1. Melanoma – Natural History and Principles of Treatment
Melanoma Patient Symposium
YNHH – Smilow Cancer Hospital
Sept 11, 2014

2. 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

3. A - asymmetry B – borders irregular C – color variation D - diameter
E- evolution
F – funny looking 3

4. Skin
Ocular
Nasal
Vulvar
Anorectal
Acral-lentiginous 4

5. ? Primary Tumor Skin Mucosa Ocular Biology of Dormancy Not Understood
Local (Lymphatic) Dissemination
Local recurrence
In-transit metastases
Regional node involvement
Hematogenous Dissemination
Skin
Lung
Lymph node
Liver
Bone
GI/mesentery
CNS (+ leptomeninges) ?
years

9. 25-30% at presentation of systemic mets, 60-70% of all patients subsequently

10. 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)

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

12. Staging is Used to Provide Risk for Distant Recurrence (Distant Metastases)
Risk Factors
Depth of primary
Ulceration under the microscope
Presence of cancer cells in the regional nodes (from the sentinel node biopsy and complete lymph node dissection)

13. Prognostic Factors for Patients with Metastatic Disease

14. 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)

15. 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

16. 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)

17. 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

18. Chemotherapy
Biochemotherapy
2014 – Treatment Options for Metastatic Melanoma
Targeted therapies
Immune therapies
mBRAF
mNRAS
mCKIT
Interleukin-2
Vemurafenib
CDK4i + MEKi
cKITi
Ipilimumab (anti-CTLA4)
Dabrafenib
Anti-PD1
(nivolumab)
(pembrolizumab)
Trametinib (MEKi)
Nivolumab + ipilimumab
Dabrafenib + Trametinib
Vemurafenib + cometinib

19. Eligible for Immunotherapy yes
GKS/SRS
Brain mets
Eligible for Immunotherapy
yes
C-kit mutation
Ckit inhibitor No
Mutation
analyses
Yes
NRAS mutation
CDK4i + MEKi PD
NO mutation
BRAF mutation
Anti-PD1
Anti-CTLA-4
High dose IL-2
Adoptive Immunotherapy
Other Investigational Immunotherapy Trials
Yes
Phase 1
Other targeted Rx
Anti-angiogenesis
Supportive care
Chemotherapy
BRAFi + MEKi
BRAFi + other
ERKi
Yale Cancer Center Melanoma
Treatment Algorithm

20. Il-2 Induced Regression of Melanoma Liver Metastases
Persistent/progressing disease in spleen, SQ buttock, and lung removed; NED x 7 years

21. Response to Ipilimumab 10 mg/kg x 2 doses
2 baseline brain mets regressed also:
No disease progression 5+ years

22. Metastatic Melanoma,
Anti-PD1 1 mg/kg every other week

26. Response to ipi/anti-PD1, 3/1 dose level

27. Response to ipi/anti-PD1, 3/1 dose level

28. Response to ipi/anti-PD1, 3/1 dose level

29. Cohort 8 response at 12 weeks

30. Overall Survival for Concurrent Therapy by Dose Cohort
100 90 80 70 60 50 40 30 20 10
2 Yr OS 79%
Concurrent Cohorts 1-3 (n=53)
2 Yr OS 50%
1 Yr OS 94%
2 Yr OS 88%
1 Yr OS 85%
Survival (%)
1 Yr OS 57%
Censored
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) 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 14 17 16 6 53 13 52 11 15 48 10 46 8 44 7 40 4 31 2 28 9 3 19 5 1
Pts at Risk
Nivo 0.3_IPI 3
Nivo 1 _IPI 3
Nivo 3_IPI 1
Nivo 3_IPI 3
Concurrent
Months
Presented by: