CI-1
Quizartinib in Relapsed/Refractory FLT3-ITD Acute Myeloid Leukemia
US Food & Drug Administration Oncologic Drugs Advisory Committee May 14, 2019 CI-2
Introduction
Eric Richards, MS, MPH Vice President, Oncology Head Regulatory Affairs Daiichi Sankyo, Inc. CI-3
Proposed Indication and Dosing Regimen Proposed Indication: Quizartinib is indicated for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML) which is FLT3-internal tandem duplication (ITD) positive Proposed dosage – 30 mg once daily for the first 2 weeks – 60 mg once daily thereafter CI-4
What You Will Hear Today
Disease • FLT3-ITD mutation is a negative prognostic factor in AML Background • R/R FLT3-ITD AML has a dismal prognosis
• Treatment results in a early, clinically relevant survival benefit versus an active Efficacy control, and demonstrates efficacy consistent with its unique pharmacology
Safety • Well-characterized and acceptable safety profile • Risk of QTc prolongation is manageable
Clinical • Quizartinib, as an oral monotherapy, is a novel effective treatment option for Perspective patients that provides improvement to the existing standard of care
QTc=corrected QT interval; R/R=relapsed/refractory. CI-5
Topics for Discussion Favorable Benefit-Risk Profile – Efficacy Data Are Credible • Updated OS analysis reduced the amount of missing data • Sensitivity analyses show nearly identical outcomes as the primary OS analysis • Corrected EFS analysis is consistent with the OS treatment effect • Higher HSCT rate with quizartinib is a direct result of the treatment effect
– QTc Risks Are Manageable • QTc has been thoroughly studied • Proposed dosing regimen & monitoring manage this risk
EFS=event-free survival; HSCT=hematopoietic stem cell transplantation; OS=overall survival. CI-6
Agenda
Introduction Eric Richards, MS, MPH Daiichi Sankyo, Inc.
Disease Background/Unmet Need Mark Levis, MD, PhD Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Clinical Development and Efficacy Jorge Cortes, MD MD Anderson Cancer Center
Safety Youngsook Choi, MD Daiichi Sankyo, Inc.
Clinical Perspective Jorge Cortes, MD MD Anderson Cancer Center CI-7
List of Consultants
Gary G. Koch, PhD Professor, Department of Biostatistics Gillings School of Global Public Health University of North Carolina at Chapel Hill
Peter R. Kowey, MD Professor of Medicine and Clinical Pharmacology Jefferson Medical College Lankenau Hospital CU-1
Disease Background/Unmet Need
Mark Levis, MD, PhD Program Co-Leader, Hematologic Malignancies and Bone Marrow Transplant Program Director, Adult Leukemia Service Johns Hopkins Sidney Kimmel Comprehensive Cancer Center CU-2
AML in the United States
~19,520 new cases annuallya 30 Age-specific SEER incidence report rates for AML 25.1 25 ~10,670 deaths annually 22.7
Primarily a disease of older adults 20 16.8
– Median age 68 years 15 Outcomes have improved 11.0 10 9.1 but prognosis remains poor 5.7 5.3 4.5 5
FLT3-ITD mutations are a % group, age by AML cases New recognized negative prognostic 0 b <20 20-34 35-44 45-54 55-64 65-74 75-84 >84 factor Age, yr
a Reprinted from NCI SEER, https://seer.cancer.gov/statfacts/html/amyl.html. b Pratz KW, Levis M. Blood. 2017;129(5):565-571. CU-3
Relapsed AML: Duration of First Remission Is Prognostic for OS
ECOG-ACRIN meta-analysis R/R AML, n=3012a Cephalon 204 trial FLT3-ITD AML, n=48b – CR1 duration ≤12 mo = 4.8 mo median OS – CR1 duration ≤6 mo = 3.5 mo median OS – CR1 duration >12 mo = 10.8 mo median OS – Treated with intensive salvage chemotherapy (MEC)
1.0 100 0.9 0.8 80 0.7 CR1 ≤12 months CR/CRp rate 12.5% CR1 >12 months 0.6 60 0.5 0.4 40
0.3 survival Percent 0.2 20
Probability of overall survival of overall Probability 0.1 0.0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 0 10 20 30 40 Year Months
CR1=first complete response; CRp=complete remission with incomplete platelet recovery; MEC=mitoxantrone, etoposide, intermediate-dose cytarabine. a Reprinted from Ganzel C, et al. Am J Hematol. 2018;93:1074-1081. b Reprinted with permission of Pratz KW, Levis M. Blood. 2017;129(5):565-571; conveyed through Copyright Clearance Center, Inc. CU-4
FLT3—Internal Tandem Duplications (ITD)
