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2019 ASH: Durable Remission and Long-Term Survival in Relapsed/Refractory (r/r) AML Patients Treated with Guadecitabine, Median Survival Not Reached for Responders after Long Term Follow up from Phase 2 Study of 103 Patients

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Durable Remission and Long-Term Survival in Relapsed/Refractory (r/r) AML Patients Treated with Guadecitabine, Median Survival Not Reached for Responders after Long Term Follow up from Phase 2 Study of 103 Patients

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 103 r/r AML patients. We present here duration of response and long-term survival results.

Methods: We conducted a phase 2 study of guadecitabine using different regimens and doses (randomized 5-day regimen cohorts of 60 mg/m2/d vs 90 mg/m2/d SC) and a cohort of 10-day regimen in the first 1-4 cycles at 60 mg/m2/d followed by subsequent cycles of 5-day regimen). Response and duration of response were assessed using IWG 2003 criteria: Complete Response (CR), CR with incomplete platelet recovery (CRp), and CR with incomplete count recovery (CRi). CR+CRp+CRi was defined as composite CR (CRc). Overall survival (OS) was assessed using the Kaplan-Meier (KM) method. Response status for each dose/regimen cohort and the overall treated population were assessed with analyses of duration of response and long-term survival.

Results: The study completed enrolment of 103 r/r AML patients: 50 patients received 5-day regime at 60 mg/m2/d (24 patients) or 90 mg/m2/d (26 patients), and 53 patients received the 10-day (60 mg/m2/d). Median follow up was 2.4 years (29.1 months). Patients’ characteristics for the 103 r/r AML patients enrolled included median age of 60y (range 22-82y), poor risk cytogenetics in 41%, prior hematopoietic cell transplant (HCT) in 18%, median number of prior regimens 2 (range 1-10), primary refractory to induction therapy in 47%, and 41% had a high disease burden of BM blasts >40%. There was no significant difference in CR or OS between 60 and 90 mg/m2/d 5-day regimen but the CR and CRc rates were higher on the 10-day regimen (19% and 30% respectively) vs the 5-day regimen (8% and 16%). When all regimens analyzed together, 24/103 patients (23.3%) achieved CRc. Responses (CRc) were achieved in several poor prognosis subgroups including 19% in patients with poor risk cytogenetics, 31% of refractory patients, 26% of patients who relapsed after prior HCT, and 22% in patients with early relapse (< 6 months from their prior treatment). Of the 24 CRc patients, 15 (63%) were refractory to induction, 8 (33%) had poor risk cytogenetics, and 5 (21%) had prior HCT, and 14 (58%) went on to receive HCT following response. Median overall duration of response for patients with CR, and CRc were 7 and 7.8 months respectively. After long term follow up, median OS has not been reached in patients who achieved CRc (either CR or CRp/CRi). The 2-year survival rate was 57% for CR, and 50% for CRp/CRi (Fig. 1). Median OS has not yet been reached and was similar in CRc patients who went on to receive HCT post CRc (14 patients) compared to CRc patients who did not receive HCT post treatment (10 patients) (Fig.2). The 2-year survival rate was also similar for both groups (50% for those receiving HCT vs 60% for those who did not undergo HCT). Most patients were still on guadecitabine treatment until death, progression, or HCT with no other subsequent treatment. Guadecitabine was well tolerated in all cohorts with Grade 3 or higher AEs related to the drug seen in 42% of patients predominantly myelosuppression and related infections. There was no related serious AEs leading to death. The results highlight the long survival benefit for guadecitabine responders that exceeds duration of response and seems irrespective of post treatment HCT. The results also suggest that in r/r AML patients treated with guadecitabine, CRp/CRi seem to confer a similar survival benefit to CR patients suggesting that the incomplete peripheral blood count recovery may reflect continued treatment-related myelosuppression rather than active residual disease.

 Summary/Conclusions: In a phase 2 study of HMA guadecitabine in heavily pretreated r/r AML patients, 47% of whom had refractory disease, CR, CRp, and CRi all conferred long survival benefit. With a median follow up of almost 2.5 years, more than half of responding patients were still alive at 2 years and their median OS has not yet been reached. In addition, treatment with guadecitabine allowed post treatment HCT in 58% of responders.

 

2019: Dual-mechanism ERK1/2 inhibitors exploit a distinct binding mode to block phosphorylation and nuclear accumulation of ERK1/2

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Summary
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date ERKi display two distinct mechanisms of action (MoA); catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevent the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterised the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signalling, gene expression and antiproliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS mutant cell lines. In contrast, dual mechanism ERKi exploit a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared to catalytic ERKi, resulting in increased efficacy across BRAF and RAS mutant cell lines.

