Slide 1: New Data Presentation: KRAS-mutated Metastatic Colorectal Cancer (mCRC)
New Data Presentation: KRAS-mutated Metastatic Colorectal Cancer (mCRC) September 8, 2021
Slide 2: Forward-looking statements
2021 Corporation Presentation I 2 Certain statements in this presentation are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as "anticipate," "believe," "forecast," "estimated" and "intend" or ot
Slide 3: Agenda
2021 Corporation Presentation I 3 Agenda KRAS-mutant Metastatic Colorectal Cancer Remains an Unmet Need for New Therapeutic Options Afsaneh Barzi, M.D., Ph.D., (City of Hope Comprehensive Cancer Center) Cardiff Oncology’s Key Clinical Advisor New Data: Onvansertib in Combination With FOLFIRI and Bev
Slide 4: Katherine Ruffner, M.D. – Chief Medical Officer
2021 Corporation Presentation I 4 • Joined Cardiff as CMO July 6 • Education: – BS Biology, Duke University – MD, University of Tennessee – Internal Medicine residency, University of Michigan – Medical Oncology fellowship, Fred Hutch Cancer Research Center/University of Washington • Academic experie
Slide 5: Afsaneh Barzi, M.D., Ph.D. – Key Clinical Advisor
2021 Corporation Presentation I 5 • Dr. Barzi serves as a key clinical advisor to Cardiff Oncology. • Academic appointments – Current: • Associate Professor for GI oncology at City of Hope Comprehensive Cancer Center (COH-CCC) • Clinical Director of AccessHope at COH-CCC – Previous: • Associate Prof
Slide 6: KRAS-Mutant mCRC Remains an Unmet Need for New Therapeutic Options
AFSANEH BARZI, M.D., PH.D. Associate Clinical Professor of Medical Oncology GI Oncology and Clinical Director of AccessHope City of Hope Comprehensive Cancer Center 6 KRAS-MUTANT METASTATIC COLORECTAL CANCER REMAINS AN UNMET NEED FOR NEW THERAPEUTIC OPTIONS
Slide 7: Objectives
Objectives 7 01 02 03 Discuss the clinical burden of KRAS-mutated colorectal cancer Review ongoing areas of clinical research and their limitations Highlight the opportunity for onvansertib in KRAS- mutated mCRC
Slide 8: Mutated KRAS: a negative biomarker
Mutated KRAS: a “negative” biomarker to avoid selecting an inappropriate treatment 1Khambata-Ford S et al. Journal of Clinical Oncology 2007 253230-3237 8 For most biomarkers, their presence is associated with benefit from a targeted agent o BRAF mutation: Encorafenib Presence of KRAS is not ass
Slide 9: KRAS mutations are highly prevalent in metastatic CRC
KRAS mutations are highly prevalent in metastatic CRC Prevalence of metastatic disease 9 M et as ta tic p op ul at io n (5 0K p er y ea r) Recurrence (20K per year) Localized colon cancer Localized rectal cancer Metastatic at diagnosis (colon or rectal) (30K per year) Actionable biomarkers Actionabl
Slide 10: Treatment landscape for KRAS mutated CRC
Treatment landscape for KRAS mutated CRC First line: FOLFOX/FOLFIRI/FOLFOXIRI + Bevacizumab Second line: FOLFIRI/FOLFOX + Bevacizumab Third line: Regorafenib/TAS-102 Fourth line: TAS-102/Regorafenib Subsequent lines: Others 1NCCN Recommendations
Slide 11: KRAS mutation, a negative prognostic indicator in metastatic CRC
KRAS mutation, a negative prognostic indicator in metastatic CRC A pooled analysis of German Oncology trials included 1239 patients: 664 KRAS wild type and 462 KRAS mutation 11 1Modest P et al. Ann Oncol 2016 Sep;27(9):1746-53; 2Petrelli F et al. Med Oncol. 2013;30(3):650 A meta-analysis of pati
Slide 12: Challenges in targeting KRAS
