Slide 1: Development of a brain-penetrant EGFR inhibitor and non-invasive predictive biomarker for glioblastoma
Development of a brain-penetrant EGFR inhibitor and non-invasive predictive biomarker of response for glioblastoma David A. Nathanson, Ph.D. Associate Professor of Molecular and Medical Pharmacology UCLA Brain Tumor Program David Geffen School of Medicine at UCLA
Slide 2: Disclosures
Disclosures o Co-Founder and Shareholder o Katmai Pharmaceuticals, Trethera Corporation o Shareholder o Sofie Biosciences o Contracted Research/MTA/Consulting Agreements o Abbvie o Roche o Sanofi o Astra Zeneca o Erasca
Slide 3: Glioblastoma (GBM): A universally fatal malignancy
Glioblastoma (GBM): A universally fatal malignancy Standard of Care Targeted Therapy Immunotherapy Surgery/Chemo/Radiation 100 Checkpoint blockade CARs Percent survival Vaccine (e.g., EGFRvIII) 75 Median surivial: T cells 50 ~15 months 25 tumor 0 No improvement over Too early, yet ‘signal’ Steka B,
Slide 4: The epidermal growth factor receptor (EGFR) is frequently altered in GBM
The epidermal growth factor receptor (EGFR) is frequently altered in GBM 60 GBM Patients with Alteration (%) 40 20 0 FR ET FR M RA G K4 AS M M4 FGM2 PD CD3K PI M EG R F D D Targetable Oncogenic Drivers Brennan, Cameron W., et al. Cell. (2013) TCGA Cell, 2013
Slide 5: EGFR tyrosine kinase inhibitors (TKIs) have failed for GBM patients
EGFR tyrosine kinase inhibitors (TKIs) have failed for GBM patietns NSCLC or Breast Cancer Glioblastoma GBM Clinical Therapy Clinical Trial Result Therapy Result Trial Recurrent disease: NSCLC Improved PFS and OS vs Erlotinib Erlotinib Phase II (2004) Failed Phase III (2005) chemo Recurrent disease:
Slide 6: EGFR TKIs – designed for non-CNS cancer - have low brain penetration
EGFR TKIs – designed for non-CNS cancer - have low brain penetration Compound Penetration Company (Brand Name) Rate (%) Afatinib (Gilotrif) 0.7 Erlotinib (Tarceva) 8 Gefitinib (Iressa) 1.1 Lapatinib (Tykerb/Tyberb) 0.1 Bohn et. al., Targ. Oncol, 2016. Vivanco et. al., Can Discov, 2012.
Slide 7: Intracranial GBM fail to recapitulate responses to EGFR TKIs in subcutaneous models
Intracranial GBM fail to recapitulate responses to EGFR TKIs in subcutaneous models Subcutaneous PDX Erlotinib (10mg/kg) EGFR Intracranial PDX altered GBM Patient Erlotinib (10mg/kg)
Slide 8: The type of EGFR alteration impacts EGFR TKI affinity
The type of EGFR alteration impacts EGFR TKI affinity 35% of GBM 30% of patients NSCLC patients O N O O O N 25% of HN GBM patients Vivanco et. al, Cancer Discovery 2012 Graphic adapted from Gomez et. al., Cancer Biology & Medicine 2013
Slide 9: In patients with ECD mutations, both amplified WT EGFR and EGFRvIII are highly expressed
In patients with ECD mutations (e.g., EGFRvIII), both amplified Wild-Type EGFR and EGFRvIII are highly expressed WT EGFR EGFRvIII EGFRwt EGFRvIII vIII/WT co- expression EGFRvIII + cells co- express EGFRwt EGF EGF EGF wt wt wt viii WT only Biernat et. al., Brain P P P P Pathology, 2004 Fan et al, Can
Slide 10: Need for BBB penetrant EGFR TKI to target both EGFRvIII and amplified wild-type EGFR
Need for BBB penetrant EGFR TKI to target both EGFRvIII and amplified wild-type EGFR Tim Cloughesy, MD Michael Jung, PhD Professor Distinguished Professor An ideal EGFR TKI for GBM: (Neurology/Pharm) (Chemistry, Pharm) Tim Cloughesy, MD Michael Jung, PhD Available Professor Distinguished Professor P
Slide 11: Improved BBB penetrating properties of ERAS-801
Improved BBB penetrating properties of ERAS-801 4-anilinoquinazoline Core Scaffold Optimal for FDA Property BBB Approved ERAS-801 penetrance EGFR TKI ✔ Rotatable ≤5 Bonds Gefitinib Erlotinib Lipophilicity (clogP) ≤4 ✔ H-Bond Donors ≤4 ✔ H-Bond Acceptors ≤5 ✔ Polar Surface Area (Å2) ≤80 ✔ Molecular ≤
Slide 12: ERAS-801 shows high unbound brain exposures
ERAS-801 shows high unbound brain exposures Brain Penetrance (Unbound Drug) 150 Brain/Plasma (%) ** 100 ERAS-801 50 0 La inib 01 Ta ib AS o ER iss tin -8 t gr lo pa Er
Slide 13: ERAS-801 has potent activity against activated WTEGFR
ERAS-801 has potent activity against activated WTEGFR Erlotinib Lapatinib Tagrisso ERAS-801 1000 1000 1000 1000 100 100 100 100 10 10 10 10 EGFRi (nM) 0 1 0 1 0 1 0 1 p-EGFR Actin pEGFR Activity (%) pEGFR Signal 100 Erlotinib (4.13nM) Lapatinib (32.2nM) 75 Tagrisso (40.4nM) 50 ERAS-801 (1.13nM) 25 0
Slide 14: ERAS-801 is potent against EGFRvIII
