AU GU ST 7 , 2 0 2 3 mCRC Program Update and Clinical Development Plan |
PFIZER We expect clinical data from our 1st line RAS-mutated mCRC trial in mid-2024 |
mCRC clinical development program agreed with FDA • • • • • • |
5 3 Annual eligible U.S. patients (’000s)* 15 12 40 0 50 23 48 |
Line of Therapy Ph2 Ph3 Investigator-initiated trials Trial Combination with: |
CLINICAL FINDINGS FROM 2L Ph 1b/2 TRIAL SCIENTIFIC BASIS FOR CLINICAL FINDINGS CLINICAL DEVELOPMENT PATH FORWARD Onvansertib clinical development plan in mCRC |
CLINICAL FINDINGS FROM 2L Ph 1b/2 TRIAL SCIENTIFIC BASIS FOR CLINICAL FINDINGS CLINICAL DEVELOPMENT PATH FORWARD Onvansertib clinical development plan in mCRC |
Onvansertib PROPERTIES SPECIFICITY • • • |
1st LINE 2nd Normal LINE RAS Mutated |
2nd Normal 1st LINE LINE RAS Mutated |
MOA 21 RAS-mutations in mCRC1 |
28 DAY CYCLE ENROLLMENT CRITERIA EFFICACY ENDPOINTS 1 2 3 |
PHASE 1b PHASE 2 ITT population (N) 50 68 Evaluable population* (N) 48 66 We enrolled 50 initial patients, and then an additional 18 patients, in our trial TOTAL |
1st LINE 2nd Bev exposed vs bev naïve patients LINE |
KRAS Variant CR+PR SD PD Total G12C G12D G12V G13D G12S G12A Q61H G13C |
• • • • • • • TEAE GR1 GR2 GR3 GR4 TOTAL TEAE GR1 GR2 GR3 GR4 TOTAL Fatigue 24 22 7 0 53 78% Cough 11 0 0 0 11 16% Neutropenia 1 18 23 7 49 72% Pyrexia 8 1 1 0 10 15% Nausea 29 13 4 0 46 68% Dyspnea 7 3 0 0 10 15% Diarrhea 21 13 4 0 38 56% AST Increase 7 2 1 0 10 15% Leukopenia 9 14 5 1 29 43% Lymphocytopenia 2 7 0 0 9 13% Anemia 22 5 2 0 29 43% Dyspepsia 9 0 0 0 9 13% Alopecia 20 5 0 0 25 37% ALT Increase 8 0 1 0 9 13% Abdominal Pain 14 8 3 0 25 37% Hypocalcemia 9 0 0 0 9 13% Stomatitis 15 6 3 0 24 35% Insomnia 9 0 0 0 9 13% Hypertension 4 10 9 0 23 34% Dehydration 1 5 2 0 8 12% Thrombocytopenia 17 5 1 0 23 34% Hypokalemia 6 2 0 0 8 12% Constipation 17 2 1 0 20 29% Arthralgia 6 2 0 0 8 12% Vomiting 11 6 3 0 20 29% Hand / Foot Syndrome 5 2 0 0 7 10% Epistaxis 15 0 0 0 15 22% Hemorrhoids 5 2 0 0 7 10% Headache 13 0 0 0 13 19% Non-Cardiac Chest Pain 6 1 0 0 7 10% Decreased Appetite 4 6 2 0 12 18% ALP Increase 5 1 1 0 7 10% Back Pain 10 2 0 0 12 18% |
CLINICAL FINDINGS FROM 2L Ph 1b/2 TRIAL SCIENTIFIC BASIS FOR CLINICAL FINDINGS CLINICAL DEVELOPMENT PATH FORWARD Onvansertib clinical development plan in mCRC |
Our findings establish the scientific basis of our bev naïve clinical finding |
Tumor volume (mm 3 ) 0 10 20 30 0 500 1000 1500 2000 2500 SW620 (KRAS G12V) The combination had significant superior anti-tumor activity compared to the single agents |
KRAS-mut tumors from mice treated with onv + bev appear smaller and pale (less vascularized) |
•••••• |
PLK1 inhibition using siRNA against PLK1 (siPLK1) prevented hypoxia-induced HIF1a expression In 4 RAS-mutant CRC cell lines*, onvansertib inhibited hypoxia-induced HIF1a expression |
This new MOA, which inhibits a “survival switch” of tumorigenesis, may underlie the increased efficacy observed clinically |
• • • – – • • |
RAS-mutations in mCRC1 MOA 2 1 3 |
CLINICAL FINDINGS FROM 2L Ph 1b/2 TRIAL SCIENTIFIC BASIS FOR CLINICAL FINDINGS CLINICAL DEVELOPMENT PATH FORWARD Onvansertib clinical development plan in mCRC |
• • 2nd line mCRC 1st line mCRC • …and FDA agreed with Cardiff Oncology’s proposed 1st line clinical program FDA suggested we consider moving to a 1st line clinical development path… |
• • • Clinical Commercial • • Transition from 2L to 1L Regulatory • • • • |
ENROLLMENT CRITERIA ENDPOINTS Primary Secondary Benchmark of success |
2 nd Line mCRC 1 st line mCRC 2 nd Line mCRC 1 st line mCRC |
BREAKTHROUGH GROWTH INITIATIVE • • • PFIZER PFIZER Ignite • • |
2023 2024 2025 |
PFIZER We expect clinical data from our 1st line RAS-mutated mCRC trial in mid-2024 |
Appendix: Additional Ph 1b/2 Clinical Data |
As an independent cohort in the Ph 1b/2 trial, the expansion cohort replicated the finding of improved responses from the bev naïve patients |
No single patient characteristic explains the difference in response rates by prior bev status |
Appendix: Additional Preclinical Data |
0 5 10 15 20 -50 0 50 100 150 200 200 400 600 Treatment time (days) C1143 (KRAS G12D) ** *** 0 5 10 15 20 0 50 100 150 200 250 Treatment time (days) C1144 (KRAS G12C) ** **** Vehicle Onv+Irino Onvansertib Irinotecan |
0 5 10 15 20 0 100 200 300 Treatment time (days) C1138 (KRAS G13D) ** *** 0 5 10 15 20 0 200 400 600 800 Treatment time (days) B8239 (KRAS G12C) *** *** 5 10 15 20 0 100 200 300 Treatment time (days) C1143 (KRAS G12D) * **** |