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Dual-mechanism ERK1/2 inhibitors exploit a distinct binding mode to block phosphorylation and nuclear accumulation of ERK1/2

A novel ERK inhibitor has potent activity in NRAS-mutant melanoma cancer models

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Introduction

  • NRAS mutations occur in 15-20% of mutant melanoma cancer patients. Currently there is no approved therapy for NRAS-mutant melanoma, an indication which is associated with aggressive clinical outcome and a poor prognosis.
  • The NRAS mutation leads to constitutive activation of the MAPK pathway. ERK is the primary downstream effector of MAPK and its direct inhibition may provide an attractive therapeutic approach for the treatment of NRAS-mutant
    melanoma.
  • As previously described, using fragment-based drug discovery we have identified a novel and selective inhibitor of ERK which inhibits in vitro ERK catalytic activity as well as ERK phosphorylation1.
  • Here, we demonstrate the in vitro and in vivo activity of a novel, highly potent, elective ERK inhibitor in models of NRAS-mutant melanoma.

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A novel ERK inhibitor has potent activity in NRAS-mutant melanoma cancer models

2019 EORTC: Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 118 patients with solid tumors or lymphoma

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Preliminary results of ASTX660, a novel non-peptidomimetic cIAP1/2 and XIAP antagonist, in 118 patients with solid tumors or lymphoma

Abstract
Background:
ASTX660 is an oral, novel nonpeptidomimetic, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first-in-human phase 1‒2 study in patients (pts) with advanced solid tumors or lymphoma (ClinicalTrials.gov NCT02503423). In the ongoing phase 2, ASTX660 has demonstrated preliminary evidence of clinical activity in the relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) cohorts (Mehta et al, presented at the EHA Conference 2019, abs PS1073). Here, we report overall efficacy and safety data from the solid tumors (head and neck squamous cell carcinoma [HNSCC]; cervical carcinoma and other solid tumors) and lymphoma (diffuse large B-cell lymphoma [DLBCL], PTCL, CTCL,) phase 2 cohorts.

Method:
Pts received treatment with ASTX660 orally at the RP2D 180mg/day on days 1 to 7, and 15 to 22 in a 28-day cycle. In the first stage 14 evaluable pts were enrolled in each of the 6 phase 2 cohorts with the option to expand the cohort if activity was observed. The primary endpoint was response rate as assessed by the investigator according to the Lugano criteria (DLBCL and PTCL), Global Assessment (CTCL), or RECIST 1.1 (solid tumors). Adverse events (AEs) were assessed per CTCAE V4.03.

Result:
As of June 4, 2019, a total of 107 pts have received ASTX660 in the solid tumors and lymphoma phase 2 cohorts (HNSCC n=14; DLBCL n=16; PTCL n=26; CTCL n=23; cervical carcinoma n=14; other solid tumors n= 14). Median age (range) was 61 (23-84) years and median number (range) of prior anticancer regimens was 3 (0-12). Among all pts, the most common related AEs of any grade (≥ 10%) were rash (35%), lipase elevation (34%), amylase elevation (29%), diarrhea (14%), fatigue (14%), AST elevation (13%), nausea (13%), and anemia (11%). Related AEs ≥ Grade 3 occurring in ≥ 5% of pts were rash (18%), lipase elevation (16%) and amylase elevation (9%). As of 4 June 2019, 86 pts (80%) discontinued study treatment: 64 (60%) due to progressive disease, 13 (12%) due to AE, 4 (4%) due to death, 4 (4%) due to withdrawal by participant and 1 (1%) for investigator’s decision. At the time of analysis, the ORR was 36% in the PTCL cohort and 15% in the CTCL cohort. One PR was reported in a pt with metastatic melanoma after 12 cycles of treatment. No objective responses were reported in the HNSCC, DLBCL or cervical cohorts. Accrual in the PTCL and CTCL continues; updated efficacy and safety data will be presented at the meeting.

Conclusion: In the phase 2 part of the study ASTX660 monotherapy has demonstrated a manageable safety profile and encouraging activity in PTCL and CTCL warranting cohort expansion. Future plans include evaluation of ASXT660 both as mono- or combination therapy in selected malignancies.

2019 ACOP: A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

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A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

Abstract

Objectives:
Cytidine deaminase (CDA) rapidly degrades decitabine (DAC), an approved treatment for myelodysplastic syndromes, resulting in poor and variable bioavailability. Low doses of oral DAC co-administered with a novel and potent CDA inhibitor, cedazuridine (E7727), have been shown in clinic to produce exposures similar to IV DAC with acceptable inter-patient variability. The objective of this work was to further develop a semi-physiological population PK model ([1]) to characterize the PK enhancement of oral DAC when co-administered with cedazuridine and to identify potential covariates that impact the PK of DAC and/or cedazuridine.

Methods:
Model development utilized serial cedazuridine and DAC plasma concentration observations of IV DAC, oral DAC, and cedazuridine monotherapies and DAC+cedazuridine combinations. Observations from Phase 1/2 Study ASTX727-01 included dose escalation data (n=43; cohorts of 40:20, 60:20, 100:20, 100:40, and 100:30 mg cedazuridine:DAC with n=6 per cohort), dose confirmation data (n=42; 35:100 mg cedazuridine:DAC), and an FDC formulation extension (n=26). R was used for data processing, exploratory analysis, and visual predictive checks, while model development and parameter estimation utilized NONMEM. Covariate effects were explored using a full model approach.

Results:
Mono- and combination therapy data were sequentially integrated into a semi-physiological population PK model. Semi-physiological structural modeling elements included an IV DAC depot, oral DAC and cedazuridine transit compartment absorption, and portal vein, liver, central, and peripheral compartments. CDA metabolism of DAC primarily occurs in the liver compartment, with additional extra-hepatic metabolism. A maximum effect (Emax) inhibition model, dependent on local cedazuridine concentrations, described the drug effect of the oral ASTX727 combination therapy on CDA metabolism of DAC. IV DAC data were used to parameterize distribution and metabolism of DAC, while oral DAC monotherapy data was used to parameterize oral absorption. cedazuridine mono- and combination therapy data were used to parameterize cedazuridine PK parameters. Stratified individual-level random effects did not demonstrate systematic biases for any covariates, including weight-based effects.

Conclusions:
A semi-physiological population PK model was sequentially developed from mono- and combination therapy observations of plasma concentrations from the ASTX727-01 dose escalation and confirmation study. The analysis characterized the PK enhancement of oral DAC when co-administered with cedazuridine across a range of dose regimens and found no significant covariate effects, including weight-based effects. The resulting model will be used to interpret outcomes from an ongoing Phase 3 study (FDC ASTX727 of 35 mg DAC / 100 mg cedazuridine), while simulations will quantitatively inform future clinical development of ASTX727.

Xiao, et al. “Dual Antagonist of cIAP/XIAP ASTX660 Sensitizes HPV−and HPV+ Head and Neck Cancers to TNFα, TRAIL, and Radiation Therapy”

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https://clincancerres.aacrjournals.org/content/early/2019/09/20/1078-0432.CCR-18-3802

Abstract

Purpose: Human papillomavirus–negative (HPV−) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, with or without concurrent amplification of Baculovirus inhibitor of apoptosis repeat containing (BIRC2/3) genes encoding cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2). Antagonists targeting cIAP1 have been reported to enhance sensitivity of HPV−, but not HPV+ tumors, to TNF family death ligands (TNF and TRAIL) and radiation.

Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV− cell lines in combination with death ligands TNFα and TRAIL, and in preclinical xenograft models with radiation, an inducer of death ligands. The dependence of activity on TNF was examined by antibody depletion.

Results: ASTX660 sensitized subsets of HPV− and HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor effects of ASTX660 are the result of both apoptosis and/or necroptosis among HPV− cells, and primarily by apoptosis (caspase 3 and caspase 8 cleavage) in HPV+ cells. ASTX660 enhanced restoration of protein expression and inhibitory activity of proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both HPV− and HPV+ human tumor xenografts, an effect attenuated by anti-TNFα pretreatment blockade.

Conclusions: IAP1/XIAP antagonist, ASTX660, sensitizes HPV+ HNSCC to TNFα via a mechanism involving restoration of TP53. These findings serve to motivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV− HNSCC.

Savona et al., An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study

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Savona et al, “Savona et al., An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study”, The Lancet Haematology, Volume 6, Issue 4, e194 – e203  DOI:10.1016/S2352-3026(19)30030-4

Abstract

BACKGROUND:

Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.METHODS:

In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Eligible patients were assigned to cohorts to receive escalating oral doses of decitabine and cedazuridine. The starting dose was decitabine 20 mg and cedazuridine 40 mg. Treatment cycles lasted 28 days, with 5 days of drug administration. In cycle 1, each patient received a cohort-defined dose of oral decitabine on day -3, a 1-h intravenous infusion of decitabine 20 mg/m2 on day 1, and cohort-defined doses of oral decitabine plus cedazuridine on days 2-5. In cycles 2 and beyond, the oral decitabine and cedazuridine were given on days 1-5. The dose of cedazuridine was escalated first and decitabine was escalated once CDA inhibition by cedazuridine approached the maximum effect. The drug dose was escalated if mean decitabine area under the curve (AUC) of the oral drug was less than 90% of that for intravenous decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range set as the primary endpoint, and established with intravenous decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for decitabine exposure similar to that for intravenous decitabine exposure. This study is registered with ClinicalTrials.gov, number NCT02103478.

FINDINGS:

Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1-4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 decitabine AUCs (146 ng × h/mL for decitabine 30 mg, and 221 ng × h/mL for decitabine 40 mg) closest to the mean intravenous-decitabine AUC (164 ng × h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]).

INTERPRETATION:

Oral decitabine plus cedazuridine emulated the pharmacokinetics of intravenous decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous decitabine treatment for 5 days. Further study of decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted.

 

de Witte, Effective oral hypomethylating drugs in intermediate-risk or high-risk myelodysplasia: a breakthrough?

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“Effective oral hypomethylating drugs in intermediate-risk or high-risk myelodysplasia: a breakthrough?” The Lancet Haematology, Volume 6, Issue 4, PE170-E171, DOI 10.1016/S2352-3026(19)30025-0•

 

Curative treatment options for patients with intermediate-risk or high-risk myelodysplasia are intensive chemotherapy and allogeneic stem cell transplantation, but most patients with myelodysplasia are too frail to be treated with these demanding interventions because of advanced age and comorbidities. Alternative treatment approaches are either ineffective or result in short response durations with little survival benefit.

 

 

2019 ICTXV: Nonclinical Development of Cedazuridine, a Novel Cytidine Deaminase Inhibitor for use in Combination with Decitabine to Enable Oral Administration to Patients with Myelodysplastic Syndromes (MDS)

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Nonclinical Development of Cedazuridine, a Novel Cytidine Deaminase Inhibitor for use in Combination with Decitabine to Enable Oral Administration to Patients with Myelodysplastic Syndromes (MDS)

Abstract:

Cedazuridine (E7727) is a synthetic nucleoside analog derived from tetrahydrouridine (THU) and designed as a potent inhibitor of cytidine deaminase (CDA) with improved stability over THU. It is currently being developed in combination with hypomethylating agent decitabine (ASTX727) as an oral option for treatment of MDS and CMML. Concomitant administration of cedazuridine enhances oral bioavailability of decitabine and achieves therapeutic AUC exposures in the clinic at low doses of decitabine (similar to IV dose, in mg) that are well tolerated.

Nonclinical development of cedazuridine included full toxicological and DMPK evaluation. Cedazuridine is well tolerated in mice and monkeys (tox species) over 1-cycle of 7 days dosing, (followed by recovery), with NOAEL at 1000 mg/kg and 200 mg/kg, respectively. Subchronic studies of 13-weeks duration with multi-cycles (28 days/cycle with dosing on days 1-7) resulted in NOAEL of 100/300 mg/kg in mice (females/males) and 60 mg/kg in cynomolgus monkeys. The highest non-severely toxic dose (HNSTD) in multi-cycle study was 200 mg/kg/dose in monkeys. Target organs at the NOAEL were lymph nodes in mice and GI mucosa and bone marrow (RBC parameters) in monkeys. These dose levels offer a large safety margin over the clinical dose (and systemic exposures) used for cedazuridine (100 mg fixed dose, in combination with 35 mg decitabine). Cedazuridine in mouse in vivo micronucleus study was negative at up to 2000 mg/kg and was negative in in vitro Ames and chromosome aberration tests at concentrations that were not cytotoxic.

Co-administration with decitabine in mice and monkeys resulted in significant increase in systemic exposures compared with decitabine administered alone. Cedazuridine is metabolically stable in liver microsomes and hepatocytes, does not inhibit major human CYP enzymes, and is not a substrate and/or inhibitor of major human drug transporters. It does not accumulate in tissues and is excreted mainly renally. The main metabolite was its epimer, to which it partially converts in acidic environment in the stomach prior to absorption.

In summary, cedazuridine has been well characterized in nonclinical toxicology and DMPK studies and its nonclinical data profile supports late-stage clinical development.

