Avelumab

Merkel Cell Carcinoma

Avelumab is used to treat a rare type of skin cancer called Merkel cell carcinoma in adults and children 12 years of age and older. It is typically prescribed when the cancer has spread to other parts of the body (metastatic).

Urothelial Carcinoma

This medication is used to treat advanced bladder cancer or cancer of the urinary tract (urothelial carcinoma). It may be used in the following situations:

• As a maintenance treatment when the cancer has responded to initial platinum-based chemotherapy.
• When the cancer has worsened during or after treatment with platinum-based chemotherapy.

Renal Cell Carcinoma

Avelumab is used as a first-line treatment for advanced kidney cancer (renal cell carcinoma). In these cases, it is used in combination with another drug called axitinib.

Mechanism of Action

Avelumab belongs to a class of drugs known as PD-L1 inhibitors. It works by targeting a specific protein called programmed death-ligand 1 (PD-L1), which is found on the surface of some cancer cells and certain immune cells.

The immune system uses "checkpoints" to prevent it from attacking healthy cells. Some cancer cells exploit these checkpoints by producing PD-L1. When PD-L1 binds to receptors on T-cells (a type of white blood cell), it sends a signal that tells the T-cell to remain inactive. This allows the cancer to grow and spread undetected by the body's natural defenses.

Avelumab works in the following ways:

• Blocking the "Off" Signal: By binding to PD-L1, avelumab prevents it from interacting with the receptors on T-cells. This removes the "brakes" on the immune system, allowing T-cells to identify and destroy the cancer cells.
• Direct Immune Attack: Avelumab may also help the immune system kill cancer cells through a process called antibody-dependent cell-mediated cytotoxicity. In this process, the drug flags the cancer cells so that other immune cells can find and eliminate them.

Common Side Effects

Many people receiving avelumab experience mild to moderate side effects. These may include:

• Feeling very tired or weak (fatigue)
• Pain in the muscles, bones, or joints
• Diarrhea or nausea
• Skin rash or itching
• Decreased appetite
• Swelling in the hands, feet, or ankles
• Urinary tract infections

Serious Side Effects

Avelumab works by affecting the immune system, which can sometimes cause the body to attack its own healthy tissues and organs. These reactions can be severe or life-threatening and may include:

• Lung problems: New or worsening cough, shortness of breath, or chest pain (pneumonitis).
• Intestinal problems: Severe diarrhea, stomach pain, or blood in the stool (colitis).
• Liver problems: Yellowing of the skin or eyes, dark urine, or severe nausea and vomiting (hepatitis).
• Hormone gland problems: Changes in energy levels, weight changes, or mood changes affecting the thyroid, adrenal, or pituitary glands.
• Kidney problems: Changes in the amount or color of urine.
• Infusion reactions: Fever, chills, shaking, or dizziness occurring during or shortly after the injection.
• Heart problems: Chest pain, shortness of breath, or irregular heartbeat.

It is important to report any new or worsening symptoms to a healthcare provider immediately, as early treatment of side effects is often necessary.

Immune-Mediated Adverse Reactions

Avelumab works by stimulating the immune system, which can sometimes cause it to attack healthy organs and tissues. These reactions can occur at any time during or after treatment and may become life-threatening. Key areas of concern include:

• Lungs: Inflammation of the lungs (pneumonitis) can occur. Symptoms may include new or worsening cough, chest pain, or shortness of breath.
• Liver: Inflammation of the liver (hepatitis) may develop. Monitoring of liver function tests is typically required.
• Digestive Tract: Inflammation of the intestines (colitis) can lead to diarrhea or severe abdominal pain.
• Hormone Glands: The drug can affect the thyroid, pituitary, and adrenal glands, as well as blood sugar levels (Type 1 diabetes).
• Kidneys: Inflammation of the kidneys (nephritis) can lead to changes in urine color or volume.
• Skin: Severe skin reactions, including rashes or blistering, have been reported.

Infusion-Related Reactions

Severe or life-threatening reactions can occur during the intravenous infusion of avelumab. Patients are often given premedication, such as an antihistamine and acetaminophen, before the first few doses to reduce this risk. Symptoms may include chills, shaking, back pain, flushing, or difficulty breathing.

Embryo-Fetal Toxicity

Avelumab can cause harm to a developing fetus. Individuals of reproductive potential should use effective contraception during treatment and for at least one month after the last dose. Breastfeeding is generally not recommended during treatment and for at least one month following the final dose.

Monitoring and Management

Regular blood tests are necessary to monitor organ function, including liver enzymes, kidney function, and hormone levels. If severe immune-mediated reactions occur, treatment may need to be delayed or permanently discontinued, and corticosteroid medications may be prescribed.

Pregnancy

Avelumab can cause harm to a developing fetus. Healthcare providers typically require a pregnancy test before starting treatment to confirm the patient is not pregnant. Individuals who can become pregnant should use effective birth control during treatment and for at least one month after the last dose. If a person becomes pregnant while receiving this medication, they should contact their healthcare provider immediately.

Breastfeeding

It is not known whether avelumab passes into breast milk. Because of the potential for serious side effects in a nursing infant, breastfeeding is not recommended during treatment and for at least one month after the final dose. Patients should discuss their options for feeding an infant with their healthcare team.

Dosage Forms

Avelumab is supplied in the following form:

• Intravenous Injection: A sterile, preservative-free solution provided in a single-dose vial.

This medication is a concentrated solution that must be diluted by a healthcare professional before being administered into a vein.

FDA Approval and Indications

Avelumab is approved by the U.S. Food and Drug Administration (FDA) for several specific oncological indications:

• Merkel Cell Carcinoma: It is approved for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).
• Urothelial Carcinoma: It is indicated as a maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed on first-line platinum-containing chemotherapy. It is also approved for patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy.
• Renal Cell Carcinoma: In combination with axitinib, it is approved for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Regulatory Status

Avelumab was initially granted accelerated approval for certain indications, which was later transitioned to full approval based on confirmatory clinical data. There are currently no boxed warnings or Risk Evaluation and Mitigation Strategy (REMS) programs associated with this medication. The FDA monitors the drug for immune-mediated adverse reactions, which are a known risk with this class of therapy.

FDA Approval History

Avelumab has received several approvals from the U.S. Food and Drug Administration (FDA) for the treatment of specific types of cancer:

• Merkel Cell Carcinoma: In March 2017, the FDA granted accelerated approval for avelumab to treat adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This marked the first FDA-approved therapy for this rare and aggressive form of skin cancer.
• Urothelial Carcinoma: The FDA approved avelumab in May 2017 for patients with locally advanced or metastatic bladder cancer (urothelial carcinoma) that progressed during or after platinum-containing chemotherapy. In June 2020, it received further approval as a maintenance treatment for patients whose cancer had not progressed following first-line platinum-based chemotherapy.
• Renal Cell Carcinoma: In May 2019, the FDA approved avelumab in combination with axitinib for the first-line treatment of patients with advanced kidney cancer (renal cell carcinoma).

Accelerated Approval Status

Some indications for avelumab were approved under the FDA's accelerated approval pathway. This program allows for the earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint, such as tumor shrinkage. Continued approval for these specific uses may depend on the results of ongoing clinical trials that confirm the drug's clinical benefit.