Vemurafenib in the Treatment of Metastatic Melanoma

Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group.

N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5.

• The BRAF gene is often mutated in metastatic melanoma (BRAF V600E mutation)
• Braf inhibitors are a new approved modality therapeutic agents for metastatic melanoma and we have been very impressed by the initial reports and spectacular visible results. We must stress, however, thet the results do not work in everyone and the degree of response is also highly variable.
• This article is the phase 3 randomized control trial (funded by Hoffmann-La Roche) comparing responses for vemurafenib (960mg orally twice a day) and dacarbazine (1000mg per square meter of body surface are intraveinously every 3 weeks).
• Results show survival of 84% (vemurafenib) vs 64% (dacarbazine). Response rates were 48% for vemurafinib vs 5% for dacarbazine
• Side effects are principally on the skin and in 10% of cases, patients develop keratoacanthoma, squamous-cell carcinoma or a verrucous-like prolliferation.
• However the initial spectacular clinical response needs to be maintained over time (phase 2 studies have shown that resistance develops within 6 months of the initial response).           Its like going from work to the office and many alternative roads are possible if one is blocked, it goes for the same with a melanoma cell: block on proliferation pathway and it will use another to achieve its means. There it might be a good idea to target different pathways (“roads”) even though the risk for more or more severe side effects becomes bigger. Trials are underway by Glaxo Smith Kline (GSK) with an association of the MEK pathway inhibition. Other trials combine BRAF inhibitors with p-13 k and akt pathway inhibitors.
• It is important to know, however that new melanomas have developed in treated patients and that it is mandatory to regularly check the skin (Thomas L. Journées Dermatologiques de Paris 2011)

*A drug commonly used in the traetment of metastatic melanoma