Progression Free Survival (PFS), and Event Free Survival (EFS) from a Global Randomized Phase 3 Study of Guadecitabine (G) Vs Treatment Choice (TC) in 815 Patients with Treatment Naïve (TN) AML Unfit for Intensive Chemotherapy (IC): ASTRAL-1 Study
Authors: Issa Jean-Pierre , Gobbi Marco , Kropf Patricia L. , Fenaux Pierre , Roboz Gail J. , Mayer Jiri , Krauter Jürgen , Robak Tadeusz , Kantarjian Hagop M. , Novak Jan , Jedrzejczak Wieslaw W. , Thomas Xavier , Ojeda-Uribe Mario , Miyazaki Yasushi , Min Yoo Hong , Yeh Su-Peng , Brandwein Joseph M , Gercheva Liana , Demeter Judit , Griffiths Elizabeth A. , Yee Karen W.L. , Hao Yong , Azab Mohammad , Döhner Hartmut 
Published: November 2019

Background: Guadecitabine (G) is a next generation subcutaneous hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study of G vs TC of azacitidine (AZA), decitabine (DEC), or low dose Ara-C (LDAC) in 815 TN AML patients unfit for IC (ASTRAL-1 study). The ITT results for the primary endpoints of Complete Response (CR), and Overall Survival (OS) were previously presented (Fenaux et al, EHA abstract S879, 2019). There is no consensus on definition of disease progression particularly with HMA treatment which may continue to benefit patients in the absence of objective response. EFS analysis based on end of treatment benefit (treatment discontinuation, or start of an alternative therapy, or death) regardless of progression may offer a simpler way of assessing HMA treatment benefit. We describe here the results of the study based on both PFS and EFS analyses and how they compare with OS analyses in the overall ITT population, and in subgroups of patients based on number of cycles administered.
M ethods: TN-AML ineligible for IC due to age ≥ 75 y, or comorbidities, or ECOG PS 2-3 were randomized 1:1 to either G (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at their standard regimens. AML diagnosis, and response status by IWG 2003 criteria, were assessed by an independent central pathologist blinded to randomization assignment. CR and OS were co-primary endpoints. PFS was a secondary endpoint calculated from date of randomization to the earliest date of progression by investigators or central assessment, relapse after response, start of an alternative therapy, or death. Since progression date is sometimes difficult to ascertain under HMA treatment, an EFS analysis was conducted post hoc using the concept of time to treatment failure. EFS was therefore calculated from date of randomization to the earliest date of discontinuation of randomized treatment, start of an alternative therapy, or death. PFS, EFS, and OS data are presented for the overall ITT population, and for patients who received at least 4 cycles or 6 cycles, and patients who had an objective response.
Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs prior to randomization were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were well balanced across the 2 treatment arms. The majority of patients were randomized to receive an HMA: 759 patients (93%) with only 56 patients (7%) randomized to receive LDAC. In the primary ITT analysis, CR (19.4% for G and 17.4% for TC), and OS Hazard Ratio (0.97; 95% CI 0.83-1.14) were not significantly different between G and TC. An equal proportion of patients received at least 4 cycles (57.6% for G vs 59.2% for TC), or 6 cycles (45.8% for G vs 46.2% for TC) so there was no obvious bias in terms of adherence to treatment in the 2 study arms. Table shows OS, PFS, and EFS median survival, G/TC HR with 95% CI, and p values for the primary ITT population as well as for patients who received at least 4 cycles (N=476 patients), and those who received at least 6 cycles (N=375 patients). G/TC HR for all analyses favored guadecitabine (HR <1). However only OS, and EFS seemed to significantly favor G in patients who received adequate treatment duration by number of cycles. EFS was also the only analysis to significantly favor G in the overall ITT population suggesting that it may be a better predictor of OS benefit in patients who went on to receive adequate treatment with at least 4 or 6 cycles (Table). In addition, EFS also significantly favored G in patients who achieved an objective response (CR, CRp, CRi, or PR): median EFS for G 17.4 vs 14.6 m for TC, HR 0.68, 95% CI 0.5-0.93, p 0.016.
Summary/Conclusions: In a large global 815-patient randomized study of G vs TC (composed mainly of first generation HMAs), EFS analyses that do not rely on progression date which is sometimes difficult to define favored G over TC in the ITT population, and seemed to better predict OS benefit in patients who went on to receive at least 4 or 6 cycles. EFS calculated from date of randomization to the earliest date of randomized treatment discontinuation, start of alternative therapy, or death as conducted here could be a simple surrogate for cessation of treatment benefit particularly for patients treated with HMAs.
Table

Disclosures
Fenaux: Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Roche: Consultancy, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding. Novak:Janssen: Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jedrzejczak:Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Novartis: Research Funding; Takeda: Consultancy; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) . Thomas:ABBVIE: Honoraria; PFIZER: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Chugai: Research Funding; Otsuka: Honoraria. Brandwein:Jazz Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Research Funding. Demeter:Pfizer: Other: Advisory Board; Amgen: Other: Advisory Board; Bristol Myers Squibb: Other: Advisory Board; Novartis: Other: Advisory Board; Amicus: Other: Advisory Board; Angelini: Other: Advisory Board; Roche: Other: Advisory Board. Griffiths:Celgene, Inc: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Celgene, Inc: Consultancy, Research Funding; Persimmune: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Boston Scientific: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding. Yee:Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding.