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Timothy E Byun, MDHematology-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.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 rateHR=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 1976Response rate <10% and median time to
progression of <2 months Immunotherapy: high-dose interleuken-2 (IL-2)
FDA approval 1998 based on phase II dataResponse 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
Dendritic cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
CTLA4 Receptors Are Up-Regulated Following T-Cell Activation
Dendritic cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
Dendritic cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
CTLA4 Negatively ModulatesT-Cell Activation
Dendritic cell T cell
MHC
B7
TCR
CD28
Antigen
CTLA4
Blocking Antibodies to CTLA4 Allow Positive Signaling from Costimulatory Molecules to T Cells
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
TCRCTLA4
APC
MHCB7
T-cell inhibition
T cell
TCR
CTLA4
APC
MHC B7
T-cell activation
T cell
TCR
CTLA4
APC
MHC B7
T-cell potentiation
IPILIMUMABblocksCTLA-4
CD28CD28
MDX010-20: Study Design
RANDOMIZE
Pre-treatedMetastaticMelanoma
(N=676)(N=137)
(N=136)
(N=403)
gp100 + placebo
Ipilimumab + placebo
Ipilimumab + gp100
MDX010-20: Study Design Details
Accrual: September 2004 – July, 2008125 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 dosesgp100: 1mg q 3 weeks X 4 doses
Re-induction (same regimen) in eligible patients
= 1st tumor assessment as per protocol
Ipilimumab Improves Progression Free Survivial Compared to Control
Ipi + gp100 (A)Ipi + gp100 (A)Ipi alone (B) Ipi alone (B)
gp100 alone (C)gp100 alone (C)
1 2 3 4Years
ComparisonComparison Hazard Ratio (C.I.) Hazard Ratio (C.I.) pp-value-value Arms A vs Arms A vs C 0.81 (0.66–1.00) 0.0464 C 0.81 (0.66–1.00) 0.0464Arms B vs C 0.64 (0.50–0.83) 0.0007Arms B vs C 0.64 (0.50–0.83) 0.0007Arms A vs Arms A vs B 1.25 (1.01–1.53) 0.0371 B 1.25 (1.01–1.53) 0.0371
Ipi + pbo gp100 + pbo P-value
Secondary Comparison
N 137 136
0.0026
Number of deaths
100 119
Hazard ratio
(95% CI)0.66 (0.51, 0.87)
Median OS,
Month (95% CI)10.1
(8.0,13.8)
6.4
(5.5, 8.7)
Ipilimumab Improves Overall Survival Compared to Control
Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137
gp100 + pbo N=136
1 year 44% 46% 25%
2 year 22% 24% 14%
Ipilimumab Improves Overall Survival compared to control
Ipi + gp100 (A)Ipi + gp100 (A)Ipi alone (B) Ipi alone (B)
gp100 alone (C)gp100 alone (C)
1 2 3 4Years
What mediates anti-CTLA4-induced durable tumor regressions?
Brown: CD8+ T cells
Blue: melanoma2005
Durable response > 5 years
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 PatientsIpi + gp100
N=380Ipi + pbo
N=131gp100 + pbo
N=132
Any adverse event (AE) 98.4 96.9 97.0
Treatment - related
Any AE88.9 80.2 78.8
Treatment - related
Grade 3/4 AE17.4 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
irAEIpi + gp100
N=380Ipi + pbo
N=131gp100 + pbo
N=132Grade 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
1.3 1.5 0
*Across entire study duration
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 Effect2 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
NATURE|Vol 445|22 February 2007|doi:10.1038/nature05661
~55%~55%
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
pERK
cyclin D
Ki67
Day 15
Cyclin D
B-RafV600E
MEK
ERK
P
P
Cell cycle(Ki67)
PLX4032
RECIST Responses to PLX4032 (960 mg bid) in 32 Patients with BRAFV600E Mutant Melanoma
(Response Rate Over 80%)
-100
-75
-50
-25
0
25
50
75
100
%C
han
ge
Fro
m B
asel
ine
(Su
m o
f L
esio
n S
ize)
Threshold for RECIST response
Flaherty, Puzanov, Kim, Ribas, McArthur, Sosman, O’Dwyer, Lee, Grippo, Nolop, Chapman. New England Journal of Medicine 2010.
RECIST 30% Decrease
******
RECIST Responses to PLX4032 (960 mg bid) in 132 Patients with BRAFV600E Mutant Melanoma
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
McDermott U et al. N Engl J Med 2011;364:340-350.
Dramatic Response to PLX 4032
0 2 4 6 8 10 12
64
66
59
69
86
63
84
57
58
81
92
68
105
65
103
60
97
71
91
93
85
76
82
79
77
73
75
74
70
67
62
61
Months on Study
Pt
Duration of responses with PLX4032: Median PFS ~ 7 months
Legend M1a M1b
M1c
Threshold reached for PR
PD
Patient remaining in study
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
Jan 10 (64 d)
Dec 09 (42 d)
Spontaneous regression
on continued therapy
Progressive KA/SCC
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!