Compound: guadecitabine

Title: 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: Jean-Pierre Issa, MD^1*, Marco Gobbi, MD^2*, Patricia L. Kropf, MD^3*, Pierre Fenaux, MD, PhD⁴, Gail J. Roboz, MD⁵, Jiri Mayer, MD⁶, Jürgen Krauter, MD^7*, Tadeusz Robak, MD⁸, Hagop M. Kantarjian, MD⁹, Jan Novak, MD, PhD^10*, Wieslaw W. Jedrzejczak, MD, PhD^11*, Xavier Thomas, MD, PhD¹², Mario Ojeda-Uribe, MD^13*, Yasushi Miyazaki, MD, PhD¹⁴, Yoo Hong Min, MD, PhD¹⁵, Su-Peng Yeh, M.D.^16*, Joseph M Brandwein, MD¹⁷, Liana Gercheva, MD^18*, Judit Demeter, MD^19*, Elizabeth A. Griffiths, MD²⁰, Karen W.L. Yee, MD²¹, Yong Hao, MD, PhD^22*, Mohammad Azab, MD²² and Hartmut Döhner, MD²³

¹Fels Institute, Temple University, Philadelphia, PA; ²Ospedale Policlinico San Martino, Genova, Italy; ³Fox Chase Cancer Center at Temple University Hospital, Philadelphia; ⁴Hôpital St Louis/Université Paris 7 / Service d’hématologie séniors, Hôpital Saint-Louis, Paris, France; ⁵New York-Presbyterian/Weill Cornell Medical Center, New York, NY; ⁶Fakultní Nemocnice Brno, Brno, Czech Republic; ⁷Städtisches Klinikum Braunschweig gGmbH, Braunschweig, Germany; ⁸Medical University of Lodz, Lodz, Poland; ⁹The University of Texas MD Anderson Cancer Center, Houston, TX; ¹⁰Univerzita Karlova, Praha, Czech Republic; ¹¹MTZ Clinical Research, Medical University of Warsaw, Warsaw, Poland; ¹²Hematology department 1 G, Centre Hospitalier Lyon Sud, Pierre Benite, France; ¹³GHR Mulhouse Sud-Alsace, Mulhouse, France; ¹⁴Atomic Bomb Disease Institute, Nagasaki University Hospital, Nagasaki, Japan; ¹⁵Severance Hospital, Yonsei University Health System, Seoul, Korea, Republic of (South); ¹⁶China Medical University Hospital, Taichung, Taiwan; ¹⁷University of Alberta, Edmonton, AB, Canada; ¹⁸Clinical Hematology Clinic, Multiprofile Hospital for Active Treatment “Sveta Marina”, Varna, Bulgaria; ¹⁹Semmelweis Egyetem, Budapest, Hungary; ²⁰Roswell Park Comprehensive Cancer Center, Buffalo, NY; ²¹Princess Margaret Cancer Centre, Toronto, ON, Canada; ²²Astex Pharmaceuticals, Inc., Pleasanton, CA; ²³University Hospital of Ulm, Ulm, Germany

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.

Methods: 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.