1.5 times but not more than 3 times the ULN, avelumab therapy should be interrupted.^[1] Once the toxicity has resolved to grade 0 or 1, avelumab may be restarted following completion of the corticosteroid taper.^[1] (See Immune-mediated Hepatic Effects under Cautions: Warnings/Precautions.)

For ALT or AST elevations exceeding 5 times the ULN or total bilirubin concentrations exceeding 3 times the ULN, avelumab therapy should be permanently discontinued.^[1]

Immune-mediated GI Effects

If grade 2 or 3 immune-mediated colitis or diarrhea occurs, avelumab therapy should be interrupted.^[1] Once the toxicity has resolved to grade 0 or 1, avelumab may be restarted following completion of the corticosteroid taper.^[1] If grade 3 colitis or diarrhea recurs, avelumab therapy should be permanently discontinued.^[1] (See Immune-mediated GI Effects under Cautions: Warnings/Precautions.)

If grade 4 immune-mediated colitis or diarrhea occurs, avelumab therapy should be permanently discontinued.^[1]

Immune-mediated Endocrine Effects

If grade 3 or 4 immune-mediated endocrinopathies (e.g., hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes mellitus) occur, avelumab therapy should be interrupted.^[1] Once the toxicity has resolved to grade 0 or 1, avelumab may be restarted following completion of the corticosteroid taper.^[1] (See Immune-mediated Endocrine Effects under Cautions: Warnings/Precautions.)

Immune-mediated Renal Effects

For serum creatinine concentrations exceeding 1.5 times but not more than 6 times the ULN, avelumab therapy should be interrupted.^[1] Once the toxicity has resolved to grade 0 or 1, avelumab may be restarted following completion of the corticosteroid taper.^[1] (See Immune-mediated Renal Effects under Cautions: Warnings/Precautions.)

For serum creatinine concentrations exceeding 6 times the ULN, avelumab therapy should be permanently discontinued.^[1]

Other Immune-mediated Adverse Effects

If any other immune-mediated adverse effects with moderate or severe signs or symptoms occur, avelumab therapy should be interrupted while an evaluation is performed to exclude other causes.^[1] Once the toxicity has resolved to grade 0 or 1, avelumab may be restarted following completion of the corticosteroid taper.^[1] (See Other Immune-mediated Effects under Cautions: Warnings/Precautions.)

Avelumab should be permanently discontinued in patients experiencing persistent grade 2 or 3 immune-mediated adverse effects lasting 12 weeks or longer and in those unable to reduce corticosteroid dosage to less than 10 mg of prednisone daily (or equivalent) within 12 weeks.^[1]

Avelumab should be permanently discontinued in patients experiencing life-threatening immune-mediated adverse effects (except for endocrinopathies).^[1] Therapy with the drug also should be permanently discontinued if severe immune-mediated adverse effects recur.^[1]

Infusion-related Reactions

If grade 1 or 2 infusion-related reactions occur, the infusion should be interrupted or the infusion rate should be reduced.^[1] (See Infusion-related Effects under Cautions: Warnings/Precautions.)

If grade 3 or 4 infusion-related reactions occur, avelumab therapy should be permanently discontinued.^[1]

Special Populations

The manufacturer makes no special population dosage recommendations at this time.^[1] (See Specific Populations under Cautions: Warnings/Precautions.)

Contraindications

The manufacturer states there are no known contraindications to the use of avelumab.^[1]

Warnings/Precautions

Immune-mediated Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, has occurred in patients receiving avelumab therapy.^[1] Immune-mediated pneumonitis was reported in 21 of 1738 patients (1.2%) receiving avelumab in clinical studies and was fatal in one patient.^[1] The median time to occurrence of immune-mediated pneumonitis was 2.5 months (range: 3 days to 11 months) and the median duration was 7 weeks (range: 4 days to more than 4 months).^[1] Corticosteroid therapy was administered in all 21 patients and avelumab therapy was permanently discontinued in 6 patients.^[1] Most patients (81%) experiencing immune-mediated pneumonitis received high-dose corticosteroid therapy for a median duration of 8 days.^[1] At the time of analysis, immune-mediated pneumonitis had resolved in 12 of 21 patients (57%).^[1]

Patients receiving avelumab should be monitored for manifestations of pneumonitis, and those with suspected pneumonitis should be evaluated with radiographic imaging.^[1] Temporary interruption or discontinuance of avelumab may be necessary if immune-mediated pneumonitis occurs during therapy with the drug.^[1] (See Immune-mediated Pneumonitis under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.) If grade 2 or greater pneumonitis occurs, systemic corticosteroid therapy should be initiated (1-2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.^[1]

Immune-mediated Hepatic Effects

Immune-mediated hepatitis, sometimes fatal, has occurred in patients receiving avelumab therapy.^[1] Immune-mediated hepatitis occurred in 16 of 1738 patients (0.9%) receiving avelumab in clinical studies and was fatal in 2 patients.^[1] The median time to occurrence of immune-mediated hepatitis was 3.2 months (range: 1 week to 15 months) and the median duration was 2.5 months (range: 1 day to more than 7.4 months).^[1] Corticosteroid therapy was administered in all 16 patients and avelumab therapy was permanently discontinued in 9 patients.^[1] Most patients (94%) experiencing immune-mediated hepatitis received high-dose corticosteroid therapy for a median duration of 14 days.^[1] At the time of analysis, immune-mediated hepatitis had resolved in 9 of 16 patients (56%).^[1]

Patients receiving avelumab should be monitored for manifestations of hepatitis.^[1] Liver function tests should be assessed prior to initiation of avelumab therapy and then monitored periodically during treatment.^[1] Temporary interruption or discontinuance of avelumab may be necessary if immune-mediated hepatitis occurs during therapy with the drug.^[1] (See Immune-mediated Hepatic Effects under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.) If grade 2 or greater hepatitis occurs, systemic corticosteroid therapy should be initiated (1-2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.^[1]

Immune-mediated GI Effects

Immune-mediated colitis has occurred in patients receiving avelumab therapy.^[1] Immune-mediated colitis occurred in 26 of 1738 patients (1.5%) receiving avelumab in clinical studies and was grade 3 in 7 patients.^[1] The median time to occurrence of immune-mediated colitis was 2.1 months (range: 2 days to 11 months) and the median duration was 6 weeks (range: 1 day to more than 14 months).^[1] Corticosteroid therapy was administered in all 26 patients and avelumab therapy was permanently discontinued in 9 patients.^[1] Approximately one-half of patients (58%) experiencing immune-mediated colitis received high-dose corticosteroid therapy for a median duration of 19 days.^[1] At the time of analysis, immune-mediated colitis had resolved in 18 of 26 patients (70%).^[1]

Patients receiving avelumab should be monitored for manifestations of colitis.^[1] Temporary interruption or discontinuance of avelumab may be necessary if immune-mediated colitis occurs during therapy with the drug.^[1] (See Immune-mediated GI Effects under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.) If grade 2 or greater colitis occurs, systemic corticosteroid therapy should be initiated (1-2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.^[1]

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, such as thyroid dysfunction (i.e., hypothyroidism, hyperthyroidism), adrenal insufficiency, and diabetes mellitus (including ketoacidosis), have occurred in patients receiving avelumab therapy.^[1]

Adrenal Insufficiency

Immune-mediated adrenal insufficiency occurred in 8 of 1738 patients (0.5%) receiving avelumab in clinical studies; grade 3 immune-mediated adrenal insufficiency occurred in one patient.^[1] The median time to occurrence of immune-mediated adrenal insufficiency was 2.5 months (range: 1 day to 8 months).^[1] Corticosteroid therapy was administered in all 8 patients and avelumab therapy was permanently discontinued in 2 patients.^[1] One-half of patients experiencing immune-mediated adrenal insufficiency received high-dose corticosteroid therapy for a median duration of one day.^[1]

Patients receiving avelumab should be monitored for manifestations of adrenal insufficiency.^[1] Temporary interruption of avelumab may be necessary if immune-mediated adrenal insufficiency occurs during therapy with the drug.^[1] (See Immune-mediated Endocrine Effects under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.) Systemic corticosteroid therapy should be initiated as appropriate.^[1]

