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Vemurafenib

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Vemurafenib
Clinical data
Pronunciation/ˌvɛməˈræfənɪb/VEM-ə-RAF-ə-nib
Trade namesZelboraf
Other namesPLX4032, RG7204, PLX4720, RO5185426
AHFS/Drugs.comMonograph
MedlinePlusa612009
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • N-(3-{[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.287.801Edit this at Wikidata
Chemical and physical data
FormulaC23H18ClF2N3O3S
Molar mass489.92g·mol−1
3D model (JSmol)
  • CCCS(=O)(=O)Nc1ccc(F)c(c1F)C(=O)c2c[nH]c3c2cc(cn3)c4ccc(Cl)cc4
  • InChI=1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28)checkY
  • Key:GPXBXXGIAQBQNI-UHFFFAOYSA-NcheckY
(verify)
vemurafenib
Drug mechanism
Crystallographic structureof B-Raf (rainbow colored,N-terminus= blue,C-terminus= red) complexed with vemurafenib (spheres, carbon = white, oxygen = red, nitrogen = blue, chlorine = green, fluorine = cyan, sulfur = yellow).[2]
Therapeutic usemelanoma
Biological targetBRAF
Mechanism of actionprotein kinase inhibitor
External links
PDBligand id032:PDBe,RCSB PDB
LIGPLOT3og7

Vemurafenib(INN), sold under the brand nameZelboraf,is amedicationused for the treatment of late-stagemelanoma.[2]It is an inhibitor of theB-Rafenzymeand was developed byPlexxikon.[2]

Mechanism of action

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Vemurafenib causesprogrammed cell deathinmelanomacell lines.[3]Vemurafenib interrupts theB-Raf/MEK stepon theB-Raf/MEK/ERK pathway− if the B-Raf has the common V600E mutation.

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, atamino acidposition number 600 on the B-Raf protein, the normalvalineis replaced byglutamic acid).[4]About 60% of melanomas have this mutation. It also has efficacy against the rarer V600K BRAF (the normal valine is replaced bylysine) mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.[5][6]

Resistance

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Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:

Side effects

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At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal.[2]The BRIM-2 trial investigated 132 patients; the most common adverse events werearthralgiain 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, 91% of the MTD.[10]

History

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In aphase I clinical study,vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group.[11][12][13][14]

A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months.[15]

In early 2010 aPhase Itrial[16]for solid tumors (includingcolorectal cancer), and aphase IIstudy (for metastatic melanoma) were ongoing.[17]

A phase III trial (vsdacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[18]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[19]The BRIM3 trial reported good updated results in 2012.[20]

Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), aMEK-inhibitor.[19]After good results in 2014, the combination was submitted to the European Medical Agency and the USFood and Drug Administrationfor marketing approval.[21]

In January 2015, trial results compared vemurafenib with the combination ofdabrafenibandtrametinibfor metastatic melanoma.[22]

Society and culture

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Vemurafenib was approved in the United States for the treatment of late-stage melanoma in August 2011,[23]making it the first drug designed usingfragment-based lead discoveryto gain regulatory approval.[24]

Vemurafenib was approved for use in Canada in February 2012.[25]

In February 2012, theEuropean Commissionapproved vemurafenib as a monotherapy for the treatment of adults with BRAFV600Emutationpositive unresectable ormetastatic melanoma,the most aggressive form of skin cancer.[26]

In November 2017, the USFood and Drug Administration(FDA) approved vemurafenib for the treatment of people withErdheim–Chester disease(ECD), a rare type of histiocytic neoplasm.[27][28]

Research

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A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs ofliver toxicity.[29]

Treating Hairy Cell Leukemia

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In 2012, a grant from theHairy cell leukemiaFoundation supported the discovery of the BRAF mutation in classic HCL. This discovery charted a new path forward for many patients. It improved diagnosis and opened the door for additional therapies to be used in managing HCL.[30]In a phase II clinical trial, Memorial Sloan Kettering is testing Vemurafenib, plus Obinutuzumab, in patients with previously untreated classical hairy cell leukemia.[31]A separate clinical study treatment with only Vemurafenib (or monotherarpy) demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL), achieving an overall response rate of 86%, including 33% complete response (CR) and 53% partial response. However, after a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months).[32]

