What is the mechanism of action and side effects of Keytruda (Pembrolizumab)?

From the Guidelines

Keytruda (pembrolizumab) is an immune checkpoint inhibitor that works by blocking the PD-1 receptor on T cells, and its use in patients with MSI-H or dMMR metastatic castration-resistant prostate cancer (mCRPC) is supported by the panel, as it has shown durable responses in this population 1. The mechanism of action of Keytruda involves preventing the binding of PD-L1, a protein often overexpressed by cancer cells, which normally helps tumors evade immune detection. By inhibiting this interaction, Keytruda effectively "removes the brakes" from the immune system, allowing T cells to recognize and attack cancer cells. Some key points to consider when using Keytruda include:

• The medication is administered as an intravenous infusion, typically every 3-6 weeks depending on the specific cancer type and treatment protocol.
• Common side effects of Keytruda include fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain.
• More serious immune-related adverse events can occur, such as colitis, hepatitis, endocrinopathies, pneumonitis, or nephritis, which require prompt medical attention and sometimes necessitate corticosteroid treatment.
• Regular monitoring of organ function through blood tests and clinical evaluation is essential throughout Keytruda therapy to detect and manage these potential complications early.
• The prevalence of MMR deficiency in metastatic CRPC is estimated at 2%–5%, and testing for MSI-H or dMMR can be performed using DNA testing or immunohistochemistry, with referral to genetic counseling for consideration of germline testing for Lynch syndrome if tumor MSI-H or dMMR is identified 1. The most recent and highest quality study, published in 2023, supports the use of pembrolizumab in patients with MSI-H or dMMR mCRPC whose disease has progressed through docetaxel and a novel hormone therapy, with durable responses observed in this population 1.

From the FDA Drug Label

KEYTRUDA can cause serious side effects. Common side effects of KEYTRUDA when used alone include: feeling tired, pain, including pain in muscles, rash, diarrhea, fever, cough, decreased appetite, itching, shortness of breath, constipation, bones or joints and stomach-area (abdominal) pain, nausea, and low levels of thyroid hormone Side effects of KEYTRUDA when used alone that are more common in children than in adults include: fever, vomiting, headache, stomach area (abdominal) pain, and low levels of white blood cells Common side effects of KEYTRUDA when given with certain chemotherapy or chemotherapy with radiation therapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs, swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, mouth sores, headache, weight loss, stomach-area (abdominal) pain, joint and muscle pain, trouble sleeping, bleeding, blisters, or rash on the palms of your hands and soles of your feet, urinary tract infection, and low levels of thyroid hormone

The mechanism of action of KeyTruda (pembrolizumab) is not explicitly stated in the provided drug label. The side effects of KeyTruda include:

• Common side effects when used alone: feeling tired, pain, rash, diarrhea, fever, cough, decreased appetite, itching, shortness of breath, constipation, and low levels of thyroid hormone
• Side effects more common in children: fever, vomiting, headache, stomach area pain, and low levels of white blood cells
• Side effects when given with certain chemotherapy or radiation therapy: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, and low levels of thyroid hormone 2

From the Research

Mechanism of Action

• Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that works by blocking the PD1 receptor on lymphocytes, enhancing immunity against cancer cells 3, 4.
• The PD1 receptor is one of the checkpoints that regulates the immune response, and its ligation with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells 3.
• Blockade of PD1 is an important immunotherapeutic strategy for cancers, as it enables the immune system to recognize and attack cancer cells more effectively 3, 4.

Side Effects

• Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases 3.
• Immune-related adverse events (irAEs) are a common side effect of pembrolizumab, including thyroid dysfunction, hepatitis, pneumonitis, and colitis 3, 5, 6, 7.
• irAEs can be serious and may lead to cessation of treatment, highlighting the importance of early recognition and appropriate intervention 5, 6, 7.
• The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in patients with NSCLC with PD-L1 expression ≥ 50% 6.

Specific Side Effects

• Pneumonitis is a rare but known complication of pembrolizumab treatment, with a median time frame of appearance of 2.8 months, but can occur as early as 48 hours after treatment initiation 7.
• Colitis is another common irAE, which can develop 6-8 weeks after ICI initiation and can involve any part of the gastrointestinal system 5.
• Thyroid dysfunction, hepatitis, and rheumatologic irAEs are also common side effects of pembrolizumab 3, 6.