Jump to content

Vemurafenib: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
remove medical text based on primary; need WP:MEDRS
Rescuing 3 sources and tagging 0 as dead.) #IABot (v2.0.9.2) (Whywhenwhohow - 10792
Line 85: Line 85:


== Clinical trials ==
== Clinical trials ==
In a [[Phases of clinical research|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. The treated group had a median increased survival time of 6 months over the control group.<ref>{{cite news | url = http://news.bbc.co.uk/2/hi/health/8076743.stm | title=Drug hope for advanced melanoma | publisher=BBC News | access-date=2009-06-07 | date=2009-06-02}}</ref><ref name="urlTarget Cancer - A Roller Coaster Chase for a Cure - Series ">{{cite news | url = https://www.nytimes.com/2010/02/22/health/research/22trial.html | title = A Roller Coaster Chase for a Cure | author = Harmon, Amy | date = 2010-02-21 | work = [[The New York Times]] }}</ref><ref name="pmid20019269">{{cite journal | author = Garber K | title = Melanoma drug vindicates targeted approach | journal = Science | volume = 326 | issue = 5960 | pages = 1619 |date=December 2009 | pmid = 20019269 | doi = 10.1126/science.326.5960.1619 | bibcode = 2009Sci...326.1619G }}</ref><ref name="urlPhase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. - ASCO">{{cite web | url = http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34909 | title = Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer | author = Flaherty K | work = 2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000) }}</ref>
In a [[Phases of clinical research|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. The treated group had a median increased survival time of 6 months over the control group.<ref>{{cite news | url = http://news.bbc.co.uk/2/hi/health/8076743.stm | title=Drug hope for advanced melanoma | publisher=BBC News | access-date=2009-06-07 | date=2009-06-02}}</ref><ref name="urlTarget Cancer - A Roller Coaster Chase for a Cure - Series ">{{cite news | url = https://www.nytimes.com/2010/02/22/health/research/22trial.html | title = A Roller Coaster Chase for a Cure | author = Harmon, Amy | date = 2010-02-21 | work = [[The New York Times]] }}</ref><ref name="pmid20019269">{{cite journal | author = Garber K | title = Melanoma drug vindicates targeted approach | journal = Science | volume = 326 | issue = 5960 | pages = 1619 |date=December 2009 | pmid = 20019269 | doi = 10.1126/science.326.5960.1619 | bibcode = 2009Sci...326.1619G }}</ref><ref name="urlPhase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. - ASCO">{{cite web | url = http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34909 | title = Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer | author = Flaherty K | work = 2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000) | access-date = 2010-09-10 | archive-date = 2013-01-27 | archive-url = https://web.archive.org/web/20130127201543/http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34909 | url-status = dead }}</ref>


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.<ref name="pmid20818844">{{cite journal |vauthors=Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB | title = Inhibition of mutated, activated BRAF in metastatic melanoma | journal = N. Engl. J. Med. | volume = 363 | issue = 9 | pages = 809–19 |date=August 2010 | pmid = 20818844 | doi = 10.1056/NEJMoa1002011 | pmc = 3724529 }}
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.<ref name="pmid20818844">{{cite journal |vauthors=Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB | title = Inhibition of mutated, activated BRAF in metastatic melanoma | journal = N. Engl. J. Med. | volume = 363 | issue = 9 | pages = 809–19 |date=August 2010 | pmid = 20818844 | doi = 10.1056/NEJMoa1002011 | pmc = 3724529 }}
Line 92: Line 92:
In early 2010 a [[Clinical trial#Phase I|Phase I]] trial<ref name="P1ST">{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT00405587 | title = Safety Study of PLX4032 in Patients With Solid Tumors | date = 18 August 2017 |website= ClinicalTrials}}</ref> for solid tumors (including [[colorectal cancer]]), and a [[Clinical trial#Phase II|phase II]] study (for metastatic melanoma) were ongoing.<ref name="P2MM">{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT00949702 | title = A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma | date = 2010-02-15 |website=ClinicalTrials}}</ref>
In early 2010 a [[Clinical trial#Phase I|Phase I]] trial<ref name="P1ST">{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT00405587 | title = Safety Study of PLX4032 in Patients With Solid Tumors | date = 18 August 2017 |website= ClinicalTrials}}</ref> for solid tumors (including [[colorectal cancer]]), and a [[Clinical trial#Phase II|phase II]] study (for metastatic melanoma) were ongoing.<ref name="P2MM">{{cite web | url = http://clinicaltrials.gov/ct2/show/NCT00949702 | title = A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma | date = 2010-02-15 |website=ClinicalTrials}}</ref>


