Avelumab

12.1 Mechanism of Action PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-tumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

1 INDICATIONS AND USAGE BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody indicated for: Merkel Cell Carcinoma (MCC) Adults and pediatric patients 12 years and older with metastatic MCC. ( 1.1 , 14.1 ) Urothelial Carcinoma (UC) Maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy. ( 1.2 , 14.2 ) Patients with locally advanced or metastatic UC who: Have disease progression during or following platinum-containing chemotherapy. ( 1.2 , 14.2 ) Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. ( 1.2 , 14.2 ) Renal Cell Carcinoma (RCC) First-line treatment, in combination with axitinib, of patients with advanced RCC. ( 1.3 , 14.3 ) 1.1 Metastatic Merkel Cell Carcinoma BAVENCIO (avelumab) is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) [see Clinical Studies (14.1) ] . 1.2 Locally Advanced or Metastatic Urothelial Carcinoma First-Line Maintenance Treatment of Urothelial Carcinoma BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy [see Clinical Studies (14.2) ] . Previously-treated Urothelial Carcinoma BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.2) ]. 1.3 Advanced Renal Cell Carcinoma BAVENCIO in combination with axitinib is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC) [see Clinical Studies (14.3) ] .

2 DOSAGE AND ADMINISTRATION Premedicate for the first 4 infusions and subsequently as needed. ( 2.1 ) Merkel Cell Carcinoma : 800 mg every 2 weeks. ( 2.2 ) Urothelial Carcinoma ; 800 mg every 2 weeks. ( 2.3 ) Renal Cell Carcinoma : 800 mg every 2 weeks in combination with axitinib 5 mg orally twice daily. ( 2.4 ) Administer BAVENCIO as an intravenous infusion over 60 minutes. 2.1 Premedication Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO. Premedication should be administered for subsequent BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions [see Dosage and Administration (2.5) and Warnings and Precautions (5.2) ]. 2.2 Recommended Dosage for MCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for UC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for RCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes 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. When axitinib is used in combination with BAVENCIO, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for axitinib prior to initiation. 2.5 Dose Modifications No dose reduction for BAVENCIO is recommended. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for 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. Dosage modifications for BAVENCIO for adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Monotherapy Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 Dosage Modification ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrosis, DRESS = drug rash with eosinophilia and systemic symptoms Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold Resume 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 per day or less (or equivalent) within 12 weeks of initiating corticosteroids. Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy, see Table 2 AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue BAVENCIO based on recommendations for hepatitis where there is no tumor involvement of the liver. Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times 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 Withhold Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2) ] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue Table 2 presents dosage modifications that are different from those described above in Table 1

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1) ] Infusion-related reactions [see Warnings and Precautions (5.2) ] Complications of allogeneic HSCT [see Warnings and Precautions (5.3) ] Major adverse cardiovascular events [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥ 20%) in patients were: MCC : Fatigue, musculoskeletal pain, infusion-related reaction, rash, nausea, constipation, cough, and diarrhea. ( 6.1 ) UC : Maintenance treatment: fatigue, musculoskeletal pain, urinary tract infection, and rash. ( 6.1 ) Previously-treated: fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection. ( 6.1 ) RCC (with axitinib) : diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to BAVENCIO 10 mg/kg intravenously every 2 weeks as a single agent in 1854 patients enrolled in the JAVELIN Merkel 200 and JAVELIN Solid Tumor trials and to BAVENCIO 10 mg/kg intravenously every 2 weeks in combination with axitinib 5 mg orally twice daily in 489 patients enrolled in the JAVELIN Renal 100 and JAVELIN Renal 101 trials. In the BAVENCIO monotherapy population, 25% of patients were exposed for ≥ 6 months and 9% were exposed for ≥ 12 months. The population characteristics of BAVENCIO in combination with axitinib are shown below. When BAVENCIO was used in combination with axitinib, 70% of patients were exposed for ≥ 6 months and 31% were exposed for ≥ 12 months. The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of BAVENCIO, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or other immunosuppressant or hormone replacement therapy, biopsy consistent with immune-mediated reaction, and no other clear etiology. Metastatic Merkel Cell Carcinoma The safety of BAVENCIO was evaluated in 204 patients enrolled in the JAVELIN Merkel 200 trial with metastatic MCC. Patients received BAVENCIO 10 mg/kg intravenously every 2 weeks or 800 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to BAVENCIO was 4.1 months (range: 2 weeks to 48 months). [see Clinical Studies (14.1) ] . Serious adverse reactions occurred in 52% of patients receiving BAVENCIO. The most frequent serious adverse reactions (≥ 2% of patients) were general physical health deterioration, anemia, abdominal pain, acute kidney injury, sepsis, hyponatremia, and infusion-related reaction. Permanent discontinuation of BAVENCIO due to an adverse reaction occurred in 27% of patients. The most frequent adverse reactions (> 1% of patients) that resulted in permanent discontinuation were infusion-related reaction, anemia, increased ALT, and increased AST. Dosage interruptions of BAVENCIO due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 29% of patients. The most frequent adverse reactions (> 1% of patients) that required dosage interruption were nasopharyngitis, anemia, diarrhea, lung infection, and ALT increased. The most common adverse reactions (≥ 20%) that occurred in patients receiving BAVENCIO were fatigue, musculoskeletal pain, infusion-related reaction, rash, nausea, constipation, cough, and diarrhea. Table 3 and Table 4 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving BAVENCIO. Table 3: Adverse Reactions in ≥ 10% of Patients with Metastatic MCC Receiving BAVENCIO in the JAVELIN Merkel 200 Trial Adverse Reactions BAVENCIO (N=204) All Grades % Grade 3-4 % General Disorders Fatigue Includes fatigue and asthenia. 47 2.9 Infusion-related reaction Includes infusion-related reaction, chills, pyrexia, back pain, hypotension, drug hypersensitivity, dyspnea, flushing and hypersensitivity. 26 0.5 Edema Includes peripheral edema, peripheral swelling, and genital edema. 17 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes musculoskeletal pain, back pain, pain in extremity, myalgia, musculoskeletal pain, and neck pain. 29 1.5 Arthralgia 13 0.5 Skin and Subcutaneous Tissue Disorders