ERAS-801 is potent against EGFRvIII Erlotinib Lapatinib Tagrisso ERAS-801 1000 1000 1000 1000 100 100 100 100 10 10 10 10 EGFRi (nM) 0 1 0 1 0 1 0 1 p-EGFRvIII Actin pEGFRvIII Signal pEGFR Activity (%) 100 Erlotinib (15.24nM) Lapatinib (4.14nM) 75 Tagrisso (17.65nM) 50 ERAS-801 (2.50nM) 25 0 -2 -1 0
Slide 15: ERAS-801 is specific for EGFR
ERAS-801 is specific for EGFR Primary Screen of ~490 WT and mutant kinases @ 10µM ERAS-801 Full IC50 of “hits” 4000 200nM 2000 IC50 (nM) 15 “hits” (>50% 100 inhibition at 10µM) 2 1 0.454nM 0 FG 1 HK LY R2 R R4 L YN B H A H 1 K3 R 2 HK Y R R B2 A6 B4 H FR AK EP ES D IPK EPLC EP A N IP E E EG G Eurofi
Slide 16: ERAS-801 is potent against EGFR altered patient derived GBM cells
ERAS-801 is potent against EGFR altered patient derived GBM cells with negligible activity against normal brain cells 80000 70000 Growth Inhibition (GI50, nM) 60000 50000 40000 ~100x selectivity for EGFR mutant and/or 30000 amp GBM cells vs normal astrocytes 20000 10000 8000 6000 4000 2000 0 GS220 G
Slide 17: ERAS-801 significantly extends EGFRvIII PDX survival at clinically relevant exposures
ERAS-801 significantly extends EGFRvIII PDX survival at clinically relevant exposures EGFRvIII PDOX Probability of Survival 100 Vehicle Erlotinib ALL at human Lapatinib equivalent plasma exposures *** Tagrisso 50 < lapatinib and ERAS-801 erlotinib human equiv exposures 0 0 25 50 75 100 Treatment (Da
Slide 18: A Preclinical Trial of ERAS-801
A Preclinical Trial of ERAS-801 GBM patient derived models Tumor Recurrence Tumor Recurrence Patient Sex MGMT Methylation Primar Subtype y Recurrent EGFRvIII Patient Sex Male EGFR Female PDGFRA RTK MET MGMT Methylation FGFR3 Unmethylate FGFR2 d Methylate FGFR1 d PIK3CA Molecular Subtype PIK3R1 Class
Slide 19: ERAS-801 improves outcome of >90% of EGFR mutant and/or amplified GBM PDXs
ERAS-801 improves outcome of >90% of EGFR mutant and/or amplified GBM PDXs All models -50 Significant survival benefit 0 60% Survival Benefit Tumor Recurrence 40% No Survival Benefit Primary 50 Survival Benefit (%) Recurrent Patient Sex 100 Male Total=30 Female 150 MGMT Methylation Unmethylated Meth
Slide 20: Challenge for Clinical Translation in GBM
Challenge for Clinical Translation in GBM – How do we know drug is reaching the tumor and having a meaningful biological effect
Slide 21: GBM tumor metabolism is regulated by aberrant EGFR signaling
GBM tumor metabolism is regulated by aberrant EGFR signaling 18F-fluorodeoxygluocse (18FDG) PET Mai et. al., Nature Medicine 2017 Babic et. al., Cell Metabolism 2013
Slide 22: Rapid dynamics in FDG PET may serve as a non-invasive biomarker
Rapid dynamics in FDG PET may serve as a non-invasive biomarker for biologically meaningful inhibition of EGFR signaling RAPID (hrs) Non-Invasive Biomarker of Metabolic Stress EGFRi Growth Arrest High Low Mai et. al., Nature Medicine 2017
Slide 23: ERAS-801 can robustly inhibit intracranial EGFR signaling at predicted clinically relevant doses
ERAS-801 can robustly inhibit intracranial EGFR signaling at predicted clinically relevant doses ERAS-801 Dose (mg/kg) Veh 3 10 25 75 Mouse # 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 pWTEGFR pEGFRvIII WTEGFR EGFRvIII pERK ERK pS6 S6
Slide 24: Dose dependent changes in FDG associated with changes in EGFR signaling
Dose dependent changes in FDG is associated with dose dependent change in EGFR signaling with ERAS-801 Vehicle 3 mg/kg 25mg/kg Coronal Sagittal Coronal Sagittal Coronal Sagittal High Low
Slide 25: ERAS-801 induced changes in FDG uptake predict outcome in orthotopic GBM PDX
ERAS-801 induced changes in FDG uptake predict outcome in an orthotopic EGFR altered GBM PDX Probability of Survival 100 Vehicle * ERAS-801 (3 mg/kg) 75 ERAS-801 (10 mg/kg) * 50 ERAS-801 (25 mg/kg) * ERAS-801 (75 mg/kg) ns 25 0 0 30 60 90 120 Treatment (Days)
Slide 26: FDG PET delineates ineffective EGFR TKIs compared to ERAS-801
Same PDX model: FDG PET delineates ineffective EGFR TKIs compared to ERAS-801 all administered at equivalent dose pre ERAS-801 pre Erlotinib High Low pre Tagrisso
Slide 27: Summary
Summary • EGFR is genetically altered in ~60% of GBM patients, yet available EGFR TKI have failed in GBM clinical trials ERAS-801 • Failure due to 1) insufficient BBB penetration and 2) inability to potently inhibit all oncogenic forms of EGFR found in GBM, including amp WT EGFR and ECD mutants • ER
Slide 28: Acknowledgment
Acknowledgment Funding and Support • R01 CA227089 (PI: NATHANSON) • UCLA SPORE (Project PIs: Cloughesy, Nathanson) • National Brain Tumor Society (NBTS) • Uncle Kory Foundation • Erasca