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1 Vaccine-Associated! Sarcoma! Hemangiosarcoma! Mast Cell Tumor! Osteosarcoma! 10

2 11! Survival! Survival Migration/Invasion! Survival Migration/Invasion Angiogenesis! Survival Migration/Invasion Angiogenesis Metastasis! Production of By Tumor Cell

3 Production of By Tumor Cell Autocrine Receptor Activation Overexpression Overexpression Spontaneous dimerization Truncation/Point Mutation/ Duplication RTK Inhibition Monoclonal Antibodies (Herceptin, Avastin, Erbitux ) Truncation/Point Mutation/ Duplication Constitutive/ Enhanced Activation 12

4 RTK Inhibition Suramin! RTK Inhibition Suramin! mab, Immunotoxin, RIT! mab, Drugs Soluble decoy receptors mab, Immunotoxin, RIT! RTK Inhibition mab, Drugs Soluble decoy receptors Suramin! mab, Immunotoxin, RIT! Canine MCT and KIT TKI"s (Gleevec, Iressa, Toceranib, Masitinib) KIT (stem cell factor receptor) expressed on normal and malignant mast cells KIT expression more intense, more likely to be cytoplasmic in high-grade K9 MCT 20-40% of canine MCT have a juxtamembrane mutation in c-kit, leading to constitutive activation Other activating mutations recently identified London et al. J Comp Pathol 1996: Reguera et al. Am J Dermatopathol 2000; Letard et al. Mol Cancer Res

5 Drugs Targeting KIT Others Imatinib (Gleevec) - Masitinib (Kinavet)! "#$%&'(%$%")("**+,,"-.%$%"! "/"'0"**"1$%&'(%$%"2$1$"3#"! "#$%&'(%$%"4'1$"5)6$57")(" 8'9%"2):;".-<=.<(9" 4>:.<'(%"'0"!"#$%& Liao AT, et al. Blood 2002 Evaluation of Toceranib in Canine MCT Phase I Toceranib Randomized Phase-III Trial in Canine MCT Entry Criteria: 2 cm or larger Grade II or III Recurrent Up to 1 regional lymph node involved Dogs randomized to receive 3.25 mg/kg toceranib q48h or placebo for 6 weeks Eligible dogs received open-label toceranib thereafter Pryer NK et al: Clin Cancer Res 9: , London CA et al, Clin Cancer Res

6 Toceranib Randomized Phase-III Trial in Canine MCT Overall response rate = 37.2% (7 CR, 25 PR) vs. 7.9% (all PR) Entry Criteria: 1 cm or larger Grade II or III Non-resectable or recurrent No regional LN involvement 60% in mutant vs 30% in wt Median TTP = 18 weeks No difference in severe AEs AEs generally manageable with drug holiday and supportive care Dogs randomized to receive 12.5 mg/kg masitinib q24h or placebo until failure London CA et al, Clin Cancer Res 2009 Masitinib / Masivet No difference in SAEs AEs manageable with holiday and support American Journal of Veterinary Research 2010, Survival in non-resectable tumours 12-months Survival rates 24-months Masitinib Placebo Masitinib Placebo N=106 N=26 N=106 N= Alive 59 (62.1%) 9 (36.0%) 33 (39.8%) 3 (15.0%) Dead Observed cases Fisher's p-value Kaplan-Meier estimate (%) [95%CI] % [55.1; 73.5] Median overall survival (days) [95%CI] Masitinib Placebo N=106 N= [433; 937] 322 [224; 721] % [18.9; 55.1] 48.9% [38.4; 58.5] 29.5% [12.0; 49.6] Hazard ratio [95%CI] LogRank p-value 1.54 [0.89; 2.66] Disease control at 6 months predicts long term survival Alive at 12mo Alive at 24mo Complete Response (CR) 93.3% 76.9% Partial Response (PR) 100% 75.0% Overall Response (CR+PR) 95.7% 76.2% Stable disease (SD) 94.4% 81.3% PR+SD 96.2% 79.2% Controlled disease (CR+PR+SD) 95.1% 78.4% Progressive disease (PD) 43.4% 16.5% Tumour Response 15

7 CRs observed at 24 months RTKI adverse effects 9% of dogs treated long term with masitinib had CR at 24 months Are these dogs cured??? How long do we continue treatment in dogs experiencing CR? GI ** (Diarrhea, vomiting, anorexia, gastrointestinal bleeding) Myelosuppression Protein-losing nephropathy Muscle cramping (toceranib) Depigmentation (toceranib) Weight loss Others rarely - hepatotoxicity, IMHA with masitinib, epistaxis with toceranib RTKIs Adverse effects Unanswered Questions Warn owners to be vigilant Dose reductions and drug holidays Monitoring Prophylactic measures Note that licensed dose for toceranib may be higher than necessary from clinical experience 3.25 mg/kg EOD! mg/kg EOD or MWF) What about postoperative use? Incomplete excision High-risk tumors What about use in combination with chemotherapy/radiation therapy? What about use in other tumor types? Who should get TKI vs traditional chemo? What about use in cats? ORR = 76% (13/17): CR = 10, PR = 3, SD = 3, PD = 1 * Maximum tolerated doses were 3.25 mg/kg toceranib QOD and 1.6 mg/m 2 VBL every other week Neutropenia dose-limiting 71% ORR despite significant reduction in dose-intensity * Abstracts suggest that masitinib can be safely combined with doxorubicin and carboplatin as well * Withdrawn prior to starting RT 16

8 Toceranib plus Palliative RT Outcome Median PFI = 316 days Median follow up time = 374 days Median survival time not yet reached Masitinib in cats JVIM 2011; 25: * Withdrawn prior to starting RT Pulse-toceranib plus CCNU Pfizer Animal Health Short-term toceranib as pure chemosensitizer Reduction in toxicity, cost Fixed-dose toceranib, escalating-dose CCNU Run-in phase-i leading to phase-ii cohort expansion at MTD Toceranib vs. Vinblastine AKC Response-adaptive, randomized phase-ii design KIT localization and c-kit mutation status as predictors ORR at 5 weeks as outcome criterion 17