پمبروليزوماب

پمبروليزوماب
Pembrolizumab 5DK3.png
From PDB entry 5dk3
الأجسام المضادة وحيدة النسيلة
النوعجسم مضاد كامل
المصدرHumanized (from mouse)
الهدفPD-1
البيانات السريرية
الأسماء التجاريةكي‌ترودا
License data
فئة السلامة
أثناء الحمل
  • not for pregnant women
مسارات
الدواء		علاج وريدي
رمز ATC
الحالة القانونية
الحالة القانونية
المعرفات
رقم CAS
PubChem SID
DrugBank
ChemSpider
  • none
UNII
KEGG
ECHA InfoCard100.234.370 Edit this at Wikidata
Chemical and physical data
التركيبC6534H10004N1716O2036S46
الكتلة المولية146 kDa

پمبروليزوماب Pembrolizumab (سابقاً MK-3475 و lambrolizumab، والاسم التجاري كي‌ترودا Keytruda‏)[1] هو جسم مضاد مؤنسن يُستخدم في العلاج المناعي للسرطان. يقوم هذا الدواء بمنع آلية الحماية على الخلايا السرطانية، ويسمح للنظام المناعي بتدمير تلك الخلايا السرطانية. يستهدف الدواء مستقبـِل پروتين موت الخلية المبرمجة 1 (PD-1). في البداية كان هذا الدواء يستخدم لعلاج الميلانوما منتقل (منتشر). وفي مايو 2017، أجيز لأي ورم صلب غير مقطوع أو منتقل بمواصفات وراثية معينة بغض النظر عن نوع النسيج أو مكان الورم، وكانت سابقة لإدارة الغذاء والدواء.

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الاستخدامات الطبية

وحتى 2017، كان پمبروليزوماب يُستخدم عبر الحقن الوريدي لعلاج الميلانوما غير القابلة للجراحة أو المنتشرة، سرطان الرئة ذو الخلايا غير الصغيرة في حالات معينة، مثل العلاج الثانوي السرطان الخلايا الحرشفية في الرأس والعنق (HNSCC)، بعد العلاج الكيميائي المعتمد على الپلاتين، ولعلاج المرضى البالغين والأطفال المصابين بلمفومة هودجكين.[2][3][4][5][6]

فيما يخص سرطان الخلايا الحرشفية في الرأس والعنق، يستخدم الپمبروليزوماب لعلاج أولي إذا ما كان السرطان مرتبط بلجين الموت المبرمج 1المفرط، مستقبل لجين الموت المبرمج 1، وكان السرطان غير مصحوب بطفرتي مستقبل عامل نمو البشرة (EGFR) أو كيناز الليمفومة الكشمي (ALK)؛ إذا كان العلاج الكيميائي تم استخدامه بالفعل، فعندها يمكن استخدام الپمبروليزوماب كعلاج ثانوي لكن بشرط أن يكون السرطان يصاحبه طفرات EGFR أو ALK، حيث ينبغي استخدام العوامل التي تستهدف هذه الطفران أولاً.[2][7] ينبغي أن يتم تقييم لجين الموت المبرمج 1 للتحقق من صلاحية المرافق التشخيصي والموافقة عليه.[2]


الموانع

If a person is taking corticosteroids or immunosuppressants those drugs should be stopped before starting pembrolizumab because they may interfere with pembrolizumab; they can be used after pembrolizumab is started to deal with immune-related adverse effects.[3]

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 and increases the risk of miscarriage. It is not known if pembrolizumab is secreted into breast milk or not.[3]

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.[3]

الآثار الجانبية

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.[3][8]

The common adverse reactions have been fatigue (24%), rash (19%), itchiness (pruritus) (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia) (10%).[3]

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, and flu-like symptoms.[3]

