Therapeutic landscape in AML

Transcription

1 Therapeutic landscape in AML Andrew Wei

2 1955: From the sea to Ara-C Cryptotethya crypta Werner Bergman Robert Feeney Bergmann W. & Burke D. C Marine products. The nucleosides of sponges. 3: Spongothymidine and spongouridine. Journal of Organic Chemistry 20:

3 1963: Antibiotics from Streptomyces 1963 Grein S. peucetius 1963 Dubost S. cerulorubidus la daunomicina la rubidomycine A. Grein. Descrizione e classificazione di un attinomicete (Streptomyces peucetius sp. nova) produttore di una sostanza ad attivita antitumorale: la Daunomicina, Giorn. Microbiol. 11 (1963) M. Dubost, Un nouvel antibiotique a proprie te s cytostatiques; la rubidomycine, C. R. 257 (1963)

4 Evolution of modern chemotherapy for AML Regimen Daunorubicin 45mg/m2 x 3d CR 25% Ref Bernard 1967 Ara-C 100 mg/m2 IVI x 7d 25% Ellison in 1973 Yates and Wallace 16 patients Cytarabine 100 mg/m2 x 7 days, by cont. IVI Daunorubicin 45 mg/m2 x 3 days Complete remission achieved in 5/8 (untreated AML) 2/8 (previously treated) J. Bernard, Presse Med. 75 (1967) Ellison and Holland, Acute Leukemia Group B J Yates, Cancer ther. Rep. 57 (1973)

5 Evolution of adult AML therapy in Australia LFS HiDAC Etoposide Ind: Con: (5+2+5)x2 AML M2-Blood 1990 Ind: 7+3D Con: (5+2)x2 Idarubicin ICE consol Ind: HiDAC+3+7 Ind: ICE Ind: ICE Con: (5+2+5)x2 Con: (IcE)x2 Con: ICE AML M4-Blood 1996 AML M7- Blood 2005

6 Evolution of adult AML therapy in Australia LFS HiDAC Etoposide Ind: Con: (5+2+5)x2 AML M2-Blood 1990 Ind: 7+3D Con: (5+2)x2 Idarubicin Ind: HiDAC+3+7 Ind: ICE Con: (5+2+5)x2 Con: (IcE)x2 AML M4-Blood 1996 AML M7- Blood 2005 ICE induction 77% C1 CR 3y OS 49% 30d TRM of 10%

7 Evolution of adult AML therapy in Australia Ida 3 consol Ind: ICE LFS Con: I(3)cEx2 HiDAC Etoposide Ind: Con: (5+2+5)x2 AML M2-Blood 1990 Ind: 7+3D Con: (5+2)x2 Idarubicin Ind: HiDAC+3+7 Ind: ICE Con: (5+2+5)x2 Con: (IcE)x2 AML M4-Blood 1996 AML M7- Blood 2005 ICE induction 77% C1 CR 3y OS 49% 30d TRM of 10% AML M12- JCO 2017 ICE induction 77% C1 CR 3y OS ~57% 30d TRM of 4%

8 Idarubicin intensification improved LFS censored for HSCT 3y LFS HR 0.68 P= % Intensive 27% Standard

9 Idarubicin intensification and overall survival 3y OS HR 0.75 P= % Intensive 50% Standard

10 CR/CRi 7+3(I-12) R Non-CBF Ara-C (5) 100mg/m2 IDAC-3(I-12) IDAC mg/m2 36mg/m2 Ara-C 25g/m2 72.7g/m2 Cycles 3 5 C1 CR 77% 54% Ida Ara-C 3000mg/m2 BD (D1,3,5) Ida (3) 9mg/m2 Etop (5) 75mg/m2 x4 x2 Primary endpoint: Non-inferiority EFS Secondary endpoints: OS censored/not censored for SCT Transplant realization Time to SCT CRMRD Days in hospital to achieve CR Deliverability of cycles Long-term cardiac function Early death rates (30, 60d)

11 D90: CR 52% 64% D45: CR 35% 54% Intensive chemotherapy in elderly (60-83yo) AML Bob Loẅenberg, N Engl J Med 2009;361: (D45 vs D90) 1g/m 2 IV D1-6