A phase III trial (vs [[dacarbazine]]) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.<ref name="PLX4032_phase_3_trial">{{cite press release | url = http://www.plexxikon.com/view.cfm/74/Press-Releases | title = Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma | date = 2010-01-08 | publisher = Plexxikon }}</ref>
A phase III trial (vs [[dacarbazine]]) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.<ref name="PLX4032_phase_3_trial">{{cite press release | url = http://www.plexxikon.com/view.cfm/74/Press-Releases | title = Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma | date = 2010-01-08 | publisher = Plexxikon | access-date = 2011-02-03 | archive-date = 2020-12-01 | archive-url = https://web.archive.org/web/20201201091352/https://www.plexxikon.com/view.cfm/74/Press-Releases | url-status = dead }}</ref>


In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.<ref name=BRIM3-1>{{cite news |url=http://www.genengnews.com/gen-news-highlights/plexxikon-and-roche-report-positive-data-from-phase-iii-braf-mutation-melanoma-study/81245246/ |title=Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study |date=6 June 2011 }}</ref> The BRIM3 trial reported good updated results in 2012.<ref name=ASCO2012>{{cite web |url=http://www.chemotherapyadvisor.com/vemurafenib-improves-overall-survival-in-patients-with-metastatic-melanoma/article/244197/# |title=Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma }}</ref>
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.<ref name=BRIM3-1>{{cite news |url=http://www.genengnews.com/gen-news-highlights/plexxikon-and-roche-report-positive-data-from-phase-iii-braf-mutation-melanoma-study/81245246/ |title=Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study |date=6 June 2011 }}</ref> The BRIM3 trial reported good updated results in 2012.<ref name=ASCO2012>{{cite web |url=http://www.chemotherapyadvisor.com/vemurafenib-improves-overall-survival-in-patients-with-metastatic-melanoma/article/244197/ |title=Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma |access-date=2012-12-17 |archive-date=2022-01-11 |archive-url=https://web.archive.org/web/20220111060630/https://www.optimizely.com/idio/ |url-status=dead }}</ref>


Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 ([[cobimetinib]]), a [[MEK inhibitor|MEK-inhibitor]].<ref name=BRIM3-1/> After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.<ref>{{Cite web |url=http://www.exelixis.com/pipeline/GDC_0973_xl518 |title=Cobimetinib at exelixis.com |access-date=2015-02-04 |archive-url=https://web.archive.org/web/20150204043254/http://www.exelixis.com/pipeline/GDC_0973_xl518 |archive-date=2015-02-04 |url-status=dead }}</ref>
Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 ([[cobimetinib]]), a [[MEK inhibitor|MEK-inhibitor]].<ref name=BRIM3-1/> After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.<ref>{{Cite web |url=http://www.exelixis.com/pipeline/GDC_0973_xl518 |title=Cobimetinib at exelixis.com |access-date=2015-02-04 |archive-url=https://web.archive.org/web/20150204043254/http://www.exelixis.com/pipeline/GDC_0973_xl518 |archive-date=2015-02-04 |url-status=dead }}</ref>

Revision as of 05:08, 9 October 2022

Vemurafenib
Clinical data
Pronunciation/ˌvɛməˈræfənɪb/ VEM-ə-RAF-ə-nib
Trade namesZelboraf
Other namesPLX4032, RG7204, RO5185426
AHFS/Drugs.comMonograph
MedlinePlusa612009
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth (tablets)
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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.287.801 Edit this at Wikidata
Chemical and physical data
FormulaC23H18ClF2N3O3S
Molar mass489.92 g·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-N checkY
  (verify)
vemurafenib
Drug mechanism
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]
Therapeutic usemelanoma
Biological targetBRAF
Mechanism of actionprotein kinase inhibitor
External links
ATC codeL01XE15
PDB ligand id032: PDBe, RCSB PDB
LIGPLOT3og7

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

Approvals

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011,[2] making it the first drug designed using fragment-based lead discovery to gain regulatory approval.[3]

Vemurafenib later received Health Canada approval on February 15, 2012.[4]

On February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.[5]

On November 6, 2017, the FDA approved Vemurafenib for the treatment of some patients with Erdheim–Chester disease (ECD), a rare type of histiocytic neoplasm.[6][7]

Mechanism of action

Vemurafenib causes programmed cell death in melanoma cell lines.[8] 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).[9] 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.[10][11]

Resistance

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

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. The treated group had a median increased survival time of 6 months over the control group.[15][16][17][18]

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.[19]

In early 2010 a Phase I trial[20] for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.[21]

A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[22]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[23] The BRIM3 trial reported good updated results in 2012.[24]

Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK-inhibitor.[23] After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.[25]

In January 2015 trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.[26]

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, 91% of the MTD.[27]

A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.[28]

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. (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. PMC 2948082. PMID 20823850.
  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. ^ 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". Nat Rev Drug Discov. 11 (11): 873–86. doi:10.1038/nrd3847. PMID 23060265. S2CID 9337155.
  4. ^ "Notice of Decision for ZELBORAF". Archived from the original on 2012-05-02. Retrieved 2012-04-21.
  5. ^ 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 from the original on April 11, 2012. Retrieved February 18, 2013.
  6. ^ Commissioner, Office of the. "Press Announcements - FDA approves first treatment for certain patients with Erdheim–Chester disease, a rare blood cancer". www.fda.gov. Retrieved 2018-05-20.
  7. ^ Diamond, Eli L.; Subbiah, Vivek; Lockhart, A. Craig; Blay, Jean-Yves; Puzanov, Igor; Chau, Ian; Raje, Noopur S.; Wolf, Jurgen; Erinjeri, Joseph P. (2018-03-01). "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. ISSN 2374-2445. PMC 5844839. PMID 29188284.
  8. ^ 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.
  9. ^ Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F (2015). "Metastatic melanoma - a review of current and future treatment options". Acta Derm Venereol. 95 (5): 516–524. doi:10.2340/00015555-2035. PMID 25520039.
  10. ^ 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. Bibcode:2010Natur.464..431H. doi:10.1038/nature08833. PMID 20130576.
  11. ^ 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.
  12. ^ 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. Bibcode:2010Natur.468..973N. doi:10.1038/nature09626. PMC 3143360. PMID 21107323.
  13. ^ Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (July 2012). "Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion". Nature. 487 (7408): 500–4. Bibcode:2012Natur.487..500S. doi:10.1038/nature11183. PMC 3711467. PMID 22763439.
  14. ^ Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J (July 2012). "Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors". Nature. 487 (7408): 505–9. Bibcode:2012Natur.487..505W. doi:10.1038/nature11249. PMC 3724525. PMID 22763448.
  15. ^ "Drug hope for advanced melanoma". BBC News. 2009-06-02. Retrieved 2009-06-07.
  16. ^ Harmon, Amy (2010-02-21). "A Roller Coaster Chase for a Cure". The New York Times.
  17. ^ Garber K (December 2009). "Melanoma drug vindicates targeted approach". Science. 326 (5960): 1619. Bibcode:2009Sci...326.1619G. doi:10.1126/science.326.5960.1619. PMID 20019269.
  18. ^ 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 from the original on 2013-01-27. Retrieved 2010-09-10.
  19. ^ 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. PMC 3724529. PMID 20818844.
  20. ^ "Safety Study of PLX4032 in Patients With Solid Tumors". ClinicalTrials. 18 August 2017.
  21. ^ "A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma". ClinicalTrials. 2010-02-15.
  22. ^ "Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma" (Press release). Plexxikon. 2010-01-08. Archived from the original on 2020-12-01. Retrieved 2011-02-03.
  23. ^ a b "Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study". 6 June 2011.
  24. ^ "Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma". Archived from the original on 2022-01-11. Retrieved 2012-12-17.
  25. ^ "Cobimetinib at exelixis.com". Archived from the original on 2015-02-04. Retrieved 2015-02-04.
  26. ^ "MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma". 2015.
  27. ^ "BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma". Oncology & Biotech News. 5 (7). July 2011.
  28. ^ "Getting close and personal". The Economist. January 4, 2014. ISSN 0013-0613. Retrieved 2016-04-15.

Further reading

  • "Vemurafenib". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=Vemurafenib&oldid=1114963931"