Thyroid Dysfunction

Immune-mediated thyroid dysfunction occurred in 98 of 1738 patients (6%) receiving avelumab in clinical studies and was grade 3 in 3 patients.^[1] Immune-mediated hypothyroidism occurred in 90 of 1738 patients (5%), immune-mediated hyperthyroidism occurred in 7 patients (0.4%), and immune-mediated thyroiditis occurred in 4 patients (0.2%).^[1] The median time to occurrence of thyroid dysfunction was 2.8 months (range: 2 weeks to 13 months); however, thyroid dysfunction may occur at any time during treatment.^[1] The median duration of thyroid dysfunction was not estimable (range: 6 days to more than 26 months).^[1] Avelumab therapy was discontinued in 2 patients.^[1] Immune-mediated thyroid dysfunction resolved in 7 of 98 patients (7%).^[1]

Patients receiving avelumab should be monitored for manifestations of thyroid dysfunction.^[1] Thyroid function should be evaluated prior to initiation of avelumab therapy, periodically during therapy, and as clinically indicated.^[1] Temporary interruption of avelumab may be necessary if immune-mediated thyroid dysfunction occurs during therapy with the drug.^[1] (See Immune-mediated Endocrine Effects under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.) In patients who develop immune-mediated hypothyroidism, thyroid hormone replacement therapy should be initiated.^[1] If immune-mediated hyperthyroidism occurs, appropriate medical therapy should be initiated.^[1]

Diabetes Mellitus

Immune-mediated type 1 diabetes mellitus and ketoacidosis have occurred in patients receiving avelumab therapy.^[1] Type 1 diabetes mellitus of no clear alternate etiology occurred in 2 of 1738 patients (0.1%) receiving avelumab in clinical studies and was grade 3 in both patients.^[1] Avelumab therapy was permanently discontinued in both patients.^[1]

Patients receiving avelumab should be monitored for manifestations of type 1 diabetes mellitus.^[1] If severe or life-threatening (grade 3 or greater) immune-mediated type 1 diabetes mellitus occurs, avelumab therapy should be temporarily interrupted and antidiabetic agents (i.e., insulin therapy) should be initiated.^[1] Avelumab may be resumed once blood glucose concentrations have stabilized on antidiabetic therapy.^[1]

Immune-mediated Renal Effects

Immune-mediated nephritis has occurred in patients receiving avelumab therapy.^[1] Immune-mediated nephritis occurred in 1 of 1738 patients (0.1%) in clinical studies and avelumab therapy was permanently discontinued in this patient.^[1]

Patients receiving avelumab should be monitored for manifestations of renal dysfunction.^[1] Serum creatinine concentrations should be assessed prior to initiation of avelumab therapy and then monitored periodically during treatment.^[1] Temporary interruption or discontinuance of avelumab may be necessary if immune-mediated nephritis occurs during therapy with the drug.^[1] (See Immune-mediated Renal Effects under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.) If grade 2 or greater nephritis occurs, systemic corticosteroid therapy should be initiated (1-2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.^[1]

Other Immune-mediated Effects

Other immune-mediated adverse effects, sometimes severe or fatal, have occurred in patients receiving avelumab therapy.^[1] In clinical studies, immune-mediated adverse effects such as myocarditis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barre syndrome, and systemic inflammatory responses were each observed in less than 1% of patients receiving avelumab.^[1] Additional immune-mediated adverse effects, including bullous dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis, have been reported with other anti-programmed-death 1 (anti-PD-1) and anti-PD ligand 1 (anti-PD-L1) antibodies.^[1] Immune-mediated adverse effects may initially occur during avelumab therapy, but may also occur following discontinuance of the drug.^[1]

If an immune-mediated adverse effect is suspected, adequate evaluation should be performed to exclude other causes.^[1] Depending on the severity of the immune-mediated adverse effect, avelumab therapy should be temporarily interrupted or discontinued and high-dose corticosteroid therapy initiated; hormone replacement therapy also should be initiated, if indicated.^[1] (See Other Immune-mediated Effects under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.)

