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Vemurafenib

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Vemurafenib
Clinical data
Trade namesZelboraf
Other namesPLX4032, RG7204, RO5185426
AHFS/Drugs.comFDA Professional Drug Information
MedlinePlusa612009
License data
Routes of
administration		Oral
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.287.801 Edit this at Wikidata
Chemical and physical data
FormulaC23H18ClF2N3O3S
Molar mass489.92 g/mol g·mol−1
3D model (JSmol)
  • CCCS(=O)(=O)Nc1ccc(c(c1F)C(=O)c2c[nH]c3c2cc(cn3)c4ccc
  • 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-N checkY
  (verify)
Crystallographic structure of 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).[1]

Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma.[1] The name "vemurafenib" comes from V600E mutated BRAF inhibition.

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011,[2] Health Canada approval on February 15, 2012[3] and on February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600 mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.[4]

Mechanism of action

Vemurafenib has been shown to cause programmed cell death in melanoma cell lines.[5] Vemurafenib interrupts the B-Raf/MEK step on the B-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, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K 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.[6][7]

Resistance

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

  • The cancer cells begin to overexpress a cell surface protein PDGFRB creating an alternate survival pathway.
  • A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.[8]

Clinical trials

In a phase 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, and the treated group had a median increased survival time of 6 months over the control group.[9][10][11][12] A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. However the regression only lasted from 2 to 18 months.[13]

In early 2010 a Phase I trial[14] for solid tumors (including colorectal cancer), and a phase II study (for Metastatic Melanoma) were ongoing,[15] and a phase III trial (vs dacarbazine) in patients with previously untreated Metastatic Melanoma had been started.[16]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[17] Further trials are planned including a trial where vemurafenib will be co-administered with GDC-0973, a MEK-inhibitor.[17]

The BRIM3 trial reported good updated results in 2012.[18]

Side effects

At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal.[1] The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 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, which is 91% of the MTD.[19]

References

  1. ^ a b c PDB: 3OG7​; Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G; et al. (2010). "Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma". Nature. 467 (7315): 596–599. doi:10.1038/nature09454. PMC 2948082. PMID 20823850. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ "FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer" (Press release). Genentech. Retrieved 2011-08-17.
  3. ^ Notice of Decision for ZELBORAF
  4. ^ First Personalized Cancer Medicine Allows Patients with Deadly Form of Metastatic Melanoma to Live Significantly Longer, Onco'Zine - The International Cancer Network, February 20, 2012
  5. ^ Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (2008). "BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells". Mol. Cancer Res. 6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001. PMID 18458053. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (2010). "RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth". Nature. 464 (7287): 431–5. doi:10.1038/nature08833. PMID 20130576. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (2010). "PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells". Pigment Cell Melanoma Res. 23 (2): 190–200. doi:10.1111/j.1755-148X.2010.00685.x. PMC 2848976. PMID 20149136. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010). "Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation". Nature. 468 (7326): 973–977. doi:10.1038/nature09626. PMC 3143360. PMID 21107323. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ "Drug hope for advanced melanoma". BBC News. 2009-06-02. Retrieved 2009-06-07.
  10. ^ Harmon, Amy (2010-02-21). "A Roller Coaster Chase for a Cure". The New York Times.
  11. ^ Garber K (2009). "Melanoma drug vindicates targeted approach". Science. 326 (5960): 1619. doi:10.1126/science.326.5960.1619. PMID 20019269. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ 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).
  13. ^ Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010). "Inhibition of mutated, activated BRAF in metastatic melanoma". N. Engl. J. Med. 363 (9): 809–19. doi:10.1056/NEJMoa1002011. PMID 20818844. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ "Safety Study of PLX4032 in Patients With Solid Tumors". ClinicalTrials.gov.
  15. ^ "A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma". ClinicalTrials.gov. 2010-02-15.
  16. ^ "Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma" (Press release). Plexxiko. 2010-01-08.
  17. ^ a b "Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study". 6 June 2011.
  18. ^ "Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma".
  19. ^ "BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma". Oncology & Biotech News. 5 (7). 2011. {{cite journal}}: Unknown parameter |month= ignored (help)
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