12 Deaths Rising AML deaths in Australia NHL Acute Myeloid Leukaemia Multiple Myeloma CML MDS ALL HL CLL Source: AIHW

13 Challenges in targeting AML Dx Rel

14 Selected overview of therapeutic options Kinase inhibitors - FLT3 - KIT - mtor - Aurora/PLK therapy - CPX Vosaroxin - Nucleosides Pro-apoptotic - BCL-2 inh - MDM2 inh - MCL1 inh Immunotherapy - BiTEs/CARTs - MoAb- CD123, CD33, CD47, CLEC12A, KIR - ImmunoconjugatesMyelotarg, SGN33A, - Vaccines- WT1 - Checkpoint inh Epigenetic - Azacitidine - Decitabine - Guadecitabine - Pracinostat - IDH inh - BET inh - DOT1L - Spliceosome inh

15 Emerging landscape for first-line AML therapy- fit patients Trial 1 st option FIT Induction 7+3-like FRONTLINE THERAPY Consolidation HiDAC-based Risk assessment Observation Maintenance SCT SALVAGE e.g. IDAC, FLAG-Ida, MEC UNFIT Hypomethylating agents Low-dose cytarabine BSC BSC Drug: Midostaurin Registration trial: MIDO vs PBO Subgroup: FLT3 mut Size: N=717 Survival: Median 75 m vs 26m Response: CR 65% vs 58% Likely registration Drug: CPX-351 Registration trial: CPX-351 vs 7+3 Subgroup: taml, saml ± prior HMA, AML with MDS CG Size: N=309 Survival: Median 9.6 vs 6.0m Response: CR 48% vs 33% Breakthrough designation

16 RATIFY (CALGB 10603) Induction 3279 AML (18-59) ITD/TKD 27% N=714 1 MIDO Consolidation MIDO MIDO Maintenance MIDO PKC (34%) 355 R 1 Placebo MIDO Placebo Placebo Placebo Placebo Placebo 85 (24%) 354 SCT in CR1 25% MIDO: 50mg bd D8-21 (D1-28 in maintenance) Induction: Cytarabine 200 mg/m2 D1-7, Daunorubicin 60mg/m2 D1-3 Consolidation: Cytarabine 3g/m2 bd D1,3,5 Stone R et al. ASH 2015 (oral presentation)

17 FLT3 subgroup benefit

18 ALLG AML M16 Sorafenib in newly diagnosed FLT3-ITD+ AML AML M16 2 Sorafenib Sorafenib Sorafenib Sorafenib 12 months PLACEBO PLACEBO PLACEBO Placebo 12 months FLT3 ITD N=100 Screen ~450 Ambisome 5mg/kg 2x/week 2 year event-free survival (relapse, death)

19 Emerging landscape in elderly AML Trial 1 st option FIT UNFIT Induction 7+3-like FRONTLINE THERAPY Consolidation HiDAC-based Risk assessment Hypomethylating agents Low-dose cytarabine BSC Observation Maintenance SCT SALVAGE e.g. IDAC, FLAG-Ida, MEC BSC Drug: AZA Registration trial: AZA vs CCR Size: N=488 Survival: Median 10.4 m vs 6.5m (NS) Response: CR 28% vs 25% HMA salvage in CCR arm confounded primary endpoint First-line elderly AML regimens: VEN + AZA (breakthrough status) VEN + LDAC Pracinostat + AZA: (breakthrough status) Vadastuximab + HMA: OS ~12m Guadecitabine Decitabine 10d HMA failure: unmet need

20 Who is unfit for intensive chemotherapy? Unfit AML FDA Kantarjian (Cancer 2004) Clinical Age 75 OR 60 to 74 with one of: ECOG 2-3 CHF or EF 50% or chronic stable angina DLCO 65% or FEV1 65%; Cr clearance 30 ml/min to < 45 ml/min Bilirubin > 1.5 to 3.0 ULN Age 75 or >65 and 1 of ECOG 2 No LAFR Prior MDS for 12mo Creat >1.3mg/dL Disease-related Complex CG

21 Selected therapies under development for elderly AML ( 65) N Treatment CR/CRi CR CRi 241 AZA 28% 20% 8% 242 DAC 26% 16% 10% 21 DAC 10d (TP53m) 62% 34 Venetoclax + AZA/DAC** 71% 35% 35% 61 Venetoclax + LDAC$$ 54% 21% 33% 56 Vosaroxin + DAC 63% 54% 9% 103 Guadecitabine (SGI110) 58% 34% 24% 50 Pracinostat + AZA** 56% 42% 14% (inc MFLS) 33 Tosedostat + LDAC 49% 49% N/A Di Nardo et al. ASH Abstract 327 Jacoby et al. ASH Abstract 1686 Garcia-Manero, et al. ASH Abstract 453 Daver, et al. ASH Abstract 461 Visani et al, ASH 2015, Abstract 329 Kantarjian et al. J Clin Oncol Jul 20;30(21): Dombret H et al. Blood Jul 16;126(3):291-9 Wei et al ASH 2016 Welch et al NEJM 2017 ** US FDA fast-track designation $$ 17 (28%) had prior HMA

