Dr. Michael Davies presents the latest information on targeted melanoma therapies at the MRF's Patient Symposium at MD Anderson Cancer Center on January 31, 2015.

1. Melanoma: From
Prevention to Cure
Houston, Texas
January 31, 2015
Targeted Therapy for Melanoma:
A Personalized Approach
Michael A. Davies, M.D., Ph.D.
Associate Professor, Melanoma Medical Oncology, & Systems
Biology, The University of Texas MD Anderson Cancer Center
CCR, 2012
Day 1 Day 15
Flaherty NEJM, 2010

2. Disclosure Information
I have the following financial relationships to disclose:
Consultant for:
GSK, Roche/Genentech, Novartis, Sanofi-Aventis
Grant/Research support from:
GSK, Roche/Genentech, Astrazeneca, Merck, Myriad,
Oncothyreon, Sanofi-Aventis
I will discuss off-label or investigational use of:
Imatinib, TAK-733

3. New Agents for Stage IV Melanoma
US Approval
Targeted TherapyImmunotherapy
Pre-1998 Approvals w/o (+) randomized trials
1998-2011 No approvals
2011-2014 7 new regimens approved
1975 DTIC
1998 HD-IL2
1998
-
2011
2011
Ipilimumab
Vemurafenib
2012 2013
Dabrafenib
Trametinib
2014
Dabrafenib
+Trametinib
Pembrolizumab
Nivolumab
Chemotherapy

4. Targeted Therapy:
A Personalized Approach
• What is targeted therapy?
• Why do we use targeted therapy
for melanoma?
• What have we learned & what are
we working on

5. A Brief History of Chemotherapy
• WW I: Nitrogen mustards gas
• → 1946 1st successful systemic treatment of
cancer with chemotherapy
• 1950s-1980s most standard chemotherapies
• 1977 First report of an oncogene
• 1980s-2000s Oncogenes in most cancers
Dr. Sidney Farber
And Patient
‘Targeted Therapy’:
Treat cancer by targeting the genes activated in cancer cells

6. Targeted Therapy: Why Melanoma?
• Overall melanomas have more mutations than
any other type of cancer
• Targetable mutations can be identified in
~70% of patients with cutaneous melanoma

7. PET
CT
BRAFi
6 Weeks
The Promise of Targeted Therapy:
BRAF

8. Effective for Brain Metastases
Long et al, Lancet Oncology, 2013
BRAFi
32 Weeks

9. Clinical Activity of BRAF Inhibitors
Tumor Grew
Tumor Shrank
• 50% of patient achieve a “clinical response”
• 90% achieve disease control, usually very quickly (<1 month)
• KEY: Only work in patients that have a BRAFV600 mutation
• If don’t have a mutation they will make the tumors grow faster
FDA-Approved BRAF Inhibitors
• Vemurafenib, 2011
• Dabrafenib, 2013
Champman et al, NEJM, 2011

10. Baseline 2 Weeks 16 Weeks
Resistance to BRAF Inhibitors
Average response duration ~6 months

11. BRAFi: Why Does Resistance Happen
MAPK & PI3K
Pathway
Re-Activated
MAPK
Pathway
Re-Activated
Unknown
Mechanism
of Resistance
Shi,… Lo, Cancer Discovery, 2013
All patients still have the BRAFV600 mutation at the time of resistance
→ Rationale to combine BRAF with other MAPK inhibitors

12. Combinations to Overcome Resistance:
Targeted Therapy + Targeted Therapy
Testing of other combinations underway
-100
-80
-60
-40
-20
0
20
40
60
80
100
Tumor Shrank
BRAFi + MEKi
• ~100% disease control rate
• Average response duration 11 months (~2X BRAFi)
• Less skin toxicity than BRAFi alone
Flaherty et al, NEJM, 2012

13. A New Challenge: Heterogeneity
Shi,… Lo, Cancer Discovery, 2013
Tumor #
Different tumor with different resistance mechanisms
in the same patient

14. A New Hypothesis:
Combining BRAF Inhibitors & Immunotherapy
BRAF Inhibitors
• High rates of responses
• Responses generally < 1 yr
Immunotherapies
• Lower rates of responses
• Responses can → cures
Can BRAF Inhibitors + Immunotherapy →
High rate of cures?

