Slide 1: Preliminary Results from a Phase 2 Proof of Concept Trial of Tipifarnib in SCCs with HRAS Mutations
PRELIMINARY RESULTS FROM A PHASE 2 PROOF OF CONCEPT TRIAL OF TIPIFARNIB IN SQUAMOUS CELL CARCINOMAS (SCCS) WITH HRAS MUTATIONS Alan Ho1, Nicole Chau2, Jessica Bauman3, Keith Bible4, Ashish Chintakuntlawar4, Maria E. Cabanillas5, Deborah J. Wong6, Irene Brana7, Marcia S. Brose8, Valentina Boni9, Caro
Slide 2: Disclosure Slide
DISCLOSURE SLIDE Advisory Boards/Consulting: Kura Oncology (travel/lodging/conference fees only), Regeneron, Eisai, Ayala, TRM Oncology, Sun Pharmaceuticals, Merck, Sanofi Aventis, BMS, Genentech, Genzyme, Novartis, Janssen (travel only), AstraZeneca, Hai-II, Guidepoint Global Advisors (no payment r
Slide 3: Mutant HRAS Oncogene Activity is Uniquely Dependent on Farnesylation
Mutant HRAS Oncogene Activity is Uniquely Dependent on Farnesylation • Members of the RAS superfamily (KRAS / NRAS / HRAS) require covalent addition of a hydrophobic group to their C- terminal tail (“prenylation”) for membrane localization and downstream signaling. • Farnesyltransferase (FT) enzyme
Slide 4: HRAS Mutations are part of a Unique Molecular Subset of HNSCC
HRAS Mutations are part of a Unique Molecular Subset of HNSCC HRAS mutations are observed in a distinct molecular subset of HNSCC1 characterized by: – Reduced copy number alterations – Inactivating caspase 8 mutations – p53 WT 4 4 1Cancer Genome Atlas Network 2015. Nature 517:576-82. Reproduced with
Slide 5: Phase 2 Trial in HRAS Mutant Solid Tumors
Phase 2 Trial in HRAS Mutant Solid Tumors Solid Tumors with HRAS mutations Cohort 1: Cohort 2: Cohort 3: Thyroid Cancer Other / HNSCC SCC (excluding HNSCC) Enrollment ongoing • Key Eligibility: HNSCC Extension – No curative therapy available Enrollment ongoing – HRAS mutation – Measurable disease (R
Slide 6: Patient Disposition
Patient Disposition HNSCC Other SCC Total Treated n (%) 17 (100) 6 (100) Oral Cavity, including tongue n 8 -- Other HNSCC n 9 -- Non-HNSCC n -- 6 Prior Lines of Therapy Median (Range) 2 (1 – 5) 1 (1 – 2) Age, yrs Median (Range) 59 (20 – 76) 63 (49 – 81) Treatment Discontinuations n (%) 12 (76) 3 (50
Slide 7: HNSCC Patients (n=17 on study, +1 pt treated off protocol)
HNSCC Patients (n=17 on study, +1 pt treated off protocol) Preliminary Results as of 9/7/2018 7 * Response confirmed on 10/15/2018
Slide 8: HNSCC Patients – Response By Prior Therapy
HNSCC Patients – Response By Prior Therapy 8 Preliminary Results as of 9/7/2018
Slide 9: Other SCC Patients (n=6)
Other SCC Patients (n=6) 9 Preliminary Results as of 9/7/2018
Slide 10: Tipifarnib Regression of Widely Metastatic Laryngeal SCC
Tipifarnib Regression of Widely Metastatic Laryngeal SCC 55 yo male with metastatic laryngeal SCC (mediastinal LNs, muscle, adrenal gland, lung, bone) 80 pk-years, no current ETOH, HRAS G13V, TP53 R248Q ~2 mo, PD ~8 mo, SD PR at Cycle 4 Patient 05-012 Cetuximab + Pembrolizumab + (Laryngeal) Paclitax
Slide 11: Association of HRAS Mutant Allele Frequency with Clinical Benefit from Tipifarnib
Association of HRAS Mutant Allele Frequency with Clinical Benefit from Tipifarnib (HNSCC, SCC, n=20) Study KO-TIP-001 pts with HN and non-HN SCC tumors with available HRAS mutant allele data (10.17.2018). One additional HNSCC pt was treated off protocol. (Pending AF analysis: 1 HNSCC PR, 1 HNSCC pen
Slide 12: TEAEs
TEAEs • Dose limiting (Grade >3) treatment emergent AEs in HNSCC patients (n=17) included anemia (23%), neutropenia (14%) and GI disturbances (18%). • Grade 2 creatinine elevations reported in 3 HNSCC patients (18%). Grade 3 hypokalemia observed in 2 HNSCC patients during sponsor’s review of safety
Slide 13: Conclusions
Conclusions • Proof-of-concept for tipifarnib activity in recurrent/metastatic HNSCC carrying HRAS mutations. • Rapid and durable responses. • Activity in disease resistant to chemotherapy, cetuximab and immunotherapy. • Association between allele frequency and clinical benefit. • TEAEs consistent w
Slide 14: Acknowledgements
Acknowledgements • Patients, their families and caregivers • Study Investigators and their study teams Robert Haddad, MD Laurence Faugeras, MD Myung-Ju Ahn, MD Lara Iglesias, MD Dana Farber Cancer Institute CHU UCL Namur, Site Godinne Samsung Medical Center Hospital Universitario 12 de Octubre Keith