Keytruda (pembrolizumab) is an immunotherapy designed to harness the body’s defense system against tumor cells. Brain metastases are secondary tumors that form when cancer cells from a primary site, such as the lung or skin, travel through the bloodstream and establish growths within the brain. Treating these secondary tumors has historically been challenging because the brain is a protected organ. Systemic treatments like Keytruda offer a new therapeutic strategy for patients facing tumors that have spread to the central nervous system.
Targeting Metastases: Keytruda’s Mechanism and the Blood-Brain Barrier
Keytruda functions as an immune checkpoint inhibitor by blocking the interaction between the Programmed Death-1 (PD-1) receptor on immune cells and its ligands (PD-L1 and PD-L2) found on tumor cells. This PD-1/PD-L1 pathway acts as a “brake” on the immune system, allowing cancer cells to evade detection and destruction. By interrupting this signaling pathway, Keytruda removes the inhibition, allowing T-cells to target the cancer.
The central nervous system (CNS) presents a unique challenge for drug delivery due to the blood-brain barrier (BBB), which strictly regulates the passage of substances from the blood into the brain. Many traditional chemotherapy agents, being large molecules, are largely excluded by this barrier, limiting their concentration at the tumor site. Keytruda, while a large monoclonal antibody, has shown therapeutic effect within the CNS.
The mechanism of its success is thought to be twofold, relating to the drug’s action and the nature of the metastases. The drug activates T-cells systemically, and these activated immune cells can then infiltrate the brain and attack the tumor. Furthermore, the integrity of the BBB is often compromised or “leaky” around metastatic tumors, which facilitates the infiltration of T-cells into the tumor microenvironment.
Clinical Applications by Cancer Type
The therapeutic benefit of Keytruda against brain metastases has been demonstrated in patients with melanoma and non-small cell lung cancer (NSCLC). Melanoma is one of the cancers where immunotherapy has shown significant activity in the central nervous system. Clinical trials indicate that Keytruda monotherapy can achieve a brain metastasis response rate of around 22%.
A response is considered durable when tumor shrinkage or disappearance is maintained over a long period. In some studies, combining Keytruda with other therapies, such as the anti-angiogenic drug bevacizumab, has amplified this effect, yielding intracranial response rates exceeding 50%. This combination aims to enhance the immune response and normalize the blood vessels around the tumor.
For NSCLC, Keytruda’s efficacy is often tied to the level of PD-L1 expression on the tumor cells. Patients with high expression (a tumor proportion score of 50% or greater) are the most likely to respond. In this group, retrospective studies have reported brain metastasis response rates as high as 70% with first-line Keytruda monotherapy.
A prospective Phase II trial specifically investigating Keytruda in NSCLC patients with brain metastases found a brain metastasis response rate of 33% in patients whose tumors expressed PD-L1. The use of Keytruda provides both systemic control of the primary cancer and extracranial metastases, alongside intracranial control of the brain lesions.
Efficacy is also being explored across other cancer types in histology-agnostic trials that enroll patients based on the presence of brain metastases. These studies have shown that Keytruda can provide an intracranial benefit in a variety of tumor types, including subsets of breast cancer and renal cell carcinoma. One such trial demonstrated an overall intracranial benefit rate of 42.1% across diverse histologies. While the objective response rate (confirmed tumor shrinkage) may be lower, the overall benefit rate suggests the drug can stabilize or slow the growth of tumors in the brain.
Treatment Logistics and Potential Adverse Effects
Keytruda is administered intravenously as an infusion. The standard dosing schedule for adults is either 200 mg every three weeks or 400 mg every six weeks. Treatment continues until the disease progresses, the patient experiences unacceptable toxicity, or for a maximum of 24 months without disease progression.
The drug’s mechanism can lead to side effects known as immune-related adverse events (irAEs), where the activated T-cells mistakenly attack healthy tissues. Common irAEs include fatigue, rash, diarrhea, and endocrinopathies, such as inflammation of the thyroid gland. These effects can occur anytime during treatment or months after the final dose.
When treating brain metastases, the focus shifts to potential CNS-specific side effects. Neurological symptoms such as headache, confusion, or seizures can occur due to inflammation or swelling around the brain lesions. A challenge is distinguishing between true tumor progression and pseudoprogression, a temporary enlargement of the tumor on imaging caused by immune cell infiltration. Managing these neurological effects often involves the temporary use of corticosteroids, which can sometimes interfere with the immunotherapy’s effectiveness.