Pembrolizumab

from Wikipedia, the free encyclopedia
Pembrolizumab
Mass / length primary structure 146.3 kDa
Identifier
External IDs
Drug information
ATC code L01 XC18
Drug class Monoclonal antibody

Pembrolizumab (trade name Keytruda ; manufacturer Merck / MSD ) is a humanized monoclonal antibody and drug for the treatment of various tumors. Pembrolizumab one of the immune checkpoint inhibitors , especially PD-1 - inhibitors , and is already approved in several indications. Thanks to its cross-indication mode of action, it is examined for more than 30 tumor types in more than 500 clinical trials (as of 2017).

description

Pembrolizumab is an immune checkpoint inhibitor , specifically PD-1 inhibitor , which is produced using recombinant DNA technology . It is given as a powder for concentrate that is made up into a solution for infusion. The recommended dose of pembrolizumab ( Keytruda ) is 2 mg / kg body weight every 3 weeks and is given as an intravenous infusion over 30 minutes. The most common side effects (> 10%) with Keytruda were fatigue (24%), rash (19%), pruritus (18%), diarrhea (12%), nausea (11%), and arthralgia (10%). Clinically relevant side effects were mostly immune-mediated side effects, such as B. pneumonitis , colitis , hepatitis , nephritis and endocrinopathies . Most of these side effects were reversible and manageable by interrupting therapy with pembrolizumab, administering corticosteroids and / or supportive measures.

There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted, but mouse model results (mechanism of action) indicate a potential risk of fetal harm, including increased rates of abortion and stillbirth. It is also not yet known whether pembrolizumab is excreted in breast milk. If women are of childbearing potential, they must use effective contraception during treatment with pembrolizumab for at least four months after the last dose.

Pembrolizumab received the Breakthrough Therapy Designation from the US FDA in the indications of malignant melanoma , non-small cell lung cancer and colorectal cancer . The prerequisite for this status is that the new drug z. B. shows a significantly improved response rate than the comparator preparation. This enables an accelerated approval process. Keytruda (pembrolizumab) received the Prix ​​Galien USA in 2015 for best biotechnological product. In October 2016, the Galenus von Pergamon Prize in the “Specialist Care” category was awarded to both nivolumab from Bristol-Myers Squibb and pembrolizumab.

Immune Checkpoint Inhibitors

The cancer immunotherapy using immune Checkpoint inhibitors is one of the most important developments in oncology. Antibodies such as B. ipilimumab , nivolumab and pembrolizumab specifically change the communication between tumor cells and T lymphocytes . This results in an improved recognition of the tumor cells by the immune system . The mechanism of action is not limited to one tumor entity. After success with malignant melanoma, results have now also been achieved in the treatment of bronchial carcinoma, for example. In particular, the PD-1 blockade has proven to be effective in numerous malignant diseases, which underlines the general importance of the immune system in tumor control. Both nivolumab and pembrolizumab are approved for monotherapy in inoperable metastatic melanoma.

Mechanism of action

Pembrolizumab binds to a receptor called programmed cell death-1 ("programmed cell death receptor 1", PD-1 receptor) and blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 . This receptor usually turns off the activity of certain cells in the immune system (the body's natural defenses) called T cells. By blocking this PD-1 receptor, pembrolizumab prevents the PD-1 receptor from turning these immune cells off, thereby increasing the immune system's ability to e.g. B. kill melanoma cells. Pembrolizumab can reactivate the body's own anti-tumor immune response.

PD ‑ L1 and PD ‑ L1 expression

PD ‑ L1 (programmed cell death ligand 1) is a protein that is expressed by many cell types, including certain cancer cells . Typically, the interaction between PD ‑ L1 and another protein called PD ‑ 1 (programmed cell death receptor ‑ 1) serves as an important checkpoint that maintains the balance of the immune system and prevents the body from breaking down in the event of inflammation or infection attacks own cells. However, when malignant tumors express PD-L1, they can prevent them from being recognized and destroyed by cytotoxic T-lymphocytes - immune cells that kill cancer cells. This allows the tumor to survive and grow. The expression of PD-L1 can be observed to varying degrees in many types of tumors, including breast, bronchial, bladder, and nasopharyngeal cancers. Research is currently being conducted into whether high PD ‑ L1 expression - a so-called "overexpression" - can be used to identify patients who are more likely to respond to certain immunotherapies.