ITDs most common mutations in FLT3a – Found in ~25% of newly diagnosed Extracellular b Immunoglobulin-like loops domain AML patients – Median age is 55 yearsc FLT3-ITD AML evolves from diagnosis Cell Membrane Transmembrane domain to relapse – More dependent on FLT3 pathway ITDs Juxtamembrane at relapse (insertion of 3 to > 400 bp) domain TKD1 Tyrosine kinase TKD2 domain
a Reprinted from Patnaik MM, et al. Leuk Lymphoma. 2018;59(10):2273-2286. b Levis M. Blood. 2011;117;6987-6990. c Schneider F, et al. Ann Hematol. 2012;91(1):9-18. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/Licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. CU-5 More Treatment Options Are Needed 2019 NCCN Guidelines for R/R AML
Early • Clinical trial (strongly preferred) (<12 mo) • Chemotherapy followed by HSCT
Age <60 Less aggressive therapy: • Clinical trial (strongly preferred) • Hypomethylating agents Late • Chemotherapy followed by HSCT (azacitidine or decitabine) (≥12 mo) • Repeat prior successful induction • Low-dose cytarabine (category 2B) regimen R/R AML Therapy for AML with FLT3 mutation • Clinical trial (strongly preferred) Early • Gilteritinib • Chemotherapy followed by HSCT (<12 mo) • Hypomethylating agents • Best supportive care (azacitidine or decitabine) + sorafenib Age ≥60 • Clinical trial (strongly preferred) (FLT3-ITD mutation) • Repeat prior successful induction Late regimen (≥12 mo) • Chemotherapy followed by HSCT • Best supportive care
NCCN=National Comprehensive Cancer Center. a Reprinted from NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3. 2019. CU-6
Quizartinib: The Most Potent and Selective FLT3 TKI Type II tyrosine kinase inhibitor (TKI)a High selectivity and potency (Kd 1.3 nM)b Stabilizes the inactive conformation of FLT3a Blocks FLT3-ITD–dependent cell proliferationc Long terminal half-life (~ 3 days)d
a Zorn JA, et al. PLoS ONE. 2015;10(4):e0121177. b Davis MI, et al. Nat Biotechnol. 2011;29:1046-1051. c Quizartinib Module 2.5. d Li et al. Blood. 2012;120:4327. CU-7 Quizartinib Induces Rapid and Potent Blast Reduction, Often With Incomplete Hematologic Recovery (CRi)
FLT3 inhibition FLT3 Partial, selective c-Kit inhibition c-Kit
Quizartinib (μM in plasma)
Pre-treatment Day 15 Day 29
Quizartinib Potent and selective Type II TKI
Blasts Myelocytes Neutrophils Quizartinib nM Complete remission with incomplete Top left panel: Cortes JE, et al. J Clin Oncol. 2013;31:3681-3687. hematologic recovery Bottom left panel: Sexauer A, et al. Blood. 2012;120:4205-4214. Top right panel: Galanis A, et al. Blood. 2014;123:94-100. Center panel: Davis MI, et al. Nat Biotechnol. 2011;29:1046-1051. Bottom left panel: Galanis A, et al. Haematologica. 2015;100:e77-79. CU-8 IWG Criteria Modified to Better Reflect Pharmacologic Effect of Quizartinib and Guide Treatment Decisions
QuANTUM-R response criteria IWG definition Sponsor modification CR • <5% blasts in a bone marrow aspirate • Transfusion independent: No RBC sample transfusion within 4 weeks and no platelet • No blasts with Auer rods transfusion within 1 week of assessment • No extramedullary disease • ANC >1000/μL • Platelets ≥100,000/μL • Absence of circulating blasts • Transfusion independent CRp N/A • Meet criteria for CR except for incomplete platelet recovery (<100,000/μL) CRi • Meet criteria for CR except ANC • Meet criteria for CR except ANC <1000/μL <1000/μL or platelets <100,000/μL and/or platelets <100,000/μL • Transfusion independent • Transfusion independence not required CRc N/A • CR + CRp + CRi
ANC=absolute neutrophil count; IWG=International Working Group; N/A=not applicable; RBC=red blood cell. CU-9
Summary
Relapsed/refractory FLT3-ITD AML associated with poor prognosis – Limited treatment options despite recent advances Inhibition of FLT3-ITD effective across multiple clinical scenarios Quizartinib is most potent and selective FLT3 inhibitor with unique pharmacology – Type II TKI yielding rapid and prolonged suppression of FLT3-ITD clones – Partial suppression of c-Kit at proposed clinical doses results in delayed hematologic recovery – CRi is the most accurate measure of its pharmacological activity CE-1
Clinical Development and Efficacy
Jorge Cortes, MD Deputy Chair and Professor of Medicine, Department of Leukemia MD Anderson Cancer Center CE-2 Comprehensive Clinical Development Program Across Ages, Disease Stages, and Dose Ranges
PHASE 1 PHASE 2 PHASE 2b PHASE 3 Safety Efficacy and Safety Efficacy and Safety Efficacy and Safety FLT3-ITD or WT FLT3-ITD or WT FLT3-ITD FLT3-ITD AML R/R AML R/R AML R/R AML ≥18 years Cohort 1: ≥18 years ≥18 years Unfit or ≥1st salvage ≥60 years, 1st salvage 2nd salvage Mostly 1st salvage Cohort 2: POPULATION ≥18 years, 2nd salvage
N n=76 n=333 n=76 n=367 12 mg - 450 mg × 14 days Initially: 200 mg 30 mg or 60 mg 30 mg 60 mg (n=51); Subsequently: 200 mg - 300 mg QD 135 mg (males) and DOSE (n=25) 90 mg (females)
QD=once daily; WT=wild type. CE-3
Phase 2 Key Efficacy Results Phase 2a (FLT3-ITD population only) Phase 2bb Cohort 1 Cohort 2 n=112 n=136 n=38 n=38 >60 years, >18 years, 30-mg arm, 60-mg arm, 1st salvage 2nd salvage 2nd salvage 2nd salvage
Best response, % CRc (CR+CRp+CRi) 56 46 47 47 PR 21 29 13 24 Duration of CRc, weeks Median 12 11 4 9 Survival, weeks Median 25 24 21 27 (95% CI) (21, 30) (21, 27) (18, 25) (17, 35) CI=confidence interval; PR=partial response. Also included patients who had been refractory to or relapsed after hematopoietic stem cell transplant. a Cortes J, et al. Lancet Oncol. 2018;19(7):889-903. b Cortes JE, et al. Blood. 2018;132(6):598-607. CE-4
Pivotal Phase 3: QuANTUM-R Study Design
FLT3-ITD AML • Age, ≥18 years • Refractory AML or relapse within Quizartinib Quizartinib HSCT 6 months of first remission or HSCT continuation up • ≥1 cycle of standard-dose - anthracycline- or mitoxantrone- containing induction therapy Follow randomization Salvage chemotherapy 1 • ≥3% FLT3-ITD allelic ratio :
2 HSCT (LoDAC, MEC, or FLAG-IDA)
Primary endpoint Optional treatments Overall survival (OS) HSCT based on institutional policies • Disease control and reduction Secondary and exploratory endpoints • Performance Status Event-free survival (EFS), • Comorbidities CRc rate and duration, transplant rate • Donor availability
FLAG-IDA=fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin; LoDAC=low-dose cytarabine; MEC=mitoxantrone, etoposide, intermediate-dose cytarabine. CE-5
Dosing Regimen for Phase 3
Initial dose 30 mg once daily for 2 weeks
Escalate to 60 mg once daily if QTc ≤450 ms
Dose adjustments – Reduce for AE (including QTc prolongation) – Reduce for concomitant strong CYP3A inhibitor • 30 mg 20 mg • 60 mg 30 mg
AE=adverse event; CYP3A=cytochrome P450 3A. CE-6
CONSORT Diagram
Screened (n=563) Randomized 2:1 (n=367)
Randomized to quizartinib Randomized to salvage chemotherapy (n=245) (ITT) (n=122) (ITT)
Did not receive treatment (n=4) Did not receive treatment (n=28) Received treatment (n=241) Received treatment (n=94) –FLAG-IDA (n=47) –MEC (n=25) –LoDAC (n=22)
Deaths (n=190) Deaths (n=86) Censored (n=55) Censored (n=36) –Censored <8 weeks (n=1) –Censored <8 weeks (n=17)
ITT=intent to treat. CE-7
Baseline Patient Characteristics Quizartinib Salvage monotherapy chemotherapy n=245 n=122 Median age, yr (range) 55 (19-81) 58 (18-78) <65 yr, % 74 73 ≥65 to <75 yr, % 22 25 ≥75 yr, % 5 3 ECOG performance status, % 0 36 39 1 54 44 2 11 17 Antecedent hematologic disorder, % 7 7 Cytogenetic risk status, % Favorable 5 7 Intermediate 78 66 Unfavorable 9 12 Unknown 8 16
ECOG=Eastern Cooperative Oncology Group. CE-8
Baseline Characteristics
Quizartinib Salvage monotherapy chemotherapy Disease characteristic n=245 n=122 Refractory, n (%) 80 (33) 41 (34)
Relapse, Post-HSCT, n (%) 56 (23) 27 (22)
Relapse, No-HSCT, n (%) 109 (45) 54 (44)
Median duration of prior CR, months 3.5 3.7 CE-9
Quizartinib Prolongs Overall Survival (ITT)
HR (95% CI): 0.76 (0.58, 0.98) P=0.0177 (1-sided, stratified log-rank) 1.0 <0.0231 (significance boundary) Median overall Patients Patients survival, months with events censored 0.8 (95% CI) n, (%) n, (%) Quizartinib 6.2 190 55 (n=245) (5.3, 7.2) (77.6%) (22.4%) 0.6 Salvage chemo 4.7 86 36 (n=122) (4.0, 5.5) (70.5%) (29.5%) 0.4
0.2 Probability of alive of patients Probability 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Patients at risk Time, months Quizartinib 245 224 173 122 89 71 53 48 38 36 27 20 20 16 11 10 Salvage chemo 122 77 59 38 28 21 15 13 13 12 12 10 9 7 7 6 HR=hazard ratio. CE-10
