Slide 1: Preliminary evidence of clinical activity with tipifarnib in HRAS-mutant SCCHN
Preliminary evidence of clinical activity with tipifarnib in squamous cell carcinomas of the head & neck (SCCHN) with HRAS mutations Alan Ho1, Nicole Chau2, Deborah Wong3, Maria E. Cabanillas4, Ranee Mehra5, Keith Bible6, Marcia S. Brose7, Valentina Boni8, Francis Burrows9, Carrie Melvin9, Catherine
Slide 2: Alan Ho MD PhD disclosures
Alan Ho MD PhD 1. Kura Oncology Research Support 2. AstraZeneca Research Support, Consulting 3. Eisai Research Support, Advisory Board 4. Bristol Myers Squibb Research Support, Advisory Board 5. Novartis Research Support, Advisory Board 6. Merck Advisory Board 7. Genzyme Advisory Board
Slide 3: Farnesyltransferase inhibitors (FTIs): Targeting HRAS
Farnesyltransferase inhibitors (FTIs): Targeting HRAS • The RAS superfamily (KRAS/NRAS/HRAS) require the covalent addition of a hydrophobic group to the C-terminal tail (known as “prenylation”) for membrane localization and downstream signaling. • Farnesyltransferase (FT) catalyzes the attachment of
Slide 4: Tipifarnib: First-in-class FTI
Tipifarnib: First-in-class FTI • Potent/highly selective inhibitor of farnesyltransferase (FT) that competitively binds the CAAX binding site1. • Previously studied in > 5,000 patients (70+ studies) • Previous trials without genetic selection yielded insufficient clinical activity to support registr
Slide 5: HRAS Mutant Tumors: Tipifarnib Susceptibility
HRAS Mutant Tumors: Tipifarnib Susceptibility HRAS G12V WT >80% KRAS MUTANT xenografts 50% <10% 5 End et al. 2001 Cancer Res 61:131-37
Slide 6: Phase II Design to Evaluate Tipifarnib in HRAS Mutant Cancers
Phase II Design to Evaluate Tipifarnib in HRAS Mutant Cancers Tumors with mutant HRAS Primary Objective Objective Response Rate Secondary Objectives: COHORT 2 COHORT 1 PFS and DOR Other Solid Thyroid Ca Safety/tolerability Tumors Tipifarnib: 900 mg bid daily on Days 1 – 7 and 15 – 21 in 28-day cycle
Slide 7: Tipifarnib in HRAS Mutant Squamous Cell Carcinomas of the Head and Neck
Tipifarnib in HRAS Mutant Squamous Cell Carcinomas of the Head and Neck (SCCHN) • Cohort 1 (HRAS mutant thyroid carcinomas) still enrolling to the Stage I. • Cohort 2 enrollment to Stage I has been completed (n=11): o HRAS mutant SCCHN (3): 2 cPRs and 1 SD (~7 mos) o HRAS mutant salivary gland tumor
Slide 8: KO-TIP-001 Best Response and Status
KO-TIP-001 Best Response and Status (- 41%) (- 8%) (- 30%) (- 20%) (+14%, PD NTL) (- 14%) (+14%) (- 4%) 001-001: epithelial-myoepithelial ca; 005-001: mucoepidermoid ca; 005-008: Poorly differentiated adenoca; 006-001: Salivary duct ca; 008-002: Oncocytic ca SD: Sum of Diameters; PD NTL: Progression
Slide 9: HRAS Mutations Define a Unique SCCHN Molecular Subset
HRAS Mutations Define a Unique SCCHN Molecular Subset • SCCHN express high levels of HRAS2. • HRAS mutant SCCHN (~6% at initial diagnosis) characterized by frequent CASP8 mutations and low rate of TP53 mutation3. • HRAS mutation may result from carcinogenesis (e.g. tobacco 1 exposure)4. 1. TCGA data
Slide 10: Emergence of RAS Mutations Is Associated with Acquired Cetuximab Resistance
Emergence of RAS Mutations Is Associated with Acquired Cetuximab Resistance in SCCHN Patients • 2/46 (4.3%) SCCHN tumors possessed an HRAS mutation. • 20 SCCHN pts receiving cetuximab plus platinum/5-fluoruracil had ctDNA collected/analyzed during and after therapy. o 6/13 (46%) patients with on-tre
Slide 11: HRAS Mutant SCCHN PDXs are Sensitive to Tipifarnib and Resistant to Cetuximab
HRAS Mutant SCCHN PDXs are Sensitive to Tipifarnib and Resistant to Cetuximab and Chemotherapy HN2606 900 HN3504 1500 HRAS G13R HRAS K117N 800 700 Tumor Volume (mm³) Tumor Volume (mm³) 600 1000 500 400 300 500 200 100 0 0 0 10 20 30 0 5 10 15 20 25 30 35 Study Days Study Days Vehicle Tipifarnib Vehi
Slide 12: Patient 005-005
Patient 005-005 ~ 6 mos. SD (systemic) PD PR Patient 005-005 Cetuximab/Carboplatin/ ~ 8 mos. SD Tipifarnib (metastatic tracheal tumor) paclitaxel/RT Ongoing in C19 • Elderly white male with a metastatic SCCHN (primary tracheal tumor and prior history of nasal SCC) o Received 2 cycles of paclitaxel,
Slide 13: 005-005: Partial Response
005-005: Partial Response 08/17/2015 12/22/2015 (Baseline) (Cycle 4 Day 22) 13
Slide 14: Patients 005-007 and 005-009
Patients 005-007 and 005-009 PD C2 SD C2 SD C6 Patient 005-007 Cetuximab (oral cavity SCCNH) Tipifarnib PD C2 PR C2 Patient 005-009 Cetuximab (oral cavity SCCNH) Paclitaxel Tipifarnib Ongoing in C11 Patients 005-007 and 005-009 are two male subjects with advanced oral cavity SCCHN tumors that carry
Slide 15: Summary
Summary • HRAS mutant SCCHN represents a biologically and clinically distinct subset of disease. • Acquired resistance to cetuximab in RAS WT SCCHN may be related to emergence of RAS mutations. • A subset of HRAS mutant SCCHN may be sensitive to tipifarnib, potentially representing a therapeutic alt
Slide 16: Acknowledgements
Acknowledgements • KO-TIP-001 investigators and research personnel • Kura Oncology • Our patients and their families 16