Melanoma Overview 2009Frances Collichio

Associate Professor, University of North Carolina, Chapel Hill

Disclosure: OncoVex

Novartis

What is Melanoma?

• A Cancer of Melanocytes

• All Melanomas are malignant

• Melanocytes?– Cells that Make Pigment

• Melanoma therefore can start from any pigmented cell.

Extracutaneous Melanomas,

• Mucosal– GI tract, Head and Neck, vagina– Older pts– Poorer px– Disporportionally non-white

Ocular

• UvealCiliary body/Choroidal

Poor prognosisIris

Better px

Unknown Primary

– 2-4% of all melanoma– 9% of melanoma with lymph node

involvement– Search for the primary

• Ocular exam when there are liver mets

When you cannot find the primary, treat these as if they started in the skin.

““Silent”Silent” NationalNational EpidemicEpidemic

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1935 1950 1980 1985 1987 2000 2005 2010

• The incidence per year is rising faster than any other cancer!

Rate

/100,0

00

1:1500 1:600 1:250 1:150 1:135 1:75 1:65 1:60

estimated Lifetime RiskLifetime Risk

New Melanoma Patients to UNC

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25

50

75

100

125

150

175

200

225

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275

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325

350

375

# o

f P

ati

en

ts

98 99 0 1 2 3 4 5 6 7

Year

2007 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.

Men766,860

Women678,060

•26% Breast

•15% Lung & bronchus

•11% Colon & rectum

•6% Uterine corpus

• 4% Non-Hodgkin lymphoma

•4% Melanoma of skin

• 4% Thyroid

• 3% Ovary

• 3% Kidney

•3% Leukemia

•21% All Other Sites

Prostate 29%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Non-Hodgkin4% lymphoma

Melanoma of skin 4%

Kidney 4%

Leukemia 3%

Oral cavity 3%

Pancreas 2%

All Other Sites 19%

Melanoma US 2008

• 108,000 estimated new cases

–62,480 invasive

–48,290 in situ

–8,420 deaths

www.cancer.org

Etiology• Inheritance

-Chromosome 9 (10-40%)• Environment

– Sun• Greater than 3 blistering sunburns under age 20• Freckles on the back

– Tanning Booths• Genes-Environment Interactions

Melanoma

A—AsymmetryB—BorderC—ColorD—DiameterE—Evolution: A changing mole

Types of Melanoma

Nodular Amelanotic Melanoma

Invasive Melanoma

After diagnosing a skin lesion as melanoma, what is next?

• Surgery on the primary by an experience surgeon or dermatologist

• The margins of resection around the primary depend on the depth of the primary– Less than 1mm deep, 1cm margin– 1 to 2mm deep, a 1 to 2cm margin– Greater than 2 mm deep, a 2 cm margin

Staging and Survival

Stage 4 Melanoma

Staging, 2002 AJCC • T

–Breslow depth–Clark level---used only in T1 melanomas–Ulceration

• N–N1: Metastasis to one node–N2: Metastasis to two or three nodes–N3: Mets to 4 or more, or matted nodes, or in transit disease, or satellites (tumor w/in 5cm of the primary). –Micromets are defined by sentinel node. Macro mets are clinically detectable.

• M –M1a-skin, subcutaneous tissue or distant lymph nodes–M1b-lung–M1c-other sites

T stage

• TX: Primary cannot be assessed (shave bx)• T0: no evidence of primary• T1 1mm or less

– T1a: 1mm or less and Clarks level II or III w/o ulceration

• T2 >1mm and <2mm• T3 >2mm and <4mm• T4 >4mm

– A:w/o ulceration– B:w ulceration

Nodal Stage

• N– N1: Metastasis to one node

• N1a:micromet• N1b: Macromet

– N2: Metastasis to two or three nodes• N2a: Micromet• N2b: Macromet• N2c:in-transit met(s)/satellite(s) without metastatic lymph

nodes

– N3: Mets to 4 or more, or matted nodes, or in transit disease, or satellites (tumor w/in 5cm of the primary).

Sentinel Node procedure

• Stages the patient• Directs further diagnostic studies• May have a therapeutic impact• Avoid unnecessarily complex

dissections.

