Post on 05-Feb-2021
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
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>60 >60 >60
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20
30
40
50
60
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ian
Su
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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
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ar S
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ival
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, %
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