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!