Challenges in targeting KRAS • Direct targeting (not feasible) - RAS high affinity for GTP (activation mechanism) >>> impossible competition as normal functioning will be disrupted - Different KRAS mutations result in different conformational change - The shape of the conformation in G12C is permiss
Slide 13: G12C mutation in CRC: a small subset of patients
G12C mutation in CRC: a small subset of patients 1Janakiraman M et al. Cancer Res. 2010 Jul 15;70(14):5901-11; 2Jones R et al. Br J Cancer. 2017 Mar 28;116(7):923-929 Somatic Mutations N (%) C.35G>A p.G12D 49 (29.2%) C.35G>C p.G12A 15 (8.9%) C.34G>T p.G12C 15 (8.9%) C.34_35delinsTT p.G12F 1 (0.6%) C
Slide 14: Not all G12C's are the same: CRC vs. NSCLC
Not all G12C’s are the same: Colorectal Cancer vs. NSCLC 1DS Hong et al. N Engl. J Med 2020;383:1207-1217 14
Slide 15: Combination therapy: a requirement in KRAS-mutated CRC
Combination therapy: a requirement in KRAS-mutated CRC 1Amodio V et al. Cancer Discovery, 2020 Inclusion Criteria: Phase 3 Study: MRTX849 + Cetuximab vs Chemotherapy in Advanced Colorectal Cancer With KRAS G12C Mutation (KRYSTAL-10) Prior treatment with a therapy targeting KRAS G12C mutation (e.g.,
Slide 16: Other therapeutic efforts: adoptive transfer of KRAS G12D specific T cells
1Tran E et al. N Engl J Med 2016; 2Bardi MS et al. Rev Bras Hematol Hemoter. 2012;34(1):25-30 Other Therapeutic Efforts: Adoptive Transfer of KRAS G12D Specific T Cells Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in
Slide 17: SOS1: Pan KRAS inhibitor
SOS1: Pan KRAS inhibitor Phase I : BI 1701963 Alone and Combined With Trametinib in Patients With Solid Tumors With KRAS Mutation Expansion in NSCLC Phase I + expansion: BI 1701963 Alone and Combined With Irinotecan in Patients With colorectal cancer Tumors With KRAS Mutation 1Nyiri k et al. Cancer
Slide 18: MEK-inhibitor (trametinib) in KRAS-mutated cancers
MEK-inhibitor (trametinib) has been studied as single agent and in combination in KRAS-mutated cancers 1Infante JR et al. Lancet Oncol 2012 Aug;13(8):773-81 18
Slide 19: Toxicity of MEK Inhibitors (Trametinib)
Toxicity of MEK Inhibitors (Trametinib) 1Infante JR et al. Lancet Oncol 2012 Aug;13(8):773-81 19
Slide 20: Toxicity of MEK Inhibitors (CH-5126766/VS-6766)
Toxicity of MEK Inhibitors (CH-5126766/VS-6766) 1Guo C et al. Lancet Oncol 2020 Nov; 21(11): 1478-1488 20
Slide 21: Beyond MEK
Beyond MEK Bi Cityof Hope Published in final edited form as: Cancer Cell. 2014 May 12; 25(5): 697-710. doi:10.1016/j.cer.2014.03.011. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors Piro Lito’.2.°, Anna SaborowskI®®, Jingyin Yue®, Martha Solo
Slide 22: PLK1 Promotes Cancer Cell Survival by Facilitating DNA Repair
PLK1 Promotes Cancer Cell Survival by Facilitating DNA Repair of Irinotecan-induced DNA Damage • Topoisomerase I inhibitors such as irinotecan induce double strand DNA breaks (DSBs) during replication (broken replication fork) • PLK1 is recruited at the broken replication fork to promote DNA repair
Slide 23: PLK1 and RAS Cooperative Relationship
PLK1 and RAS Cooperative Relationship • RAS activates PLK1 through a MEK/ERK-independent mechanism • The downstream target of KRAS, pCRAF localizes to the mitotic spindle poles at mitosis where it interacts with PLK1 and promotes PLK1 activation, leading to mitosis and tumor progression1 • These dat
Slide 24: Conclusions
Conclusions • Drug development for KRAS mutated cancers including colorectal cancer has been a long and tortuous way with no success thus far: remains an area of unmet need • Data suggests that targeting KRAS alone is unlikely to be effective for colorectal cancer: combination therapy is being pursu
Slide 25: Dr. Lenz – Principal Investigator
2021 Corporation Presentation I 25 • Dr. Lenz is the Principal Investigator for the Phase 1b/2 trial of onvansertib with FOLFIRI- bevacizumab in KRAS-mutated, metastatic colorectal carcinoma. • Academic appointments at Southern California Norris Comprehensive Cancer Center: – Professor of Medicine a
Slide 26: Onvansertib With FOLFIRI and Bevacizumab for Second Line KRAS-Mutated mCRC
Heinz-Josef Lenz, M.D., FACP Professor of Medicine and Preventive Medicine Associate Director, Clinical Research J Terrence Lanni Chair in Cancer Research Co-Director, USC Center for Molecular Pathways and Drug Discovery USC/Norris Comprehensive Cancer Center Los Angeles, California Onvansertib in C
Slide 27: Clinical Trial Rationale Based on Preclinical Data
Clinical Trial Rationale Based on Preclinical Data Synthetic Lethality: KRAS mutant cells are hypersensitive to PLK1 inhibition Synergy: onvansertib synergizes with irinotecan and 5-FU in preclinical models • Onvansertib induced synergistic anti-tumor activity in combination with both standard-of-ca
Slide 28: Trial design, endpoints and eligibility
Primary Endpoints: • Phase 1b: characterization of DLTs, adverse events and tolerability • Phase 2: objective response rate (ORR) in patients who receive at least 1 cycle of treatment and had radiographic scan Secondary Endpoints: • Progression-free survival (PFS) • Reduction in KRAS allelic burden
Slide 29: Phase 1b/2: Patient Enrollment and Baseline Characteristics
As of 02-Jul-21 Total patients N=45 Median [range] or n (%) Age, years 58 [36-83] Sex Male 25 (56%) Female 20 (44%) ECOG 0 29 (64%) 1 15 (33%) Primary tumor site Right Colon 16 (36%) Left Colon 7 (16%) Rectum 15 (33%) Other/Unknown/Not Provided 7 (16%) Liver metastasis None 10 (22%) Liver and other
Slide 30: Safety: Most Common Treatment-Emergent Adverse Events
• 8 patients had a total of 10 G4 adverse events: – Neutropenia (n=6); Decreased WBC (n=2); Neutropenic fever (n=1); Hyperphosphatemia (n=1) • Combination regimen was well tolerated: – Of all TEAEs only 10% (49/490) were G3/G4 – The only G3/G4 AEs reported in ≥2 patients were Neutropenia (n=17 event
Slide 31: Summary of Preliminary Efficacy
All Doses of Onvansertib (12 mg/m2, 15mg/m2, 18 mg/m2) RP2D Dose of Onvansertib (15 mg/m2) Response-Evaluable Patients Partial Response (PRs) 32* 12 (38%) 19** 8 (42%) Summary of Preliminary Efficacy 31 As of 02-Jul-21 Response-Evaluable Patients = completed at least 1 cycle of treatment and had at
Slide 32: Efficacy and Treatment Duration Across All Dose Levels
• Of the 32 patients from Phase 1b/2 evaluable for efficacy*: – 12 (38%) achieved a partial response (PR) • 6 confirmed and 6 unconfirmed PRs as of 02-Jul-21 • Further follow-up: 10 confirmed and 2 unconfirmed PRs as of 08-Sept-21 • 2 patients went off study to have potentially curative surgery Trea
Slide 33: Efficacy at the RP2D of Onvansertib 15 mg/m2
19 of 22 patients treated per protocol* with onvansertib at the RP2D (15 mg/m2) were evaluable for efficacy:** • 8 (42%) achieved a partial response (PR) • 3 confirmed and 5 unconfirmed PRs as of 02-Jul-21 • Further follow-up: 7 confirmed and 1 unconfirmed PRs as of 09-08-21 33 Efficacy at the RP2D
Slide 34: Median Progression-Free Survival Has Not Yet Been Reached
Median Progression-Free Survival (mPFS) Has Not Yet Been Reached To-Date 34 As of 02-Jul-21 • Patients treated at the RP2D 15 mg/m2 have not yet reached the mPFS to-date All Phase 1b/2 Evaluable Patients (N=32): mPFS is 9.4 (95% CI 7.8 –NA) Months to-Date
