Novel Induction and Targeted Strategies in Acute Myeloid Leukemia Eytan M. Stein, MD Leukemia Service Memorial Sloan Kettering Cancer Center Weill Cornell Medical College New York, New York
Current Paradigms for Treating Newly Diagnosed AML Comorbid Medical Conditions Age: 18 65 75 95 Intensive Induction 7+3 HMA/LDAC Supportive Care
Novel Strategies: Intensive Induction Chemotherapy Eligible
CPX-351 100 nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin 4
Phase 3 Study of CPX-351 vs Standard Induction in Older Patients with Newly Diagnosed Secondary AML CPX-351 n=153 Key Eligibility Previously untreated Ages 60-75 years Able to tolerate intensive therapy PS 0-2 Stratifications: Therapy-related AML AML with history of MDS w/ and w/out prior HMA therapy AML with history of CMML de novo AML with MDS karyotype 60-69 years 70-75 years Induction (1-2 cycles) Patients in CR or CRi: Consolidation (1-2 cycles) Follow-up: Death OR 5 years 7 + 3 n=156 Primary Endpoint: Overall survival Lancet J, ASCO 2016
Survival (%) Overall Survival Was Greater in the CPX-351 Arm Compared to the 7+3 Arm 100 Events/N Median Surv. (95% CI) 80 CPX-351 7+3 104/153 132/156 9.56 (6.60, 11.86) 5.95 (4.99, 7.75) 60 Hazard Ratio = 0.69 p-value = 0.005 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months from Randomization CPX-351 7+3 153 156 122 110 92 77 79 56 62 43 46 31 34 20 21 12 16 7 11 3 5 2 1 0 Lancet J, ASCO 2016
FLT3 inhibitors in the treatment of acute myeloid leukemia FLT-3 ITD found in 30% of cytogenetically normal AML Constitutive activation of FLT-3 receptor Confers a poor prognosis Multiple attempts to target FLT-3 Cancer; pages 3293-3304, 11 FEB 2011 DOI: 10.1002/cncr.25908
A Phase III Randomized Double-blinded Study Of Chemotherapy +/- Midostaurin (PKC412) In Newly Diagnosed Adults aged 18-60 with FLT3 Mutated Acute Myeloid Leukemia (AML) Richard M. Stone, Sumithra Mandrekar, Ben L Sanford, Susan Geyer, Clara D. Bloomfield, Konstanze Dohner, Christian Thiede, Guido Marcucci, Francesco Lo-Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Richard A. Larson, and Hartmut Dohner
Key Eligibility Criteria Age 18-60, normal end-organ function Documented AML (non-apl) FLT3 mutation centrally determined prior to enrollment Assessed at one of 9 academic labs around the world Results within 48h Up to 5 days of hydroxyurea allowed prior to start of treatment while awaiting results of mutation analysis Stone R, ASH 2015 9
Schema P R E - R E G I S T E R F L T Stratify* 3 FLT3 S ITD C or R TKD E E N R A N D O M I Z E DNR ARA-C Midostaurin DNR ARA-C Placebo CR CR HidAC Midostaurin HidAC Placebo X 4 X 4 Midostaurin MAINTENANCE 12 months Placebo MAINTENANCE 12 months FLT3 WILD TYPE not eligible for enrollment Stratification: TKD; ITD with allelic ratio <0.7 vs 0.7 Stone R, ASH 2015
Overall Survival (Primary Endpoint) 23% reduced risk of death in the Mido arm Arm 4-year Survival MIDO 51.4% (95%CI: 46, 57) PBO 44.2% (95%CI: 39, 50) + Censor Hazard Ratio*: 0.77 1-sided log-rank p-value*: 0.0074 Stone R, ASH 2015
Novel Combinations with Hypomethylating Agents
