From PDB entry
|Source||Humanized (from mouse)|
| Routes of|
|ECHA InfoCard|| 100.234.370 |
|Chemical and physical data|
|Molar mass||146 kDa g·mol−1|
Pembrolizumab (formerly MK-3475 and lambrolizumab, trade name Keytruda)is a humanized antibody used in cancer immunotherapy. It is an IgG4 isotype antibody that blocks a protective mechanism of cancer cells and thereby, allows the immune system to destroy them. It targets the programmed cell death protein 1 (PD-1) receptor of lymphocytes. The FDA initially approved it to treat metastatic melanoma. In 2017 the FDA approved it for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or microsatellite instability). This was the first time the FDA approved a cancer drug based on tumor genetics rather than tissue type or tumor site, therefore, Pembrolizumab is a so-called tissue-agnostic drug.
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans. Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system. The protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and are therefore potentially immunogenic when administered to human patients. There are other types of antibodies developed. The International Nonproprietary Names of humanized antibodies end in -zumab, as in omalizumab.
Cancer immunotherapy is the artificial stimulation of the immune system to treat cancer, improving on the system's natural ability to fight cancer. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology. It exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can be detected by the antibody proteins of the immune system, binding to them. The tumor antigens are often proteins or other macromolecules. Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill.
Programmed cell death protein 1, also known as PD-1 and CD279, is a protein on the surface of cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
As of 2017, pembrolizumab is used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) in certain situations, as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL).
Melanoma, also known as malignant melanoma, is a type of cancer that develops from the pigment-containing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye. In women, they most commonly occur on the legs, while in men they are most common on the back. Sometimes they develop from a mole with changes such as an increase in size, irregular edges, change in color, itchiness, or skin breakdown.
Platinum-based antineoplastic drugs are chemotherapeutic agents used to treat cancer. They are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemotherapy for cancer. In this form of chemotherapy, popular drugs include cisplatin, oxaliplatin, and carboplatin, but several have been proposed or are under development. Addition of platinum-based chemotherapy drugs to chemoradiation in women with early cervical cancer seems to improve survival and reduce risk of recurrence.
Hodgkin's lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cells called lymphocytes. Symptoms may include fever, night sweats, and weight loss. Often there will be non-painful enlarged lymph nodes in the neck, under the arm, or in the groin. Those affected may feel tired or be itchy.
For NSCLC, pembrolizumab is a first-line treatment if the cancer overexpresses PD-L1, a PD-1 receptor ligand, and the cancer has no mutations in EGFR or in ALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second-line treatment, but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first.Assessment of PD-L1 expression must be conducted with a validated and approved companion diagnostic.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.
In 2017 the FDA approved pembrolizumab for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or microsatellite instability).
Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome and by several other names.
Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.
If a person is taking corticosteroids or immunosuppressants, those drugs should be stopped before starting pembrolizumab because they may interfere with pembrolizumab; they may be used after pembrolizumab is started to deal with immune-related adverse effects.
Women of child-bearing age should use contraception when taking pembrolizumab; it should not be administered to pregnant women because animal studies have shown that it can reduce tolerance to the fetus, increasing the risk of miscarriage. It is not known whether pembrolizumab is present in breast milk.
Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. It is studied within the field of reproductive immunology.
As of 2017, the drug had not been tested in people with active infections (including any HIV, hepatitis B or hepatitis C infection), kidney or liver disease, active CNS metastases, active systemic autoimmune disease, interstitial lung disease, prior pneumonia, and people with a history of severe reaction to another monoclonal antibody.
People have had severe infusion-related reactions to pembrolizumab. There have also been severe immune-related adverse effects including lung inflammation (including fatal cases) and inflammation of endocrine organs that caused inflammation of the pituitary gland, of the thyroid (causing both hypothyroidism and hyperthyroidism in different people), and pancreatitis that caused Type 1 diabetes and diabetic ketoacidosis; some people have had to go on lifelong hormone therapy as a result (e.g. insulin therapy or thyroid hormones). People have also had colon inflammation, liver inflammation, kidney inflammation due to the drug.
The common adverse reactions have been fatigue (24%), rash (19%), itchiness (pruritus) (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia) (10%).
Other adverse effects occurring in between 1% and 10% of people taking pembrolizumab have included anemia, decreased appetite, headache, dizziness, distortion of the sense of taste, dry eye, high blood pressure, abdominal pain, constipation, dry mouth, severe skin reactions, vitiligo, various kinds of acne, dry skin, eczema, muscle pain, pain in a limb, arthritis, weakness, edema, fever, chills, myasthenia gravis, and flu-like symptoms.
Pembrolizumab is a therapeutic antibody that binds to and blocks PD-1 located on lymphocytes. This receptor is generally responsible for preventing the immune system from attacking the body's own tissues; it is a so-called immune checkpoint.Many cancers make proteins that bind to PD-1, thus shutting down the ability of the body to kill the cancer on its own. Inhibiting PD-1 on the lymphocytes prevents this, allowing the immune system to target and destroy cancer cells; this same mechanism also allows the immune system to attack the body itself, and checkpoint inhibitors like pembrolizumab have immune-dysfunction side effects as a result.