آلية العمل

الخلايا المناعية تحفز مستقبل الموت الخلوي المبرمج رقم واحد (PD-1) لقتل اي خلية يشتبه انها خلية سرطانية، لكن تجنبا لرد فعل مبالغ فيه، مثل مرض المناعة الذاتية، فيتم تأمين هذا المستقبل من الاستثارة الزائدة عن الحد، وذلك عبر  جزء  معين موجود على نفس المستقبل. بمبروليزوماب عبارة عن اجسام مضادة علاجية تصد هذا الجزء المثبط للمستقبل, اي تمنع اي مادة تقوم بتثبط هذا المستقبل، وعندها تتمكن الخلايا المناعية  من قتل الخلايا السرطانية، وبهذا  يعيد بمبروليزوماب  نظام المناعة ويسمح باستهداف وتدمير الخلايا السرطانية. Pembrolizumab هي واحدة من عدد من العلاجات ذات صلة وثيقة اطلق عليها اسم المناعة الحصار نقطة تفتيش. التجارب السريرية أدت المحاكمة المرحلة الأولى كبيرة إلى معدلات الاستجابة من 37-38٪ في المرضى الذين يعانون من سرطان الجلد المتقدم ومعدل الاستجابة الكلي من 26٪ في المرضى الذين لديهم المرض تدريجيا بعد العلاج مع إيبيليموماب. هذا الدواء في المرحلة الثانية من التجارب السريرية لسرطان غير الخلايا الصغيرة في الرئة (NSCLC) في المرضى الذين يعانون من مرض oligometastatic.

الصيدلة

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.[3] The systemic clearance [rate] is about 0.2 L/day and the terminal half-life is about 25 days.[3]

الكيمياء والتصنيع

Pembrolizumab is an immunoglobulin G4, with a variable region against the human programmed cell death 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.[9]

It is recombinantly manufactured in Chinese hamster ovary (CHO) cells.[10]

التاريخ

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.[11] Carven, van Eenennaam and Dulos were recognized as Inventors of the Year by the Intellectual Property Owners Education Foundation in 2016.[12]

The development program for pembrolizumab was seen as high priority at Organon, but low at Schering, and then at Merck, and in early 2010 Merck terminated development and began preparing to outlicense it.[13] But then 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 metastatic melanoma and that a second Bristol-Myers Squibb checkpoint inhibitor, nivolumab, (Opdivo) was also promising.[13] Merck at that time has little commitment and expertise in oncology or immunotherapy, but understood the opportunity and reacted strongly, reactivating the program and filing its IND by the end of 2010.[13] As an 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 ended up stepping down from his role and led clinical development of pembrolizumab for lung cancer.[13]

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; management agreed and some people, including shareholders and analysts, criticized this decision as it limited the potential market size for the drug, but others argued that it increased the chances of proving the drug would work, and made clinical trials faster and needing fewer patients due to the likelihood of greater effect size, and moving quickly and reducing the risk of failure was essential for catching up with Bristol-Myers Squibb, which had an approximately five year lead over Merck.[13] 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 roughly divided between melanoma and lung cancer, the largest Phase I study ever run in oncology.[13] 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, which reduces the risk of developers making mistakes or misunderstandings arising between regulator's 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 why management was willing to put company resources behind the development.[13]

In 2013, the USAN name was changed from lambrolizumab to pembrolizumab.[9] In that year clinical trial results in advanced melanoma were published in the New England Journal of Medicine.[14]

On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab under the FDA Fast Track Development Program.[15] 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.[16]

As of 2015, the only PD-1/PD-L1 targeting drugs on the market were pembrolizumab and Bristol-Myers Squibb's Yervoy and Opdivo, and clinical developments in the class of drugs received coverage in the New York Times.[17]

By April 2016, Merck had applied for approval to market the drug in Japan and had signed an agreement with Taiho Pharmaceutical to co-promote it there.[18]

In July 2015, pembrolizumab received marketing approval in Europe.[3][19]

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.[20]

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,[21] and gave an accelerated approval on August 9, 2016.[22]

In August 2016, the FDA granted an accelerated approval to pembrolizumab as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (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.[22] Full approval depends on the results of the phase III KEYNOTE-040 study (NCT02252042), running until Jan 2017.[22]

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.[23][24][25] 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.[24] Because the clinical trial was fairly small, Merck was obligated to conduct further post-marketing studies to ensure that the results are valid.[26]

التجارب السريرية

تمت تجربة سريرية كبيرة في المرحلة الاولى واظهرت استجابة بنسبة 37-38% في المرضى المصابينبورم ميلانيني متقدم مع معدل استجابة عام يقدر ب 26% في المرضى الذين قد تم معالجتهم مسبقا بعقار ابيليموماب[27]