Venetoclax: Selective BCL-2 Inhibitor Venetoclax is a potent, orally bioavailable agent 1 with demonstrated single-agent activity in AML cell lines and primary patient samples 2 Heavily pretreated relapsed/refractory AML patients 3 Venetoclax was shown to synergize with HMA in preclinical models, suggesting that combination with HMA may be a promising approach in AML 4. 1. Souers A, et al. Nat Med. 2013;19:202-8; 2. Pan R, et al. Cancer Discov. 2014;4:362-75; 3. Konopleva M, et al. 56 th Annual American Society of Hematology; December 6 9, 2014; Abstract 118; 4. Tsao T, et al. Ann Hematol. 2012;91:1861-70. 13
Methods: Phase 1, Open-Label, Nonrandomized, 2-Arm, 2-Stage Study Eligibility Adult patients 65 years of age with untreated AML who are not eligible for standard induction therapy due to comorbidity or other factors Adverse or intermediate-risk cytogenetic Phase 1b Safety PK & Dose Finding VEN + DEC (ARM A) 20 mg/m 2 D1 5, IV 28-D cycles N=~24 VEN + AZA (ARM B) 75 mg/m 2 D1 7, IV/SC 28-D cycles N=~24 One HMA combo at RP2D Expansion stage for confirmation of safety and efficacy VEN + HMA N=40 Endpoints Safety maximum tolerated dose, DLTs, RP2D, tolerability (# cycles), early deaths, AEs (assessed throughout the study), PK Pollyea D, Dinardo C, ASCO 2016
Outcomes Best Response, n (%) VEN + DEC (n=23) VEN + AZA (n=22) Total Responses (N=45 CR 5 7 12 (27%) CRi 10 5 15 (33%) PR 1 0 1(2%) MLFS 1 3 4 (9%) RD 3 5 8 (18%) Not evaluable 3 2 5 (11%) ORR (CR/CRi/PR) 16 (65%) 12 (55%) 28 (62%) Pollyea D, Dinardo C, ASCO 2016
Vadastuximab Talirine (SGN-CD33A; 33A) Proposed Mechanism of Action in Combination with HMA Anti-CD33 antibody, engineered cysteines to enable uniform site-specific conjugation Cleavable dipeptide linker, highly stable in circulation Pyrrolobenzodiazepine (PBD) dimer, binds DNA with high intrinsic affinity Apoptotic cell death Binds to CD33 antigen Increased CD33 cell surface density Increased PBD dimer binding to DNA Complex is internalized and traffics to lysosome PBD dimer is released PBD dimer crosslinks DNA DNA repair failed Vadastuximab talirine (SGN-CD33A; 33A) is an investigational agent, and its safety and efficacy have not yet been established. 2015 Seattle Genetics, Inc. All rights reserved.
Study Design (NCT01902329) Key Eligibility Criteria CD33+ AML Declined intensive therapy No prior HMA
Efficacy Evaluable Remission Rate (CR + CRi) ORR (CR + CRi + mlfs + PR) Best Clinical Response Response Assessment per Investigator All N=49 Adverse Cyto. Risk per MRC n= 18 Underlying Myelodysplasia n= 22 71% 83% 73% CR 41% 50% 32% CRi (p) a 18% 22% 32% CRi (n) b 12% 11% 9% mlfs c 2% - 5% PR 2% - - 76% 83% 77% a CRi (p)= CR with ANC 1000/uL, incomplete platelet recovery b CRi (n)= CR with platelets 100,000/uL, incomplete neutrophil recovery c mlfs = morphologic leukemia-free state Fathi A, EHA 2016
33A+HMA: Estimated Overall Survival (N=53) Interim Data, Evolving Fathi A, EHA 2016
Inhibitors of Mutated Molecular Targets
Dose Escalation FLT3 inhibitor - Gilteritinib 450 mg 300 mg 200 mg N=3 120 mg N=3 80 mg N=3 N=3 No DLT No DLT No DLT No DLT ex vivo FLT3 inhibition observed ex vivo FLT3 inhibition observed ex vivo FLT3 inhibition observed CR/CRp/CRi CR/CRp/CRi CR/CRp/CRi ex vivo FLT3 inhibition observed CR/CRp/CRi Expand (N=14 17) Expand (N=14 17) Expand (N=14 17) Expand (N=14 17) Further expanded with subjects with FLT3 mutations 40 mg N=3 No DLT ex vivo FLT3 inhibition observed CR/CRp/CRi Expand (N=14 17) 20 mg N=3 No DLT ex vivo FLT3 inhibition observed CR/CRp/CRi Expand (N=14 17) CR indicates complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; DLT, dose limiting toxicity; FLT3, fms-related tyrosine kinase 3. Altman J, ASH 2015
