Emerging Concepts in Therapeutic
Guidance for Metastatic Melanoma
Short Presentations in Emerging
Concepts (SPEC)
Melanoma
• Leading cause of death from skin disease
• Discovery of genes that play a key role in
oncogenesis
– e.g. BRAF, NRAS, MEK, c-KIT
• Emerging therapies focus on targeting the
activated pathways in melanoma
Molecular Subtypes of Melanoma?
BRAF
• About 50% of nodular melanomas
– Acquired mutation
– RAS/RAF/MEK pathway is constitutively
activated driving proliferation
• Most common mutation: V600E
– Mutation in DNA causes change in protein amino
acid sequence: Valine at amino acid 600 to
GlutaminE
• Second common mutation: V600K
– Same amino acid – Valine to Lysine
BRAF Inhibitors
• Vemurafenib (Aug 2011)
• Dabrafenib (May 2013)
• Oral inhibitors of BRAF tyrosine kinase
• Can have dramatic tumor regression
– Subject of 3 part series in New York Times,
Feb 2010
New York Times – Feb 2010
Phase 3 Trial Results
J Clin Oncol. 2011 Apr 1;29(10):1239-46.
BRAF Mutation Analysis
• Either primary or metastatic tissue
– Formalin-fixed paraffin-embedded (FFPE)
• Performed using PCR
– Very good analytic sensitivity - about 1%
– Detects the BRAF mutation with less than 5%
tumor cells in the tissue.
– More sensitive than sequencing
• Can be significant in samples with low amount of tumor
Resistance to BRAF Inhibitors
• Resistance develops through alternate
pathway activation of NRAS/MEK
• Therapeutic option for MEK inhibition using
trametinib
– FDA approval for monotherapy in BRAF mutated
tumors
– Not approved as a combination treatment.
Preliminary results from a clinical trial suggest
that use in combination with dabrafenib
significantly improved progression-free survival,
although the incidence of pyrexia was increased
c-KIT and Melanoma
• Mucosal or acral melanomas with
activating mutations or amplifications in cKIT may be sensitive to a variety of c-KIT
inhibitors
• Phase II and phase III trials are available
for patients with unresectable stage III or
stage IV melanoma harboring the c-KIT
mutation
c-KIT testing
• Response to inhibitors is limited to
mutations in certain exons
– Amplification not associated with response
Image from: Lyle M, Long GV. Diagnosis and Treatment of KIT-Mutant Metastatic Melanoma. J Clin Oncol. 2013 Sep 10;31(26):
Selected Resources
Improved survival with vemurafenib in melanoma with BRAF
V600E mutation
Chapman PB et al, Improved survival with vemurafenib in
melanoma with BRAF V600E mutation. N Engl J Med. 2011;
364:2507-2516 June 30, 2011.
Vemurafenib (Zelboraf®) package insert
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