Sentinel Lymph Node Evaluation

MS01-1234Level 1 S-100

Doe, John

Lymph node serially sectioned while fresh

Alternate sections paraffin-embedded;remainder snap frozen

MS01-1234Level 2 H&E

Doe, John

MS01-1234Level 3 H&E

Doe, John

MS01-1234Level 4 H&E

Doe, John

MS01-1234Level 5 H&E

Doe, John

MS01-1234Level 6 H&E

Doe, John

MS01-1234Level 7 S-100

Doe, John

Five H&E-stained sections flanked by two S-100 sections

Indications for the Sentinel Lymph Node Procedure

• Thin melanomas (< 1 mm)• Consider for ulcerated primaries or Clarks IV, V

• Intermediate thickness melanomas (1-4 mm)– Risk: 18-20%

• Thick melanomas (>4 mm)– Risk: 40%+ nodal, 15-20% systemic

Patients with Postive Lymph Nodes

• Have completion Lymph node surgery.

In Transit Melanoma

After treating the primary and completing lymph node surgery,

what is next?

Now

• You know the T stage

• You know the N stage

• You base the extent of additional studies on those two facts.

Additional Studies?

• Stage I to IIA: (up to a 4mm thick with no ulceration) No additional Studies

• Stage IIB, IIC: Additional Studies as clinically indicated (CT, PET, MRI)

• Stage III: Baseline studies for staging or symptoms---Chest x-ray, CT + PET, MRI brain

Why PET/CT

• CT commonly used alone– Can miss visceral/lung

metastases

Sensitivity Specificity

Initial

CT .734 .882

PET .890 .952

CT/PET

.988 .976

P-Value

CT v P <0.01 <0.01

CT v C/P <.00001 <.00001

P v C/P <0.01 NSReinhardt, MJ et al. J Clin Oncol 2006;24:1178

Treatment of Stage IIb (T4), IIc, and III Melanoma when all of the visible tumor has

been removed• Observation

• Clinical Trial

• Or Interferon alpha

Adjuvant Therapy

• Only one FDA Approved Therapy– Interferon- 2b (Brand Name: Intron)– Meta-Analysis ~ 10% Absolute Benefit in RFS

• Improved QoL versus Observation• Cost Effective• Patient Preference compared to increased risk• 3% survival benefit but not statistically significant

Cole, BF et al. J Clin Oncol 1996;14:2666Hillner, BE et al. J Clin Oncol 1997;15:2351Killbridge, KL et al. J Clin Oncol 2001;19:812

Interferon Regimen

• IFN 2b– 20 Million Units/m2/Day IV

– (15MU often new starting point)

• 5 Days per week for 4 weeks

– 10 Million Units/m2/Day Subcutaneous• 3 times per week for 11 months

Side Effects:– Flu-like Sx, Hepatic Transaminitis, Fatigue,

HA, Nausea, Wt Loss, Myelosuppression, Depression

Adjuvant Radiation Therapy

• Consider RT to the nodal basin when there are multiple nodes involved or extranodal extension

(category IIb evidence NCCN)

Stage IV

• Median survival is 9 months and less than 5% probability of survival beyond 5 years.

Stage IV disease local Therapies

• Surgery– Best for skin/lymph nodes>lung>GI tract

• Radiation– Palliation of symptomatic sites– High dose fractions (?)– Brain Mets

Systemic Treatments

• Where is this going– Genetic Footprint

• What Categories of treatment do we see?– Immune-therapy sensitive– Chemotherapy– Targetted Therapy

MAPK and PI3K/AKT pathwaysCell Membrane---------------------------------------------------------

SHC PI3K→AKTRAS PTEN ↓BRAFMEK ½ CCND1MAPK3 ↓

MAPK1 CDK4/6

↓ ↓ ↓ VEG CFOS ELK Proliferation Proliferation ↓

Cell cycle progression

MAPK and PI3K/AKT pathways

• Ras/Ras PI3/AKTCutaneous Not chronically sun exposed Cutaneous, Chronically sun exposed

Mucosal, Acral

Proliferative pathway Antiapototic pathway

CDKN2A gene mutations

CDK4 amplifcation in acral and mucosal

KIT

• Receptor tyrosine kinase• Critical regulator of growth of melanocytes.

• Dysfunctional KIT pigmentary defects. • Expression is lost in nevi• Amplification in chronically sun exposed

melanoma• Amplification in KIT exons 11, 13, 17 and

18 may correlate with Rx response

KIT

Case• 79 yo rectal melanoma• 12/06 recurrence, anal rectal junction and near the

kidney• Strong staining for KIT• KIT exons 11, 13, 17 were amplified• Additional peak in exon 11• Imatinib 400mg daily• Marked improvement in all disease

J Clin Oncol 2008

Imatinib Study

• For patients with KIT amplification or mutation

• Gleevac 400mg PO daily

Immunotherapy

• IL2

• Vaccines

• Other Modulators of the immune system– CTLA 4– New agents

Immune Modulating AgentsHigh Dose IL 2

• Increases CD 4 positive cells

• Pooled analysis ORR 14%

• CR 5%

• Highly selected patients

• Most durable response of the known therapies

• Toxic. Requires ICU care and expert personnel

Any hope for Vaccines ?

