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

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

New Agents for Stage IV Melanoma

US Approval

Targeted TherapyImmunotherapy

Pre-1998 Approvals w/o (+) randomized trials1998-2011 No approvals

2011-2014 7 new regimens approved

1975 DTIC

1998 HD-IL2

1998-

20112011

Ipilimumab

Vemurafenib

2012 2013

Dabrafenib

Trametinib

2014

Dabrafenib +Trametinib

PembrolizumabNivolumab

Chemotherapy

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

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 FarberAnd Patient

‘Targeted Therapy’:Treat cancer by targeting the genes activated in cancer cells

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

PET

CT

BRAFi

6 Weeks

The Promise of Targeted Therapy: BRAF

Effective for Brain Metastases

Long et al, Lancet Oncology, 2013

BRAFi

32 Weeks

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

Baseline 2 Weeks 16 Weeks

Resistance to BRAF Inhibitors

Average response duration ~6 months

BRAFi: Why Does Resistance Happen

MAPK & PI3KPathway

Re-Activated

MAPK Pathway

Re-Activated

UnknownMechanism

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

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

A New Challenge: Heterogeneity

Shi,… Lo, Cancer Discovery, 2013

Tumor #

Different tumor with different resistance mechanisms

in the same patient

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?

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

Targeted Therapy:

Beyond BRAFV600

‘Wild-type’ BRAF>50% cutaneous MM>80% non-cutaneous

BRAFV600

Mutant

BRAFV600

Wild-Type

Different Types of Melanomas Have Different Mutations

Cutaneousw/o Chronic Sun Damage (C.S.D)

Acral MelanomaMucosal Melanoma Uveal

20-30% mutations in c-KIT

45% BRAF Mutations20% NRAS Mutations

Acral: 20% BRAF 10% NRASMucosal: 3% BRAF 5% NRAS

Virtually No BRAF/NRAS

~80% mutations in GNAQ/GNA11

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

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

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

MelanomaBRAF L597V

TAK-733(MEKi)

Targeted Therapy for Melanoma:

What Have We Learned

& What Are We Working On

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

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

Thank you for your attentionand to our patients

Michael Davies, M.D., Ph.D.

Departments of Melanoma Medical Oncology and Systems BiologyUniversity of Texas M. D. Anderson Cancer Center

mdavies@mdanderson.orgResearch SupportNIH/NCICancer Prevention Research Institute of Texas (CPRIT)Melanoma Research AllianceMelanoma Research FoundationAmerican Society for Clinical OncologyMDACC SPORE in MelanomaMDACC Physician-Scientist ProgramDunn Foundation for Chemical Genomics

GlaxoSmithKline

AstraZeneca

Genentech

Merck

Myriad

Oncothyreon

Sanofi-AventisDr. John E. Davies, 1921 - 1999