2019 EHA: RESULTS OF ASTRAL-1 STUDY, A PHASE 3 RANDOMIZED TRIAL OF GUADECITABINE (G) VS TREATMENT CHOICE (TC) IN TREATMENT NAÏVE ACUTE MYELOID LEUKEMIA (TN-AML) NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY (IC)

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RESULTS OF ASTRAL-1 STUDY, A PHASE 3 RANDOMIZED TRIAL OF GUADECITABINE (G) VS TREATMENT CHOICE (TC) IN TREATMENT NAÏVE ACUTE MYELOID LEUKEMIA (TN-AML) NOT ELIGIBLE FOR INTENSIVE CHEMOTHERAPY (IC)

 

Background: Guadecitabine is a next generation hypomethylating agent (HMA) given subcutaneously (SC) which provides prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. A multicenter phase 2 study reported a 38% CR rate, and a 54% composite CR (CR+CRp+CRi) rate using 5-day regimen at 60 mg/m2/d SC Q28 days in TN-AML not eligible for IC (Kantarjian et al, Lancet Oncology 2017). This led to ASTRAL-1 study, an international phase 3 randomized trial comparing guadecitabine to TC of azacitidine (AZA), decitabine (DEC) or Low Dose Ara-C (LDAC).
Aims: To report ASTRAL-1 study primary analyses results.
Methods: TN-AML not eligible for IC due to age ≥ 75 y or comorbidities including ECOG PS 3 were randomized 1:1 to either guadecitabine (60 mg/m2/d SC for 5-days Q28 days) or a preselected TC of AZA, DEC, or LDAC at standard regimens. AML diagnosis and response status were assessed by an independent central pathologist blinded to randomization assignment. CR and Overall Survival (OS) were co-primary endpoints.
Results: 815 patients were randomized to guadecitabine (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), and LDAC (15%). Baseline variables were balanced across the 2 arms. Median age 76 y for both arms, patients ≥75 y were 62% vs 62.4%, PS 2-3 in 50.5% vs 50.4% (including 10.8% vs 8.8% PS 3), poor risk cytogenetics 34.3% vs 34.6%, secondary AML 36.3% vs 36.9%, WBCs ≥20×109/L 15.2% vs 14.3%, and median BM blasts 56% vs 53% for G vs TC respectively. Median follow up was 25.5 m and median number of treatment cycles was 5 for both arms. Many patients (41.6%) received ≤ 3 cycles mainly due to early death or progression with no difference between the 2 arms (42.4% on G, and 40.8% on TC). The co-primary endpoints ITT analyses showed a CR rate of 19.4% vs 17.4% for G vs TC (p = 0.48). The median, 1-y, and 2-y survival were 7.1 m, 37%, and 18% for guadecitabine, and 8.4 m, 36%, and 14% for TC (Figure 1). OS HR was 0.91, 0.98, and 0.96 for G vs AZA, DEC, and LDAC respectively. Landmark survival analyses showed potential benefit of guadecitabine vs TC in patients who received >3 cycles (median, 1-y, and 2-y OS 15.6 m, 60% and 29% on guadecitabine vs 13 m, 52%, and 20% on TC; log-rank p value=0.02, HR 0.78, 95% CI 0.64-0.96), and those who achieved any CR (CR, CRp, or CRi): OS HR 0.72, 95% CI 0.50-1.05. Analyses of predefined clinical, cytogenetics, and molecular genetics variables assessed by PCR (Flt-3 ITD, CEBPA, NPM1, and TP53) did not show significant differences of primary outcomes between guadecitabine and TC in any subgroup except for TP53. Patients with identified baseline TP53 mutations did worse on G vs TC while those without identified TP53 mutations had a more favorable outcome on guadecitabine vs TC. Both treatment arms showed overall similar safety profiles with slightly higher but not significant serious AEs incidence (81% vs 75.5%) and Grade ≥ 3 AEs (91.5% vs 87.5%) on guadecitabine vs TC respectively. There was no difference in AEs leading to death (28.7% for guadecitabine vs 29.8% for TC).
Conclusions/Summary: The trial did not achieve its primary endpoints of statistically significant superiority of guadecitabine vs TC for CR or OS. However due to the large sample size and narrow 95% CI for OS difference, the trial suggests that G is an active drug with an overall similar efficacy and safety profiles to standard therapy. Potential benefit of guadecitabine vs TC was observed in patients who were able to receive adequate treatment (>3 cycles), and those who achieved any CR. The significance of TP53 mutations needs to be further explored.
Figure 1: Kaplan-Meier Survival Plot of guadecitabine vs TC