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
Structure of KIT N-terminal Extracellular Exons 1-9 Juxtamembrane Proximal Kinase Exon 11 Exons 12-16 Distal Kinase Exons 18-21 C-terminal KIT Expression and Melanoma Progression Benign Melanocytes Primary Melanoma Distant Metastasis Natali et al, Montone et al, Shen et al, 1992 1997 2003 (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 1992. Lassam et al. Oncogene 1992. Montone et al. Mod Pathol 1997. Shen et al. J Cutan Pathol 2003. 2
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 ++ 23 cutaneous Ugurel et al, British Journal of Cancer, 2005 Kim et al, British Journal of Cancer, 2008 1 mucosal 2 ocular n = 18 11 non-csd 1 acral 1 mucosal 1 ocular 4 unk primary n = 21 20 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 2011. 3
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 2003. 69 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. 2008 Apr 20;26(12):2046-51. 79 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
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 2011. 5
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
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 (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 < 0.001 001 15 vs 9 months p =.036 Guo et al. JCO 2011; Carvajal et al. JAMA 2011. Distribution of Identified KIT Mutations N-terminal Extracellular Juxtamembrane Proximal Kinase Distal Kinase Carvajal et al. JAMA 2011. C-terminal 8
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 = 0.02 9
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
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