KIT Inhibition in Advanced Melanoma: Rationale and Clinical i l Results

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Sloan-Kettering Cancer Center Disclosures Consultant or Advisory

1 KIT Inhibition in Advanced Melanoma: Rationale and Clinical i l Results Richard D. Carvajal, M.D. Assistant Attending Physician Melanoma/Sarcoma Service Memorial Sloan-Kettering Cancer Center Disclosures Consultant or Advisory Roles: Novartis BlissPR Stock Ownership: None Discussion of Off-Label Uses of Commercial Products or Investigational Agents: Imatinib mesylate Nilotinib Dasatinib Sunitinib Sorafenib Masatinib 1

2 Structure of KIT N-terminal Extracellular Exons 1-9 Juxtamembrane Proximal Kinase Exon 11 Exons Distal Kinase Exons C-terminal KIT Expression and Melanoma Progression Benign Melanocytes Primary Melanoma Distant Metastasis Natali et al, Montone et al, Shen et al, (IHC) (IHC) (IHC) 63% (19/30) 74% (34/46) 31% (10/32) 100% (65/65) 74% (25/31) 30% (6/20) 59% (10/17) 96% (22/23) 45% (14/31) Di t t 31% 30% 45% Natali et al. Int J Cancer Lassam et al. Oncogene Montone et al. Mod Pathol Shen et al. J Cutan Pathol

Phase II Studies of Imatinib 400 mg BID in Advanced Melanoma n (subgroups) RR Correlative Studies Wyman et

et al, British Journal of Cancer, 2008 1 mucosal 2 ocular n = 18 11 non-csd 1 acral 1 mucosal 1 ocular 4 unk

these 3 harbored a KIT mutation ti 1/21 Required to be IHC+ (>25%) for c-kit for enrollment Distinct Melanoma

Sun Damage 22% BRAF 0% NRAS 19% KIT Arising from Mucosal Surfaces 9% BRAF 12% NRAS 25% KIT Arising from Acral

3 Phase II Studies of Imatinib 400 mg BID in Advanced Melanoma n (subgroups) RR Correlative Studies Wyman et al, Cancer, 2006 n = 26 0/25 3/17 IHC KIT cutaneous Ugurel et al, British Journal of Cancer, 2005 Kim et al, British Journal of Cancer, mucosal 2 ocular n = non-csd 1 acral 1 mucosal 1 ocular 4 unk primary n = non-csd 1 acral No mutation analysis performed 0/16 1/12 IHC KIT +++ 2/12 IHC KIT++ None of these 3 harbored a KIT mutation ti 1/21 Required to be IHC+ (>25%) for c-kit for enrollment Distinct Melanoma Subtypes Arising from Skin Without Chronic Sun Damage 50% BRAF 20% NRAS 0% KIT Arising from Skin With Chronic Sun Damage 22% BRAF 0% NRAS 19% KIT Arising from Mucosal Surfaces 9% BRAF 12% NRAS 25% KIT Arising from Acral Surfaces 22% BRAF 16% NRAS 24% KIT Curtin et al. NEJM 2005; Curtin et al. JCO 2006; Carvajal et al. JAMA

KIT Mutations and Response to Imatinib in GIST (n=127)

48% 84% Adapted from Heinrich, et al. J Clin Oncol 2003.

mutated/amplified Started imatinib 11/27/06 Remains

seven-codon duplication Dramatic clinical benefit

4 KIT Mutations and Response to Imatinib in GIST (n=127) RR 0% Gastrointestinal Stromal Tumor (No Mutation: 7%) 48% 84% Adapted from Heinrich, et al. J Clin Oncol yo f w/ metastatic rectal melanoma Exon 13 K642E KIT mutated/amplified Started imatinib 11/27/06 Remains without evidence of disease > 3 years on therapy J Clin Oncol Apr 20;26(12): yo f w/ metastatic rectal melanoma Exon 11 with seven-codon duplication Dramatic clinical benefit within 3 days of starting imatinib 400 daily PET response observed after 4 weeks of therapy 4

5 Study Design Phase II, open-label, multicenter, 2-stage study of imatinib in molecularly selected patients based on the presence of a mutation (exons 9, 11, 13, 17, 18) or amplification of KIT (FISH) Screening Phase KIT sequencing (Bastian)and FISH performed (Antonescu) Tumor MUST have either a mutation or amplification to proceed to treatment phase Treatment Phase Eligible pts receive imatinib 400 BID in 6-week cycles Restaging imaging studies performed after each cycle Patients with a response or SD continue daily treatment until disease progression or unacceptable toxicity Phase II Study of Imatinib in Melanoma Harboring KIT Alterations CONSORT Diagram Carvajal et al. JAMA