Infusion-related Effects

Infusion-related reactions, sometimes severe or life-threatening, have occurred in patients receiving avelumab therapy; infusion-related reactions also have occurred following completion of the infusion.^[1] Infusion-related reactions occurred in 25% of patients receiving avelumab in clinical studies.^[1] Grade 3 or 4 infusion-related reactions occurred in 0.5 or 0.2% of avelumab-treated patients, respectively; 92% of patients experiencing grade 3 or 4 infusion-related reactions received IV corticosteroid therapy.^[1] Most patients (93%) receiving avelumab were premedicated with an antihistamine and acetaminophen.^[1] Infusion-related effects may include pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria.^[1]

Patients receiving avelumab should be premedicated with acetaminophen and an antihistamine prior to the initial 4 infusions of the drug.^[1] (See Dosage and Administration: General.) Patients should be monitored for manifestations of infusion-related reactions.^[1] In patients experiencing infusion-related reactions, interruption of the infusion, reduction in the infusion rate, or permanent discontinuance of the drug may be necessary.^[1] (See Infusion-related Reactions under Dosage: Therapy Interruption for Toxicity, in Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

Avelumab may cause fetal harm if administered to pregnant women.^[1] Blockade of signaling of the programmed death 1 (PD-1) and ligand 1 (PD-L1) pathway in animals has been shown to disrupt maternal immune tolerance to the fetus and has been associated with increased fetal loss (e.g., abortion, stillbirth) and immune-mediated disorders; however, teratogenicity has not been observed.^[1]

Pregnancy should be avoided during avelumab therapy.^[1] Women of childbearing potential should be advised to use an effective method of contraception while receiving avelumab and for at least 1 month after discontinuance of therapy.^[1] If avelumab is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.^[1]

Immunogenicity

There is a potential for immunogenicity with avelumab therapy.^[1] Development of anti-avelumab antibodies was detected in 64 of 1558 patients (4.1%) receiving avelumab.^[1][3][5] No effects on safety (including risk of infusion-related reactions) or pharmacokinetics of the drug were observed in clinical studies.^[1][2]

Specific Populations

Pregnancy

Avelumab may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.^[1] (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether avelumab is distributed into human milk.^[1] Because many drugs and human immunoglobulin G (IgG) are distributed into human milk and because of the potential for serious adverse reactions to avelumab in nursing infants, women should be advised to discontinue nursing during avelumab therapy and for at least 1 month after discontinuance of therapy.^[1] The effects of the drug on nursing infants or on milk production are unknown.^[1]

Pediatric Use

Safety and efficacy of avelumab have not been established in pediatric patients younger than 12 years of age.^[1]

Because the clinical course and treatment of Merkel cell carcinoma are similar in adults and pediatric patients, safety and efficacy of avelumab for the treatment of metastatic Merkel cell carcinoma in adolescents 12 years of age or older are supported by extrapolation of data from clinical studies evaluating avelumab in adults, population pharmacokinetic analyses indicating that age (range of 20-91 years)^[2] and body weight (range of 30-90 kg)^[2] do not have clinically important effects on systemic exposure to the drug, and evidence that exposure to monoclonal antibodies generally is similar in adults and adolescents.^[1]

In one case, a 10-year-old girl with metastatic Merkel cell carcinoma experienced pain, nausea, and vomiting during and following avelumab therapy.^[2] The child initially received 6 cycles of cisplatin and etoposide and experienced disease progression following 3 doses of avelumab 10 mg/kg.^[2]

Geriatric Use

Clinical studies evaluating avelumab in patients with metastatic Merkel cell carcinoma did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.^[1]

In the JAVELIN Solid Tumor study, 68% of patients receiving avelumab for the treatment of locally advanced or metastatic urothelial carcinoma were 65 years of age or older, while 29% were 75 years of age or older; among 153 patients 65 years of age or older who were assessed for a minimum of 13 weeks, 14% responded to avelumab and 58% experienced a grade 3 or 4 adverse effect.^[1] In this study, no overall differences in safety or efficacy were observed between geriatric patients and younger adults.^[1]

Hepatic Impairment

Analysis of population pharmacokinetic data indicates that the pharmacokinetics of avelumab are not influenced by mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration between 1-1.5 times the ULN) or moderate (total bilirubin concentration between 1.5-3 times the ULN) hepatic impairment.^[1] Pharmacokinetic data in patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the ULN) are limited.^[1]

Renal Impairment

Analysis of population pharmacokinetic data indicates that the pharmacokinetics of avelumab are not influenced by mild, moderate, or severe renal impairment (creatinine clearance 15-89 mL/minute).^[1]

