Transcript Slide 1
Timothy E Byun, MD
Hematology-Oncology Medical
Group of Orange County, Inc.
May 14, 2011
Objectives
Review current treatment options for
patients with advanced melanoma
Discuss newly approved adjuvant therapy
option in high risk melanoma
Discuss newly approved therapeutic
approach in advanced melanoma
Discuss emerging therapeutic options in
metastatic melanoma
Interferon α-2b as the only FDA approved
adjuvant therapy for high-risk Melanoma
High-dose Inteferon has shown to improve
relapse-free survival compared to
observation
Its impact on overall survival has been less
clear
Meta-analysis of 14 randomized trials from
1990 to 2008 shows statistically significant
improvement in both Disease Free Survival
and Overall Survival
S Mocellin, et al. JNCI 2010;102(7):493-501.
IFN-α increases Disease Free Survival rate
HR=0.82 [0.77-0.87; p<0.001]
Mocellin S et al. JNCI J Natl Cancer Inst 2010;102:493-501
© The Author 2010. Published by Oxford University Press.
IFN-α increases Overall Survival rate
HR=0.89 [0.83-0.96; p=0.002]
Mocellin S et al. JNCI J Natl Cancer Inst 2010;102:493-501
© The Author 2010. Published by Oxford University Press.
Peginterferon α-2b (Sylantron) is approved
for Stage III Melanoma Adjuvant Therapy
Based on an open-label multi-center trial of
1256 patients
Microscopic or Gross lymph nodal disease
with complete resection
Sylantron or placebo 1:1 randomization for 5
year treatment
33 % of patients discontinued treatment due to
adverse reactions
Most common adverse reactions were fatigue,
depression, anorexia, elevated AST/ALT,
myalgia, nausea, headache, and pyrexia
Peginterferon α-2b (Sylantron) is approved
for Stage III Melanoma Adjuvant Therapy
Increased Relapse-Free Survival Time
compared to placebo: 34.8 months vs 25.5
months (HR 0.82 [0.71-0.96]; p = 0.011]
No Difference in Overall Survival (HR 0.98
[0.82-1.16]
Unknown efficacy compared to high-dose
interferon therapy
Probably better tolerated compared to
high-dose interferon therapy
Prognosis is poor for metastatic
melanoma patients
Less than 10% survive 5 years
Median survival of 6-9 months
Very low response to current existing
chemotherapy or immunotherapy
Up until now, no randomized study has
ever demonstrated survival benefit
Many studies failed to show
survival benefit
Treatment Options for Metastatic
Melanoma
Surgical resection of metastases
Chemotherapy: IV Dacarbazine (DTIC)
FDA approval 1976
Response rate <10% and median time to
progression of <2 months
Immunotherapy: high-dose interleuken-2 (IL-2)
FDA approval 1998 based on phase II data
Response rate ~17%, durable response rate ~6%
Requires hospitalization, manageable but severe
side effects
Avril MF, Aamdal S, Grob JJ, et al. JCO 2004;22:1118-1125.
Atkins MB, Lotze MT, Dutcher JP, et al. JCO 1999;17:2105-2116.
Few patients experience durable
response to high dose IL-2
Adapted from ASCO 2008 meeting. Suzanne Louise Topalian, MD
T Cell Activation by TCR and
Co-stimulation Through CD28
MHC Antigen
TCR
Dendritic
cell
T cell
B7
CD28
CTLA4
CTLA4 Receptors Are Up-Regulated Following T-Cell
Activation
MHC Antigen
TCR
Dendritic
cell
T cell
B7
CD28
CTLA4
CTLA4 Negatively Modulates
T-Cell Activation
MHC Antigen
TCR
Dendritic
cell
T cell
CD28
B7
CTLA4
Blocking Antibodies to CTLA4 Allow Positive Signaling
from Costimulatory Molecules to T Cells
MHC Antigen
TCR
Dendritic
cell
T cell
B7
CD28
CTLA4
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736.
Ipilimumab(Yervoy) in Treatment of
Cancer
CTLA-4:
Down-regulates T-cell activation
Ipilimumab(Yervoy):
Fully human monoclonal antibody
Blocks CTLA-4 receptor
Potentiates T cell activation
Korman, Peggs and Allison: Adv. In Immunol. 2006;90:297-339
Ipilimumab: Mechanism of Action
T-cell
activation
T-cell
inhibition
T-cell
potentiation
CTLA4
T cell
CD28
TCR
MHC
APC
T cell
T cell
CD28
TCR
B7
MHC
APC
CTLA4
CTLA4
B7
TCR
MHC
APC
B7
IPILIMUMAB
blocks
CTLA-4
MDX010-20: Study Design
Pre-treated
Metastatic
Melanoma
(N=676)
R
A
N
D
O
M
I
Z
E
Ipilimumab + gp100
(N=403)
Ipilimumab + placebo
(N=137)
gp100 + placebo
(N=136)
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
Ipilimumab Improves Progression Free
Survivial Compared to Control
Ipi + gp100 (A)
Ipi alone
(B)
gp100 alone (C)
Comparison
Arms A vs C
Arms B vs C
Arms A vs B
1
2
= 1st tumor assessment as per protocol
Hazard Ratio (C.I.)
0.81 (0.66–1.00)
0.64 (0.50–0.83)
1.25 (1.01–1.53)
p-value
0.0464
0.0007
0.0371
3
4
Years
Ipilimumab Improves
Overall Survival Compared to Control
Ipi + pbo gp100 + pbo P-value
Secondary Comparison
N
Number of
deaths
Hazard ratio
(95% CI)
Median OS,
Month (95% CI)
137
136
100
119
0.66 (0.51, 0.87)
10.1
(8.0,13.8)
6.4
(5.5, 8.7)
0.0026
Ipilimumab Improves Overall Survival
compared to control
Ipi + gp100 (A)
Ipi alone
(B)
gp100 alone (C)
1
Survival Rate
2
3
Years
Ipi + pbo
Ipi + gp100 N=403
N=137
4
gp100 + pbo
N=136
1 year
44%
46%
25%
2 year
22%
24%
14%
What mediates anti-CTLA4-induced
durable tumor regressions?
2005
Durable
response
> 5 years
Blue:
melanoma
Brown:
CD8+ T cells
Treatment with anti-CTLA4
antibodies
The great majority of responses last years without relapses:
- Longest responder: Ongoing since May 2001
- Response rate: ~10%
Ipilimumab improved Survival in all subgroups
Ipilimumab is associated with increased
serious adverse effects
% of Patients
Ipi + gp100
N=380
Ipi + pbo
N=131
gp100 + pbo
N=132
Any adverse event (AE)
98.4
96.9
97.0
Treatment - related
Any AE
88.9
80.2
78.8
Treatment - related
Grade 3/4 AE
17.4
22.9
11.4
Treatment - related
Deaths
2.1
3.1
1.5
Most Common Immune-Related
Adverse Events* (Grades 3, 4 and 5)
% of Patients
irAE
Ipi + gp100
N=380
Ipi + pbo
N=131
gp100 + pbo
N=132
Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Any
9.7
0.5
12.2
2.3
3.0
0
Dermatologic
2.1
0.3
1.5
0
0
0
GI
5.3
0.5
7.6
0
0.8
0
Endocrine
1.1
0
2.3
1.5
0
0
Hepatic
1.1
0
0
0
2.3
0
Death due to
irAE
*Across entire study duration
1.3
1.5
0
Summary
First Randomized Phase III Study to
Show Survival Benefit
FDA approved for first-line or
subsequent-line of therapy
Suggests a long-term Survival Effect
2 year survival rate: 24%
Some patients alive 10 years disease-free
so far
Immune mediated adverse effects
require prompt medical attention and
early administration of corticosteroids
Summary
Ipilimumab represents a new class of T-cell
potentiators and an important advance for the field
of immuno-oncology
Further development of ipilimumab is ongoing
Diversification to a variety of cancer types and
settings
Alternative combination regimens
Refinements in dose and schedule
Next generation of anti-CTLA4 antibody?
