|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Synonyms||PLX4032, RG7204, RO5185426|
|Molecular mass||489.92 g/mol|
|(what is this?)|
|Mechanism of action||protein kinase inhibitor|
|PDB ligand id||032:,|
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. The name "vemurafenib" comes from V600E mutated BRAF inhibition.
Approvals and indications
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011, making it the first drug designed using fragment-based lead discovery to gain regulatory approval. Vermurafenib later received Health Canada approval on February 15, 2012 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.
Mechanism of action
Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.
(See BRAF_(gene)#Vemurafenib for details of drug structure interaction with B-Raf.)
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.
Three 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 alternative survival pathway.
- A second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.
- Stromal cell secretion of hepatocyte growth factor (HGF).
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. 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.
In early 2010 a Phase I trial for solid tumors (including colorectal cancer), and a phase II study (for Metastatic Melanoma) were ongoing, and a phase III trial (vs dacarbazine) in patients with previously untreated Metastatic Melanoma showed an improved rates of overall and progression-free survival.
Further trials are planned including a trial where vemurafenib will be co-administered with GDC-0973(Cobimetinib), a MEK-inhibitor. After good results in 2014 the combination has been submitted to EC and FDA for marketing approval.
At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. 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.
- "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.; Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, et al. (September 2010).
- "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.
- 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.
- Notice of Decision for ZELBORAF
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. PMC 3143360. PMID 21107323. Lay summary – Genetic Engineering & Biotechnology News.
- 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. doi:10.1038/nature11183. PMID 22763439.
- 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. doi:10.1038/nature11249. PMID 22763448.
- "Drug hope for advanced melanoma". BBC News. 2009-06-02. Retrieved 2009-06-07.
- Harmon, Amy (2010-02-21). "A Roller Coaster Chase for a Cure". The New York Times.
- Garber K (December 2009). "Melanoma drug vindicates targeted approach". Science 326 (5960): 1619. doi:10.1126/science.326.5960.1619. PMID 20019269.
- 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).
- 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.
- "Safety Study of PLX4032 in Patients With Solid Tumors". ClinicalTrials.gov.
- "A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma". ClinicalTrials.gov. 2010-02-15.
- "Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma" (Press release). Plexxiko. 2010-01-08.
- "Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study". 6 June 2011.
- "Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma".
- Cobimetinib at exelixis.com
- "MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma". 2015.
- "BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma". Oncology & Biotech News 5 (7). July 2011.