Avelumab Immunotherapy (BAVENCIO®) For Merkel Cell Carcinoma, Urothelial Carcinoma & Renal Cell Carcinoma

Avelumab is FDA approved Immunotherapy that blocks a programmed death ligand1 (PD-L1)

 Avelumab (BAVENCIO)- is a human IgG1 lambda monoclonal antibody produced in Chinese hamster ovary cells and has a molecular weight of approximately 147 kDa. 

Indication of Aveluman (BAVENCIO)

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. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Urothelial Carcinoma (UC) 

• Maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy.  
• Patients with locally advanced or metastatic 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. 

Renal Cell Carcinoma (RCC) 

• First-line treatment, in combination with axitinib, of patients with advanced RCC 

Avelumab Warnings and Precautions

Immune-Mediated Adverse Reactions: Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and may result in solid organ transplant rejection. 

Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue BAVENCIO based on the severity of the reaction.

Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. 

Major adverse cardiovascular events: Optimize management of cardiovascular risk factors. Discontinue BAVENCIO in combination with axitinib for Grade 3-4 events. 

Embryo-fetal toxicity: BAVENCIO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception

Adverse Reaction Related to Avelumab Immunotherapy

Most common adverse reactions (> 20%) in patients were:

MCC: fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema. (6.1)

UC: Maintenance treatment: fatigue, musculoskeletal pain, urinary tract infection, and rash.  Previously-treated: fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection. 

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

Avelumab/BAVENCIO Formulations

BAVENCIO (avelumab) Injection for intravenous use is a sterile, preservative-free, nonpyrogenic, clear, colorless to slightly yellow solution. Each single-dose vial contains 200 mg avelumab in 10 mL (20 mg/mL). Each mL contains 20 mg avelumab, D-mannitol (51 mg), glacial acetic acid (0.6 mg), polysorbate 20 (0.5 mg), sodium hydroxide (0.3 mg), and Water for Injection. The pH range of the solution is 5.0 – 5.6.

Mechanism of Action of Avelumab/BAVENCIO

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. The 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.

Pharmacokinetics:

The pharmacokinetics of avelumab was studied in 1629 patients who received doses ranging from 1 to 20 mg/kg every 2 weeks. The data showed that the exposure of avelumab increased dose-proportionally in the dose range of 10 to 20 mg/kg every 2 weeks. Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing, and the systemic accumulation was approximately 1.25-fold. 

Distribution: The geometric mean volume of distribution at steady state for a subject receiving 10 mg/kg was 4.72 L. 

Elimination: The primary elimination mechanism of avelumab is proteolytic degradation. Based on population pharmacokinetic analyses in patients with solid tumors, the total systemic clearance was 0.59 L/day and the terminal half-life was 6.1 days in patients receiving 10 mg/kg.

In a post hoc analysis, avelumab clearance was found to decrease over time in patients with MCC, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline value of approximately 41.7% (40.0%)