New Treatment Options in Advanced Melanoma

Reinhard Dummer, MD

Department of Dermatology, University Hospital

Zürich, Switzerland

By permission from American Academy of Dermatology,

Rigel DS, et al. J Am Acad Dermatol. 1996;35:1012-1013

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19351935

1:1,5001:1,500

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19801980

1:2501:250

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1:1501:150

19871987

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20002000

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Lifetime Melanoma Risk

GENETICS, UV?

http://www.usz.unizh.ch/derma/hautkrebs/

Enhanced UV irradiation

�Out-door activities

�Life expectancy

�UV intensity

Functional unit of melanocyte/keratinocytes

� Mutations

� Amplifications

� Translocations

� Deletions

Melanocyte-Melanoma

Courtesy of Dept. of Dermatology, University Hospital Zürich

Distinct Sets of Genetic Alterations in Melanoma

array-based comparative genomic hybridization

By permission from N Engl J Med, John A. Curtin et al.

N Engl J Med 2005;353:2135-2147

Courtesy of Dept. of Dermatology, University Hospital Zürich

High-throughput oncogene mutation profiling in human cancer

Melanoma

By permission from Macmillan Publishers Ltd: Nature Genetics,.

Vol. 39, n3, 347-351, Figure 1, Roman K.Thomas et al. 11 Feb 2007

Targeting signalling pathways

nuclearmembrane

plasmamembrane

RTK

ras

raf

mek1/2

SOS

erk1/2

Growth factor

DNA

Shc

Grb-2

erk1/2

Farnesylproteintransferase-inhibitors

RAF 265, GSK2118436

AZD6244, GSK1120212PLX4032V600E only

Courtesy of Dept. of Dermatology, University Hospital Zürich

Tumorthickness (Breslow)

Epidermis

Corium

Subcutis

Courtesy of Dept. of Dermatology, University Hospital Zürich

10 Year-Survival of Melanoma patients

Thin primary tumors

Thick primary tumors

Lymph node metastases

distant metastases

Survival in %

Months

By permission from Br J Cancer

A.C. Häffner et al., Br J Cancer 1992; 66:856-861

Final results of the EORTC 18871/DKG 80-1 randomised phase III trial

� rIFN-α2b versus rIFN-γ versus ISCADOR M® versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis

By permission from European Journal of Cancer

U.R. Kleeberg et al. European J Cancer 40 (2004):390-402

Stratified by:• Microscopic (N1) vs. palpable (N2)• 1 vs. 2-4 vs. 5+ nodes

• Breslow• Ulceration• Gender • Site

Observation

Peg-IFN alfa-2b

• Induction (8 weeks) 6 µg/kg/week

• Maintenance (5 years or distant metastasis) 3 µg/kg/week

• Dose reduction to 3, 2, 1 to maintain performance status

Primary Endpoints:• Relapse-free survival (RFS)• Distant metastasis-free survival (DMFS)

Randomization

By permission of A. Eggermont

and from Lancet, Eggermont et

al. Lancet, 2008; 372:117-26

N1 (micro met in SN)

DMFSDMFS

HR 0.75 HR 0.75

OSOS

HR 0.88 HR 0.88

66 66661212 1818 2424 3030 3636 4242 4848 5454 6060 7272TimeTime

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Pro

babili

tyP

robabili

ty

RFSRFS

HR 0.73HR 0.73

++ ++++++++++++++++++

66 66661212 1818 2424 3030 3636 4242 4848 5454 6060 7272TimeTime

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Pro

babili

tyP

robabili

ty

66 66661212 1818 2424 3030 3636 4242 4848 5454 6060 7272TimeTime

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Pro

babili

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PEGPEG--IFNIFN

OBSOBS

CensoredCensored

Hazard rate over timeHazard rate over time0.30.3

0.20.2

0.10.1

0.00.0

00 11 22 33 44 55

YearsYears

OBSOBS

PEGPEG--IFNIFN

By permission of Prof. Alexander M.M Eggermont (EORTC Trial 18991)

N2 (macro met)

RFSRFS

HR 0.86HR 0.86DMFSDMFS

HR 0.94HR 0.94

66 66661212 1818 2424 3030 3636 4242 4848 5454 6060 7272TimeTime

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Pro

babili

tyP

robabili

ty

66 66661212 1818 2424 3030 3636 4242 4848 5454 6060 7272TimeTime

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Pro

babili

tyP

robabili

ty

66 66661212 1818 2424 3030 3636 4242 4848 5454 6060 7272TimeTime

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Pro

babili

tyP

robabili

ty

PEGPEG--IFNIFN

OBSOBS

CensoredCensored

Hazard rate over timeHazard rate over time

0.50.5

0.20.2

0.10.1

0.00.0

00 11 22 33 44 55

YearsYears

OBSOBS

PEGPEG--IFNIFN

0.60.6

0.30.3

0.40.4H

aza

rd r

ate

Ha

za

rd r

ate

OSOS

HR 1,01HR 1,01

By permission of Prof. Alexander M.M. Eggermont (EORTC Trial 18991)

