Comparative Results of Azacitidine (AZA) and Decitabine (DEC) from a Large Prospective Phase 3 Study in Treatment Naive (TN)

AML Not Eligible for Intensive Chemotherapy

Amer M. Zeidan* 1, Pierre Fenaux2, Marco Gobbi3, Jiří Mayer4, Gail J. Roboz5, Jürgen Krauter6, Tadeusz Robak7, Hagop M. Kantarjian8, Jan Novák9, W.W. Jedrzejczak10, Xavier Thomas11, Mario Ojeda-Uribe12, Yasushi Miyazaki13, Yoo Hong Min14, Su-Peng Yeh15, Joseph Brandwein16, Liana

Gercheva17, Judit Demeter18, Elizabeth A. Griffiths19, Karen W.L. Yee20, Jean-Pierre Issa21, Yong Hao22, Mohammad Azab22, Hartmut Döhner23

1Yale University and Yale Cancer Center, New Haven, United States, 2Hôpital Saint Louis, Paris, France, 3Ospedale Policlinico San Martino, Genova, Italy, 4Fakultní Nemocnice, Brno, Czech Republic, 5Weill Cornell Medical College, New York, United States, 6Städtisches Klinikum Braunschweig, Braunschweig, Germany, 7Wojewódzkie

Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi, Łódź, Poland, 8The University of Texas MD Anderson Cancer Center, Houston, United States, 9Fakultní Nemocnice Královské Vinohrady, Praha, Czech Republic, 10Samodzielny Publiczny Centralny Szpital Kliniczny, Warsaw, Poland, 11Centre Hospitalier Lyon Sud, Pierre Bénite, 12GHR Mulhouse Sud-Alsace, Mulhouse, France, 13Nagasaki University Hospital, Nagasaki, Japan, 14Severance Hospital, Yonsei University Health System, Seoul, Korea, Republic Of, 15China Medical University Hospital, Taichung, Taiwan, Republic of China, 16University of Alberta Hospital, Edmonton, Canada, 17Multiprofile Hospital for

Active Treatment Sveta Marina EAD, Varna, Bulgaria, 18Semmelweis Egyetem, Budapest, Hungary, 19Roswell Park Cancer Institute, Buffalo, United States, 20Princess Margaret Hospital, Toronto, Canada, 21Fels Institute, Temple University, Philadelphia, 22Astex Pharmaceuticals, Inc., Pleasanton, United States, 23Universität Ulm, Ulm, Germany

Abstract # S142 Friday June 12, 2020 AML Therapy

AMZ Disclosures

Received research funding (institutional) from Trovagene, Celgene, AbbVie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics

Consultancy with and received honoraria from Trovagene, AbbVie, Otsuka, Pfizer, Celgene, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Takeda, Ionis, Janssen, Amgen, and Epizyme

Received travel support for meetings from Pfizer, Novartis, and Trovagene

Serves on Clinical trial Steering committees for Novartis

Serves on Clinical trial Independent Review Committee for Janssen

Friday June 12, 2020AML Therapy

Disclosures

Amer M. Zeidan, MBBS, MHSAssociate Professor of Medicine

Department of Internal Medicine

Section of Hematology

Yale University School of Medicine

Yale Cancer Center

Amer.Zeidan@yale.eduDr_AmerZeidan

2.67 3.76 4.47 5.476.47 7.47 8.47 9.47

10.4711.47

>60 >60 >60

0

10

20

30

40

50

60

Med

ian

Su

rviv

al, m

on

ths

Older AML patients have very poor outcomes

2019 Jul;36:70-87

AML

• Survival among older AML patients in USA has not substantially improved over last 4 decades

Median OS (diagnosed 1975-1979): 2 months

Median OS (diagnosed 2015-2016): 4 months 2000-2016 (SEER)

Median survival (months) by cancer type (≥ 65 years of age)1 One-year survival % by cancer type (≥ 65 years of age)1

21.8 21.8 23.236.0 38.9

41.4

66.7 68.1 71.174.1 75.7

92.7 95.0

0102030405060708090

100

1-ye

ar S

urv

ival

Pro

bab

ility

, %

AML

Shallis RM, et al. Blood Rev. 2020;40:100639. Epub 2019 Nov 8; Zeidan A et al. ASH 2019; Abstract 646.

1. Figures reproduced from SEER Acute Myeloid Leukemia Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/amyl.html. Dr_AmerZeidan

https://seer.cancer.gov/statfacts/html/amyl.html

Many older patients with AML in the United States do not even receive active therapy

59.7

%

57.5

%

58.9

%

57.2

%

60.3

%

55.3

%

54.0

%

55.1

%

51.4

%

47.7

%

45.9

%

44.8

%

42.8

%

0%

20%

40%

60%

80%

100%

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Treatmentinitiated after 90daysTreatmentinitiated within61-90 daysTreatmentinitiated within31-60 days

66-69 70-74 75-79 80-84 85+

0%

20%

40%

60%

80%

100%

Overall Male Female

Perc

en

tag

e o

f P

ati

en

ts N

ot

Receiv

ing

Acti

ve T

hera

py

SEER-Medicare:

52% of older AML

patients in USA

diagnosed

2001-2013 did not

receive active therapy

Zeidan A, et al. Cancer. 2019;125:4241-4251; Wang R, et al. J Clin Oncol. 2017;35:3417-3424. Dr_AmerZeidan

Year of diagnosis

Age at diagnosis

How Do HMAs Perform in First-Line Therapy of Older Unfit AML Patients?