Overall Survival Across All Pre-Specified Subgroups
Favors Favors Quizartinib Salvage chemo Quizartinib Salvage chemo Category Subgroup n HR (95% CI) Category Subgroup n HR (95% CI)
All 276 0.76 (0.58, 0.98) All 276 0.76 (0.58, 0.98)
Age group <65 yr 194 0.81 (0.59, 1.09) FLT3-ITD VAF ≥3-≤25% 71 0.88 (0.54, 1.44)
≥65 yr 82 0.64 (0.40, 1.02) >25-≤50% 99 0.69 (0.45, 1.05)
Sex Female 147 0.94 (0.65, 1.36) >50% 104 0.69 (0.45, 1.05)
Male 129 0.62 (0.43, 0.89) Prior HSCT Yes 74 0.64 (0.39, 1.05)
Pre-selected High-intensity chemo 209 0.83 (0.62, 1.11) No 202 0.79 (0.59, 1.07) salvage therapy Low-intensity chemo 67 0.52 (0.31, 0.88) Cytogenetics Favorablea 16
Response to Refractory 81 0.79 (0.49, 1.26) Intermediate 208 0.76 (0.56, 1.03) prior therapy Relapsed, no HSCT 125 0.78 (0.53, 1.14) Unfavorable 23 0.49 (0.21, 1.16)
Relapsed, post-HSCT 70 0.70 (0.42, 1.16) Unknown 29 1.15 (0.55, 2.41)
0.1 1 0.1 1 Hazard ratio (95% CI) Hazard ratio (95% CI)
VAF=variant allelic frequency. a HR (95% CI) not calculated for subgroups with <30 patients. CE-11
Evaluation of Factors Impacting the Interpretation of OS
Two factors that may impact OS: – Patients who were randomized, but not treated (RNT) – Patients who were censored for OS early (<8 weeks)
Approach to evaluating their impact: – Targeted OS update – Sensitivity analyses CE-12
Targeted OS Data Update Significantly Reduced Early Censoring
Original OS Analysis Updated OS Analysisa Censored <8 weeks Censored <8 weeks Quizartinib (n=245) 1 1 Salvage chemo (n=122) 17 9 HR (95% CI) 0.76 (0.58, 0.98) 0.77 (0.60, 0.99) P valueb 0.0177 0.0190
a FDA-requested targeted OS analysis for patients whose last contact came more than 3 months before the date of the study cutoff. b Stratified log-rank test, 1-sided P value. CE-13
Sensitivity Analysis: Assumes RNT and RT Patients Are Similar
ITT RNT RT Quizartinib 245 4 241
Salvage chemotherapy 122 28 94
Original Analyses HR (95% CI) ITT Population 0.76 (0.58, 0.98)
Sensitivity Analyses Median HR (95% CI) 28 RNT would have had a similar OS distribution as the 94 RTa 0.75 (0.58, 0.98)
RT=randomized and treated. a Resampling considering randomization strata. CE-14
Sensitivity Analysis: Assumes RNT and RT Patients Are Different
RNT Censored Remaining Total <8 wk Patients Quizartinib 4 0 4 Salvage chemotherapy 28 7 21
Original Analyses HR (95% CI) ITT Population 0.76 (0.58, 0.98)
Sensitivity Analyses Median HR (95% CI) 28 RNT could have had a different OS distribution as the 94 RTa 0.76 (0.59, 0.98)
a Resampling without considering randomization strata. CE-15
Sensitivity Analysis for Early OS Censoring (Updated OS)
Censored Remaining Total (ITT) <8 weeksa Patients Quizartinib 245 1 244 Salvage chemotherapy 122 9 113
Original Analyses HR (95% CI) ITT Population 0.76 (0.58, 0.98)
Sensitivity Analysis Median HR (95% CI) 10 patients censored early would have had similar outcomes as the 0.76 (0.59, 0.98) remaining patients who were not censored earlyb a Corresponding to EC8 in the FDA briefing document. b Resampling considering randomization strata. CE-16
FDA Stress Tests for OS
Optimistic imputation of survival for the salvage chemotherapy arm For patients censored <8 weeks: – Assumes that patients censored early could not have died before 8 weeks • However, 22% of patients treated with chemotherapy experienced early death
For RNT patients with survival follow-up >8 weeks: – Assumes patients would have survived as long or longer had they received study treatment CE-17
Secondary Endpoint: Event-Free Survival (ITT)
Planned EFS analysis: – HR (95% CI): 0.90 (0.70, 1.16) – P=0.1071 (1-sided, stratified log-rank) – We noted incorrect timing for censoring patients who were alive without post-baseline response assessments
Corrected EFS analysis: – HR (95% CI): 0.78 (0.61, 1.01) – P=0.0147 (1-sided, stratified log-rank)
EFS is defined as the time from randomization to the earliest of the following events: failure to achieve CRc, relapse, or death from any cause. CE-18
Best Response Rates (ITT)