Admission overview

Pembrolizumab is approved in Europe for several indications:

The FDA (USA) has also approved pembrolizumab in PD-L1-positive patients with advanced cervical cancer and, under certain conditions, for the treatment of primary mediastinal large B-cell lymphoma (a type of diffuse large B-cell Lymphoma ).

Early benefit assessment (AMNOG)

The Institute for Quality and Efficiency in Health Care (IQWiG) - on behalf of the G-BA - checked in accordance with the Medicines Market Reform Act (AMNOG) whether pembrolizumab offers an additional benefit compared to the previous standard therapies , and has this for the indication of advanced melanoma in certain affected people Pretreatment and for those not pretreated without tumor mutation and the indication locally advanced or metastatic non-small cell lung cancer in those affected for whom further chemotherapy with docetaxel or pemetrexed or treatment with nivolumab is possible, affirmed.

See also

literature

  • Lothar Bergmann and others: What chances does immuno-oncology offer for long-term survival across all indications? In: Oncol Res Treat . tape 38 , April 2015, p. 6-11 , doi : 10.1159 / 000381363 .

Web links

Individual evidence

  1. ^ New ATC WHO Collaborating Center for Drug Statistics Methodology, accessed November 9, 2015.
  2. ↑ New and Updated Data for KEYTRUDA® (pembrolizumab) from Merck's Extensive Immuno-Oncology Program to be Presented at the ESMO 2017 Congress | Merck Newsroom Home. Retrieved September 6, 2017 .
  3. ↑ a b c d e Keytruda specialist information , accessed on January 23, 2017.
  4. ↑ Merck Receives Accelerated Approval of Keytruda (pembrolizumab), the First FDA-Approved Anti-PD-1 Therapy , Merck PM, September 4, 2014, accessed November 9, 2015.
  5. ↑ Merck Receives FDA Breakthrough Therapy Designation for Keytruda (pembrolizumab) in Advanced Non-Small Cell Lung Cancer , Merck PM, October 27, 2015, accessed November 9, 2015.
  6. ↑ Merck Receives Breakthrough Therapy Designation from US Food and Drug Administration for Keytruda (pembrolizumab) in Advanced Colorectal Cancer , Merck PM, November 2, 2015, accessed November 9, 2015.
  7. ↑ Keytruda (pembrolizumab) from Merck Awarded Prix Galien USA 2015 Best Biotechnology Product Award , PM from Merck October 28, 2015, accessed November 9, 2015.
  8. ↑ Galenus von Pergamon Prize and Springer Medicine CharityAward for outstanding achievements , Springer, October 21, 2016
  9. ↑ Patrick Terheyden, Angela Krackhardt, Thomas Eigenler: System therapy of melanoma. Use of immune checkpoint inhibitors and inhibition of intracellular signal transduction. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., (July 22) 2019, pp. 497-504, especially p. 503.
  10. ↑ Summary of the EPAR for the public of the EMA (German), accessed on November 9, 2015.
  11. ↑ European Cancer Congress - MSD Study KEYNOTE-028 shows the antitumor effect of Keytruda in two tumor entities of the gastrointestinal tract and in advanced nasopharyngeal carcinoma , PM from MSD of October 8, 2015, password protected, accessed on November 9, 2015.
  12. ^ European Medicines Agency - Find medicine - Keytruda. Accessed May 5, 2019 .
  13. ↑ American Society of Clinical Oncology (Ed.): FDA Approves Pembrolizumab for Advanced Cervical Cancer with Disease Progression During or After Chemotherapy . June 12, 2018 ( asco.org [accessed June 13, 2018]).
  14. ↑ Approved Drugs - FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL. Center for Drug Evaluation and Research, accessed June 16, 2018 .
  15. ↑ Fewer side effects in certain pretreated / non-pretreated people without tumor mutation survive longer PM IQWiG of November 16, 2015, accessed on November 16, 2015.
  16. ↑ Compared to docetaxel, advantages clearly outweigh the advantages / Compared to best supportive care additional benefit not proven PM IQWiG of November 16, 2016, accessed on May 10, 2016