Transcript Melanoma * Natural History and Principles of Treatment

Melanoma – Natural History
and Principles of Treatment
Melanoma Patient Symposium
YNHH – Smilow Cancer Hospital
Sept 11, 2014
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
A - asymmetry
B – borders irregular
C – color variation
D - diameter
E- evolution
F – funny looking
Skin
Ocular
Nasal
Vulvar
Anorectal
Acral-lentiginous
Primary Tumor
Skin
Mucosa
Ocular
Biology of Dormancy Not Understood
Local (Lymphatic) Dissemination
Local recurrence
In-transit metastases
Regional node involvement
years
?
Hematogenous Dissemination
Skin
Lung
Lymph node
Liver
Bone
GI/mesentery
CNS (+ leptomeninges)
25-30% at presentation of systemic mets, 60-70% of all patients subsequently
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)
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?
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)
Prognostic Factors for Patients with Metastatic Disease
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)
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
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)
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
Chemotherapy
Biochemotherapy
2014 – Treatment
Options for Metastatic
Melanoma
Targeted therapies
mBRAF
mNRAS
Vemurafenib
CDK4i + MEKi
Dabrafenib
Trametinib (MEKi)
Dabrafenib + Trametinib
Vemurafenib + cometinib
mCKIT
cKITi
Immune therapies
Interleukin-2
Ipilimumab (anti-CTLA4)
Anti-PD1
(nivolumab)
(pembrolizumab)
Nivolumab + ipilimumab
no
GKS/SRS
Eligible for Immunotherapy
Brain mets
yes
C-kit mutation
No
Mutation
analyses
Yes
Anti-PD1
Anti-CTLA-4
High dose IL-2
Adoptive Immunotherapy
Other Investigational Immunotherapy Trials
Yale Cancer Center Melanoma
Treatment Algorithm
PD
NRAS mutation
BRAF mutation
Ckit inhibitor
CDK4i + MEKi
NO mutation
Yes
BRAFi + MEKi
BRAFi + other
ERKi
Phase 1
Other targeted Rx
Anti-angiogenesis
Supportive care
Chemotherapy
Il-2 Induced Regression of Melanoma Liver Metastases
6-24-05
11-23-05
Persistent/progressing disease in spleen, SQ buttock, and lung removed; NED x 7 years
Response to Ipilimumab 10 mg/kg x 2 doses
2 baseline brain mets regressed also:
No disease progression 5+ years
Metastatic Melanoma,
Anti-PD1 1 mg/kg every other week
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4
Response to ipi/anti-PD1, 3/1 dose level
Response to ipi/anti-PD1, 3/1 dose level
Response to ipi/anti-PD1, 3/1 dose level
Cohort 8 response at 12 weeks
Overall Survival for Concurrent
Therapy by Dose Cohort
100
2 Yr OS 88%
1 Yr OS 94%
90
80
Survival (%)
70
2 Yr OS 79%
1 Yr OS 85%
60
50
1 Yr OS 57%
40
2 Yr OS 50%
30
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)
Concurrent Cohorts 1-3 (n=53)
20
10
0
Pts at Risk
Nivo 0.3_IPI 3
Nivo 1 _IPI 3
Nivo 3_IPI 1
Nivo 3_IPI 3
Concurrent
0
3
6
9
12
15
18
21
14
17
16
6
53
13
17
16
6
52
11
16
15
6
48
10
15
15
6
46
8
15
15
6
44
7
14
13
6
40
7
14
4
6
31
7
13
2
6
28
24
27
30
33
36
39
42
45
48
7
4
0
0
11
5
3
0
0
8
2
3
0
0
5
2
3
0
0
5
2
2
0
0
4
1
0
0
0
1
1
0
0
0
1
0
0
0
0
0
Months
7
9
0
3
19
Presented by: