Pembrolizumab (formerly MK-3475 and lambrolizumab , trade name Keytruda ) are humane antibodies used in cancer immunotherapy. These are IgG4 isotype antibodies that block the protective mechanisms of cancer cells, and allow the immune system to destroy cancer cells. It targets cell death 1 (PD-1) lymphocyte receptor. The FDA initially agreed to treat metastatic melanoma. By 2017 the FDA approves for inoperable solid tumors or metastases with certain genetic anomalies (deficiency of microsatellite incompatibility or instability). It was the first time the FDA approved cancer drugs based on tumor genetics rather than tissue types or tumor sites.
Video Pembrolizumab
Medical use
In 2017, pembrolizumab is used by intravenous infusion to treat an inoperable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) under certain circumstances, as second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum. chemotherapy-based, and for the treatment of adult and child patients with classical Hodgkin's lymphoma refractory (cHL).
For NSCLC, pembrolizumab is first-line treatment if overexpresses PD-L1, PD-1 receptor ligand, and cancer have no mutations in EGFR or in ALK; if chemotherapy has been given, then pembrolizumab may be used as second-line treatment but if the cancer has a mutation of EGFR or ALK, the agent that targets the mutation should be used first. The PD-L1 assessment should be performed with a validated and approved companion diagnosis.
By 2017 the FDA approves for inoperable solid tumors or metastases with certain genetic anomalies (deficiency of microsatellite incompatibility or instability).
Maps Pembrolizumab
Contraindications
If a person is taking corticosteroids or immunosuppressants, they should be discontinued before starting pembrolizumab because they can interfere with pembrolizumab; they can be used after pembrolizumab begins to deal with immune-related side effects.
Women of childbearing age should use contraception when taking pembrolizumab; it should not be given to pregnant women because animal studies show that it can reduce fetal tolerance and increase the risk of miscarriage. It is not known whether pembrolizumab is secreted into breast milk or not.
By 2017, the drug has not been tested in people with active infection including HIV infection, hepatitis B or hepatitis C, kidney or liver disease, active CNS metastasis, active systemic autoimmune disease, interstitial lung disease; pneumonia, and people with a history of severe reactions to other monoclonal antibodies.
Adverse effects
People have a severe infusion-related reaction to pembrolizumab. There are also severe immune-related side effects including pulmonary inflammation (including fatal cases) and endocrine organ inflammation that causes inflammation of the pituitary gland, from the thyroid (causing hypothyroidism and hyperthyroidism in different people), and pancreatitis caused. 1 diabetes and diabetic ketoacidosis; some people have to undergo lifelong hormone therapy as a result (eg insulin therapy or thyroid hormone). People also experience inflammation of the large intestine, inflammation of the liver, inflammation of the kidney due to drugs.
Common adverse reactions were fatigue (24%), rash (19%), pruritus (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia) (10%).
Other side effects that occur between 1% and 10% of people who use pembrolizumab include anemia, decreased appetite, headache, dizziness, sensory distortion, dry eyes, high blood pressure, abdominal pain, constipation, dry mouth,. reactions, vitiligo, various types of acne, dry skin, eczema, muscle pain, pain in the limbs, arthritis, weakness, edema, fever, chills, and flu-like symptoms.
Action mechanism
Pembrolizumab is a therapeutic antibody that binds and blocks the programmed cell death protein PD-1 located in the lymphocytes. These receptors are generally responsible for preventing the immune system from invading the body's own tissues; it is a so-called immune checkpoint. Many cancers make proteins that bind PD-1, thus shutting down the body's ability to kill its own cancer. Inhibiting PD-1 in lymphocytes prevents this, enabling 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 such as pembrolizumab have side effects of immune dysfunction as a result.
Tumors that have mutations that cause repair of DNA mismatch, which often leads to microsatellite instability, tend to produce many mutated proteins that can function as tumor antigens; pembrolizumab appears to facilitate the removal of such tumors by the immune system, by preventing self-checking systems blocking blocking.
Pharmacology
Because pembrolizumab is cleared of the circulation through non-specific catabolism, no expected metabolic drug interactions and no studies are conducted on the elimination route. Systemic clearance is about 0.2 L/day and the half-life of the terminal is about 25 days.
Chemical and manufacturing
Pembrolizumab is a G4 immunoglobulin, with a variable region against receptors of human 1 cell receptor death, human monoclonal mice [228-L-proline (H10-S & gt; P)]? 4 weight chains (134-218 ') disulphide and humanized monoclonal mice? dimer light chain (226-226 : 229-229 ) - bisdisulfide.
This is a recombinant produced in Chinese ovary hamster cells (CHO).
History
Pembrolizumab was discovered by scientists Gregory Carven, Hans van Eenennaam and John Dulos in Organon after they worked with the Medical Research Council Technology (now known as LifeArc) beginning in 2006 to humanize antibodies; Schering-Plow acquired Organon in 2007 and Merck & amp; Co acquired Schering-Plow two years later. Carven, van Eenennaam and Dulos were recognized as Inventors of the Year by the Intellectual Property Rights Education Foundation in 2016.
The development program for pembrolizumab is seen as a high priority in Organon, but low in Schering and then Merck. In early 2010 Merck stopped development and began preparing to legalize it. Then in 2010 scientists from Bristol Myers Squibb published a paper in the New England Journal of Medicine showing that their inhibitory checkpoint, ipilimumab (Yervoy) has shown strong promise in treating metastatic melanoma and that the second check-point inhibitor Bristol-Myers Squibb, nivolumab, (Opdivo) is also promising. Merck at the time had little commitment or expertise in either oncology or immunotherapy, but understood the opportunities and reacted strongly, reactivated the program and submitted the IND at the end of 2010. As an example, Martin Huber is one of several senior people at Merck with strong experience in lung cancer drug development, but has been promoted to senior management and is no longer involved in product development. He withdrew from his role to lead the development of clinical pembrolizumab for lung cancer.
