Vemurafenib

Vemurafenib
Clinical data
Trade names Zelboraf
AHFS/Drugs.com FDA Professional Drug Information
Licence data US FDA:link
Pregnancy cat. D(US)
Legal status ℞-only (US)
Routes Oral
Identifiers
CAS number 1029872-54-5
ATC code L01XE15
PubChem CID 42611257
ChemSpider 24747352 Y
UNII 207SMY3FQT
ChEMBL CHEMBL1229517
Chemical data
Formula C23H18ClF2N3O3S 
Mol. mass 489.92 g/mol
 Y(what is this?)  (verify)

Vemurafenib (INN, also known as PLX4032, RG7204 or RO5185426, 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]

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.[2]

Contents

Mechanism of action

Vemurafenib has been shown to cause programmed cell death in melanoma cell lines.[3] 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. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.[4][5]

In vitro, a melanoma cell line A375 is inhibited by silencing the BRAF gene by short hairpin RNA.[3]

Resistance

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

Clinical trials

In a phase I clinical study, vemurafenib 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.[7][8][9][10] 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.[11]

Phase I[12] and phase II studies are ongoing,[13] and a phase III trial has been started.[14]

In 2010, it was also in phase I trials for colorectal cancer.[12]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[15] Further trials are planned including a trial where vemurafenib will be co-administered with GDC-0973, a MEK-inhibitor.[15]

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 arthralgias 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.[16]

References

  1. ^ a b c PDB 3OG7; Bollag G; Hirth P, Tsai J, et al. (September 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2948082. 
  2. ^ "FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer" (Press release). Genentech. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=13567. Retrieved 2011-08-17. 
  3. ^ a b 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". Mol. Cancer Res. 6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001. PMID 18458053. 
  4. ^ 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 (February 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. 
  5. ^ Halaban R; Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (February 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2848976. 
  6. ^ 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 (November 2010). "Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation". Nature 468 (7326): 973–977. doi:10.1038/nature09626. PMID 21107323. Lay summary – Genetic Engineering & Biotechnology News. 
  7. ^ "Drug hope for advanced melanoma". BBC News. 2009-06-02. http://news.bbc.co.uk/2/hi/health/8076743.stm. Retrieved 2009-06-07. 
  8. ^ Harmon, Amy (2010-02-21). "A Roller Coaster Chase for a Cure". The New York Times. http://www.nytimes.com/2010/02/22/health/research/22trial.html. 
  9. ^ Garber K (December 2009). "Melanoma drug vindicates targeted approach". Science 326 (5960): 1619. doi:10.1126/science.326.5960.1619. PMID 20019269. 
  10. ^ 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). http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34909. 
  11. ^ Flaherty KT; Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (August 2010). "Inhibition of mutated, activated BRAF in metastatic melanoma". N. Engl. J. Med. 363 (9): 809–19. doi:10.1056/NEJMoa1002011. PMID 20818844. Lay summary – Corante: In the Pipeline. 
  12. ^ a b "Safety Study of PLX4032 in Patients With Solid Tumors". ClinicalTrials.gov. 2009-10-28. http://clinicaltrials.gov/ct2/show/NCT00405587. Retrieved 2010-02-23. 
  13. ^ "A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma". ClinicalTrials.gov. 2010-02-15. http://clinicaltrials.gov/ct2/show/NCT00949702. Retrieved 2010-02-23. 
  14. ^ "Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma" (Press release). Plexxiko. 2010-01-08. http://www.plexxikon.com/view.cfm/74/Press-Releases. Retrieved 2010-03-04. 
  15. ^ a b "Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study". 6 June 2011. http://www.genengnews.com/gen-news-highlights/plexxikon-and-roche-report-positive-data-from-phase-iii-braf-mutation-melanoma-study/81245246/. 
  16. ^ "BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma". Oncology & Biotech News 5 (7). July 2011. http://www.onclive.com/publications/obtn/2011/july-2011/BRIM-2-Upholds-Benefits-Emerging-with-Vemurafenib-in-Melanoma.