Melanoma and Vemurafenib

Vemurafenib (sold as Zelboraf) is a recently approved chemotherapy available for melanoma treatment. For the 60% of melanoma patients whose cancer is caused by the V600E BRAF mutation,it restores normal cell growth by blocking the mutation's overactive cell growth. 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.

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.^1 ^ Research, with results like these are promising for the future of personalized medicine.

Read more details about Vemurafenib.

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.¹ 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. The results of these trials led to 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 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 (first identified as PLX4032) began over five years ago. The original PLX4032 was identified in experiments designed to target theV600E mutation ⁷.

The conventional treatment is with the chemotherapy drug dacarbazine, which was approved thirty six years before. 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. This treatment is a key example of personalized medicine and targeted cancer therapy.

First patients are screened with Cobas 4800, to confirm the BRAF V600 mutation - only patients with this mutation are expected to respond to Zelforab (Vemurafenib.)

Vemurafenib is taken twice a day in pill form, approximately every 12 hours. In contrast, dacarbazine is administered every three weeks by IV. Patients should inform any other doctor or dentist that you are taking Vemurafenib before they care for you. Avoid sunlight and sunlamps. They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher. It is necessary to get regularly screened for new moles (squamous cell carcinomas), that grow more frequently when using Vemurafenib, and that will need to be quickly removed.

Vemurafenib is a treatment that extends life and reduces tumors. It is not a cure. While 74% of the patients showed regression, compared with ~5% for Dacarbazine, the regression only lasted from 2-18 months. Two explanations for the recurrence have been identified. The cancer cells find an alternative path to excessive growth through cell surface protein, or an upstream gene on the pathway, N-ras mutates and the cancer growth resumes. ³ The successful results are encouraging for metastatic melanoma patients as well as other cancers that are caused through these pathways, especially by the same V600E mutation.

At this time vemurafenib treatment costs ~$10,000 per month.

Vemurafenib caused a number of side effects, including diarrhea, fatigue, nausea, hair loss, rash, joint pain and squamous cell skin cancer. About 31% of the patients grew these moles, which were monitored and removed promptly. About 45% of Vemurafenib patients had to modify their dose because of these side effects. The side effects were more frequent and significant for vemurafenib than for the dacarbazine group(1).

Possible serious side effects of Zelboraf include severe allergic reactions; severe skin reactions; changes in the electrical activity of the heart called QT prolongation, which can potentially be life-threatening; abnormal liver function tests; eye problems; or new melanoma lesions.

1. “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.

2. 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>.

3. “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>.

4. Tsao, MD, PhD, Hensin. "Improved Survival with Vemurafenib in Melanoma." MedScape. 1 Aug. 2011. Web. 19 Oct. 2011. <http://www.medscape.com/viewarticle/745813>.

5. 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>.

6. 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>.

7. 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>.

8. 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>.

9. "Vemurafenib." Wikipedia, the Free Encyclopedia. Web. 19 Oct. 2011. <http://en.wikipedia.org/wiki/Vemurafenib>.