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Melanoma – Natural History and Principles of Treatment

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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:

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