Percentage (95% CI) Quizartinib monotherapy Salvage chemotherapy n=245 n=122 CRca 48 (42, 55) 27 (19, 36) CR 4 (2, 7) 1 (0, 5) CRp 4 (2, 7) 0 (0, 3) CRi 40 (34, 47) 26 (19, 35) PR 21 (16, 27) 3 (1, 8) No response 25 (20, 31) 37 (28, 46) Non-evaluable 5 (3, 9) 33 (25, 42)
a Modified IWG criteria. CE-19
Additional Efficacy Endpoints
Quizartinib Salvage monotherapy chemotherapy n=245 n=122 Median time to CRc, weeks 4.9 4.0 12.1 5.0 Median duration of CRc, weeks (95% CI) (10.4, 27.1) (3.3, 12.6) % patients proceeding to HSCT, (n) 32% (79a) 12% (14)
a Includes 1 autologous HSCT. CE-20
Transfusion Independence With Quizartinib
Independent Days Dependent at post-baseline independent N baseline, n (≥56 days) (mean) All patients 241 205 22% 255 Achieved CRc 118 102 34% 294 Failed to achieve CRc 123 103 11% 131 CE-21
Quizartinib Demonstrates OS Benefit in R/R FLT3-ITD AML
OS benefit established in a randomized, active-controlled, Phase 3 study – HR: 0.76; P=0.0177 Efficacy results are credible and consistent – Sensitivity analyses for missingness support the primary analysis – Secondary endpoint of EFS is consistent with the OS results – Additional efficacy endpoints are supportive Anti-leukemic activity observed across Phase 2 and 3 studies CS-1
Safety
Youngsook Choi, MD Executive Director, Clinical Safety Daiichi Sankyo, Inc. CS-2 Quizartinib Safety Experience QuANTUM-R and R/R AML Pool QuANTUM-R Dosing Quizartinib Monotherapy Salvage chemotherapy (N=94) Regimen (Oral QD) (N=241) • MEC/FLAG-IDA (IV) • LoDAC (SC) Median age, 55 (19, 81) 57 (21, 78) years ≥65 years 64 (27%) 24 (26%) R/R AML Pool (N=673) Doses 30 mg (n=38) 60 mg (n=277; 241 from QuANTUM-R) >60 mg [90, 135, 200, 300 mg] (n=358) Median age, 59 (19-86) years ≥65 years 237 (35%) CS-3 Differences in Treatment Duration and Safety Observation Periods QuANTUM-R
Quizartinib (oral once daily) Median: 97 days (1, 1182) N=241 101.9 patient-years Safety Monitoring
Chemotherapy Median: 1 (28-day) cycle N=94 3.7 patient-years
MEC Safety Monitoring
FLAG-IDA Safety Monitoring
LoDAC Safety Monitoring
Treatment duration for salvage chemotherapy (MEC, FLAG-IDA, and LoDAC) was a median of 1 cycle (max: 2 cycles). Overall treatment duration includes exposure before and after HSCT. CS-4 Safety Experience in Full Study Period QuANTUM-R
Quizartinib Salvage monotherapy chemotherapy n=241 n=94 Subjects with TEAEs, n (%) 238 (98.8) 93 (98.9) Grade ≥3 211 (87.6) 74 (78.7) Grade ≥4 143 (59.3) 51 (54.3) Serious adverse events 168 (69.7) 37 (39.4) Associated with study drug discontinuation 44 (18.3) 1 (1.1) Associated with fatal outcome 36 (14.9) 11 (11.7) CS-5 Safety Experience in Cycle 1 QuANTUM-R (Days 1 to 28)
Patients, n (%) Quizartinib Salvage monotherapy chemotherapy n=241 n=94 TEAEs 227 (94.2) 93 (98.9) Grade ≥3 160 (66.4) 69 (73.4) Serious adverse events 80 (33.2) 33 (35.1) Associated with fatal outcome 4 (1.7) 11 (11.7) Associated with discontinuation 10 (4.1) 1 (1.1) CS-6 Common TEAEs in Cycle 1 (≥10%) QuANTUM-R (Days 1 to 28)
Nausea Anemia Electrocardiogram QT prolonged Thrombocytopenia Pyrexia Hypokalemia Febrile neutropenia Vomiting Fatigue Diarrhea Neutropenia WBC count decreased Platelet count decreased Neutrophil count decreased Headache Quizartinib (n=241) Decreased appetite Edema peripheral Salvage chemotherapy Constipation LoDAC (n=22) Cough Stomatitis Med/High intensity (n=72) Abdominal pain Insomnia -5050 -4040 -3030 -2020 -1010 0 10 20 30 40 50 Patients, % CS-7 Time Spent With Selected Serious or Severe AEs in Cycles 1 and 2 QuANTUM-R (56 Days) Selected events: Febrile neutropenia; pneumonia; lung infection; sepsis; septic shock; intracranial, subdural, and cerebral hemorrhage; syncope; QT prolongation
Quizartinib Salvage monotherapy chemotherapy n=241 n=94 Patients with selected serious or severe AEs, % 29.0 34.0 Mean % of time 6.8 13.9 SD 16.0 25.9 Min, max (%) 0, 100 0, 96 CS-8 Common TEAEs All Grades (≥20%) and Grade ≥ 3 in Quizartinib Arm QuANTUM-R Full Study Period
Nausea Pyrexia Anemia Febrile neutropenia Vomiting Hypokalemia Diarrhea Fatigue Electrocardiogram QT prolonged Thrombocytopenia Cough Headache Edema peripheral TEAEs any grade Neutropenia Grade ≥3 Decreased appetite Dyspnea 0 10 20 30 40 50 60 70 80 90 100 Patients, % Other TEAEs ≥5% include: leukopenia, pneumonia, sepsis, and WBC, platelet and neutrophil count decreased. TEAEs Associated With Discontinuation of CS-9 Study Drug in ≥1% Patients QuANTUM-R Full Study Period
