Melanoma frontline approach

1. melanocyte melanoma
epidermis
dermis
Frontline Approach to Metastatic
BRAF-Mutant Melanoma
Diagnosis, Molecular Evaluation,
and Treatment Choice
By
Ereny S. Poles
Ass.lecutrer of clinical oncology, Assuit university

2. 45 yo man with
‘mole’ on his back
for years
presented with
headaches and
was found to have
widespread (brain,
liver, lung, bowel
spread) liver
biopsy showed
metastatic
melanoma

3. Patients with metastatic melanoma had few
treatment options

5. When we begin to understand the biology , it
is the real beginning

6. BRAF
mutation
Melanoma is
immunogene
ic tumour

7. BRAF mutation

8. • BR AF is a serine/threonine protein kinase, encoded on chromosome
7q34, that activates the M AP kinase/ERKsignaling pathway. BR AF is
the family member most easily activated by Ras (1)
• In fact , approximately 50 % of melanomas harbor
activating
• BR AF mutations. Among the BRAF mutations observed in
melanoma, over 90 % are at codon 600, and among these,
over 90 % are a single nucleotide mutation resulting in
substitution of glutamic acid for valine (BR AF V600E:
nucleotide 1799 T > A; codon GTG > GAG).
• The second most common mutation is BRAF V600K
substituting lysine for valine, that represent s 5-6 % (GTG
> AAG), followed by BR AF V600R (GTG > AGG), an
infrequent two-nucleotide variation of the predominant
mutation, BR AF V600 ′ E2′(GTG > GAA), and BR AF
V600D (GTG > GAT ) [2].
1.Niault TS, Baccarini M: Targets of Raf in tumorigenesis. Carcinogenesis 2010,31:1165–1174
2.Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF: Prognostic and
clinicopathologic associations of oncogenic BRAF in metastaticmelanoma. J Clin Oncol 2011, 29:1239–1246.

9.  BR AF V600E has been implicated in different
mechanisms of melanoma progression, and principally
the activation of the downstream MEK/ERK pathway,
evasion of senescence and apoptosis, unchecked
replicative potential, angiogenesis (through MEK-
dependent activation of HIF-1α and VEGF)*
*Maurer G, Tarkowski B, Baccarini M: Raf kinases in cancer-roles andtherapeutic opportunities.
Oncogene 2011, 30:3477–3488.

10. The second step is MEK-
ERK

11. Now there are two targets
BRAF mutation
V600E
MEK – ERK
Pathway

12. First how to assess BRAF
mutation?
1-Real-time Polymerase
Chain Reaction
2-Next-generation
sequencing
3-
Immunohistochemistry
4-Circulating tumor-derived DNA
Done only
for proven
metaststic
disease

13. Therapeutic approach for BRAF
mutated metastatic malignant
melanoma
VEMURAFEN
IB

16. Dabrafenib : Second FDA approved
BRAF inhibitor

18. Do we solve the problem ?
NO

20. Now there are two targets
BRAF mutation
V600E
MEK – ERK
Pathway

21. MEK – ERK
Pathway (MAPK)
Trametinib : A First in Class Oral MEK Inhibitor
Approved for Treatment of Metastatic
Melanoma With BRAF V600 Mutations.
Trametinib (MEKINIST) is a first-in-class, orally
administered selective inhibitor of MEK1/2 serine threonine
kinase.

22. The FDA has granted an accelerated approval to the
combination of the MEK inhibitor trametinib (Mekinist)
and the BRAF inhibitor dabrafenib (Tafinlar) as a
treatment for patients with unresectable or metastatic
melanoma who harbor a BRAF V600E or V600K
mutation.
The approval for the combination was based on results
from an open-label phase I/II trial, which showed that
trametinib combined with dabrafenib nearly doubled the
duration of response and significantly improved overall
response rates (ORR) when compared with dabrafenib
alone.

23. Cobimetinib (another MEK inhibitor)

24. BRAF
mutation
Melanoma is
immunogene
ic tumour

25. Melanoma is
immunogeneic tumour

26. Why Melanoma is an
immunogeneic tumour
1-The reason underlying the immunogenicity of
melanoma is
unclear. One hypothesis relates to the high mutation
rate seen within melanomas compared with other tumor
types.
2- The majority of these mutations are passenger
mutations that are non-essential for the survival of the
tumor but offer an opportunity for immune recognition.
3- where the mutation rate is higher,
the chance of generating a mutation with the capacity
to bind major histocompatibility complex could also be
higher. Others have argued that the extensive research
in melanoma immunology is largely opportunistic and
stems from the failure of standard chemotherapeutic

27. As melanoma is immunogenic so it can be
eliminated naturally by host immune system
Immune escape
Tumors utilize a number of pathways to avoid
immune detection.
1-Antigen expression and presentation mechanisms may be
suppressed
through decreased major histocompatibility complex class I
expression.
2-Tumors are also able to limit an immune response by releasing
immunosuppressive paracrine mediators including adenosine,
transforming growth factor- b, vascular endothelial growth factor-
A and
indoleamine 2,3-dioxygenase (IDO) to suppress T-cell activation.

28. 3-Dampening of T-cell activity also occurs through the
regulatory pathways such as upregulation of cytotoxic T-
lymphocyte antigen-4 (CTLA)-4 on T cells, or
engagement of programmed death-1 (PD-1), an
inhibitory T-cell co-receptor, with its ligand, B7-H1 (PD-
L1) on tumor cells

30. T- lymphocyte antigen 4
antibody(CTLA 4)

31. Ipilimumab ( CTLA4 antibody)

32. Anti programmed death1
antibodies
(PD-1) antibodies

34. Mechanism of action of anti –
PD1

36. NOW
IS 2015 EMERGING
APROACH
Asort of permution and
combinations

38. Participating investigators randomly assigned patients 2:1 to
receive an intravenous infusion of nivolumab 3 mg/kg every 2
weeks or ICC
(dacarbazine 1000 mg/m every 3 weeks or paclitaxel 175 mg/m
combined with carboplatin area under the curve 6 every 3 weeks)
until progression or unacceptable toxic effects

40. Thank you