وهذا العلاج حاليا في المرحلة الثانية من التجارب السريرية لعلاج سرطان الرئة ذو الخلايا غير الصغيرة والذين لديهم انتشار محدود لهذا السرطان[28]


. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

المجتمع والثقافة

كان سعر پمبروليزوماب لمدة سنة هو 150.000 دولار حين أُطلِق، في أواخر 2014.[29]

الأبحاث

In 2015, Merck reported results in 13 cancer types; much attention was given to early results in head and neck cancer.[30][31]

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).[32] 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.[33]

Results of a Phase II clinical trial in Merkel-cell carcinoma were reported in the New England Journal of Medicine in June 2016.[34]

Results of a clinical trial in people with untreatable metastases arising from various solid tumors were published in Science in 2017.[35]

It is in a phase III trial in combination with epacadostat, an Indoleamine 2,3-dioxygenase (IDO1) inhibitor to treat melanoma.[36]

انظر أيضاً

الهامش

 This article incorporates public domain material from the United States Department of Health and Human Services document "FDA D.I.S.C.O.: First Tissue/Site Agnostic Approval Transcript" by Sanjeeve Bala (retrieved on 2017-06-17).

  1. ^ "Pembrolizumab". AdisInsight. Retrieved 5 November 2016.
  2. ^ أ ب ت "Pembrolizumab label" (PDF). FDA. May 2017. linked from Index page at FDA website November 2016
  3. ^ أ ب ت ث ج ح خ د ذ ر "Pembrolizumab label at eMC". UK Electronic Medicines Compendium. 27 January 2017.
  4. ^ Redman, Jason M.; Gibney, Geoffrey T.; Atkins, Michael B. (6 February 2016). "Advances in immunotherapy for melanoma". BMC Medicine. 14 (1). doi:10.1186/s12916-016-0571-0. PMC 4744430. PMID 26850630.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Fuereder, Thorsten (20 June 2016). "Immunotherapy for head and neck squamous cell carcinoma". memo - Magazine of European Medical Oncology. 9 (2): 66–69. doi:10.1007/s12254-016-0270-8. PMC 4923082. PMID 27429658.
  6. ^ Pembrolizumab (KEYTRUDA) for classical Hodgkin lymphoma, 15 Mar 2017, FDA
  7. ^ Chen, Hongbin; Vachhani, Pankit (September 2016). "Spotlight on pembrolizumab in non-small cell lung cancer: the evidence to date". OncoTargets and Therapy. 9: 5855–5866. doi:10.2147/ott.s97746. PMC 5045223. PMID 27713639.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Linardou, Helena; Gogas, Helen (July 2016). "Toxicity management of immunotherapy for patients with metastatic melanoma". Annals of Translational Medicine. 4 (14): 272–272. doi:10.21037/atm.2016.07.10. PMC 4971373. PMID 27563659.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ أ ب Statement on a Nonproprietary Name Adopted by the USAN Council. November 27, 2013. Archived from the original. You must specify the date the archive was made using the |archivedate= parameter. https://searchusan.ama-assn.org/usan/documentDownload?uri=%2Funstructured%2Fbinary%2Fusan%2Fpembrolizumab.pdf. 
  10. ^ "Assessment report: Keytruda. Procedure No. EMEA/H/C/003820/0000" (PDF). EMA. 21 May 2015.
  11. ^ "Unlocking Checkpoint Inhibition". Translational Scientist. August 9, 2016.
  12. ^ "Inventors of the Year". Inventors Digest. Retrieved 8 May 2017.
  13. ^ أ ب ت ث ج ح خ Shaywitz, David (July 26, 2017). "The Startling History Behind Merck's New Cancer Blockbuster". Forbes.
  14. ^ Hamid, O; et al. (2013). "Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma". New England Journal of Medicine. 369 (2): 134–44. doi:10.1056/nejmoa1305133. PMC 4126516. PMID 23724846. {{cite journal}}: Explicit use of et al. in: |first1= (help)
