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Blinatumomab) for Minimal Residual Disease Positive (MRD+) B-Cell Precursor Acute Lymphoblastic Leukemia (ALL

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Blinatumomab) for Minimal Residual Disease Positive (MRD+) B-Cell Precursor Acute Lymphoblastic Leukemia (ALL CI-1 BLINCYTO® (blinatumomab) for Minimal Residual Disease Positive (MRD+) B-cell Precursor Acute Lymphoblastic Leukemia (ALL) Oncologic Drugs Advisory Committee Amgen Inc March 7, 2018 CI-2 Introduction Kathy Kross, MSc Executive Director, Global Regulatory Affairs Oncology Therapeutic Area Head Amgen Inc CI-3 Presentation Overview Introduction Kathy Kross, MSc Executive Director – Global Regulatory Affairs Overview of MRD+ ALL Jerald Radich, MD & Unmet Medical Need Fred Hutchinson Cancer Center Clinical Efficacy Janet Franklin, MD, MPH & Safety Executive Medical Director – Global Development Lead for BLINCYTO Benefit-Risk Gregory Friberg, MD Vice President – Oncology Global Development Clinician’s Aaron Logan, MD, PhD Perspective Division of Hematology/Oncology, UCSF CI-4 Expert Consultant Richard Simon, DSc Former Director, Biometric Research Program of the National Cancer Institute CI-5 BLINCYTO (blinatumomab) – Current Approved Indication BLINCYTO is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children CI-6 Blinatumomab Mechanism of Action CD3+ cytotoxic T-cell Anti-CD3 mAb T-cell cytotoxicity is redirected towards leukemia cells Production of inflammatory cytokines and proliferation of cytotoxic T-cells Blinatumomab Contact with leukemia (anti-CD19/anti-CD3 BiTE®) cells leads to cytotoxic T-cell activation Anti-CD19 mAb Through serial lysis, individual cytotoxic T-cells can induce CD19+ leukemia cell apoptosis of multiple leukemic cells CI-7 Blinatumomab Regulatory History Date Milestone 2014 Accelerated Approval December • Ph- R/R B-cell precursor ALL • 1° Endpoint - hematologic complete remission (CR) • Approximately doubled CR rate vs. historical SOC control 2017 Full Approval July • R/R B-cell precursor ALL in adults and children • Broaden indication to include Ph+ R/R ALL • Confirmatory phase 3 trial demonstrated significant OS over chemotherapy • Reduction of leukemic burden (CR) correlated with OS 2017 sBLA submitted for MRD+ B-cell ALL September CI-8 Proposed Indication BLINCYTO is indicated for the treatment of minimal residual disease (MRD)-positive B-cell precursor acute lymphoblastic leukemia (ALL) CI-9 Minimal Residual Disease (MRD) in ALL MRD is a direct measurement of ALL disease burden – Presence of leukemic cells below the detection of conventional morphologic measures MRD+ patients in hematologic CR are not in full remission Presence of MRD is the strongest prognostic factor for relapse – Outcomes in MRD+ patients are quite poor Patients with MRD+ ALL have limited options – No approved therapy for MRD+ patients CI-10 3 Studies for MRD+ ALL Study 202 Study 203 (BLAST) Study 148 Exploratory Safety/Efficacy Historical Safety/Efficacy Phase 2 Comparator Phase 2 N=116 N=287 N=21 Study 203 vs Study 148 Propensity Score Analysis CI-11 Rationale for Blinatumomab Use in MRD+ ALL Blinatumomab is efficacious in MRD+ ALL – 78% achieved complete MRD response (undetectable MRD) after 1 cycle – Median relapse-free survival (RFS) • Complete MRD responders 23.6 months vs. non-responders 5.7 months • Supported by comparison to historical data (Study 148) in the propensity score analysis Clinical outcomes are better for MRD-negative patients Adverse events well characterized and managed through product labeling and existing REMS Favorable benefit-risk CI-12 Presentation Overview Introduction Kathy Kross, MSc Executive Director – Global Regulatory Affairs Overview of MRD+ ALL Jerald Radich, MD & Unmet Medical Need Fred Hutchinson Cancer Center Clinical Efficacy Janet Franklin, MD, MPH & Safety Executive Medical Director – Global Development Lead for BLINCYTO Benefit-Risk Gregory Friberg, MD Vice President – Oncology Global Development Clinician’s Aaron Logan, MD, PhD Perspective Division of Hematology/Oncology, UCSF CM-1 Overview of MRD+ ALL Jerald Radich, MD Fred Hutchinson Cancer Research Center CM-2 Overview of Acute Lymphoblastic Leukemia (ALL) 100 ALL is rare ~6,600 new cases (~2,400 adults) 75 N=609 adults – Majority of ALL cases are B-lineage, 50 Philadelphia chromosome-negative ALL Percent Male: 8% 25 2P = 0.006 Female: 3% Treatment goals 0 – CR achieved in > 80% 0 1 2 3 4 5 – Overall survival (OS) ~40% Time (years) 100 Patients Events OE Patients who do not obtain a CR or Related transplant 42 32 0.7 Matched unrelated 65 52 0.7 75 relapse have a very low likelihood of Autograft 13 11 0.6 Chemotherapy 182 171 1.3 survival 50 Auto: 15% 2P < 0.00001 Percent – 5 yr OS < 10% Sib allo: 23% 25 – Transplant can salvage some MUD: 16% Chemo: 4% relapsed patients 0 0 1 2 3 4 5 Time (years) Fielding et al. Blood 2007. CM-3 BCR-ABL MRD and Outcome in CML Relapse Post-allogeneic Transplant EFS After Imatinib Therapy Probability Relapse of Probability Clinical Radich Blood. 1997. Hughes NEJM. 2003. CM-4 Minimal Residual Disease (MRD) Has Great Clinical Utility 30-50% of adult patients with ALL who achieve hematologic CR following chemotherapy have evidence of disease using more sensitive tests (MRD) MRD reflects ALL disease burden MRD is strongest prognostic feature for relapse after achieving CR CM-5 Minimal Residual Disease (MRD) Presence of Malignant Cells Below Detection Limits of Microscopy 100 Hematologic relapse Morphology (limit 5%) 10-1 Complete remission (CR) 10-2 with MRD+ MRD Detection Methods 10-3 -3 -4 Molecular Flow cytometry (limit 10 to 10 ) relapse 10-4 PCR of Ig or TCR (10-4 to 10-5) 10-5 -5 -6 CR without MRD NGS of Ig or TCR (limit 10 to 10 ) -6 Proportion Proportion of Malignant Cells 10 0 Time Adapted from Bruggemann M, et al. Blood. 2012;120:4470-4481. CM-6 The ALL Patient Experience Chemo 12 Day 30 bone marrow – If no CR alternative RX Relapse – If CR continued therapy At relapse Cells 10 Cells – Lower chance for CR with chemo – Low chance of transplant working Remission MRD: 1. An indicator of relapse risk Day 2. A therapeutic target 30 Time CM-7 MRD Status is Associated With CR and Survival Probability of Continuous CR Probability of Survival 1.0 1.0 80% 74% (N=384) P < 0.0001 P < 0.0001 0.8 (N=384) 0.8 MRD- MRD- 0.6 0.6 42% 35% (N=120) 0.4 (N=120) 0.4 MRD+ MRD+ 0.2 0.2 0.0 0.0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 11 Years Years Adapted from Gökbuget N, et al. Blood. 2012;120:1868-1876. CM-8 MRD-Positivity is Associated with Poor Outcome in Children and Adults OS for Pediatric ALL: 5 studies with 2,876 patients OS for Adult ALL: 5 studies with 779 patients 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 Survival ProbabilitySurvival 0.2 ProbabilitySurvival 0.2 0.0 HR = 0.28 (0.19 to 0.41) 0.0 HR = 0.28 (0.20 to 0.39) 0 5 10 15 0 5 10 15 Time (years) Time (years) Adapted from Berry DA, et al. JAMA Oncol. 2017;3(7):e170580. doi:10.1001/jamaoncol.2017.0580. CM-9 Meta-Analysis: MRD and EFS in Children and Adults EFS for Pediatric ALL: 20 studies with 11,249 patients EFS for Adult ALL: 16 studies with 2,069 patients 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 Survival ProbabilitySurvival 0.2 Probability Survival 0.2 0.0 HR = 0.23 (0.18 to 0.28) 0.0 HR = 0.28 (0.24 to 0.33) 0 5 10 15 0 5 10 15 Time (years) Time (years) Adapted from Berry DA, et al. JAMA Oncol. 2017;3(7):e170580. doi:10.1001/jamaoncol.2017.0580. Association of MRD and EFS is Remarkably Similar CM-10 Across Studies EFS by ALL Peds Studies (with 95% CIs) EFS by ALL Adult Studies (with 95% CIs) Imashuku (2003) Tucunduva (2014) Eckert (2013) Bruggemann (2005) Stow (2010) Ravandi (2013) Bowman (2011) Stirewalt (2003) Kang (2009) Mortuza (2002) Pulsipher (2014) Beldjord (2014) Vilmer (2000) Foster (2011) Krampera (2002) Borowitz (2015) Gokbuget (2012) Chen (2012) Patel (2009) Vora (2013) Pane (2005) Salah-Eldin (2014) Ribera (2014) Borowitz (2008) Holowiecki (2008) Sutton (2014) Bassan (2009) Eckert (2012) Lee (2012) Velden (2012) Raff (2006) Conter (2010) Flohr (2008) Spinelli (2007) Meleshko(2011) MA – standard Zhou (2007) MA – Bayesian MA – standard 0.005 0.010 0.025 0.050 0.100 0.200 0.500 1.000 2.000 0.005 0.010 0.025 0.050 0.100 0.200 0.500 1.000 2.000 MA – Bayesian Hazard Ratio Hazard Ratio Favors No MRD Favors MRD Favors No MRD Favors MRD Relative Sample Size 0.025 0.100 0.250 0.500 CM-11 Effect of MRD is Independent of Other Covariates Subset Analysis of EFS for MRD ALL Favors Favors HR (95% Exact CI) Absence Presence Subset of MRD of MRD Adult Pediatric MRD Detection Flow cytometry 0.32 (0.20, 0.51) 0.27 (0.20, 0.36) Method: PCR 0.24 (0.18, 0.32) 0.20 (0.11, 0.35) MRD Cutoff: 10-4 0.29 (0.21, 0.39) 0.30 (0.20, 0.46) < 10-4 0.21 (0.14, 0.32) 0.18 (0.11, 0.29) MRD Detection Induction 0.33 (0.24, 0.44) 0.20 (0.15, 0.28) Period: Consolidation 0.25 (0.18, 0.36) 0.20 (0.15, 0.28) Other period 0.18 (0.08, 0.41) − Cytogenetics: Ph- 0.28 (0.22, 0.37) 0.17 (0.07, 0.42) Ph+ 0.34 (0.22, 0.53) − 0.05 0.10 0.20 0.40 0.801.0 Hazard Ratio Adapted from Berry DA, et al. JAMA Oncol.
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