Melanoma – Natural History and Principles of Treatment - PowerPoint Presentation

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Melanoma – Natural History and Principles of Treatment

Melanoma Patient Symposium

YNHH –

Smilow

Cancer Hospital

Sept 11, 2014

Slide2

What is Melanoma?

Cancer of cells which are responsible for all types of body pigmentation (melanocytes)

Melanocytes are primarily present in skin but are also present in the eye and mucous membranes (head sinuses, oral cavity, rectum/anus, vulva/vagina)

Some types of melanoma are related to sun exposure and sunburns

Malignant cells gain special properties through genetic (mutations) and other cell changes

Uncontrolled growth

Ability to travel in blood and

lymphatics

to other organs

Can implant in other organs and divide and grow (metastases)

Can remain dormant for years before growth is triggered

Dormant state cannot be detected by scans or other tests

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A - asymmetry

B – borders irregular

C – color variation

D - diameter

E- evolution

F – funny looking

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Skin

Ocular

Nasal

Vulvar

Anorectal

Acral-lentiginous

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Primary Tumor SkinMucosaOcular

Local (Lymphatic) DisseminationLocal recurrenceIn-transit metastasesRegional node involvement

Hematogenous Dissemination

SkinLungLymph nodeLiverBoneGI/mesenteryCNS (+ leptomeninges)

?

years

Biology of Dormancy Not Understood

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25-30% at presentation of systemic

mets

, 60-70% of all patients subsequently

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Treatment of Primary Melanoma

Excisional

biopsy by dermatologist

Greater than 90% present without distant metastases

Referral to

surgeon

Wide

local excision – margins ≥ 2cm for lesions > 1mm thick

Sentinel Node Biopsy in regional basin

For

lesions > 0.75 thick

For prognostic information – does not affect outcome

In very high risk patients, CT scans or PET scans to rule out distant

metastases

Completion

lymph node dissection (for positive SLNB)

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The Three Important Questions After Complete Resection of Primary Melanoma (and Regional Nodes)

What is my risk that distant metastases will be found in the future?

What can be done to lower the risk that my cancer might recur?

How will I be monitored to detect the cancer if it recurs?

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Staging is Used to Provide Risk for Distant Recurrence (Distant Metastases)

Risk FactorsDepth of primary Ulceration under the microscope Presence of cancer cells in the regional nodes (from the sentinel node biopsy and complete lymph node dissection)

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Prognostic Factors for Patients with Metastatic Disease

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Principles of Monitoring for Recurrence

No (good) data to understand the impact of frequency of type of monitoring on outcome

Both determined by risk

Views on monitoring may change as more effective therapies are introduced for advanced disease

Evaluation by oncologist every 3 months to 1 year

History, exam, blood work (CBC, liver function, LDH)

CT scans and/or PET-CT scans in high risk individuals every 6 to 12 months

Usually stop monitoring at 5-7 years

Dermatology evaluation 2-4x yearly for detection of second primaries (10% risk)

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Options to Reduce Recurrence Risk

Observation

Interferon-

alfa

Different dose and schedules

Administration for up to one year

Increases time to recurrence

Reduces overall risk of recurrence by about 10%

Can induce moderate to severe toxicity in some (fever, chills, fatigue, loss of appetite, depression, difficulty in concentration)

Possible new options

Ipilimumab

(

Yervoy

) – not yet approved, data so far similar to interferon, potential for severe toxicity

Clinical Trials – compare potential better agents to standard of care

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Management of Advanced Disease

Treat both the lesions seen on scans

and areas of disease that have not yet appeared on scans

Surgery, local injection, or radiation not sufficient to eliminate the disease

Requires systemic (intravenous or oral) medications

Use systemic therapies first that can induce long term remissions

Control pain and manage lesions early that may cause early morbidity (pain, bleeding, limitation of function, unacceptable cosmetic appearance)

Screen the brain at baseline and every 8-12 weeks

CT scans of chest/

abd

/pelvis or CT chest + MRI abdomen/pelvis to ‘stage’ disease

Repeat scans every 6-12 weeks (depends of treatment)

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Options for systemic therapies

Clinical Trials

Immune therapies (can give long term remissions)

High dose interleukin-2 (

Proleukin

)

Ipilimumab

(anti-CTLA-4) (

Yervoy

)

Pembrolizumab

(anti-PD-1) (

Keytruda

)

Nivolumab

(anti-PD-1)

(

Optiva

) – approval pending

Targeted therapies (rapid response in most but few have long term control)

BRAF mutation–

dabrafenib

(

dafinlar

)/

trametinib

(

mekinist

),

vemurafenib

(

zelboraf

)

NRAS mutation – investigation MEK + CDK4 inhibitors

C-kit (mucosal and

acral-lentiginous

melanomas) –

imatinib

,

dasatinib

,

sorafenib

, others

Cytotoxic Chemotherapy (can work rapidly but only in a few and rarely achieve long term control)

Temozolomide

(

temodar

) or

dacarbazine

Carboplatin and paclitaxel

Biochemotherapy

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Targeted therapies

Immune therapies

Chemotherapy

Biochemotherapy

mBRAF

m

NRAS

mCKIT

Vemurafenib

Dabrafenib

Trametinib

(

MEKi

)

Dabrafenib

+

Trametinib

Vemurafenib

+

cometinib

CDK4i +

MEKi

cKITi

Interleukin-2

Ipilimumab

(anti-CTLA4)

Anti-PD1

(nivolumab)(pembrolizumab)

Nivolumab

+

ipilimumab

2014 – Treatment Options for Metastatic Melanoma

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Eligible for Immunotherapy

Yes

No

Anti-PD1

Anti-CTLA-4

High dose IL-2

Adoptive ImmunotherapyOther Investigational Immunotherapy Trials

BRAF mutation

Yes

BRAFi

+

MEKi

BRAFi + otherERKi

NO mutation

Phase 1

Other targeted Rx

Anti-angiogenesisSupportive careChemotherapy

PD

Brain mets

GKS/SRS

yes

no

C-kit mutation

Ckit

inhibitor

Yale Cancer Center Melanoma

Treatment Algorithm

Mutation

analyses

NRAS

mutation

CDK4i +

M

EKi

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6-24-05

11-23-05

Il-2 Induced Regression of Melanoma Liver Metastases

Persistent/progressing disease in spleen, SQ buttock, and lung removed; NED x 7 years

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Response to Ipilimumab 10 mg/kg x 2 doses

2 baseline brain

mets

regressed also:

No disease progression 5+ years

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Metastatic Melanoma,

Anti-PD1 1 mg/kg every other week

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Response to

ipi

/anti-PD1, 3/1 dose level

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Response to

ipi

/anti-PD1, 3/1 dose level

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Response to

ipi

/anti-PD1, 3/1 dose level

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Cohort 8 response at 12 weeks

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Presented by:

Overall Survival for Concurrent Therapy by Dose Cohort

Censored

14

17

16

653

131716652

111615648

101515646

81515644

71413640

7144631

7132628

790319

740011

53008

23005

23005

22004

10001

10001

00000

Pts at RiskNivo 0.3_IPI 3Nivo 1 _IPI 3Nivo 3_IPI 1Nivo 3_IPI 3Concurrent

100

90

80

70

60

50

40

30

20

10

0

Survival (%)

Months

2 Yr OS 88%

0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

2 Yr OS 50%

2 Yr OS 79%

Concurrent Cohorts 1-3 (n=53)

Nivo 0.3 mg/kg + IPI 3 mg/kg (n=14)

Nivo 1 mg/kg + IPI 3 mg/kg (n=17)

Nivo 3 mg/kg + IPI 1 mg/kg (n=16)

Nivo 3 mg/kg + IPI 3 mg/kg (n=6)

1 Yr OS 94%

1 Yr OS 85%

1 Yr OS 57%