22 Chemical toolkit to target survival in AML ABT-199 Souers, Nature 2013 S55746 A Tao, ACS Med Chem Lett 2014 BCL-2 BCL-X L BCL-W MCL1 BFL-A1 ABT-737 Oltersdorf, Nature 2005 ABT-263 Tse, Cancer Research 2008 S63845 Kotschy, Nature 2016 Apoptosis

23 B e s t p e r c e n t c h a n g e fro m b a s e lin e P ro b a b ilit y Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged 65 Years with Acute Myeloid Leukemia R e s p o n d e r s (C R + C R i+ P R ), n = 3 7 N o n -r e s p o n d e r s, n = Phase 1 (600 mg), n=7 Phase 2 (600 mg), n= Responders (CR+CRi+PR), n=37 (61%) Non-responders, n= P a t ie n t s (n = 5 8 ) I= c e n s o r e d e v e n t M o n th s s in c e in it ia tio n o f t re a tm e n t Data cut off date: 31AUG2016 Wei, ASH 2016

24 Emerging landscape in relapsed/refractory AML Trial 1 st option FIT Induction 7+3-like FRONTLINE THERAPY Consolidation HiDAC-based Risk assessment Observation Maintenance SCT SALVAGE e.g. IDAC, FLAG-Ida, MEC UNFIT Hypomethylating agents Low-dose cytarabine BSC BSC Drug: Vosaroxin Registration trial: Vosaroxin + IDAC vs IDAC Size: N=711 Survival: Median 7.5m vs 6.1m (NS) Response: CR 30% vs 16.3% Sub-group survival benefit in >60yo SCT confounded benefit in younger adults Control arm potentially inadequate Other drugs in R/R AML: IDH1: AG120, IDH305 IDH2: AG-221 FLT3: Quizartinib, crenolanib, gilteritinib MDM2 (non TP53m) CR/CRi ~20% CR/CRi ~43-50% CR/CRi ~30-45%

25 Targeting IDH Glucose Acetyl CoA Citrate Mitochondrion Cytoplasm Citrate OAA Isocitrate Isocitrate Mal Fum IDH3 IDH2 IDH1 αkg αkg Suc 2-HG 2-HG Oncogenic pathways

26 Issues Differentiation syndrome Delayed response Molecular MRD problematic

27 Targeting mutant IDH in advanced AML AG-221 (IDH2i) AG-120 (IDH1i) N CR 17% 17% CRi 3% 2% MLFS 8% 9% ORR (ITT) 28% 28% Di Nardo Cet al. Poster presentation ASH 2015; 1306 Stein E et al. Oral Presentation ASH 2015; 323

28 Therapeutic landscape in AML Trial 1 st option FIT UNFIT Induction 7+3-like FRONTLINE THERAPY Consolidation HiDAC-based Risk assessment Hypomethylating agents Low-dose cytarabine BSC Observation Maintenance SCT SALVAGE e.g. IDAC, FLAG-Ida, MEC BSC Drug: Oral AZA (CC-486) Registration trial: CC-486 vs Placebo 24m CC mg D1-14 q month Size: N=460, Age 55+ within 120d of CR1 Primary EP: median OS from 16 to 22.9mo

29 Immunotherapy Primers Cytokines Cytotoxics Vaccines PD-1 PD-L1 CTLA4 LAG3 TIM3 OX40 Checkpoints CAR T BiTEs CD33 CD123 CLL1 CD47 CLEC12A FLT3 Expanders

30 What AML therapy might look like in 2020 FRONTLINE THERAPY SALVAGE FIT Induction 7+3-like Consolidation HiDAC-based Risk assessment CC-486 SCT e.g. IDAC, FLAG-Ida, MEC FLT3 7+3 Mido HiDAC Mido SCT Mido Quizartinib IDH AG-221 AG-120 UNFIT AZA or LDAC + venetoclax BSC BSC