6 Mutation Distribution (KIT, BRAF, NRAS, GNAQ/11) Acral Melanoma (n=85) 23.8% Mucosal Melanoma (n=93) 24.7% 22.6% 8.7% Centrally Confirmed CSD Melanoma (n=39) 18.8% 8% 21.9% Patient Characteristics 6

7 Phase II Study of Imatinib in Melanoma Harboring KIT Alterations EA: Vaginal Melanoma Exon 11 L576P / Amp Baseline Week 6 Week 18 MRI (8/28/08) (10/13/08) (1/2/09) PET (8/21/08) (10/13/08) (1/2/09) 7

Phase II Studies of Imatinib in Melanoma Harboring KIT Alterations Carvajal et al

400 mg po qd Median PFS 3.0 months n/a 3.5 months PR 8% 25% 23.

036 Guo et al. JCO 2011; Carvajal et al. JAMA 2011.

8 Phase II Studies of Imatinib in Melanoma Harboring KIT Alterations Carvajal et al (n=25) Hodi et al (n=20) Guo et al (n=43) Starting Dose 400 mg po bid 400 mg po qd 400 mg po qd Median PFS 3.0 months n/a 3.5 months PR 8% 25% 23.3% 3% CR 8% 0% 0% ORR 16% 25% 23.3% 9 vs 1.5 months p < vs 9 months p =.036 Guo et al. JCO 2011; Carvajal et al. JAMA Distribution of Identified KIT Mutations N-terminal Extracellular Juxtamembrane Proximal Kinase Distal Kinase Carvajal et al. JAMA C-terminal 8

9 Phase II Study of Imatinib in Melanoma Harboring KIT Alterations Time to Progression and Overall Survival: Mutant:WT Allelic Ratio > 1 or Recurrent Mutation Overall Survival 18.5 vs 6.5 months P = 0.04 Time to Progression 3.7 vs 1.9 months P =

Single Agent KIT Mutant Melanoma Trials Agent Lead Site Ph KIT Status Prior KIT Tx

Nilotinib Korea 2 Mut/Amp Yes Open Nilotinib Paris 2 Mut/Amp No Open Nilotinib

Any Yes Open Sorafenib Cornell 2 Any Yes Closed Dasatinib Yale 2 Any No Reported

Science 2 Exon 11 Yes Open TS: Vulvar Melanoma Exon 11 L576P Imatinib 8/14/08

10 Single Agent KIT Mutant Melanoma Trials Agent Lead Site Ph KIT Status Prior KIT Tx Status Nilotinib Novartis 2 Mut No Open Nilotinib DFCI 2 Mut/Amp Yes Open Nilotinib Korea 2 Mut/Amp Yes Open Nilotinib Paris 2 Mut/Amp No Open Nilotinib Royal Marsden 2 Mut/Amp No Open Sunitinib UCSF 2 Mut/Amp Yes Open Sunitinib DFCI 2 Any Yes Open Sorafenib Cornell 2 Any Yes Closed Dasatinib Yale 2 Any No Reported Dasatinib ECOG 2 Any No Open Dasatinib MDACC 2 Exon 11/13 Yes Open Masatinib AB Science 2 Exon 11 Yes Open TS: Vulvar Melanoma Exon 11 L576P Imatinib 8/14/08 8/20/09 Nilotinib 9/24/09 ongoing Baseline 8/5/08 Baseline 9/17/09 Month 7 3/5/09 Month 6 3/1/10 10

11 Conclusions KIT inhibition is an effective therapy in a subset of melanomas with genetic alterations of KIT Identification of predictive biomarkers of response is needed d to allow appropriate selection of patients for KIT inhibitor therapy Separate driver from passenger KIT alterations Future directions include Identification of mechanisms of primary and secondary resistance Evaluation of the efficacy of sequential KIT inhibitor use in KIT driven melanoma Assessment of the efficacy of combining KIT inhibition with other therapeutic strategies (dasatinib + ipilimumab) Acknowledgements MSKCC Gary K Schwartz Jedd Wolchok Paul Chapman Cristina Antonescu Jerrold Teitcher Ruth-Ann Roman Lauren Cane Annie Fusco Kristin Fallon Natasha Martin UCSF Boris Bastian Mt Sinai, Miami Jose Lutzky New York University Anna Pavlick (NYU) UCLA Bartosz Chmielowski DFCI Stephen Hodi CTEP/NCI Naoko Takebe Support FDA OPD Grant ASCO YIA Live4Life Foundation 11

presentation session & clinical Keith T. Flaherty, M.D. Abramson Cancer Center of the University of Pennsylvania

Melanoma: highlights from the oral presentation session & clinical science symposium at ASCO 2009 Keith T. Flaherty, M.D. Abramson Cancer Center of the University of Pennsylvania Abstracts to be discussed