Patients, n (%) Quizartinib monotherapy Preferred Term n=241 Any TEAE Associated with Discontinuation of Study Drug 44 (18.3) Infections 15 (6.2) Pneumonia 6 (2.5) Sepsis 2 (0.8) Blood & Lymphatic Disorders 7 (2.9) Febrile neutropenia 2 (0.8) Leukocytosis 2 (0.8) Intracranial/Cerebral hemorrhage 4 (1.7) Hemorrhage intracranial 3 (1.2) Cerebral hemorrhage 1 (0.4) Graft vs host disease in intestine 3 (1.2) CS-10 Differentiation Syndrome, Acute Febrile Neutrophilic Dermatosis QuANTUM-R
Quizartinib Salvage monotherapy chemotherapy n=241 n=94 Differentiation Syndrome (DS) n (%) n (%) Investigator Reported 0 0 Montesinos Criteria 67 (28) 34 (36) DS per Sponsor’s Assessment (Possible) 12 (5) N/D Treated with Steroids 8 - Investigator reported 8 (3.3) 1 (1) Acute Febrile Neutrophilic Dermatosis (AFND) Overlap with Possible DS 1 -
N/D= individual medical review not performed. CS-11
QT Prolongation
1. QT-based dosing and risk mitigation 2. QTc exposure response modeling 3. QTc Outlier Analysis 4. Clinical arrhythmia events CS-12 QT Monitoring and Risk Mitigation QuANTUM-R
Protocol-defined QT monitoring and mitigation strategy – QT-based dosing regimen • Lower starting dose for 2 weeks; escalation if QTcF ≤450 ms at Day 15 • Dose reduced for concomitant strong CYP3A inhibitors • Grade 2/3 (>480/>500 ms) → dose interruption and/or reduction • Grade 4 (torsades) → dose discontinuation – Use of QT prolonging medications when necessary – ECG monitoring • Cycle 1 (D1, D2, D8, and D15) • Day 1 of each subsequent cycle CS-13 QT Monitoring and Risk Mitigation With Quizartinib Dose Modification QuANTUM-R Median relative dose intensity (RDI) 89% ECGs obtained in 96% of all visits 73% of patients used QT-prolonging drugs
38 patients with Grade 2/3 QT prolongation – 33 (87%) dose modification/interruption – 2 (5%) QTcF normalized on follow-up – 3 (8%) withdrew due to AML disease progression/HSCT CS-14
Exposure-Related QTc Increase QT prolongation by IKs inhibition Predicted mean QTc increase (Cmax at steady state for 60 mg) – 22.1 ms (90% CI: 18.0, 26.1) No covariate influenced the QTc exposure relationship – Baseline QTcF, sex, age, body weight – Low electrolytes (K, Ca, Mg) – Concomitant QT-prolonging medications Increases in heart rate did not result in greater QT prolongation No increased QT effect of concomitant QTc prolonging medications
IKs = slow delayed rectifier potassium current. Frequency of QTc Prolongation Based on CS-15 Standardized Central Reading QuANTUM-R Full Study Period Patients, n (%) Quizartinib monotherapy n=241 QTcF, ms >450 - 480 (Grade 1) 76 (31.5) >480 - 500 (Grade 2) 30 (12.4) >500 (Grade 3) 8 (3.3) ∆ from baseline >30 - 60 121 (50.2) ∆ from baseline >60 30 (12.4)
8 patients had QTcF >500 (0.2% of all central ECGs) • 7 QTcF normalized with dose interruption/reduction • 1 withdrew due to AML progression
Central reading demonstrates that QTcF >500 was uncommon and effectively managed CS-16 Torsades Standardized MedDRA Query QuANTUM-R
No events of torsades, ventricular fibrillation, cardiac arrest, sudden death Expert Assessment Event Description on Causality Syncope/LOC (13) 1 with QTc of 503 ms, hypotension/severe Unlikely anemia 12 without QT prolongation or arrhythmias Unlikely Ventricular Non-serious, continued quizartinib for Unlikely tachycardia (1) >1000 days without recurrence
LOC = loss of consciousness. FDA’s Assessment: 4 On-Treatment Deaths Potentially due to CS-17 Cardiac Events QuANTUM-R
No documented ventricular arrhythmias Expert Assessment Expert Assessment QTc (ms) on Causality Bilateral pneumonia, intracranial hemorrhage, sepsis, 427 Unlikely hypotension after craniotomy, death in ICU, no VT reported Acute MI, AML relapse, neutropenic sepsis in CCU, no VT 472 Unlikely reported Septic shock, AML progression, hypotension, multi-organ 455 Unlikely failure, coma Acute renal failure, pneumonia, AML progression 451 Unlikely