• Stage IIIB and IV

• OncoVEXGM-CSF will be administered by injection into all injectable cutaneous, subcutaneous or nodal lesions lesions, every two weeks.

• This vaccine uses Herpes virus proteins as a co-stimulant

After 3 Injections

Resolution of un-injected disease in the lung. Injection sites in the knee/thigh

Targeting the CTLA-4

MHC

TCR

T cell

APC

CD28B7

CTLA-4

MDX-010

T cell Activation

MHC

TCR

T cell

APC

CD28

CTLA-4

T cell Inactivation

B7

MHC

TCR

T cell

APC

CD28B7

CTLA-4

MDX-010

T cell Activation

MHC

TCR

T cell

APC

CD28B7

CTLA-4

MDX-010

T cell ActivationT cell Activation

MHC

TCR

T cell

APC

CD28

CTLA-4

T cell Inactivation

B7

CTLA-4CTLA-4

T cell Inactivation

B7

T cell InactivationT cell Inactivation

B7B7

Blocking CTLA-4 Augments Immune Responses

Anti-tumor immune responses are turned off

Mechanism to promote anti-tumor immune responses

CTLA -4 Blockade: Clinical Development

• Fully human monoclonal antibodies

• Ipilimumab (MDX-010)—IgG

• Ticilimumab (CP-675,206)--IgG

Durable Complete Response in Metastatic Melanoma

• Complete resolution of 2 subcutaneous nodules, 31 lung metastases and 0.5 cm brain metastasis. Patient previously failed chemotherapy and surgery.

• Response ongoing at 40+ months

Sources: Phan et al. PNAS. 2003 Jul;100(14):8372-8377 and Medarex unpublished data

Duration as of 1/10/05.

Immune Breakthrough Events

• Colitis

• Hepatitis

• Vitiligo

• Any autoimmune

Our Case• 53 year old • Resection

– of brain melanomas 4/2005– in the small intestine 9/2005– under the skin 11/2005

• Six months of temodar• Disease free for one year• CTLA 4 inhibitor

– Recurrence in the skin, lung and bone summer 2007– Severe joint pain and decrease in performance status. – Prednisone

• After initial increase in skin mets, he went into a complete remission and has been in remission for two years

Chemotherapy

– Gold Standard – Dacarbazine [Alkylator]• Response Rate: 10-20%• Complete Remission Rate 5%• IV Regimen• No Phase III Data

Chemotherapy

• Temozolomide [Temodar™]– Oral agent converts to active metabolite of

dacarbazine– Penetrates CNS– FDA Approved for Brain Tumors only– Middleton et al: Phase III trial showing no

difference from dacarbazine

Middleton MR, Grob JJ, et al. J Clin Oncol 2000;18:158

Temodar TargetsTransmethylation of the O-6 site of guanine in DNA leads to

profound cytotoxicity

Other active chemotherapy?

• Chemotherapy Alternatives– Taxol 80mg/m2/week for 6 of 7 weeks

• MTP 13 weeks, RR 22%– Cisplatin 150 mg/m2

• RR 16.3%; OS 7 months

Collichio F, Ollila D, Huck K, et al Proc Am Soc Clin Oncol, 2005:23:726sGlover D, Ibrahim J, et al. Melanoma Res 2003;13:619

SYMMETRY• All patients received paclitaxel and ½ got

Elescomol

• First Line

• Measurable disease

• LDH less than 2.5 times normal

• No brain mets

What were the results of Symmetry

• Better response with Elesclomol and paclitaxel than paclitaxel alone

• Better time to disease progression

• But more deaths with the combination and the research is currently on hold

• UNC was number 2 in the USA for accrual

Conclusions

• Epidemiology– Sun– Tanning Booths

• Epidemic

• Types of Melanoma– Mucosal, Ocular, Cutaneous

• Recognition

Conclusion

• Surgery– With appropriate margins

• Sentinel Lymph node– For most cases except very thin– Positive nodes are followed by a completion

dissection

• Tests to do after knowing the T stage and nodal stage

• Reviewed Adjuvant Interferon Rx

Conclusions

• “Genetic footprint is the future”• Currently

– Targetted– Immune – Chemotherapy

• Research at UNC-KIT amplified or mutated-Vaccine Study of Oncolytic Virus