15. Combinations to Overcome Resistance:
Targeted Therapy + Immune Therapy
Liu, …Hwu, CCR, 2013 Frederick,…Wargo, CCR, 2013
In Mice In Patients
Challenges:
• More side effects
• Which agents to combine
• How to combine them

16. Targeted Therapy:
Beyond BRAFV600
‘Wild-type’ BRAF
>50% cutaneous MM
>80% non-cutaneous
BRAF
V600
Mutant
BRAF
V600
Wild-Type

17. Different Types of Melanomas Have
Different Mutations
Cutaneous
w/o Chronic Sun
Damage (C.S.D)
Acral Melanoma
Mucosal Melanoma Uveal
20-30% mutations
in c-KIT
45% BRAF Mutations
20% NRAS Mutations
Acral: 20% BRAF 10% NRAS
Mucosal: 3% BRAF 5% NRAS
Virtually No
BRAF/NRAS
~80% mutations
in GNAQ/GNA11

18. Targeted Therapy for KIT-Mutant
Melanoma
Hodi et al, JCO, 2008
Imatinib
Imatinib
• 1% chance of response in unselected melanoma patients
• 30-50% chance of response with recurrent KIT mutations

19. Melanoma TCGA: Initial Results
100 150 215
NRAS mut (28%)
BRAF mut (52%)
NF1 mut (14%)
MITF amp (4%)
BRAF amp (12%)
MDM2 amp(12%)
NOTCH2 amp (5%)
KIT amp (3%)
KIT mut (3%)
PDGFRα amp (3%)
PDGFRα mut (10%)
CCND1 amp (4%)
TERT amp (5%)
PPP6C mut (7%)
PTEN del (12%)
PTEN mut (8%)
CDKN2A del(40%)
CDKN2A mut (13%)
TP53 mut (7%)
50
“Wild-Type”BRAFV600NRAS
Cancer Genome
Atlas Research
Network, 2012

20. Dahlman, et al Cancer Discovery, 2012
MEKi for Non-V600 BRAF Mutations
Cutaneous & Unknown Primary melanomas WITHOUT
BRAFV600 or NRAS mutations
MDACC, n=113
Siroy, et al, J Inv Derm, 2014
Melanoma
BRAF L597V
TAK-733
(MEKi)

21. Targeted Therapy for Melanoma:
What Have We Learned
& What Are We Working On

22. Targeted Therapy:
What We Have Learned
• Virtually all patients with cutaneous melanomas
have >100 mutations
• BRAF-Mutant Melanoma (~ 50%)
– Inhibiting driver oncogenes can → benefit
– Right patient, right drug, right dose
– Combinations can be even better!
• Have to identify ways to understand, prevent &
overcome resistance

23. Targeted Therapy:
What We Are Working On
• Identify mutations that help us to manage
patients across the full continuum of melanoma
• BRAF-Mutant Melanoma
– Benefit of BRAF and MEK inhibitors in earlier stages
– New combinations
• Testing new strategies for other mutations

24. Thank you for your attention
and to our patients
Michael Davies, M.D., Ph.D.
Departments of Melanoma Medical Oncology and Systems Biology
University of Texas M. D. Anderson Cancer Center
mdavies@mdanderson.org
Research Support
NIH/NCI
Cancer Prevention Research Institute of Texas (CPRIT)
Melanoma Research Alliance
Melanoma Research Foundation
American Society for Clinical Oncology
MDACC SPORE in Melanoma
MDACC Physician-Scientist Program
Dunn Foundation for Chemical Genomics
GlaxoSmithKline
AstraZeneca
Genentech
Merck
Myriad
Oncothyreon
Sanofi-Aventis
Dr. John E. Davies, 1921 - 1999