Conclusions

� IFN-alpha is the only adjuvant therapy with repeatedly proven impact on DFS and DMFS

� Low dose IFN-alpha is well tolerated in most patients

� This treatment option should be suggested to young and healthy high risk patients with N1a disease

� For N1B and higher: clinical trials!

ESMO Clinical Practice Guidelines

… Since the overall impact of systemic

therapy on survival in advanced melanoma patients is questionable, these patients should be treated preferentially incontrolled clinical trials evaluating new treatment modalities.

By permission from Oxford University press. Annals of Oncology 21 (Supplement 5): v194-197,

2010 – extract v196, Dummer et al. Melanoma: ESMO Clinical Practice Guidelines

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

Phase I Trial:

� Tumor responses occurred in majority (81%) of patients in

V600E+ melanoma extension cohort (960 mg BID)

-100

-75

-50

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25

50

75

100

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rom

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•Investigator assessments

•Includes confirmed & unconfirmed responses

By permission from N. Engl J Med, Supplementary Appendix Figure 1A, ”Inhibition of mutated, activated BRAF in metastatic melanoma”. Flaherty K.T.

et al N Engl J Med 2010;363:809-19. Courtesy of Dr. Jeff A. Sosman, “Melanoma: What is beyond mutant BRAF?”

Endpoints:

Primary: BORR (IRC)Secondary: duration of response,

PFS, OS, and safety

Metastatic MelanomaPrior Treatment

V600E+

(n=132)

RG7204(960 mg BID)

BRIM-2 Study Design

Statistical Considerations

• Target BORR is 30%

• 10% patients considered unevaluable

• Total of 90 patients required to demonstrate the lower boundary of the exact 95% CI is at least 20%

Eligibility Criteria

• PD after prior IL-2 or standard chemotherapy (DTIC, TMZ, C/T, fotemustine)

• PS=0 or 1

• Brain metastases allowed if treatment with stereotactic RT or surgery, and stable for >3 mo

By permission of Dr. Jeff A.Sosman, Presented at the 7th International Congress for the Society of Melanoma Research 2010; Abstract 101

• BORR 52% by IRC*

• BORR 55% by investigator assessments (INV)

• RR, including unconfirmed, 68% (INV)

• BORR 52% by IRC*

• BORR 55% by investigator assessments (INV)

• RR, including unconfirmed, 68% (INV)

Tumor Responses Assessed by IRC

By permission of Dr. J. A. Sosman, Vanderbilt-Ingram Cancer Center,

“Melanoma: What is beyond mutant BRAF?”, Feb 2011

*6 patients were unevaluable

Progression Free Survival (IRC)

n=132

PD or death, n (%) 78 (59.1)

Progression-free 54 (40.9)

Median PFS, mo (95% CI) 6.2 (5.6–6.8)

6 mo PFS rate (95% CI) 0.51 (0.42–0.60)

By permission of Dr. J.A. Sosman, Vanderbilt-Ingram Cancer Center,

“ Melanoma: What is beyond mutant BRAF?”, Feb 2011

Adverse Event All Grades, % Grade 3, %

Arthralgia 57.6 6.1

Rash 51.5 6.8

Photosensitivity 49.2 3.0

Fatigue 38.6 1.5

Alopecia 33.3 -

Cutaneous SCC 24.2 24.2

Pruritis 27.3 2.3

Skin papilloma (verruca) 27.3 0

Most Commonly Reported Drug-Related AEs

• 130 patients experienced at least one drug-related AE

By permission of Dr. J.A.Sosman, Vanderbilt-Ingram Cancer Center,

“Melanoma: What is beyond mutant BRAF?”, Feb 2011

RO5185426 – B-Raf Inhibition: Comparison Day 0 – Day 17 Female, born 1948

Courtesy of Dept. of Dermatology, University Hospital Zürich

Courtesy of Dr Paul A. Chapman, Sloan-Kettering Memorial Cancer Clinic

Mechanisms of resistance to B-RAF inhibition

By permission from Macmillan Publishers Ltd: Nature, Vol. 468, n7326, v902, Figure 1, D. Solit, C. L. Sawyers, Dec 15, 2010

Ipilimumab – Phase 3 study

� A randomized, double-blind, phase 3 study which enrolled 125 centers in 13 countries in North America, South America, Europe and Africa between September 2004 and August 2008 showed:

� Improved survival in patients with metastatic melanoma treated with Ipilimumab

Hodi S et al. N Engl J Med 2010; 363: 711-723.

