Slide 1: Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations
Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations Alan Ho1, Nicole Chau2, Deborah J. Wong3, Maria E. Cabanillas4, Jessica Bauman5, Marcia S. Brose6, Keith Bible7, Valentina Boni8, Irene Brana9, Charles Ferte10, Caroline Even10, Francis Burrows11, L
Slide 2: Disclosures
Disclosures Research Funding (Trials) Consulting/Advisory Boards • AstraZeneca • AstraZeneca • Pfizer • Novartis • Bayer • Genentech/Roche • Genentech/Roche • Eisai • Lily • Merck • Eisai • BMS • Koltan • Genzyme • Kura Oncology • Regeneron • Merck • Sun Pharmaceuticals • BMS Travel/Meeting Expenses
Slide 3: Mutant HRAS Oncogene Activity is Uniquely Dependent on Farnesylation
Mutant HRAS Oncogene Activity is Uniquely Dependent on Farnesylation • RAS superfamily (KRAS/NRAS/HRAS) members require the covalent addition of a hydrophobic group to their C-terminal tail (known as “prenylation”) for membrane localization and downstream signaling. • Farnesyltransferase (FT) cataly
Slide 4: Tipifarnib: First-in-class FTI
Tipifarnib: First-in-class FTI • Potent/highly selective inhibitor of farnesyltransferase (FT) that competitively binds to the CAAX motif1. • Previously studied in > 5,000 patients (70+ studies). • Prior trials without genetic selection yielded insufficient clinical activity to support registration,
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 Enrollment ongoing HNSCC Extension Enrollment ongoing Key Eligibility: Primary Objective: ORR ‒ No curative therapy available
Slide 6: HRAS Mutations Define a Unique Molecular HNSCC Subset
HRAS Mutations Define a Unique Molecular HNSCC Subset • The HRAS mutant subset of HNSCC is characterized by low rate of genetic alterations, frequent CASP8 inactivation, and infrequent of TP53 mutation1. • It is thought that HRAS/CASP8 alteration converge on NF-kB to induce tumor cell growth and sur
Slide 7: Tipifarnib in HRAS Mutant HNSCC and Skin SCC Patients
Prelim ina ry d a ta Tipifarnib in HRAS Mutant HNSCC and Skin SCC Patients Preliminary data as of 04 October 2017 ~ 6 mos, SD PR C2 Mucosal Patient 005-005 Cetuximab, Carboplatin, Tipifarnib C21 (tracheal) Paclitaxel, RT ~ 2 mos, SD PR C2 Patient 001-005 Pembrolizumab Tipifarnib C7 (nasopharyngeal)
Slide 8: Durable Response on Tipifarnib after Cetuximab/Chemo/RT
Durable Response on Tipifarnib after Cetuximab/Chemo/RT ~ 6 mos, SD PR at Cycle 2 Patient 005-005 Cetuximab, Carboplatin, Off Therapy ~ 8 mos Tipifarnib Cycle 21 for POD (tracheal tumor) Paclitaxel, RT 76 yo man with metastatic tracheal SCC HPV/p16 (-), no tobacco/ETOH HRAS Q22K (observed in Costell
Slide 9: Tipifarnib Response in Nasopharyngeal Ca s/p Immunotherapy
Tipifarnib Response in Nasopharyngeal Ca s/p Immunotherapy ~ 6 mos, SD ~ 2 mos, SD PR at Cycle 2 Patient 001-005 Cisplatin Pembrolizumab Tipifarnib Cycle 7 (nasopharynx) 59 yo female with nasopharynx SCC with HRAS G12D Baseline Cycle 2, 40% reduction Cycle 6, 49% reduction 9 Images provided by Dr. N
Slide 10: Symptom Improvement and Stable Disease in Cutaneous SCC
Preliminary data Symptom Improvement and Stable Disease in Cutaneous SCC ~1 mo, PR SD at Cycle 2 Patient 011-001 Carboplatin, (metastatic from ~ 3 mos Tipifarnib Cycle 6 ear primary) RT Baseline 81 yo male with right ear SCC and history of aggressive disease. • HRAS G12D, TP53 R110P and R248W mutati
Slide 11: Tipifarnib Regression of Widely Metastatic Laryngeal SCC
Tipifarnib Regression of Widely Metastatic Laryngeal SCC SD at Cycle 2 ~2 mo, PD ~8 mo, PD Patient 05-012 Cetuximab + Pembrolizumab + Tipifarnib Cycle 3 (Laryngeal) Paclitaxel palliative RT 55 yo male with metastatic laryngeal SCC (mediastinal LNs, muscle, adrenal gland, lung, bone) 80 pk-years, no
Slide 12: Tipifarnib Response and Resolution of Disfiguring Skin Lesions s/p Immunotherapy Failure
Tipifarnib Response and Resolution of Disfiguring Skin Lesions s/p Immunotherapy Failure PD PR at Cycle 1 Patient 012-001 Nivolumab + Tipifarnib Cycle 5 (oral cavity) Investigational IO 69 yo man with recurrent oral cavity SCC. No tobacco/ETOH HRAS G12S, TP53 R248Q Initial PR (40% tumor reduction) o
Slide 13: Significant Tumor Size Reduction and Durable Responses Observed in HRASm HNSCC Patients
Significant Tumor Size Reduction and Durable Responses Observed in HRASm HNSCC Patients Treated with Tipifarnib 20% -41% Tumor Size Reduction/Increase 0 -8.4% Tracheal -22% Oral Cavity -30% 005-005 Laryngeal 005-007 Oral Cavity -20% 005-012 005-009 -40% -56% -49% Oral Cavity Nasopharyngeal -60% 001-
Slide 14: Conclusions
Conclusions • First clinical evidence that mutant HRAS is a targetable oncogene. • Phase 2 proof-of-concept of tipifarnib efficacy for recurrent/metastatic HNSCC carrying HRAS mutations. ‒ Confirmed PRs in 4 of 6 HNSCC patients (67%, 22-95% 95% CI) ‒ Rapid and durable responses (2 responses >1 year)
Slide 15: Acknowledgements
Acknowledgements • Patients, their families and caregivers • Study Investigators and their study teams • Kura Oncology 15