Scientists at the company argue to develop diagnostic companions and limit drug testing only to patients with biomarkers who indicate they are likely to respond, and receive approval from management. Some people, including shareholders and analysts, criticize this decision for limiting the size of the potential market for the drug, while others argue that an increased chance of proving the drug will work and will make clinical trials faster. (Experiments will require fewer patients because of the possibility of larger effect sizes.) Fast-moving and reduced risk of failure is critical to connecting with Bristol-Myers Squibb, which has an estimated five years over Merck. Phase I learning began in early 2011, and Eric Rubin, who runs melanoma trials, argues and is able to win experimental extensions of up to about 1300 people. This is the largest Phase I study ever conducted in oncology, with patients being roughly divided between melanoma and lung cancer.
In 2013 Merck secretly filed a petition and won a breakthrough therapeutic appointment for the drug. The path of this arrangement was new at the time and not well understood. One of the advantages is that the FDA holds frequent meetings with drug developers, reducing the risk of developers making mistakes or misunderstandings that arise between the regulator's expectations and what the developer wants to do. This is the first use of the appointment by Merck and the reduction in regulatory risk is one of the reasons management is willing to put company resources into development.
In 2013, the name USAN changed from lambrolizumab to pembrolizumab. In that year the results of clinical trials on melanoma continued published in the New England Journal of Medicine. This is part of a large NCT01295827 phase 1 experiment.
On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab under the FDA's Fast Track Development Program. The drug is approved for use after treatment with ipilimumab, or after treatment with Ipilimumab and BRAF inhibitors in patients with advanced melanoma carrying BRAF mutations.
By 2015, the only targeting drug PD-1/PD-L1 on the market is pembrolizumab and Bristol-Myers Squibb's Opdivo, with clinical developments in drug classes receiving coverage in the New York Times.
Until April 2016, Merck filed an application to market the drug in Japan and signed an agreement with Taiho Pharmaceutical to promote it there.
In July 2015, pembrolizumab received marketing approval in Europe.
On October 2, 2015, the FDA approved pembrolizumab for the treatment of non-small-cell metastatic lung cancer (NSCLC) in patients whose tumors expressed PD-L1 and who had failed treatment with other chemotherapy agents.
In July 2016, the US FDA accepted to review application priorities for recurrent or metastatic head and neck carcinoma (HNSCC) after platinum-based chemotherapy. They grant accelerated approval for pembrolizumab as treatment for patients with recurrent or metastasis ("regardless of PD-L1 staining") following platinum-based chemotherapy, based on objective response rates (ORR) in the Ib Ib phase KEYNOTE -012 studied at month August in the same year. Full approval depends on the results of the Phase III KEYNOTE-040 (NCT02252042) study, which lasts until January 2017.
In May 2017, pembrolizumab received accelerated approval from the FDA for use on any inoperable solid tumor or metastases with defective DNA repair incompatibility or microsatellite instability (or, in the case of colon cancer, tumors that have developed after chemotherapy). This agreement marks the first example in which the FDA approves the marketing of drugs based solely on the existence of a genetic mutation, without limitation on the location of the cancer or the type of tissue from which it originated. The approval was based on clinical trials of 149 patients with microsatellite incompatibility instability or mismatch in improving the cancer listed in one of five single-arm trials. Ninety patients had colorectal cancer, and 59 patients had one of 14 other cancers. The objective response rate for all patients was 39.6%. Response rates were similar across all types of cancer, including 36% in colorectal cancer and 46% across all other tumor types. In particular, there are 11 complete responses, with the remainder partial responses. Response lasted for at least six months in 78% of respondents. Because clinical trials are small enough, 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 cancers for PD-L1 positive patients and for the treatment of adult and childbearers with the primary mediastinal B-cell lymphoma (PMBCL) refractory, or who relapsed after two or more lines therapy before.
Society and culture
Pembrolizumab is priced at $ 150,000 per year when it is launched (end of 2014).
Research
In 2015, Merck reported results on 13 types of cancer; much attention is given to early results in head and neck cancer.
In May 2016, pembrolizumab was in clinical trials IB IB Stage for triple-negative breast cancer (TNBC), gastric cancer, urothelial cancer, and head and neck cancer (all under "Keynote-012" experiments) and in Phase II trials for TNBC (trial "Keynote-086"). At ASCO in June 2016, Merck reported that the clinical development program is directed to about 30 cancers and that it carries more than 270 clinical trials (about 100 in combination with other treatments) and has four studies that allow enrollment in the process.
Phase II clinical trial results in Merkel cell carcinoma reported in the New England Journal of Medicine in June 2016.
The results of clinical trials in people with untreatable metastasis arising from various solid tumors published at Science by 2017.
This was in a Phase III trial in combination with epacadostat, a 2,3-dioxygenase (IDO1) Indoleamine inhibitor to treat melanoma.
See also
- Check point therapy
References
This article incorporates public domain material from the United States Department of Health and Human Services documents "FDA D.I.S.C.O.: First Network/Agnostic Agreement Transcript Site" by Sanjeeve Bala. Obtained in 2017-06-17.
Source of the article : Wikipedia
0 Comments