Clinical Response to Gilteritinib Treatment by FLT3 Mutation or TKI Status Clinical Response FLT3-ITD only Mutation Type FLT3-D835 only 80 mg Gilteritinib TKI Status ITD and D835 Prior TKI TKI Naïve N=142 N=11 N=9 N=40 N=127 CR 16 (11) 0 0 2 (5) 14 (11) CRp 11 (8) 0 0 3 (8) 8 (7) CRi 38 (27) 1 (9) 4 (44) 9 (23) 35 (28) PR 15 (11) 2 (18) 0 5 (13) 13 (10) CRc (CR+CRp+CRi) 65 (46) 1 (9) 4 (44) 14 (35) 57 (45) ORR (CRc+PR) 80 (56) 3 (27) 4 (44) 19 (48) 70 (55) Data presented as n (%). CR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; ORR, overall response rate; PR, partial response. Altman J, ASH 2015
Overall Survival by Response in FLT3+ Subjects Treated with 80 mg Gilteritinib Across all FLT3+ subjects treated with gilteritinib 80 mg: Median duration of response was 111 (range: 8 383) days Median time to best response was 32 (range: 26 364) days Median overall survival was 218 (range: 12 430) days Altman J, ASH 2015
IDH in AML IDH is a critical metabolic enzyme in the citric acid cycle IDH1 in cytoplasm and IDH2 in mitochondria Cancer-associated IDHm produces 2- hydroxyglutarate (2- HG) and blocks normal cellular differentiation IDH2 R140Q more common than R172K in retrospective series Prensner and Chinnaiyan Nature, 2011
Phase 1/2 Study Design IDH2 inhibitor AG-221 (Celgene/Agios) 25 Dose Escalation Expansion Phase I Phase 2 Advanced heme malignancies with IDH2 mutation Continuous 28 day cycles Cumulative daily doses of 50-650 mg RR-AML age 60, or any age if relapsed post-bmt RR-AML age <60, excluding pts relapsed post-bmt Untreated AML pts age 60 who decline standard of care Any hematologic malignancy ineligible for other arms AG-221 100 mg PO QD RR-AML (N 125) Key Endpoints: Safety, tolerability, MTD, DLTs Response rates as assessed by local investigator per IWG criteria Assessment of clinical activity Stein EM, ASH 2015
Response Overall Response (CR, CRp, CRi, mcr, PR) RR-AML (n = 159) Untreated AML (n = 24) MDS (n = 14) All (N = 209) 59 (37%) 10 (42%) 7 (50%) 79 (38%) CR 29 (18%) 4 (17%) 3 (21%) 37 (18%) CRp 1 (1%) 1 (4%) 1 (7%) 3 (1%) CRi 3 (2%) 0 0 3 (1%) mcr 9 (6%) 1 (4%) 3 (21%) 14 (7%) PR 17 (11%) 4 (17%) 0 22 (11%) SD 72 (45%) 9 (38%) 6 (43%) 96 (46%) PD 10 (6%) 1 (4%) 0 11 (5%) Not evaluable 18 (11%) 4 (17%) 1 (7%) 23 (11%) Overall response by IDH mutation type: R140Q 36% / R172K 42% CR, complete response; CRp, CR with incomplete platelet recovery; CRi, 26 CR with incomplete hematologic recovery; mcr, marrow CR; PR, partial response; SD, stable disease; PD, progressive disease
Differentiation Effects in the Bone Marrow Patient 4 achieved a CR at Cycle 4, Day 1 Stein EM, ASH 2015
Other Differentiation Therapies
Conclusions Probable changes in the standard of care arriving for the treatment of AML. CPX-351 for secondary AML in patients between 60-75 Midostaurin in combination with induction chemo in FLT3 pos AML HMA in combination with novel agents have promising CR rates compared to HMA alone Small molecular inhibitors of mutated targets present options as single agents for R/R disease or in combination with standard of care therapies.
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