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):

IFN-α increases Disease Free Survival rate HR=0.82 [ ; p<0.001] Mocellin S et al. JNCI J Natl Cancer Inst 2010;102: © The Author Published by Oxford University Press.

IFN-α increases Overall Survival rate HR=0.89 [ ; p=0.002] Mocellin S et al. JNCI J Natl Cancer Inst 2010;102: © The Author 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 [ ]; p = 0.011]  No Difference in Overall Survival (HR 0.98 [ ]  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: Atkins MB, Lotze MT, Dutcher JP, et al. JCO 1999;17:

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 Modulates T-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:

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:

Ipilimumab: Mechanism of Action T cell TCR CTLA4 APC MHC B7 T-cell inhibition T cell TCR CTLA4 APC MHC B7 T-cell activation T cell TCR CTLA4 APC MHC B7 T-cell potentiation IPILIMUMAB blocks CTLA-4 CD28

MDX010-20: Study Design RANDOMIZERANDOMIZE Pre-treated Metastatic Melanoma (N=676) (N=137) (N=136) (N=403) gp100 + placebo Ipilimumab + placebo Ipilimumab + gp100

MDX010-20: Study Design Details  Accrual: September 2004 – July, 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

= 1 st tumor assessment as per protocol Ipilimumab Improves Progression Free Survivial Compared to Control Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) 1234 Years Comparison Hazard Ratio (C.I.) p-value Comparison Hazard Ratio (C.I.) p-value Arms A vs C 0.81 (0.66–1.00) Arms B vs C 0.64 (0.50–0.83) Arms A vs B 1.25 (1.01–1.53)

Ipi + pbogp100 + pboP-value Secondary Comparison N Number of deaths 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 RateIpi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136 1 year44%46%25% 2 year22%24%14% Ipilimumab Improves Overall Survival compared to control Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) 1234 Years

What mediates anti-CTLA4-induced durable tumor regressions? Brown: CD8+ T cells Blue: melanoma 2005 Durable response > 5 years Treatment with anti-CTLA4 antibodies The great majority of responses last years without relapses: - Longest responder: Ongoing since May 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) Treatment - related Any AE Treatment - related Grade 3/4 AE Treatment - related Deaths

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 3Grade 4Grade 3Grade 4Grade 3Grade 4 Any Dermatologic GI Endocrine Hepatic Death due to irAE *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 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 NATURE|Vol 445|22 February 2007|doi: /nature05661 ~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 BRAF V600E melanoma of patients treated with PLX4032 Baseline pERK cyclin D Ki67 Day 15 Cyclin D B-Raf V600E MEK ERK P P Cell cycle (Ki67) PLX4032

RECIST Responses to PLX4032 (960 mg bid) in 32 Patients with BRAF V600E Mutant Melanoma (Response Rate Over 80%) %Change From Baseline (Sum of Lesion Size) 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 BRAF V600E 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: Dramatic Response to PLX 4032

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!