Used for immunotherapy treatment, Keytruda® (generic name, pembrolizumab) is a new monoclonal antibody drug specifically designed to target and treat certain types of solid tumors by interfering with the growth and spread of cancer cells. Also called anti-PD-1 or anti-PD-L1, monoclonal antibody drugs are considered targeted therapies because they target specific sites, or proteins, within cancer cells. Targeted therapies have the theoretical advantage of binding to and killing cancer cells, while causing less damage to normal cells.
Keytruda® is used to treat advanced stage melanoma and has been used to treat a certain type of non-small cell lung cancer with a specific genetic marker. It was approved by the FDA to treat lung cancer on an “accelerated” basis, and clinical studies show that tumors respond to the drug. Early studies have also shown that pembrolizumab may be an effective treatment option for mesothelioma.
How Keytruda® Works
In the body, there is a type of white blood cell that watches out for signs of infection or disease and can also attack cancer cells. These white blood cells are called T cells. On the surface of these T cells are certain proteins known as programmed cell death receptors (PD-1). So that T cells don’t destroy healthy cells, they use these surface proteins, or PD-1, to bind to and communicate with PD-L1 and PD-L2, proteins that enable cells to escape attack from the body’s immune system.
In other words, when the PD-1 protein on T cells comes in contact with PD-L1 and PD-L2 proteins, they are given the signal to allow that cell to live and spread. Certain types of cancer cells, however, have been found to contain an excess of these PD-L1 and PD-L2 proteins, making them look like healthy cells to the immune system, thus allowing them to avoid getting destroyed by T cells.
Pembrolizumab blocks that signal so that the T cells aren’t misled by PD-L1 and PD-L2, allowing the body’s natural immune system to attack the cancer cells. This particular therapy is called an immune checkpoint blockade, where “checkpoint” refers to the encounter between T cells and the PD-L1 protein on tumor cells.
Keytruda® as Treatment for Melanoma, Non-small Cell Lung Cancer, and Mesothelioma
To date, Keytruda® has shown success in three cancers: melanoma, non-small cell lung cancer (NSCLC), and mesothelioma.
Clinical trials demonstrated that Keytruda® treatment increased the response rate and duration of response in patients with:
- Melanoma that was unable to be removed by surgery (unresectable)
- Melanoma that had spread to other parts of the body (metastatic)
- PD-L1 positive NSCLC that had failed to respond to chemotherapy
Based on the efficacy, safety, and tolerability of Keytruda in the studies, the intravenous treatment was approved by the FDA for those types of cancer.
Early Clinical Trial for Keytruda® as Mesothelioma Treatment
Malignant pleural mesothelioma is a cancer of the lining of the lung that is caused by exposure to asbestos. An estimated 20% to 40% of patients with pleural malignant mesothelioma have PD-L1 on the surface of their cancer cells. Additionally, in many of these PD-L1-positive tumors, the cancer cells have an abnormally high amount of PD-L1 on their surface.
In an early clinical trial (KEYNOTE-028), patients with advanced pleural mesothelioma that was not controlled by previous therapy and whose tumors showed high levels of PD-L1 on the cell surface received 10 mg/kg of pembrolizumab every 2 weeks. Treatment in the trial was planned to continue for as long as 2 years, or until the patients experienced growth of their tumors or unmanageable side effects. During the first 6 months of treatment, tumor responses to pembrolizumab were evaluated every 8 weeks for the first 6 months and then at every 12-week period.
Keytruda® was effective therapy in approximately 76% of the treated patients, which represents a promising result. Among the 25 patients who received Keytruda®:
- 28% had some shrinkage of tumors (partial responses)
- 48% of the treated patients experienced stable disease (no increase in extent of tumors)
Some patients responded positively to the treatment for longer than 24 weeks. Keytruda® also seemed to improve the effectiveness of other treatments, meaning that it could be used as part of a multimodal treatment plan.
Although it is too early to determine actual survival advantages of Keytruda® in mesothelioma, 6 months following treatment, 50% of mesothelioma patients experienced what’s known as progression-free survival (PFS), or survival where tumors either become smaller or do not increase in size. The median survival of this kind was 5.8 months.
Keytruda® also appeared to be well-tolerated by patients with mesothelioma. As of April 2015, no patients with mesothelioma in the clinical trial discontinued therapy due to drug-related side effects.
The effectiveness of Keytruda® in the early human studies of malignant mesothelioma is considered to be encouraging news and provides hope to patients, although further research is needed. At the present time, Keytruda® remains an investigational drug for mesothelioma.
A Phase II trial of Keytruda® in malignant mesothelioma, including pleural and peritoneal (in the lining of the abdomen) is recruiting patients.
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Potential Side Effects of Keytruda®
Keytruda® is well-tolerated by mesothelioma patients. Based on studies in patients with melanoma and NSCLC, common side effects include:
- High blood glucose levels
- Abnormally low sodium in the blood
- Abnormally low albumin in the serum
Based on studies in patients with melanoma and NSCLC, less common side effects include:
- Decrease in appetite
- Abnormally high levels of triglycerides in the blood
- Abnormally high level of liver enzymes
- Abnormally low level of calcium in the blood
- Constipation or diarrhea
- Joint and muscle pain and pain in limbs
- Shortness of breath
- Difficulty sleeping
- Pain in the abdomen or back
- Infection of the upper respiratory tract
During or up to months after treatment with Keytruda®, an uncommon but serious immune reaction may occur as a side effect. Symptoms include, but are not limited to, diarrhea, rash, and pain in the nerves. Laboratory signs are increases in liver enzymes and changes in the function of the thyroid gland. Some of the organs that may be affected by the immune reaction are the bowels, liver, skin, the endocrine system (organs producing hormones), the lungs, and the kidneys.
Patients receiving Keytruda® should contact their physician if they experience any side effects that are new or become more severe.Sources
Keytruda® (pembrolizumab) for injection for intravenous use. Prescribing information. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Revised 12/2015.
FDA approves Keytruda® for advanced melanoma. Press release. FDA. September 4, 2014.
FDA approves Keytruda® (pembrolizumab) for the treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1 with disease progression on or after platinum-containing chemotherapy. Press release. Merck. October 2, 2015.
Allen EW, Molife R, Santoro A, et al. Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028. Abstract CT103. Proceedings AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA.
Pembrolizumab safe, with signs of clinical benefit for patients with malignant pleural mesothelioma. Press release. AACR. April 19, 2015.
Mulcahy N. ‘Unprecedented’ disease control in mesothelioma trial. Medscape Multispecialty. April 24, 2015.
Furlow B. Second-line pembrolizumab shows ‘encouraging’ PFS for advanced mesothelioma. OncoTherapy Network. September 16, 2015.