Targeting BRAF kinase
Genetic mutations in melanomas:
BRAF is frequently mutated
~55%
NATURE|Vol 445|22 February 2007|doi:10.1038/nature05661
BRAF is an attractive target
Amena M. DeLuca, Archana Srinivas and Rhoda M. Alani (2008). Expert Rev. Mol. Med. Vol. 10, e6
Inhibition of MAPK signaling in BRAFV600E melanoma of patients
treated with PLX4032
Baseline
B-RafV600E
pERK
PLX4032
MEK
P
ERK
P
Cyclin D
cyclin D
Cell cycle
(Ki67)
Ki67
Day 15
RECIST Responses to PLX4032 (960 mg bid) in
32 Patients with BRAFV600E Mutant Melanoma
(Response Rate Over 80%)
100
%Change From Baseline
(Sum of Lesion Size)
75
50
25
0
-25
-50
-75
Threshold for
RECIST response
-100
Flaherty, Puzanov, Kim, Ribas, McArthur, Sosman, O’Dwyer, Lee, Grippo, Nolop, Chapman.
New England Journal of Medicine 2010.
RECIST Responses to PLX4032 (960 mg bid) in
132 Patients with BRAFV600E Mutant Melanoma
RECIST 30% Decrease
***
Sosman, Kim, Schuchter, Gonzalez, Pavlick, Weber, McArthur, Hutson, Lawrence, Moschos,
Flaherty, Hersey, Kefford, Chmielowski, Amaravadi, Puzanov, Li, Bhattacharya, Nolop, Lee, Joe,
Ribas. Society for Melanoma Research, Sydney, Australia, 2010
Dramatic Response to PLX 4032
McDermott U et al. N Engl J Med 2011;364:340-350.
Duration of responses with PLX4032: Median PFS ~ 7 months
Pt
61
62
67
70
74
75
73
77
79
82
76
85
93
91
71
97
60
103
65
105
68
92
81
Legend
M1a
M1b
M1c
Threshold reached for PR
PD
Patient remaining in study
58
57
84
63
86
69
59
66
64
0
2
4
6
Months on Study
8
10
12
PLX 4032 Increases Survival in a
Phase III Trial
Data to be presented at ASCO 2011 Meeting in
Chicago
675 patients randomized to PLX 4032 vs
Dacarbazine
In phase I study, response rate was over 80% and
median time to progression was over 7 months
Adverse effects are relatively well-tolearted and
include keratoacanthoma, rash, photosensitivity,
joint pain, fatigue, hair loss
Skin squamous cell carcinoma are seen, but
managed with local therapy without needing drug
discontinuation
Main Problems with PLX4032:
Acquired resistance
On target toxicity: Squamous cell
carcinomas/Keratoachantomas
Dec 09
(42 d)
Spontaneous
regression
on continued
therapy
Progressive
KA/SCC
Jan 10
(64 d)
Conclusion
Adjuvant therapy options for stage III
resected melanoma: High-dose
Interferon alpha-2b or
Peginteferon(Sylantron)
Ipilimumab is the first phase III study to
show a survival benefit in metastatic
melanoma
Immune mediated adverse reactions
need to be managed aggressively with
steroids
Conclusion
PLX
4032 produces high response
rate and prolongs survival in BRAF
mutant metastatic melanoma patients
Overcoming PLX 4032 Resistance
poses a challenge
Unclear sequencing of new drugs and
old drugs: Sequencing based on BRAF
mutation status and Tumor
burden/Performance Status?
The goal: increase the number of
long-term survivors
Adapted from ASCO2008 meeting Patrick Hwu, MD
Thank You!