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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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Lifetime riskLifetime risk
1616
1212
88
44
19351935
1:1,5001:1,500
19501950
1:6001:600
19801980
1:2501:250
19851985
1:1501:150
19871987
1:1351:135
20002000
1:751:75
00
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
tyP
robabili
ty
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
-25
0
25
50
75
100
%C
ha
ng
e F
rom
Ba
se
lin
e
(Su
m o
f L
es
ion
Siz
e)
•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 !
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