Modulation of T-cell activation

APC

B7

HLA I

HLA II

activation

L

CD28

APC

B7

HLA I

HLA II

L

CTLA4

inactivationT-regs?

CD28

Prof. R. Dummer, Dept. of Dermatology, University Hospital Zürich

APC

B7

HLA I

HLA II

L

CTLA4

inactivation

CD28

prevention of the inactivation

APC

B7

HLA I

HLA II

L

CTLA4

MDX-010

CD28

Modulation of T-cell activation by an anti-CTLA4 antibody

Prof. R. Dummer, Dept. of Dermatology, University Hospital Zürich

Autoimmunity correlates with tumor regression in:

Patients with Metastatic Melanoma treated with Anti-Cytotoxic

T-Lymphocyte Antigen-4

By permission from the American Society of Oncology, Attia P. et al. JCO 2006 Sep1;23(25):6043-6053

MDX010-20: Study Design

R

A

N

D

O

M

I

Z

E

Pre-treated

Metastatic

Melanoma

(N=676)

(N=137)

(N=136)

(N=403)

gp100 + placebo

Ipilimumab + placebo

Ipilimumab + gp100

By permission of Dr. S.O’Day: “A phase III, randomized, double blind, multicenter study

comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in

patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20.”,

O’Day S et al. Abstract 4, Plenary Session, ASCO 2010

MDX010-20: Study Design Details

� Accrual: September 2004 – July, 2008

� 125 Centers in 13 Countries

� Randomized (3:1:1), Double-Blind

� Stratified for M-Stage and prior IL-2

� Induction

� Ipilimumab: 3 mg/kg q 3 weeks X 4 doses

� gp100: 1mg q 3 weeks X 4 doses

� Re-induction (same regimen) in eligible patients

By permission of Dr. S. O’Day: “A phase III, randomized, double blind, multicenter study

comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in

patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20”,

O’Day S et al. Abstract 4, Plenary Session, ASCO 2010

Most Common Immune-Related AEs* (irAEs; All Grades)

% of Patients

irAEIpi + gp100

N=380Ipi + pboN=131

gp100 + pboN=132

All grades

Any 58.2 61.1 31.8

Dermatologic 40.0 43.5 16.7

GI 32.1 29.0 14.4

Endocrine 3.9 7.6 1.5

Hepatic 2.1 3.8 4.5

*Across entire study duration

By permission of Dr. S. O’Day: “A phase III, randomized, double blind, multicenter study

comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in

patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20.”,

O’Day S et al. Abstract 4, Plenary Session, ASCO 2010

Survival Rate Ipi + gp100 N=403 Ipi + pboN=137

gp100 + pboN=136

1 year 44% 46% 25%

2 year 22% 24% 14%

Kaplan-Meier Analysis of Survival

Ipi + gp100 (A)

Ipi alone (B)

gp100 alone (C)

1 2 3 4Years

By permission of Dr S. O’Day

Summary of MDX010-20 Data

� First randomized phase III trial to show survival improvement inmetastatic melanoma (HR=0.66, 0.68)

� Superior OS in two independent comparisons of ipilimumab vs gp100

� Survival rates in the ipilimumab arms

� 1 year: 44%, 46%

� 2 years: 22%, 24%

� Consistent superiority of ipilimumab for all secondary efficacy endpoints: PFS, BORR, DCR

By permission of Dr. S. O’Day: “A phase III, randomized, double blind, multicenter

study comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the

combination in patients with previously treated, unresectable stage III or IV melanoma

Study MDX010-20.”, O’Day S et al. Abstract 4, Plenary Session, ASCO 2010

ESMO Clinical Practice Guidelines

…Since the overall impact of systemictherapy on survival in advanced melanoma patients is

questionable, these patients should be treated preferentially incontrolled clinical trials evaluating new treatment modalities.

lesson: 2011

And apply sophisticated translational research to identify predictive

biomarkers and investigate resistance mechanism…

By permission from Oxford University press. Annals of Oncology 21 (Supplement 5): v194-197,

2010 – extract v196, Dummer et al. Melanoma: ESMO Clinical Practice Guidelines

Thank you !