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Home » FDA 2017 » FDA approves first treatment Zelboraf (vemurafenib)for certain patients with Erdheim-Chester Disease, a rare blood cancer

FDA approves first treatment Zelboraf (vemurafenib)for certain patients with Erdheim-Chester Disease, a rare blood cancer



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FDA approves first treatment for certain patients with Erdheim-Chester Disease, a rare blood cancer

The U.S. Food and Drug Administration today expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with Erdheim-Chester Disease (ECD), a rare cancer of the blood. Zelboraf is indicated to treat patients whose cancer cells have a specific genetic mutation known as BRAF V600. This is the first FDA-approved treatment for ECD. Continue reading.

//////Zelboraf, vemurafenib, fda 2017, Erdheim-Chester Disease,


Vemurafenib structure.svg
Vemurafenib ball-and-stick model.png
Clinical data
Pronunciation /ˌvɛməˈræfənɪb/ VEM-ə-RAF-ə-nib
Trade names Zelboraf
Synonyms PLX4032, RG7204, RO5185426
AHFS/ Monograph
MedlinePlus a612009
License data
  • AU: D
  • US: D (Evidence of risk)
Routes of
By mouth (tablets)
ATC code
Legal status
Legal status
CAS Number
PubChem CID
PDB ligand
ECHA InfoCard 100.226.540
Chemical and physical data
Formula C23H18ClF2N3O3S
Molar mass 489.92 g/mol
3D model (JSmol)

Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor 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.


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]

Mechanism of action

Vemurafenib causes programmed cell death in melanoma cell lines.[6] 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).[7] 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.[8][9]


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.[13][14][15][16]

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.[17]

In early 2010 a Phase I trial[18] for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.[19]

A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[20]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[21] The BRIM3 trial reported good updated results in 2012.[22]

Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK-inhibitor.[21] After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.[23]

In January 2015 trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.[24]

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.[25]

A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.[26]


  1. Jump up to:a b c PDB3OG7​; 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”Nature467 (7315): 596–599. doi:10.1038/nature09454PMC 2948082Freely accessiblePMID 20823850.
  2. Jump up^ “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. Jump up^ 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 Discov11 (11): 873–86. doi:10.1038/nrd3847PMID 23060265.
  4. Jump up^ Notice of Decision for ZELBORAF
  5. Jump up^ 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.
  6. Jump up^ 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 Res6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001PMID 18458053.
  7. Jump up^ 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 Venereol95 (5): 516–524. doi:10.2340/00015555-2035PMID 25520039.
  8. Jump up^ 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”. Nature464 (7287): 431–5. doi:10.1038/nature08833PMID 20130576.
  9. Jump up^ 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 Res23(2): 190–200. doi:10.1111/j.1755-148X.2010.00685.xPMC 2848976Freely accessiblePMID 20149136.
  10. Jump up^ 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”Nature468 (7326): 973–977. doi:10.1038/nature09626PMC 3143360Freely accessiblePMID 21107323Lay summary – Genetic Engineering & Biotechnology News.
  11. Jump up^ 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”Nature487 (7408): 500–4. doi:10.1038/nature11183PMC 3711467Freely accessiblePMID 22763439.
  12. Jump up^ 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”Nature487 (7408): 505–9. doi:10.1038/nature11249PMC 3724525Freely accessiblePMID 22763448.
  13. Jump up^ “Drug hope for advanced melanoma”. BBC News. 2009-06-02. Retrieved 2009-06-07.
  14. Jump up^ Harmon, Amy (2010-02-21). “A Roller Coaster Chase for a Cure”The New York Times.
  15. Jump up^ Garber K (December 2009). “Melanoma drug vindicates targeted approach”. Science326 (5960): 1619. doi:10.1126/science.326.5960.1619PMID 20019269.
  16. Jump up^ 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).
  17. Jump up^ 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. Med363 (9): 809–19. doi:10.1056/NEJMoa1002011PMID 20818844Lay summary – Corante: In the Pipeline.
  18. Jump up^ “Safety Study of PLX4032 in Patients With Solid Tumors”.
  19. Jump up^ “A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma”. 2010-02-15.
  20. Jump up^ “Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma” (Press release). Plexxikon. 2010-01-08.
  21. Jump up to:a b “Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study”. 6 June 2011.
  22. Jump up^ “Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma”.
  23. Jump up^ Cobimetinib at
  24. Jump up^ “MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma”. 2015.
  25. Jump up^ “BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma”Oncology & Biotech News5 (7). July 2011.
  26. Jump up^ “Getting close and personal”The Economist. January 4, 2014. ISSN 0013-0613. Retrieved 2016-04-15.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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