VT = ventricular tachyarrhythmias. CS-18 Torsades Standardized MedDRA Query R/R AML Pool (excluding QuANTUM-R data) Expert Assessment Event Description on Causality Non-fatal TdP Sepsis with respiratory arrest, QTcF normalized with discontinuation Likely (quizartinib 90 mg) Cardiac arrest Staph sepsis, arrhythmia possible Possible (quizartinib 135 mg + CYP3A4 inhibitor) Cardiac arrest Necrotic lymphadenopathy, jugular vein thrombosis with QTcF <450 ms Unlikely Cardiac arrest Off treatment for 29 days for HSCT Unlikely Syncope/LOC (12) No QT prolongation; no cardiac intervention Unlikely Ventricular Monomorphic VT resolved with amiodarone then onto HSCT Unlikely tachycardia (3) Non-serious without QT prolongation; resolved Unlikely with continued treatment Event occurred 22 days off quizartinib; resumed without recurrence Unlikely CS-19
Summary and Conclusions Common toxicities manageable with monitoring and dose modification – GI symptoms, cytopenias, and infections Differentiation syndrome was under-recognized QT prolongation occurs with quizartinib therapy – Torsades/ventricular arrhythmia events have been observed – Significant QTc increase was reduced and appropriately managed with QuANTUM-R dosing regimen Risk mitigation measures to reduce arrhythmia risk – Labeling including QTc guided dosing, correction of electrolytes, avoiding QT-prolonging medications when possible CP-1
Clinical Perspective
Jorge Cortes, MD Deputy Chair and Professor of Medicine, Department of Leukemia MD Anderson Cancer Center CP-2
Quizartinib Provides Clinical Benefit to Patients
1.0 24% reduction in risk of death, with early separation of curves 0.8 Quizartinib 0.6 (n=245) Chemotherapy 0.4 (n=122)
0.2 Probability of alive of patients Probability 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time, months Patients at risk Quizartinib 245 224 173 122 89 71 53 48 38 36 27 20 20 16 11 10 Chemotherapy 122 77 59 38 28 21 15 13 13 12 12 10 9 7 7 6 CP-3
Fast and Durable CRc With Quizartinib
Time to first CRc, weeks Duration of CRc, weeks 0 5 10 15 20 0 20 40 60 80 100 120 140
Median = 4 weeks Median = 5 weeks Patients Patients Median = 5 weeks Median = 12 weeks CP-4
Higher CRc Rates, Longer CRc and Higher Transplant Rates Quizartinib Salvage monotherapy chemotherapy n=245 n=122 CRc rate 48% 27% Median duration of CRc, 12 weeks 5 weeks (95% CI) (10, 27) (3, 13) Transplant rate 32% 12% CP-5
Quizartinib Has an Acceptable Safety Profile
Quizartinib well tolerated in patients with R/R FLT3-ITD AML – Including outpatient administration Observed AE profile typical for patients with R/R AML QTc prolongation can be managed Clear recommendations for risk mitigation CP-6
Clinical Benefit of Quizartinib
• Outpatient therapy • Improves survival • Higher response rate • Longer duration of response • Higher transplant rate • Decreased transfusion requirements • Lower toxicity profile
Quizartinib, as an oral monotherapy, is a novel, effective treatment option for patients that provides improvement to the existing standard of care
Backup Slides ST-3 EFS: Time Point for Refractory Disease and Censoring EFS definition: time from randomization date until, whichever occurs first – Followed and failed to reach CRc (assigned at date of randomization) – Relapse after CRc (assigned at date of corresponding assessment) – Death from any cause (assigned at date of death)
In the original analysis, for patients alive without post-baseline response assessment, their EFS was also censored at date of randomization, the same date of “failed to reach CRc” – 18 such patients with EFS censored at the date of randomization – 1 (0.4%) patient from quizartinib and 17 (13.9%) patients from the control arm A correct method would censor these 18 patients before the date of the first event ST-4 Secondary Endpoint: Event-free Survival (ITT)
Original EFS Analysis Corrected EFS Analysis
EFS is defined as the time from randomization to the earliest of the following events: failure to achieve CRc, relapse, or death from any cause. TR-9
CRc and HSCT Rates by Preselected Strata
Patients, n (%) Quizartinib Salvage monotherapy chemotherapy Pre-selected chemotherapy regimen n=245 n=122 Low intensity (LoDAC) n=57 n=29 CRc 30 (53) 0 HSCT rate 13 (22) 0 High intensity (MEC or FLAG-IDA) n=188 n=93 CRc 88 (47) 33 (35) HSCT rate 72 (38) 19 (20) TR-5 OS for HSCT vs No HSCT by Treatment Study 007