Slide 35: Best Radiographic Response
• PRs have been achieved across all dose levels • 4 additional PRs have been confirmed since the 02-Jul-21 data cutoff date Best Radiographic Response 35 As of 02-Jul-21 02 -01 5 02 -00 8 06 -03 6 07 -03 0 06 -02 1 03 -02 2 01 -01 1 06 -03 9 01 -01 4 02 -01 6 01 -02 0 02 -03 1 02 -02 8 06 -04 0 07 -
Slide 36: KRAS MAF Decrease Following 1 Cycle of Treatment
PR SD PD -100 -50 0 %Change in KRAS MAF % ch an ge in K R AS M AF at C yc le 2 D ay 1 fr om b as el in e Mean PR -96.83 SD -69.80 PD -40.50 ✱✱ ✱✱ -90% % KRAS MAF Decrease Following 1 Cycle of Treatment • KRAS MAF was measured by digital droplet PCR (ddPCR) at baseline (Cycle 1 Day 1, pre-dose) and o
Slide 37: KRAS Mutation Variants in Treated Patients
• 7 different variants were detected by targeted next-generation sequencing (NGS) in circulating tumor DNA (ctDNA) isolated from patient plasma at baseline • Clinical responses were observed across different KRAS variants, including the 3 most common (G12D, G12V, G13D) representing 69% of KRAS varia
Slide 38: Summary of safety, efficacy and KRAS biomarker
Safety • The combination of onvansertib and FOLFIRI/Bev is well-tolerated • Only 10% (49/490) of reported TEAEs were G3/G4 Efficacy • Of the 32 Phase 1b/2 patients evaluable for efficacy: – 12 (38%) achieved a partial response (PR) • 6 confirmed and 6 unconfirmed PRs as of 02-Jul021 • Further follow
Slide 39: The Cardiff Oncology Opportunity
The Cardiff Oncology Opportunity Mark Erlander, PhD – Chief Executive Officer
Slide 40: Second-Line Treatment of KRAS-Mutated mCRC
Second-Line Treatment of KRAS-Mutated mCRC Phase 1b/2 open-label trial of onvansertib + FOLFIRI/bevacizumab Principal Investigator: Dr. Heinz-Josef Lenz
Slide 41: Standard-of-Care Second Line mCRC Benchmarks
2021 Corporation Presentation I 41 13% 11.5 months Not Reported for Second-line 11.2 months Overall Survival (OS) 4.5 months 5.6 months 5.7 months Progression-Free Survival (PFS) 11.4% 5% Objective Response Rate (ORR) Systematic Literature-Based Analysis of 23 Randomized Trials (10,800 Patients) in
Slide 42: Efficacy Data Remain Consistent as Patient Numbers Increase
2021 Corporation Presentation I 42 Efficacy Data Remain Consistent as Patient Numbers Increase AS OF APRIL 4 AS OF JULY 2 All Doses (12mg/m2, 15 mg/m2, 18 mg/m2) 18 7 of 18 (39%) 6 of 18 (33%) All Doses (12mg/m2, 15 mg/m2, 18 mg/m2) Phase 2 Dose (15 mg/m2) 32 19 12 of 32 (38%) 8 of 19 (42%) 10 of 32
Slide 43: Onvansertib's MOA Creates a Broad Opportunity
2021 Corporation Presentation I 43 Topoisomerase-I inhibitors (Irinotecan, Topotecan) PARP inhibitors Genotoxic stress Radiation, chemotherapeutics 1Yata et al. Mol. Cell 45, 2012; 2Chabalier-Taste et al., Oncotarget 2016 Jan 19; 7(3), 3Nakamura et al., Mol. Cell 81, 2021, 4van Vuget and Yaffe, Cell
Slide 44: Onvansertib is a Platform Molecule
2021 Corporation Presentation I 44 Onvansertib is a Platform Molecule Inhibit Ability of PLK1 to Repair DNA Inhibit Ability of PLK1 to Promote Cell Division (Mitosis) DNA Damaging Agent Microtubule (MT) Targeting Agents (Disruption of Mitosis) Chemo: Irinotecan & 5-FU PARP Inhibitors Radiation Pacli
Slide 45: Cardiff Oncology At-A-Glance
2021 Corporation Presentation I 45 Clinical-stage oncology company, developing new precision medicine treatment options for cancer patients in indications with the greatest unmet medical need Cardiff Oncology At-A-Glance Exchange Nasdaq: CRDF Cash, Cash Equivalents and Investments* $140.1M Quarterly