References

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  1. ^ab"Australian Product Information: Zelboraf® (vemurafenib)".Roche Products Pty Limited.25 March 2020.
  2. ^abcdPDB:3OG7​;Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. (September 2010)."Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma".Nature.467(7315): 596–599.Bibcode:2010Natur.467..596B.doi:10.1038/nature09454.PMC2948082.PMID20823850.
  3. ^Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (May 2008). "BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells".Molecular Cancer Research.6(5): 751–759.doi:10.1158/1541-7786.MCR-07-2001.PMID18458053.S2CID16031942.
  4. ^Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, et al. (May 2015)."Metastatic melanoma - a review of current and future treatment options".Acta Dermato-Venereologica.95(5): 516–524.doi:10.2340/00015555-2035.PMID25520039.
  5. ^Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. (March 2010)."RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth".Nature.464(7287): 431–435.Bibcode:2010Natur.464..431H.doi:10.1038/nature08833.PMID20130576.
  6. ^Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, et al. (April 2010)."PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells".Pigment Cell & Melanoma Research.23(2): 190–200.doi:10.1111/j.1755-148X.2010.00685.x.PMC2848976.PMID20149136.
  7. ^Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. (December 2010)."Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation".Nature.468(7326): 973–977.Bibcode:2010Natur.468..973N.doi:10.1038/nature09626.PMC3143360.PMID21107323.
  8. ^Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. (July 2012)."Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion".Nature.487(7408): 500–504.Bibcode:2012Natur.487..500S.doi:10.1038/nature11183.PMC3711467.PMID22763439.
  9. ^Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. (July 2012)."Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors".Nature.487(7408): 505–509.Bibcode:2012Natur.487..505W.doi:10.1038/nature11249.PMC3724525.PMID22763448.
  10. ^"BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma".Oncology & Biotech News.5(7). July 2011.
  11. ^"Drug hope for advanced melanoma".BBC News. 2009-06-02.Retrieved2009-06-07.
  12. ^Harmon A (2010-02-21)."A Roller Coaster Chase for a Cure".The New York Times.
  13. ^Garber K (December 2009). "Cancer research. Melanoma drug vindicates targeted approach".Science.326(5960): 1619.Bibcode:2009Sci...326.1619G.doi:10.1126/science.326.5960.1619.PMID20019269.
  14. ^Flaherty K."Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer".2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000).Archived fromthe originalon 2013-01-27.Retrieved2010-09-10.
  15. ^Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. (August 2010)."Inhibition of mutated, activated BRAF in metastatic melanoma".The New England Journal of Medicine.363(9): 809–819.doi:10.1056/NEJMoa1002011.PMC3724529.PMID20818844.
  16. ^Clinical trial numberNCT00405587for "Safety Study of PLX4032 in Patients With Solid Tumors" atClinicalTrials.gov
  17. ^Clinical trial numberNCT00949702for "A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma" atClinicalTrials.gov
  18. ^"Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma"(Press release). Plexxikon. 2010-01-08. Archived fromthe originalon 2020-12-01.Retrieved2011-02-03.
  19. ^ab"Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study".Genetic Engineering & Biotechnology News.Mary Ann Liebert Publishers. 6 June 2011.
  20. ^"Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma".Archived fromthe originalon 2022-01-11.Retrieved2012-12-17.
  21. ^"Cobimetinib at exelixis.com".Archived fromthe originalon 2015-02-04.Retrieved2015-02-04.
  22. ^"MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma".2015.
  23. ^"FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer"(Press release). Genentech.Retrieved2011-08-17.
  24. ^Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P (November 2012). "Vemurafenib: the first drug approved for BRAF-mutant cancer".Nature Reviews. Drug Discovery.11(11): 873–886.doi:10.1038/nrd3847.PMID23060265.S2CID9337155.
  25. ^"Notice of Decision for ZELBORAF".Health Canada.11 March 2012. Archived fromthe originalon 2 May 2012.Retrieved21 April2012.
  26. ^Hofland P (February 20, 2012)."First Personalized Cancer Medicine Allows Patients with Deadly Form of Metastatic Melanoma to Live Significantly Longer".Onco'Zine.The International Cancer Network. Archived fromthe originalon April 11, 2012.RetrievedFebruary 18,2013.
  27. ^"FDA approves first treatment for certain patients with Erdheim–Chester disease, a rare blood cancer".U.S.Food and Drug Administration(FDA)(Press release).Retrieved2018-05-20.
  28. ^Diamond EL, Subbiah V, Lockhart AC, Blay JY, Puzanov I, Chau I, et al. (March 2018)."Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study".JAMA Oncology.4(3): 384–388.doi:10.1001/jamaoncol.2017.5029.PMC5844839.PMID29188284.
  29. ^"Getting close and personal".The Economist.January 4, 2014.ISSN0013-0613.Retrieved2016-04-15.
  30. ^"Hairy Cell Leukemia: Celebrating Progress?".HCLF Blog.July 29, 2022.RetrievedJuly 25,2022.
  31. ^Clinical trial numberNCT03410875for "Hairy Cell Leukemia with Vemurafebib" atClinicalTrials.gov
  32. ^Handa S, Lee JO, Derkach A, Stone RM, Saven A, Altman JK, et al. (December 2022)."Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy".Blood.140(25): 2663–2671.doi:10.1182/blood.2022016183.PMC9935554.PMID35930750.

Further reading

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