1.0 Quizartinib HSCT (n=85) Salvage chemo HSCT (n=19) 0.8 Quizartinib no HSCT (n=160) Salvage chemo no HSCT (n=103) 0.6
0.4
Survival probability Survival 0.2
0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Patients at risk Time, months Quiz HSCT 85 85 78 68 58 49 37 34 29 27 23 17 17 14 11 10 Chemo HSCT 19 19 18 14 12 10 8 6 6 6 6 5 5 4 4 3 Quiz no HSCT 160 139 95 54 31 22 16 14 9 9 4 3 3 2 0 0 Chemo no HSCT 103 58 41 24 16 11 7 7 7 6 6 5 4 3 3 3 SD-20
Response Assessment Schedule – Quizartinib and LoDAC Bone marrow samples are required – at screening for central testing (within 14 days prior to first dose; bone marrow examinations outside this window may be acceptable if agreed by the Medical Monitor), – Cycle 2 Day 1 – Cycle 3 Day 1 – End of Treatment visit – As Clinically Indicated – If the patient has achieved CR, CRp, or CRi, bone marrow testing is repeated every 3 cycles. ST-7 Sensitivity Analysis of EFS Using Resampling
Impute EFS for the 17 patients without post-baseline Quiz response assessment N=245 PHREG N=367 estimate of Salvage Chemo HR 17 imputed EFS Draw 17 samples Salvage (with replacement Chemo based on strata the Salvage Chemo N=122 patients belong) Remaining 105
• 5000 replicates to obtain 5000 HR estimates, and then provide summary of HR estimates • Resampling was performed per following strata to avoid confounding: − Response to prior therapy (relapsed in ≤6 months (not post-HSCT), refractory, or relapsed in ≤6 months post- allogeneic HSCT). − Pre-selected chemotherapy use (Low intensity chemotherapy [LoDAC], High intensity chemotherapy [MEC or FLAG-IDA]). ST-8 Outcome of Sensitivity Analysis of EFS Using Resampling
Resampling considering strata Hazard ratio* 20.0 N (simulation) 5000
17.5 Mean HR (SD) 0.77 (0.021) Median HR (min, max) 0.77 (0.71, 0.85) 15.0 (2.5th, 97.5th percentile) (0.73, 0.81) 12.5
95% CI [1] (0.60, 0.98)
t
n
e c
r 10.0
e P Resampling without considering strata 7.5 N (simulation) 5000 5.0 Mean HR (SD) 0.77 (0.024)
2.5 Median HR (min, max) 0.77 (0.72, 0.88)
th th 0 (2.5 , 97.5 percentile) (0.73, 0.82) 0.612 0.636 0.660 0.684 0.708 0.732 0.756 0.780 0.804 0.828 0.852 0.876 0.900 Hazard Ratio 95% CI [1] (0.60, 0.99) *Strata was considered [1] 95% CI is from the statistical inference using proc MIANALYZE procedure. TR-22
Best Response in Transplanted Patients (ITT Analysis)
Patients, n (%) Quizartinib Salvage monotherapy chemotherapy Best Response n=78 n=14 CRc 53 (67.9) 11 (78.6) CR 3 (3.8) 0 CRp 6 (7.7) 0 CRi 44 (56.4) 11 (78.6) PR 14 (17.9) 0 NR 11 (14.1) 3 (21.4) TR-25 OS in Patients With CRi With or Without Post-HSCT Quizartinib Arm
Median OS (95%) in CRi without post-HSCT: 5.0 (4.1, 7.3) months Median OS (95%) in CRi with post-HSCT: 11.9 (9.5, —) months EF-102
Post-Study Therapies for Randomized, Not Treated Patients
Quizartinib monotherapy Salvage chemotherapy n=4 n=28 New AML Therapy Reported 0 5 FLT3 inhibitor 0 2a,b Cytarabine 0 1 Azacitidine 0 1b HiDAC 0 1 MEC 0 1 No Information 4 23
a One patient received gilteritinib and sorafenib. One patient received sorafenib. b One patient received sorafenib and azacitidine. PH-75
Quizartinib ΔQTcF Sex ML-3 FLT3 Type I Inhibitors- bind at ATP site Tyrosine Lestaurtinib Midostaurin Crenolanib Gilteritinib Kinase
Inhibitors
Base. Base. Base. In vivo Base. Treatment Treatment Treatment Treatment P-FLT3 inhibition:
Staurosporine Type II Inhibitors- bind inactive receptor (reference compound)
Sorafenib Quizartinib Base. In vivo Treatment Base. Treatment P-FLT3 inhibition: Liu and Gray. Nat Chem Biol. 2006;2:358. A Study of ASP2215 in Combination With Induction and Consolidation ML-6 Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT02236013)
Newly- 7+3 HiDAc 120 mg recover diagnosed Gilteritinib Gilteritinib AML patient
Day: Induction Consolid. Induction Consolid. D4 D8 D15 D28 D4 D15 D4 D8 D15 D28 D4 D15
P-FLT3
Patient 1 230 Patient 2 207 144 247 ng/mL ng/mL ng/mL ng/mL ASP2215 plasma concentration
Pratz et al ASH 2017 ML-7 Quizartinib Effectively Suppresses FLT3-ITD Activity After Intensive Chemotherapy
25 mg/m2/day
40 mg/m2/day
60 mg/m2/day
Cooper et al. Clin Cancer Res 22:4014