Tumors that have mutations that cause impaired DNA mismatch repair, which often results in microsatellite instability, tend to generate many mutated proteins that could serve as tumor antigens; pembrolizumab appears to facilitate clearance of any such tumor by the immune system, by preventing the self-checkpoint system from blocking the clearance.
Since pembrolizumab is cleared from the circulation through non-specific catabolism, no metabolic drug interactions are expected and no studies were done on routes of elimination.The systemic clearance [rate] is about 0.2 L/day and the terminal half-life is about 25 days.
Pembrolizumab is an immunoglobulin G4, with a variable region against the human PD-1 receptor, a humanized mouse monoclonal [228-L-proline(H10-S>P)]γ4 heavy chain (134-218') disulfide and a humanized mouse monoclonal κ light chain dimer (226-226:229-229)-bisdisulfide.
It is recombinantly manufactured in Chinese hamster ovary (CHO) cells.
Pembrolizumab was invented by scientists Gregory Carven, Hans van Eenennaam and John Dulos at Organon after which they worked with Medical Research Council Technology (now known as LifeArc) starting in 2006 to humanize the antibody; Schering-Plough acquired Organon in 2007 and Merck & Co. acquired Schering-Plough two years later.Carven, van Eenennaam and Dulos were recognized as Inventors of the Year by the Intellectual Property Owners Education Foundation in 2016.
The development program for pembrolizumab was seen as high priority at Organon, but low at Schering and later Merck. In early 2010 Merck terminated development and began preparing to out-license it.Later in 2010 scientists from Bristol Myers Squibb published a paper in the New England Journal of Medicine showing that their checkpoint inhibitor, ipilimumab (Yervoy) had shown strong promise in treating metastatic melanoma and that a second Bristol-Myers Squibb checkpoint inhibitor, nivolumab, (Opdivo) was also promising. Merck at that time had little commitment or expertise in either oncology or immunotherapy, but understood the opportunity and reacted strongly, reactivating the program and filing its IND by the end of 2010. As one example, Martin Huber was one of the few senior people at Merck with strong experience in lung cancer drug development, but had been promoted to senior management and was no longer involved in product development. He stepped down from his role to lead clinical development of pembrolizumab for lung cancer.
Scientists at the company argued for developing a companion diagnostic and limiting testing of the drug only to patients with biomarkers showing they were likely to respond, and received agreement from management. Some people, including shareholders and analysts, criticized this decision as it limited the potential market size for the drug, while others argued it increased the chances of proving the drug would work and would make clinical trials faster. (The trials would need fewer patients because of the likelihood of greater effect size.) Moving quickly and reducing the risk of failure was essential for catching up with Bristol-Myers Squibb, which had an approximate five year lead over Merck.The phase I study started in early 2011, and Eric Rubin, who was running the melanoma trial, argued for and was able to win expansion of the trial until it reached around 1300 people. This was the largest Phase I study ever run in oncology, with the patients roughly divided between melanoma and lung cancer.
In 2013 Merck quietly applied for and won a breakthrough therapy designation for the drug. This regulatory pathway was new at the time and not well understood. One of its advantages is that the FDA holds more frequent meetings with drug developers, reducing the risk of developers making mistakes or misunderstandings arising between regulators' expectations and what the developers want to do. This was Merck's first use of the designation and the reduction in regulatory risk was one of the reasons management was willing to put company resources into development.
In 2013, the USAN name was changed from lambrolizumab to pembrolizumab.In that year clinical trial results in advanced melanoma were published in the New England Journal of Medicine. This was part of the large phase 1 NCT01295827 trial.
On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab under the FDA Fast Track Development Program.It is approved for use following treatment with ipilimumab, or after treatment with Ipilimumab and a BRAF inhibitor in advanced melanoma patients who carry a BRAF mutation.
As of 2015, the only PD-1/PD-L1 targeting drugs on the market were pembrolizumab and Bristol-Myers Squibb's Opdivo, with clinical developments in the class of drugs receiving coverage in the New York Times.
By April 2016, Merck applied for approval to market the drug in Japan and signed an agreement with Taiho Pharmaceutical to co-promote it there.
In July 2015, pembrolizumab received marketing approval in Europe.
On October 2, 2015, the FDA approved pembrolizumab for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents.
In July 2016, the US FDA accepted for priority review an application for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after a platinum-based chemotherapy.They granted accelerated approval to pembrolizumab as a treatment for patients with recurrent or metastatic (HNSCC) ("regardless of PD-L1 staining") following progression on a platinum-based chemotherapy, based on objective response rates (ORR) in the phase Ib KEYNOTE-012 study in August of the same year. Full approval depended on the results of the phase III KEYNOTE-040 study (NCT02252042), which ran until Jan 2017.
