Zelboraf is anti BRAF kinase inhibitor. ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
More than 30 mutations of the BRAF gene associated with human cancers have been identified. The most common one is BRAFE, a substitution of valine (V) glutamate (E) at codon 600, and it is referred to as BRAF600E. Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc. and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, Preclinical evidence is that most of these mutations stimulate enhanced B-Raf kinase activity toward MEK. A few mutants have reduced activity toward MEK but adopt a conformation that activates wild-type C-RAF, which then signals to ERK.
With this in mind, other BRAF mutations than E should also respond to Zelboraf. There is some evidence for that in individual cases, for example for the BRAFK mutation as well as for BRAFR. In the Chapman study, on which the FDA approval was based, there were ten patients with BRAFK and they showed some response. Ten patients in the vemurafenib group were later found to have BRAF V600K mutations; of these patients, 4 had a partial response (40%). Being that there are so many different BRAF mutations, it is not reasonable to require large studies performed for each mutation subtype.
Zelboraf, Prescribing Information, 2012
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Paul B. Chapman, M.D., Axel Hauschild, M.D., Caroline Robert, M.D., Ph.D., John B. Haanen, M.D., Paolo Ascierto, M.D., James Larkin, M.D., Reinhard Dummer, M.D., Claus Garbe, M.D., Alessandro Testori, M.D., Michele Maio, M.D., David Hogg, M.D., Paul Lorigan, M.D., Celeste Lebbe, M.D., Thomas Jouary, M.D., Dirk Schadendorf, M.D., Antoni Ribas, M.D., Steven J. O’Day, M.D., Jeffrey A. Sosman, M.D., John M. Kirkwood, M.D., Alexander M.M. Eggermont, M.D., Ph.D., Brigitte Dreno, M.D., Ph.D., Keith Nolop, M.D., Jiang Li, Ph.D., Betty Nelson, M.A., Jeannie Hou, M.D., Richard J. Lee, M.D., Keith T. Flaherty, M.D., and Grant A. McArthur, M.B., B.S., Ph.D. for the BRIM-3 Study Group, Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation, N Engl J Med 2011; 364:2507-2516
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