  15. ^ U.S. Food and Drug Administration (September 4, 2014). "FDA approves Keytruda for advanced melanoma". U.S. Food and Drug Administration. U.S. Food and Drug Administration. Retrieved 24 December 2015.
  16. ^ "FDA Approves Anti-PD-1 Drug for Advanced Melanoma". cancernetwork.com.
  17. ^ Pollack, Andrew (May 29, 2015). "New Class of Drugs Shows More Promise in Treating Cancer". New York Times. Retrieved May 30, 2015.
  18. ^ "Merck & Co and Taiho to co-promote cancer immunotherapy pembrolizumab in Japan". The Pharma Letter. April 13, 2016.
  19. ^ "Keytruda index page at EMA". European Medicines Agency. Retrieved 10 November 2016.
  20. ^ "FDA approves Keytruda for advanced non-small cell lung cancer". U.S. Food and Drug Administration. October 2, 2015.
  21. ^ Potential Biomarkers Identified for Pembrolizumab in Head and Neck Cancer. July 2016
  22. ^ أ ب ت FDA Approves Pembrolizumab for Head and Neck Cancer. Aug 2016
  23. ^ "FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication". Food and Drug Administration. May 23, 2017.
  24. ^ أ ب Bala, Sanjeeve; Nair, Abhi (30 May 2017). "Approved Drugs - FDA D.I.S.C.O.: First Tissue/Site Agnostic Approval Transcript". FDA (in الإنجليزية).
  25. ^ Ledford, Heidi (24 May 2017). "News: Tissue-independent cancer drug gets fast-track approval from US regulator". Nature. doi:10.1038/nature.2017.22054.
  26. ^ "Accelerated approval notice: BLA 125514/S-14" (PDF). FDA. 23 May 2017.
  27. ^ Science. 348. doi:10.1126/science.aaa8172. PMID 25838373. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |الأخير1= ignored (help); Unknown parameter |الأخير2= ignored (help); Unknown parameter |الأول1= ignored (help); Unknown parameter |الأول2= ignored (help); Unknown parameter |التاريخ= ignored (help); Unknown parameter |الصفحات= ignored (help); Unknown parameter |العنوان= ignored (help); Unknown parameter |المسار= ignored (help); Unknown parameter |تاريخ الوصول= ignored (help)
  28. ^ Press release, "Penn Medicine's New Immunotherapy Study Will Pit PD-1 Inhibitor Against Advanced Lung Cancer", University of Pennsylvania, February 4, 2015.
  29. ^ Amgen slaps record-breaking $178K price on rare leukemia drug Blincyto
  30. ^ Timmerman, Luke (June 2, 2015). "ASCO Wrapup: Immunotherapy Shines, Hope For Brain Tumors, & The Great Cancer Drug Price Debate". Forbes.
  31. ^ Adams, Katherine T. (24 July 2015). "Cancer Immunotherapies--and Their Cost--Take Center Stage at ASCO's 2015 Annual Meeting". Managed Care Magazine Online.
  32. ^ Jenkins, Kristin (5 May 2016). "Keytruda Impresses in Triple-Negative Breast Cancer". MedPage Today.
  33. ^ "Merck & Co updates Keytruda findings at ASCO". The Pharma Letter. June 10, 2016.
  34. ^ Nghiem (2016). "PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma". N. Engl. J. Med. 374 (26): 2542–2552. doi:10.1056/NEJMoa1603702. PMC 4927341. PMID 27093365.
  35. ^ Le, DT; Durham, JN; Smith, KN; Wang, H; Bartlett, BR; Aulakh, LK; Lu, S; Kemberling, H; Wilt, C; Luber, BS; Wong, F; Azad, NS; Rucki, AA; Laheru, D; Donehower, R; Zaheer, A; Fisher, GA; Crocenzi, TS; Lee, JJ; Greten, TF; Duffy, AG; Ciombor, KK; Eyring, AD; Lam, BH; Joe, A; Kang, SP; Holdhoff, M; Danilova, L; Cope, L; Meyer, C; Zhou, S; Goldberg, RM; Armstrong, DK; Bever, KM; Fader, AN; Taube, J; Housseau, F; Spetzler, D; Xiao, N; Pardoll, DM; Papadopoulos, N; Kinzler, KW; Eshleman, JR; Vogelstein, B; Anders, RA; Diaz LA, Jr (8 June 2017). "Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade". Science. doi:10.1126/science.aan6733. PMID 28596308.
  36. ^ A Phase 3 Study of Pembrolizumab + Epacadostat or Placebo in Subjects With Unresectable or Metastatic Melanoma (Keynote-252 / ECHO-301)
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