1: Kantarjian H, et al. J Clin Oncol. 2012;30:2670-2677. 2: Dombret H, et al. Blood. 2015;126:291-299.

Decitabine

CR+CRi, 28%

CR, 16%

Azacitidine

CR+CRi, 28%

CR, 20%

AML-AZA-0012AML-DACO-0161

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5 6 7 8 9

Su

rviv

al P

rob

ab

ilit

y

Years Since Diagnosis

Decitabine

Log-rank P < 0.01

Azacitidine Decitabine

1-year survival, % (95% CI) 30.9 (28.3-33.6) 34.3 (31.5-37.1

2-year survival, % (95% CI) 9.4 (7.8-11.3) 13.7 (11.6-15.8)

Median OS, months 7.1 8.2

• With additional analyses evaluating the impact of receiving HMA on a standard dosing schedule, the

difference between decitabine vs azacitidine (HR 1.14; 95% CI, 0.98-1.39; P = 0.08) did not reach

statistical significance

Real-life HMA performance in older AML patients in USA SEER-Medicare (N = 2,263), diagnosed 2005-2015

Figure reproduced from Zeidan A, et al. Blood. 2019;134: Abstract 646 [oral presentation]. Blood Advances, in press Dr_AmerZeidan

Proposed optimal approach to the treatment of the newly diagnosed acute myeloid leukemia patient aged ≥60 years 7+3, induction with anthracycline on days 1 to 3 plus cytarabine days 1 to 7.

AML-MRC, AML with myelodysplasia-related changes; LDAC, low-dose cytarabine.

*Based on a single-arm, phase 1b dose-escalation and expansion study

Treatment of patients with AML is getting more complicated: Which HMA backbone to use?

Figure reproduced from Shallis RM, et al. Blood Rev. 2020;40:100639. Zeidan A, et al. Blood. 2019;134: Abstract 646 [oral presentation]. Dr_AmerZeidan

Objectives

‒ Compare complete response rate, and overall survival, and safety in treatment naive (TN) older unfit patients with AML who received AZA or DEC

‒ We took advantage of ASTRAL-1 trial to compare outcomes of patients who were treated with AZA or DEC within the same prospective randomized trial

‒ ASTRAL-1 is the largest Phase 3 randomized trial in TN AML ineligible for IC (815 patients)1 . The study compared Guadecitabine to a preselected Treatment Choice of AZA, DEC, or LDAC

‒ Of those, 388 patients received AZA or DEC as the Treatment Choice in the control arm.

1 Fenaux et al, EHA 24, Amsterdam, June 2019

ASTRAL-1: Phase 3 Study Design

1Age 75 years or older; or major organ comorbidities, and poor Eastern Cooperative Oncology Group (ECOG) PS 2-3.

Guadecitabine (SGI-110)

• 60 mg/m2 SC x 5 days

Treatment Choice (TC)

• Decitabine (DEC)

• Azacitidine (AZA)

• Low Dose Ara-C (LDAC)

Treatment-naïve AML Ineligible for Intensive Induction1

N = 800 randomized

Co-Primary Endpoints:• Complete Response (CR) rate

• Overall Survival (OS)

1:1 randomization

CountriesTotal

Enrolling Sites

Total Patients

Randomized

Total Patients

Treated

24 144 815 793

ASTRAL-1 Treatment Assignments - Patient Disposition

DEC

173

G

178

G

162

G

68

AZA

178

LDAC

56

TC pre-

Randomization

Selection

Randomized

Treatment

Decitabine

351 (43%)

Azacitidine

340 (42%)

LDAC

124 (15%)

Enrollment by Region, %

N. America, 165, 20%

Asia Pacific,

167, 21%

W. Europe, 328, 40%

E. Europe, 155, 19%

G: Guadecitabine; AZA: azacitidine; DEC: decitabine; LDAC: Low Dose Ara-C

Treated DEC 167

AZA

171 N = 388+ =

Results: Baseline Characteristics

Characteristics Azacitidine (N=171) Decitabine (N=167)

Median Age (range) 76 (59,94) 76 (60, 87)

% Male/Female 61% / 39% 56% / 44%

PS ECOG 0-1 53% 46%

ECOG 2-3 47% 54%

Secondary AML 38% 37%

Poor Risk Cytogenetics 38% 34%

Total WBCs ≥20,000/µL 15% 13%

BM Blasts >30% 64% 71%

TP53 mutation % 11.7% 11.4%

Baseline Characteristics well balanced between azacitidine and decitabine treated patients