In May 2017, pembrolizumab received an accelerated approval from the FDA for use in any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsatellite instability-high state (or, in the case of colon cancer, tumors that have progressed following chemotherapy). This approval marked the first instance in which the FDA approved marketing of a drug based only on the presence of a genetic mutation, with no limitation on the site of the cancer or the kind of tissue in which it originated.The approval was based on a clinical trial of 149 patients with microsatellite instability-high or mismatch repair deficient cancers who enrolled on one of five single-arm trials. Ninety patients had colorectal cancer, and 59 patients had one of 14 other cancer types. The objective response rate for all patients was 39.6%. Response rates were similar across all cancer types, including 36% in colorectal cancer and 46% across the other tumor types. Notably, there were 11 complete responses, with the remainder partial responses. Responses lasted for at least six months in 78% of responders. Because the clinical trial was fairly small, Merck is obligated to conduct further post-marketing studies to ensure that the results are valid.
In June 2018, the FDA approved pembrolizumab for use in both advanced cervical cancer for PD-L1 positive patientsand for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy .
Pembrolizumab was priced at $150,000 per year when it launched (late 2014).
In 2015, Merck reported results in 13 cancer types; much attention was given to early results in head and neck cancer.
As of May 2016, pembrolizumab was in Phase IB clinical trials for triple-negative breast cancer (TNBC), gastric cancer, urothelial cancer, and head and neck cancer (all under the "Keynote-012" trial) and in Phase II trial for TNBC (the "Keynote-086" trial).At ASCO in June 2016, Merck reported that the clinical development program was directed to around 30 cancers and that it was running over 270 clinical trials (around 100 in combination with other treatments) and had four registration-enabling studies in process.
Results of a Phase II clinical trial in Merkel-cell carcinoma were reported in the New England Journal of Medicine in June 2016.
Results of a clinical trial in people with untreatable metastases arising from various solid tumors were published in Science in 2017.
It is in a phase III trial in combination with epacadostat, an Indoleamine 2,3-dioxygenase (IDO1) inhibitor to treat melanoma.
A cancer vaccine is a vaccine, that either treats existing cancer or prevents development of a cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines.
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Transitional cell carcinoma, also urothelial carcinoma, is a type of cancer that typically occurs in the urinary system. It is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus. It is the second most common type of kidney cancer, but accounts for only five to 10 percent of all primary renal malignant tumors.
Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Tremelimumab is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer, it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.
Oncolytics Biotech Inc. is a Canadian company headquartered in Calgary, Alberta, that is developing an intravenously delivered immuno-oncolytic virus called REOLYSIN® for the treatment of solid tumors and hematological malignancies. REOLYSIN is a non-pathogenic, proprietary isolate of the unmodified reovirus that: induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses.
REOLYSIN®, is a proprietary isolate of the unmodified human reovirus (reovirus) being developed as a first-in-class systemically administered immuno-oncology viral agent for the treatment of solid tumors and hematological malignancies. REOLYSIN is classified as an oncolytic virus, a virus that preferentially lyses cancer cells. Based on both single-arm and randomized phase 2 clinical studies, REOLYSIN also promotes an inflamed tumor phenotype through innate and adaptive immune responses. Clinical trials have demonstrated that REOLYSIN may have activity across a variety of cancer types when administered alone and in combination with other cancer therapies.
Nivolumab, marketed as Opdivo, is a medication used to treat cancer. It is used as a first line treatment for inoperable or metastatic melanoma in combination with ipilimumab if the cancer does not have a mutation in BRAF, as a second-line treatment following treatment with ipilimumab and if the cancer has a mutation in BRAF, with a BRAF inhibitor, as a second-line treatment for squamous non-small cell lung cancer, and as a second-line treatment for renal cell carcinoma. Nivolumab has recently been approved for small cell lung cancer.
A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.
Talimogene laherparepvec is a biopharmaceutical drug to treat melanoma lesions that cannot be operated on; it is injected directly into the lesion. As of 2016 there was no evidence that it extends the life of people with melanoma, or that it prevents metastasis.
Sonidegib is a Hedgehog signaling pathway inhibitor being developed as an anticancer agent by Novartis.
Durvalumab is an FDA-approved immunotherapy for cancer, developed by Medimmune/AstraZeneca. It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who either have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Atezolizumab is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).
Avelumab is a fully human monoclonal antibody developed by Merck KGaA and Pfizer as a pharmaceutical drug for use in immunotherapy, originally for the treatment of non-small-cell lung carcinoma (NSCLC).
Viralytics Ltd is an Australian biotechnology company working in the field of oncolytic viruses, that is, viruses that preferentially infect and kill cancer cells. The company's oncolytic virus product, called Cavatak, is currently in clinical trials in metastatic melanoma and other cancers. The drug was granted Orphan Drug status in advanced melanoma in December 2005.
PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitors being developed for the treatment of cancer. PD-1 and PD-L1 are both proteins present on the surface of cells. Immune checkpoint inhibitors such as these are emerging as a front-line treatment for several types of cancer.
Checkpoint inhibitor therapy is a form of cancer immunotherapy currently under research. The therapy targets immune checkpoints, key regulators of the immune system that stimulate or inhibit its actions, which tumors can use to protect themselves from attacks by the immune system. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.
Cemiplimab (REGN-2810) is a monoclonal antibody under development as a drug for the treatment of squamous cell skin cancer, myeloma, and lung cancer.