Common Adverse Effects

Adverse effects reported in 10% or more of patients receiving avelumab for the treatment of metastatic Merkel cell carcinoma include fatigue,^[1][3] musculoskeletal pain,^[1] diarrhea,^[1] infusion-related reactions,^[1][3] nausea,^[1] rash,^[1] loss of appetite,^[1] peripheral edema,^[1] cough,^[1] constipation,^[1] abdominal pain,^[1] arthralgia,^[1] decreased weight,^[1] dizziness,^[1] hypertension,^[1] vomiting,^[1] dyspnea,^[1] headache,^[1] and pruritus.^[1] Laboratory abnormalities reported in 10% or more of patients receiving avelumab include lymphopenia,^[1] anemia,^[1] elevated concentrations of aminotransferases (i.e., ALT, AST),^[1] thrombocytopenia,^[1] and elevated concentrations of lipase.^[1]

Adverse effects reported in 10% or more of patients receiving avelumab for the treatment of locally advanced or metastatic urothelial carcinoma include fatigue,^[1] infusion-related reactions,^[1] musculoskeletal pain,^[1] nausea,^[1] loss of appetite,^[1] urinary tract infection,^[1] abdominal pain,^[1] decreased weight,^[1] constipation,^[1] diarrhea,^[1] dyspnea (including dyspnea on exertion),^[1] peripheral edema,^[1] elevated concentrations of serum creatinine/renal failure,^[1] pyrexia,^[1] rash,^[1] cough,^[1] vomiting/retching,^[1] hypertension (including hypertensive crisis),^[1] and pruritus.^[1] Grade 3 or 4 laboratory abnormalities reported in 5% or more of patients receiving avelumab include hyponatremia,^[1] elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP),^[1] lymphopenia,^[1] hyperglycemia,^[1] elevated concentrations of alkaline phosphatase,^[1] anemia,^[1] and elevated concentrations of lipase.^[1]

No formal drug interaction studies have been performed to date.^[1]

Avelumab, a fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent.^[1][3] The drug is an IgG₁ lambda immunoglobulin.^[1][3]

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]

Systemic exposure to avelumab is proportional to dose over the dosage range of 3-20 mg/kg every 2 weeks.^[1][5] When avelumab is administered every 2 weeks, steady-state concentrations are reached by 4-6 weeks, and systemic accumulation of the drug is approximately 1.3-fold.^[1] Following completion of a 1-hour IV infusion of avelumab, peak plasma concentrations of the drug are reached within 1 hour.^[5] Avelumab is metabolized by proteolytic degradation.^[1] The terminal half-life of avelumab is 6.1 days.^[1]

The pharmacokinetics of avelumab does not appear to be affected by age (range of 20-91 years), gender, race, PD-L1 status, or tumor burden.^[1][2]

Importance of advising patients to read the manufacturer's medication guide.^[1]

Risk of immune-mediated pneumonitis.^[1] Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.^[1]

Risk of immune-mediated hepatitis.^[1] Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, severe nausea or vomiting, abdominal pain [particularly in the right upper quadrant], lethargy, easy bruising or bleeding) occur.^[1]

Risk of immune-mediated colitis.^[1] Importance of informing clinician immediately if diarrhea or severe abdominal pain occurs.^[1]

Risk of immune-mediated endocrinopathies.^[1] Importance of informing clinician immediately if signs and symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, or diabetes mellitus occur.^[1]

Risk of immune-mediated nephritis or renal dysfunction.^[1] Importance of informing clinician immediately if signs and symptoms of nephritis (e.g., decreased urine output, hematuria, peripheral edema, lack of appetite) occur.^[1]

Risk of infusion-related reactions.^[1] Importance of informing clinician immediately if signs and symptoms of such reactions, including chills, fever, breathing difficulty (i.e., shortness of breath, wheezing), urticaria, flushing, hypotension, and back or abdominal pain, occur.^[1]

Risk of fetal harm.^[1] Necessity of advising women of childbearing potential that they should use a highly effective method of contraception while receiving the drug and for at least 1 month after discontinuance of therapy.^[1] Importance of women informing clinicians if they are or plan to become pregnant.^[1] If pregnancy occurs, importance of advising pregnant women of potential risk to the fetus.^[1]

Importance of advising women to avoid breast-feeding while receiving the drug and for at least 1 month after discontinuance of therapy.^[1]

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^[1]

Importance of informing patients of other important precautionary information.^[1] (See Cautions.)

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.

Distribution of avelumab is restricted.^[4] (See Restricted Distribution Program under Dosage and Administration: General.)

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