Efficacy Results: Treatment Exposure - Response Rate1

Azacitidine (N=171) Decitabine (N=167) P Value2

Median #cycles (range) 6 (1, 31) 5 (1, 34)

Complete Response (CR) 30 (17.5%) 32 (19.2%) 0.78

CRp 2 (1.2%) 2 (1.2%)

CRi 6 (3.5%) 8 (4.8%)

CRc (CR+CRp+CRi) 38 (22.2%) 42 (25.1%)

1 Response was assessed by central pathologist blinded to treatment assignment 2 Co-Primary Endpoint. Fisher’s Exact TestNo difference in clinical response between azacitidine and decitabine

Efficacy – Overall Survival

++

+

++

++

++

++

+++++++++++

++++

++ +++ ++

+++ ++++++ +++ +

++

+

+

+

167 147 124 109 95 80 61 52 46 39 34 33 31 21 16 14 11 6 3 3 1 1

171 143 123 111 97 87 77 66 60 53 49 43 34 25 19 13 8 7 3 3 1

0 150 300 450 600 750 900 1050 1156

Days From Randomization

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al P

rob

abili

ty

Decitabine

Azacitidine

AZA DECMedian OS (m) 8.7 8.2 1-Year Survival 39% 32%2-Year Survival 15% 14%

OS Hazard ratio 0.97 95% CI (0.77, 1.23)Log-rank p value 0.81

Overall Survival Clinical Subgroups

➢ Survival Hazard Ratio 95% CI

include one in all subgroups

➢ No difference between AZA and DEC in any subgroup

Hazard Ratio and 95% CIUCLLCLHRN (%)Subgroup

0.0 0.5 1.0 1.5 2.0 2.5

1.23

1.96

1.04

1.29

1.37

1.42

1.3

1.03

1.49

1.2

1.57

1.82

1.19

1.21

1.88

0.77

0.91

0.58

0.63

0.75

0.67

0.72

0.48

0.82

0.61

0.83

0.78

0.68

0.73

0.57

0.97

1.33

0.77

0.9

1.01

0.98

0.97

0.7

1.11

0.86

1.14

1.19

0.9

0.94

1.03

338 (100)

128 (38)

210 (62)

139 (41)

199 (59)

126 (37)

212 (63)

121 (36)

217 (64)

167 (49)

171 (51)

110 (33)

228 (67)

292 (86)

46 (14)

All Subjects (Aza + Dec)

Age group

Sex

Secondary AML

Baseline Cytogenetic Risk

Baseline ECOG

Baseline BM blasts [b]

Baseline WBC

30%

Overall Survival Major Genetic Subgroups

➢ Survival Hazard ratio similar in all subgroups

➢ No difference between AZA and DEC in any subgroup

Hazard Ratio and 95% CIUCLLCLHRN (%)Subgroup

0.0 0.5 1.0 1.5 2.0 2.5 3.0

1.23

1.55

1.28

2.44

1.19

2.05

1.24

2.03

1.22

0.77

0.33

0.78

0.68

0.72

0.19

0.77

0.54

0.74

0.97

0.72

1

1.29

0.93

0.62

0.98

1.04

0.95

338 (100)

28 (8)

302 (89)

49 (14)

283 (84)

18 (5)

314 (93)

39 (12)

291 (86)

All Subjects (Aza + Dec)

FLT3-ITD

NPM1

CEBPA

TP53

Yes

No

Yes

No

Yes

No

Yes

No

Favor Decitabine -->

Results: Safety Azacitidine (N=171) Decitabine (N=167)

Grade ≥3 AEs with ≥ 10% Incidence

Febrile Neutropenia 29% 26%

Pneumonia 23% 19%

Thrombocytopenia 18% 23%

Neutropenia1 16% 25%

Anemia 16% 19%

Sepsis 14% 12%

Serious AE leading to death2 38% 26%

All-Cause 30-Day Mortality 12% 8%

All-Cause 60-Day Mortality3 21% 13%

Fisher’s Exact Test of differences: 1 Neutropenia difference p value 0.06 2 Fatal Serious AE difference p value 0.02 ; 3 60-Day mortality difference p value 0.08

Conclusions

‒ This is the largest comparative dataset of AZA vs. DEC treated in the same Phase 3 Trial in TN AML ineligible for IC

‒ Poor patient population with baseline ECOG PS 2-3 ~50% (47% in AZA and 54% in DEC patients). Baseline characteristics well balanced between the 2 HMAs.

‒ No difference in CR, composite CR, or Survival in the overall group and all major clinical and genetic subgroups

‒ No major safety differences although fatal SAEs and early 60-day mortality trended higher on AZA

Acknowledgments

All Investigators and Patients in the ASTRAL-1 study

Amer.Zeidan@yale.eduDr_AmerZeidan

Questions