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Vemurafenib is a recently approved chemotherapy available for melanoma treatment. It is an excellent demonstration of a targeted cancer therapy. It inhibits the activity of a mutated protein (BRAF) which bypasses the cell’s usual signals and leads to excessive cell growth (cancer). Vemurafenib only works in melanoma patients whose cancer has the V600E BRAF mutation (which means amino acid position number 600 on the BRAF protein, valine is replaced by glutamic acid). Approximately 60% of melanomas have this mutation. It is not known how often this mutation is present while melanoma is not detected. This new targeted chemotherapy was shown to extend survival time and shrink tumors better than dacarbazine, the standard of care choice for treating metastatic melanoma.
How It Works
The Phase III trials, led by Dr. Paul B Chapman of New York’s Memorial Sloan-Kettering Cancer Center, and a large multidisciplinary team treated late stage melanoma patients with dacarbazine or vemurafenib in a direct comparison. After six months, 84% of patients taking vemurafenib were alive, compared to 64% of patients on dacarbazine1. Vemurafenib also shrank the tumors in nearly half of patients, while the dacarbazine shrank tumors for only 6%. After these significant findings, the patients in the dacarbazine group were switched to vemurafenib because the observed survival rate was so much better2.
A routinely frustrating part of fighting a disease with a prescription that works for 50% of the patients, is that half the patients will be disappointed – and will suffer side effects and prolonged illness during the trial. If vemurafenib were tried on a random grouping of metastatic melanoma patients, then the success rate would be closer to 50% (60% of 84%), however the selection of those with the V600 BRAF mutation for this exact targeted cancer therapy, resulted in the significant 84% success rate. Note the overall response rate after longer testing is scored at 48% for vemurafenib and 5% for dacarbazine. Research, with results like these are promising for the future of personalized medicine.
The mutation in the B-Raf gene produces a protein that interferes with regular programmed cell death. The targeted cancer therapy, vemurafenib, pinpoints the V600E mutation and restores the function of programmed cell death, thus reducing the unwanted cell division and growth (cancer). It was observed that vemurafenib worked on other mutations in of the B-raf gene, too. The successful design and implementation of a targeted cancer therapy is a significant advance in the treatment of metastatic melanoma and a promising indicator for other key mutation based cancers. BRAF is the most frequently mutated protein kinase in human cancers5. More than 30 mutations of the B-raf gene associated with human cancers have been identified. The research on the B-raf mutation started before 1990 6 8, the work with vemurafenib (sold as Zelboraf, first identified as PLX4032) began over five years ago. The original PLX4032 was identified in experiments designed to target theV600E mutation 7. The research is a big step forward in personalized medicine.
Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011 3. Vemurafenib is sold under the name Zelboraf and produced by Genentech. At the same time, a the key matching diagnostic test, Cobas 4800, was approved to confirm the BRAF V600E mutation in metastatic melanoma patients. The conventional treatment is with the chemotherapy drug dacarbazine, which was approved thirty six years before. People who received Zelboraf also had a 74 percent reduced risk of the disease getting worse or dying compared to those who received chemotherapy. Tumor shrinkage in people who received Zelboraf was 48.4 percent compared to 5.5 percent for those who received dacarbazine chemotherapy 4. Melanoma that occurs independently of the mutation is not expected to respond to vemurafenib.
- “Improved survival with vemurafenib in melanoma with BRAF V600E mutation” N Engl J Med 2011; 364:2507-2516 June 30, 2011 Paul B. Chapman, MD, Axel Hauschild, MD, Caroline Robert, MD, Ph.D., et al.
- Chapman MD, Paul B. "Dr. Chapman Describes the Vemurafenib Clinical Trial - YouTube." YouTube - Broadcast Yourself. OncLivTV, 10 June 2011. Web. 19 Oct. 2011. <http://www.youtube.com/watch?v=ilpIwzN0VIY>.
- “FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer” Aug 17, 2011 "Genentech: Newsroom: Press Releases." Genentech: Home. Web. 19 Oct. 2011. <http://www.gene.com/gene/news/press-releases/display.do?method=detail>.
- Tsao, MD, PhD, Hensin. "Improved Survival with Vemurafenib in Melanoma." MedScape. 1 Aug. 2011. Web. 19 Oct. 2011. <http://www.medscape.com/viewarticle/745813>.
- Helen, Davies, Graham Bignell, and Charles Cox. Et al "Mutations of the : BRAF: Gene in Human Cancer : Article : Nature." Nature Publishing Group : Science Journals, Jobs, and Information. Nature, 9 June 2002. Web. 19 Oct. 2011. <http://www.nature.com/nature/journal/v417/n6892/full/nature00766.html>.
- Bollag, Gideon, Peter Hirth, and James Tsai et al. "Clinical Efficacy of a RAF Inhibitor Needs Broad Target Blockade in BRAF-mutant Melanoma." Http://www.ncbi.nlm.nih.gov. Nature 30 Sept. 2010. Web. 19 Oct. 2011. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948082/?tool=pmcentrez>.
- Tsai, James, John T. Lee, and Weiru Wang. "Discovery of a Selective Inhibitor of Oncogenic B-Raf Kinase with Potent Antimelanoma Activity." PNAS (2007). Proceedings of the National Academy of Sciences. 15 Dec. 2007. Web. 19 Oct. 2011. <http://www.pnas.org/content/105/8/3041.long>.
- Sithanandam, G., W. Kolch, FM Duh, and UR Rapp. "Complete Coding Sequence of a Human B-raf CDNA and Detection of B-raf Protein Kinase with Isozyme Specific Antibodies." Oncogene 12 (1990): 1775-780. Http://www.ncbi.nlm.nih.gov. Web. 19 Oct. 2011. <http://www.ncbi.nlm.nih.gov/pubmed/2284096>.
- "Vemurafenib." Wikipedia, the Free Encyclopedia. Web. 19 Oct. 2011. <http://en.wikipedia.org/wiki/Vemurafenib>.
- Image: http://www.noveldrugs.info/2011/08/17/vemurafenib-zelboraf-is-approved-for-the-treatment-of-melanoma/