Melanoma – Natural History and Principles

of Treatment Melanoma Patient Symposium

YNHH – Smilow Cancer HospitalSept 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 - asymmetryB – borders irregularC – color variationD - diameter E- evolutionF – funny looking

Skin

Ocular

NasalVulvarAnorectal

Acral-lentiginous

Primary Tumor SkinMucosaOcular

Local (Lymphatic) DisseminationLocal recurrenceIn-transit metastasesRegional node involvement

Hematogenous Dissemination SkinLungLymph nodeLiverBoneGI/mesenteryCNS (+ leptomeninges)

?years

Biology of Dormancy Not Understood

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

Targeted therapies Immune therapies

ChemotherapyBiochemotherapy

mBRAF mNRAS 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

Eligible for Immunotherapy

Yes

No

Anti-PD1Anti-CTLA-4High dose IL-2Adoptive ImmunotherapyOther Investigational Immunotherapy Trials

BRAF mutation

Yes

BRAFi + MEKiBRAFi + otherERKi

NO mutation

Phase 1Other targeted RxAnti-angiogenesisSupportive careChemotherapy

PD

Brain metsGKS/SRSyes

no

C-kit mutation Ckit inhibitor

Yale Cancer Center Melanoma Treatment Algorithm

Mutation analyses NRAS mutation CDK4i + MEKi

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

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

Sienkiewicz, Dina, LSienkiewicz, Dina, LUnit#: MR2263994Unit#: MR2263994Acc#: E101524698Acc#: E101524698DOB: 10/7/1967DOB: 10/7/1967F/46 YEARF/46 YEAR

Yale New Haven Hospital Yale New Haven HospitalCT NP 2506 LightSpeed VCTCT NP 2506 LightSpeed VCT

CT CHEST ABDOMEN PELVI S W I V CONTRASTCT CHEST ABDOMEN PELVI S W I V CONTRAST6.1 CHEST - ABDOMEN - PELVI S WI THOUT AND/OR WI TH6.1 CHEST - ABDOMEN - PELVI S WI THOUT AND/OR WI TH

6/5/2014 1:42:41 PMTech: DMTech: DM

ORAL OMNI & 85CC OMNI 350ORAL OMNI & 85CC OMNI 350HELI CAL MODE /1:42:41 PMHELI CAL MODE /1:42:41 PMW: 400 C: 40 Z: 1.53W: 400 C: 40 Z: 1.53600 - - -600 - - -KVp: 120KVp: 120Tilt: 0Tilt: 0FFSFFS

Page: 22 of 51Page: 22 of 51 I M: 22 SE: 601 I M: 22 SE: 601Compressed 8:1Compressed 8:1

- - - - - -- - - - - -XY: 8.60XY: 8.60

THK: 5THK: 5ASI R: SS20ASI R: SS20

NI : 135NI : 135

RR LL

HH

FF cm cm

Sienkiewicz, Dina, LSienkiewicz, Dina, LUnit#: MR2263994Unit#: MR2263994Acc#: E101726672Acc#: E101726672DOB: 10/7/1967DOB: 10/7/1967F/46 YEARF/46 YEAR

Yale New Haven Hospital Yale New Haven HospitalCT NP 2506 LightSpeed VCTCT NP 2506 LightSpeed VCT

CT CHEST ABDOMEN PELVI S W I V CONTRASTCT CHEST ABDOMEN PELVI S W I V CONTRAST6.1 CHEST - ABDOMEN - PELVI S WI THOUT AND/OR WI TH6.1 CHEST - ABDOMEN - PELVI S WI THOUT AND/OR WI TH

8/16/2014 10:53:26 AM 8/16/2014 10:53:26 AMTech: mtTech: mt

ORAL OMNI & 85CC OMNI 350ORAL OMNI & 85CC OMNI 350HELI CAL MODE /10:53:26 AMHELI CAL MODE /10:53:26 AMW: 409 C: 39 Z: 1.22W: 409 C: 39 Z: 1.22600 - - -600 - - -KVp: 120KVp: 120Tilt: 0Tilt: 0FFSFFS

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THK: 5THK: 5ASI R: SS20ASI R: SS20

NI : 135NI : 135

RR LL

HH

FF cm cm

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

Presented by:

Overall Survival for Concurrent Therapy by Dose Cohort

Censored

1417166

53

1317166

52

1116156

48

1015156

46

815156

44

714136

40

71446

31

71326

28

7903

19

7400

11

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

Surv

ival

(%)

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%