`
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`
`The path to approval for oral
`hypomethylating agents in acute myeloid
`leukemia and myelodysplastic syndromes
`
`David Kipp*,1,3 & Andrew H Wei2,3
`1Department of Haematology, University Hospital Geelong, Geelong, 3220, Australia
`2Department of Clinical Haematology, The Alfred Hospital, Melbourne, 3004, Australia
`3Australian Centre for Blood Diseases, Monash University, Melbourne, 3004, Australia
`*Author for correspondence: david.kipp@monash.edu
`
`Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have
`recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance
`therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination
`of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult
`patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or
`higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical develop-
`ment of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending
`the use of these drugs to other indications.
`
`Lay abstract: One of the key challenges in treating acute myeloid leukemia is to prevent relapse after
`remission has been achieved. This means that developing an effective maintenance treatment is very
`important. Maintenance treatment is given for a prolonged period and so it needs to be easy to give
`and well tolerated. Oral azacitidine is an example of this type of treatment and is the first drug that has
`been shown to improve survival as maintenance therapy for acute myeloid leukemia patients. This article
`describes the key studies that led to the approval of this important therapy.
`
`First draft submitted: 30 December 2020; Accepted for publication: 12 March 2021; Published online:
`26 March 2021
`Keywords: CC-486 • oral HMA • QUAZAR
`
`Acute myeloid leukemia (AML) is a heterogeneous myeloid malignancy characterized by acquired genetic and
`epigenetic mutations, resulting in impaired differentiation of hematopoietic precursors and enhanced growth
`and survival of myeloid progenitors. Conventional cytotoxic induction and consolidation chemotherapy, often
`followed by allogeneic hematopoietic cell transplantation (allo-HCT) for patients at higher risk of relapse, has been
`the standard of care for AML. A proportion of patients with AML are not eligible for allo-HCT due to older age,
`comorbidities, donor limitations or patient/physician preference. After completing intensive chemotherapy (IC),
`observation is usually recommended if allo-HCT is not possible or contraindicated.
`Maintenance therapy is the term ascribed to lower-intensity treatment aimed at preventing relapse and prolonging
`remission. Recently, the benefit of maintenance therapy with CC-486 in prolonging survival in patients with AML
`in first remission was demonstrated in a randomized Phase III study. Therefore, on 2 September 2020 the US FDA
`approved CC-486 for maintenance treatment of adult patients with AML who have achieved first complete remission
`(CR) or CR with incomplete blood count recovery (CRi) after intensive induction chemotherapy and who are
`unable to complete intensive curative therapy. This approval provides an opportunity for oral hypomethylating
`agents to be used more broadly in the postremission setting and to be explored in a variety of new indications for
`patients with myeloid and other malignancies.
`CELGENE 2091
`APOTEX v. CELGENE
`IPR2023-00512
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`10.2217/fon-2020-1318 C(cid:2) 2021 Future Medicine Ltd
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`ISSN 1479-6694 2563
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`Determination of bioavailability & the optimal dose schedule for CC-486
`Due to the short plasma half-life of azacitidine [1] and cell cycle-restricted DNA incorporation [2], a newly formulated
`oral agent allowing extended dosing schedules had the theoretical advantage of enhancing the exposure to cycling
`malignant cells to azacitidine. To validate the bioavailability of CC-486, a pilot study was conducted in four patients
`with solid malignant tumors, AML or myelodysplastic syndromes (MDS). Patients received a single CC-486 dose
`of 60 or 80 mg [3]. All four patients showed measurable plasma concentrations of azacitidine. The 80-mg dose was
`tolerable, with 17% bioavailability compared with subcutaneous (SC) exposure. No severe drug-related toxicities
`were observed.
`To determine the maximal tolerated dose of CC-486, a Phase I study was conducted (AZA PH US 2007 CL 005)
`in patients with MDS, chronic myelomonocytic leukemia (CMML) or AML [4]. A total of 41 patients received SC
`azacitidine (75 mg/m2) on days 1–7 of cycle 1, followed by CC-486 (120 to 600 mg) days 1–7 of subsequent cycles.
`Pharmacokinetic (PK) and pharmacodynamic (PD) profiles were compared between cycles 1 and 2. Adverse events
`(AEs) and hematologic responses were recorded. Crossover to SC azacitidine was permitted for nonresponders who
`received at least six cycles of CC-486.
`Dose-limiting toxicity (grade-3/4 diarrhea) occurred in two of three patients at the 600-mg dose level, resulting
`in 480 mg being declared the maximal tolerated dose. The most common grade-3/4 AEs were diarrhea (12%),
`nausea (7%), vomiting (7%), febrile neutropenia (20%) and fatigue (10%). The mean relative oral bioavailability
`ranged from 6.3 to 20%. The maximal PD effect of oral and SC azacitidine, as assessed by DNA hypomethylation
`in peripheral blood, occurred on day 15 of each cycle. As a single agent, CC-486 demonstrated impressive activity
`among patients with MDS and CMML, with the overall response rate (i.e., CR, hematological improvement [HI]
`or red blood cell [RBC]- or platelet-transfusion independence [TI]) being 35% in previously treated patients and
`73% in those with treatment-naive disease.
`
`Pharmacokinetic & pharmacodynamic properties of CC-486
`Two Phase I studies evaluated the PK characteristics of CC-486 in subjects with MDS, CMML and AML. High
`inter-subject variability in area under the curve (AUC∞) and Cmax was seen. CC-486 was rapidly absorbed (within
`1 h), with little or no effect of food on PK parameters [5]. CC-486 had modest oral bioavailability (6.3–20%).
`Clearance was mainly hepatic and extrahepatic, with minimal renal clearance [4]. The cumulative azacitidine
`exposures with CC-486 at a dose of 300 mg daily for 14 or 21 days per 28-day cycle were equivalent to 38 and
`57%, respectively, of the cumulative exposure of SC azacitidine administered for 7 days per cycle [6].
`Dynamic changes in DNA methylation after SC azacitidine and CC-486 were similar, with maximal hypomethy-
`lation achieved on day 15 and methylation levels returning to near-baseline values by the end of each cycle. Notably,
`CC-486 induced less demethylation than the SC formulation [4]. PK and PD studies were also conducted in a
`cohort of 59 patients sequentially assigned to one of four extended CC-486 dosing schedules: either 300 mg once
`daily for 14 or 21 days or 200 mg twice daily (bd) for 14 or 21 days each 28-day cycle [7]. The 300-mg once-daily
`and the 200-mg bd schedules both reduced global DNA methylation in whole blood at all measured time points
`(days 15, 22 and 28 of the treatment cycle). Maximal hypomethylation was seen at 22 days. CC-486 exposures
`and extent of DNA hypomethylation were significantly correlated. Patients who had a hematologic response had
`significantly greater reductions in methylation than nonresponding patients. These data showed that extended
`dosing schedules of CC-486 could sustain epigenetic effects throughout the treatment cycle.
`
`CC-486 in lower-risk MDS
`Part 2 of AZA PH US 2007 CL 005 evaluated extended duration CC-486 dosing in patients with lower-risk
`MDS [6]. Patients received CC-486 at a dose of 300 mg daily for 14 (n = 28) or 21 days (n = 27) in repeated 28-day
`cycles. The median patient age was 72 years and 75% had International Prognostic Scoring System intermediate-1
`risk MDS. The median duration of treatment was seven cycles for the 14-day dosing schedule and six cycles for
`the 21-day schedule. The overall response rate (CR or partial response [PR], RBC- or platelet-TI or HI) was 36%
`among patients receiving 14-day dosing and 41% in patients receiving 21-day dosing. RBC-TI rates were similar for
`both dosing schedules (31 and 38%, respectively). CC-486 was generally well tolerated. These studies concluded
`that extended dosing schedules of CC-486 could provide effective treatment for patients with lower risk MDS.
`A Phase III placebo-controlled trial in lower-risk MDS was conducted (AZA-MDS-003; ClinicalTrials.gov:
`NCT01566695) comparing CC-486 with placebo in patients with RBC-transfusion-dependent anemia and throm-
`bocytopenia [8]. The primary end point was RBC-TI lasting for at least 56 days. Key secondary end points were
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`overall survival (OS), at least 84 days of RBC-TI, and HI in erythroid and platelet lineages. The planned enrolment
`was 386 patients; however, the study was halted early due to an observed excess of early deaths in the CC-486 arm,
`potentially due to neutropenia-related complications. The final sample size was 216 patients [8]. CC-486 met the
`primary end point of RBC-TI (31% of patients in the CC-486 arm, compared with 11% in the placebo arm).
`CC-486 also resulted in durable improvements in hemoglobin and platelet counts. No difference in survival was
`seen.
`
`CC-486 in AML
`A total of 23 patients with AML (13 patients with de novo disease and ten with AML secondary to MDS) were
`treated in the AZA PH US 2007 CL 005 study [9]. Of eight patients treated with CC-486 at a dose of 120–600 mg
`daily for 7 days, three achieved a response (38%), including two with marrow CR and one with marrow PR. Of
`15 patients treated with CC-486 in extended dosing schedules (300 mg daily or 200 mg bd for 14 or 21 days),
`seven achieved a response (47%), including four with HI, four with RBC-TI, one with platelet-TI and three with
`marrow PR. No patients achieved CR or PR. One response was also observed in a patient failing prior injectable
`demethylating agent therapy. The most common AEs were gastrointestinal (GI). The most common higher-grade
`AEs (grade 3/4) were febrile neutropenia (35%), pneumonia (17%), syncope (17%) and nausea (13%).
`
`Phase III study of CC-486 as maintenance therapy in AML
`Maintenance therapy for patients with AML in first remission was considered a suitable setting for a new orally
`administered epigenetic drug. Maintenance therapy in AML was an area of unmet need. The goal of postrem-
`ission therapy is to target measurable residual disease (MRD) with the goal of prolonging remission. The term
`‘maintenance’ has mainly been intended to represent postremission therapy that is less intensive than consolidation
`chemotherapy.
`For patients with AML who were in remission after IC and not candidates for allo-HCT, there were no competing
`agents with demonstrated capacity to prolong OS. Although maintenance therapy with parenteral azacitidine has
`been shown to prolong disease-free survival in older AML patients [10], the potential to double the cycle exposure
`with a 14-day CC-486 schedule and to more conveniently deliver therapy for more cycles than with injectable
`hypomethylating agents was an important consideration in the design of the QUAZAR AML-001 study, and may
`have played a significant role in it being positive for OS (see below).
`Compared with parentally administered azacitidine, CC-486 had the advantage of being a conveniently admin-
`istered formulation that was well tolerated in the extended dosing schedules used in Phase I studies, with evidence
`that it could sustain DNA hypomethylation across the treatment cycle. Furthermore, as noted above, CC-486
`was likely to be continued for more cycles than parenterally administered therapy, due to its greater convenience.
`The current standard of care postchemotherapy for those not proceeding to transplant was observation; therefore,
`the maintenance study could be conducted using CC-486 as a single agent versus placebo. The target population
`included patients with AML aged 55 years or older, in whom allo-HCT was less likely to be performed than in
`younger patients. Patients were required to commence CC-486 within 120 days of achieving first CR or CRi, in
`order to avoid enrolling patients with a lower likelihood of relapse, which would have reduced the event rate in the
`studied population.
`The QUAZAR AML-001 study randomized 472 patients in a 1:1 ratio to CC-486, 300 mg daily, or placebo for
`14 days per 28-day cycle [11]. The 14-day schedule was chosen as it was considered to be more tolerable than the
`21-day schedule used in the Phase I studies. The 21-day schedule produced more severe cytopenic complications,
`which was considered to be undesirable in patients whose leukemia was in remission. Where there was evidence of
`early progression, however, a 21-day schedule was allowed (see below).
`The primary end point was OS. Secondary end points included relapse-free survival (RFS) and health-related
`quality of life. Patients had received a variety of induction regimens that included at least cytarabine and an anthra-
`cycline. More than one cycle of induction was permitted in order to achieve remission. Receipt of consolidation
`therapy was not a prerequisite for study entry, such that patients deemed unfit to receive any further consolidation
`therapy could receive maintenance therapy with CC-486.
`The two treatment arms in the study were well balanced. The median age was 68 years (range: 55–86). Although
`patients with favorable cytogenetic risk were excluded from the study, the population included only 9% with
`secondary AML and 14% with adverse cytogenetic risk, suggesting enrichment of patients with nonadverse disease
`characteristics who were less likely to be considered candidates for allo-HCT. The population included patients
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`who lost fitness and/or candidacy for intensive consolidation therapy; indeed, at study screening, 20% of patients
`had not received consolidation therapy, whereas 45 and 35% had received one or more than one consolidation
`cycle, respectively. The study population included patients in CR (81%) or CRi (19%) and 19% had received
`more than one induction cycle in order to achieve remission. The study included centralized multiparameter flow
`cytometry in order to assess MRD, which was detected in 46% at study baseline.
`With a median follow-up time of 41.2 months, the median OS from randomization was significantly improved
`with CC-486 versus placebo (24.7 vs 14.8 months; p = 0.0009). Survival benefits were demonstrated across patient
`subgroups, including those with adverse-risk baseline features such as poor cytogenetic risk, no prior consolidation
`therapy, CR with incomplete hematologic recovery and MRD positivity. The median RFS was also significantly
`prolonged with CC-486 (10.2 vs 4.8 months; p = 0.0001).
`One notable feature of the QUAZAR AML-001 study was the intensive MRD monitoring program, which
`included three-monthly bone marrow assessments for 24 months, followed by six-monthly assessments thereafter.
`This enabled much earlier detection of relapse, explaining the apparently shorter RFS in this study compared with
`that reported in previous maintenance studies [10]. During MRD surveillance on the QUAZAR AML-001 study,
`patients with early relapse (5–15% bone marrow blasts) were eligible for an extended dosing schedule of CC-486
`(21 days per 28-day cycle). Extended dosing was commenced in 21% of patients receiving CC-486, with CR or
`CRi being re-established in 23%, compared with 11% in the placebo arm.
`Similar to the dose-finding experience, GI toxicity was the most commonly reported AE, with nausea, vomiting
`and diarrhea reported in approximately 60%. Grade-3/4 GI toxicity, however, was uncommon (≤5%), as were
`treatment discontinuations due to GI events (5%). Although GI toxicity was more common during the first
`two cycles, the frequency was less common in subsequent cycles (∼15%), likely due to the implementation of
`prophylactic supportive care measures. Although grade-3/4 neutropenia (41%) and thrombocytopenia (23%) were
`reported, the rate of febrile neutropenia was low (12%). Patient-reported outcome studies showed no deterioration
`in quality of life during therapy with CC-486 compared with placebo. Based on the positive efficacy outcome and
`tolerable safety profile, CC-486 received FDA approval as a new maintenance therapy in AML.
`
`Oral maintenance therapy after allogeneic stem cell transplantation
`Relapse is the main cause of treatment failure after allo-HCT in AML, occurring in up to 50% of patients. Currently,
`no post-transplant maintenance therapy has been approved for AML [12].
`The Phase I/II CC-486-AML-002 study investigated the use of CC-486 maintenance after allo-HCT [13]. Adults
`with MDS or AML in morphologic CR 42–84 days after allo-HCT were included. This was a dose-optimization
`study that enrolled patients to one of four CC-486 dosing schedules for up to 12 cycles. Of 30 patients, seven
`received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle
`(150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grade-3/4 AEs were infrequent and occurred with similar
`frequency across regimens. Of 28 evaluable patients, relapse or progressive disease occurred in three of seven patients
`(43%) receiving 7-day dosing and three of 23 (13%) who had received the 14-day dosing schedule. Estimated
`1-year survival rates were 86 and 81% in the 7 and 14-day dosing cohorts, respectively. CC-486 maintenance was
`generally well tolerated, with low rates of graft-versus-host disease. A randomized controlled trial incorporating
`CC-486 as maintenance in the post-allo-HCT setting for AML aiming to enroll 324 patients is currently underway
`(NCT04173533).
`
`Oral hypomethylating agent therapy for MDS
`The convenience of CC-486 makes it an attractive option to replace injectable azacitidine in a variety of drug
`combinations. CC-486, however, has low bioavailability [4] due to rapid clearance by the enzyme CDA, which is
`ubiquitous in the gut and liver [14]. CC-486 is therefore not bioequivalent to parenteral azacitidine [6].
`Decitabine, another DNA methyltransferase inhibitor, is also not readily orally bioavailable, due to rapid
`inactivation by CDA in the GI tract and liver. The competitive CDA inhibitor tetrahydrouridine (THU) increases
`the oral bioavailability of decitabine, but THU is unstable in acidic environments, making it pharmaceutically
`difficult to develop [15,16]. Cedazuridine (CDZ) is an alternative oral inhibitor of CDA and has been shown to
`safely and effectively increase decitabine exposure following oral administration in preclinical studies [15,17].
`The first-in-human dose-escalation trial of oral cedazuridine plus decitabine (ASTX727), concurrently admin-
`istered at various doses, enrolled 44 patients with previously treated or newly diagnosed MDS or CMML [18].
`ASTX727, containing 30–40 mg of decitabine combined with 100 mg of CDZ, was associated with decitabine
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`exposure and PD activity (as assessed by demethylation of DNA) that were comparable with those of intravenous
`(iv.) decitabine. ASTX727 achieved decitabine AUC 5-day exposures (oral/iv. ratio) of 81–128%. Clinical responses
`were similar to those seen with iv. decitabine treatment for 5 days.
`A subsequent Phase II study was designed to compare systemic decitabine exposure, demethylation activity and
`safety in the first two cycles between patients receiving cedazuridine 100 mg/decitabine 35 mg and a standard
`decitabine schedule of 20 mg/m2 iv. [19]. A total of 80 patients with MDS or CMML were randomized 1:1 to
`receive ASTX727 or iv. decitabine in cycle 1, followed by crossover in cycle 2. All patients received ASTX727 in
`subsequent cycles. ASTX727 was associated with systemic decitabine exposure, DNA demethylation and safety
`profile that were similar to those of iv. decitabine during the first two cycles. Efficacy was also similar, with 21%
`of patients achieving a CR and 60% recording a clinical response. The most common grade-3 or more AEs were
`again hematological: neutropenia (46%), thrombocytopenia (38%) and febrile neutropenia (29%). Notably, GI
`AEs were predominantly grade 1 or 2 and were reported at similar incidences between oral and iv. dosing in cycles
`1 and 2, suggesting no additional GI toxicity with oral treatment, at least during the first two cycles.
`These studies led to the ASCERTAIN study, a randomized crossover Phase III study of ASTX727 compared
`with iv. decitabine [20]. In this study, 138 patients (121 with MDS and 17 with CMML) were randomized 1:1
`to either ASTX727 (100/35 mg) in cycle 1 followed by iv. decitabine (20 mg/m2) in cycle 2, or iv. decitabine in
`cycle 1 followed by ASTX727 in cycle 2, in order to compare PK and PD (DNA demethylation using the LINE-1
`assay). All patients received ASTX727 from cycle 3 onwards. The study met its end point with high confidence: the
`oral/iv. 5-day decitabine AUC ratio was 99% (90% confidence interval, 93–106%). All sensitivity and secondary
`PK AUC analyses confirmed findings from the primary analysis. There was no significant difference in LINE-1
`DNA demethylation between ASTX727 and iv. decitabine (<1% difference in each cycle). The overall response rate
`(CR, PR, marrow CR and HI) in 101 evaluable patients was 64%, comparing favorably with response rates observed
`in previous studies of CC-486 in MDS, CMML and AML (30–40%). These results supported the approval, on 7
`July 2020, of ASTX727 for adult patients with International Prognostic Scoring System intermediate-1 or higher
`MDS or CMML.
`
`Conclusion
`The pivotal QUAZAR AML-001 AML maintenance study has shown that CC-486 improves both RFS and OS
`in older patients with AML following IC. There are now two approved oral hypomethylating agents in the clinic.
`These new drug formulations provide many diverse therapeutic opportunities for patients with AML and MDS.
`Despite the lower exposure of oral as compared with injectable azacitidine, there is evidence that lowering the dose
`of a hypomethylating agent (which should decrease cytotoxic effects) and administering the dose over a longer
`period (which should increase S phase-dependent DNA incorporation) may enhance efficacy [21]. For maintenance
`therapy after AML, only CC-486 has so far been shown to improve survival in the context of a Phase III trial.
`ASTX727 has shown promise in clinical studies of patients with MDS and CMML and has better bioavailability
`and less GI toxicity than CC-486. The mechanism of action and PK exposure of ASTX727, however, are likely
`to be distinct from those of CC-486 and so a separate validation of ASTX727 in a randomized setting is needed
`before it can be supported for use as a maintenance option in AML.
`Just as ASTX727 cannot be substituted for CC-486 as maintenance therapy in AML, CC-486 cannot be used
`interchangeably with injectable azacitidine in settings where the latter is already established. In other words, for
`other disease scenarios where injectable azacitidine is used (e.g., in combination with venetoclax in AML or as a
`single agent in MDS), properly conducted safety- and efficacy-based studies must be conducted in order to identify
`the optimal dosing schedule, rather than substituting oral for parenteral azacitidine, based on the fact that CC-486
`is not pharmacokinetically equivalent to parenteral azacitidine.
`The most obvious consideration would be to use CC-486 in combination with venetoclax for the treatment
`of older patients with AML. This will, however, require validation that CC-486 combined with venetoclax will
`produce similar efficacy without increased toxicity. Currently, the approved dosing schedules of oral and injectable
`azacitidine are 14 and 7 days per cycle, respectively. It is unknown what the optimal dose or schedule of CC-486 in
`combination with venetoclax would need to be in order to maximize the therapeutic window. Therefore, carefully
`conducted dose-escalation studies would need to be performed, potentially in patients with relapsed/refractory
`disease initially. For use in the frontline setting in older patients, CC-486 would need to at least demonstrate
`noninferiority to parenteral azacitidine in combination with venetoclax. Substituting ASTX727 for iv. decitabine
`in combination with venetoclax is likely to be more straightforward, as ASTX727 has a very similar PK profile to
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`that of iv. decitabine and the combination of iv. decitabine with venetoclax has been shown to be efficacious and
`tolerable in Phase Ib studies [22].
`The population in the QUAZAR AML-001 study was limited to patients aged at least 55 years. Patients with
`core-binding factor AML were excluded. Investigating maintenance therapy in younger patients has the challenge
`of an increased frequency of allo-HCT, which could confound the interpretation of survival outcomes. One strategy
`would be to focus on patients less likely to undergo allo-HCT in first remission, such as patients with favorable-risk
`AML as defined by the European LeukemiaNet. This would include patients with core-binding factor AML, AML
`with biallelic-mutated CEBPA and AML with mutated NPM1 without FLT3-ITD. The major challenge in studying
`this patient population would be the likelihood of a long study end point, due to the better prognosis for patients
`in this more favorable AML subgroup. In order to overcome this barrier, such a study could consider the role of
`MRD as an earlier surrogate of survival outcome.
`For drugs with new indications, such as CC-486 or ASTX727 in combination with other agents in situations
`where parenterally administered hypomethylating agents have not been established, studying hybrid oral combi-
`nations would be a very worthwhile initiative. Such combinations could include oral hypomethylating agents with
`IDH, FLT3 and checkpoint inhibitors. These combinations could be utilized for patients with relapsed/refractory
`disease, as frontline therapy or in the maintenance setting. Securing registration status, however, could be chal-
`lenging. It would be highly challenging to demonstrate CC-486 to be superior to injectable azacitidine, either
`in relapsed/refractory disease or in the frontline setting in older patients unfit for IC. Therefore, the best ap-
`proach might be to consider an oral hypomethylating agent combined with venetoclax and a targeted inhibitor
`(e.g., an IDH or FLT3 inhibitor) as part of an ‘all-oral’ novel triplet combination. This will, of course, require
`dose-optimization studies to be performed. In the maintenance setting, there is greater opportunity to combine
`CC-486 with other agents in order to augment survival, highlighted by the fact that the QUAZAR AML-001 study
`demonstrated that the majority of patients eventually relapsed, even though RFS and OS were prolonged compared
`with placebo. As shown by QUAZAR AML-001, however, maintenance studies take a long time to conduct and
`complete, which would be particularly problematic for a new maintenance study if it were limited to a targeted
`sub-group.
`In conclusion, the approval of two new oral hypomethylating agents creates new opportunities, but also new
`challenges, for patients with AML. Patients are likely to benefit from new drug indications, greater convenience and
`probably less hospitalization. The potential for extended duration dosing schedules, which could be delivered for
`many more cycles than is generally feasible with injectable agents, will provide physicians with new opportunities to
`design treatment schedules that could better target S-phase-dependent leukemic populations. The exact mechanism
`of action of oral hypomethylating agents remains uncertain and so there is likely to be renewed interest in conducting
`correlative studies in order to identify ‘responder’ and ‘nonresponder’ populations, now that the place of oral
`hypomethylating agents in the growing armamentarium of AML therapy has been established.
`
`Financial & competing interests disclosure
`AH Wei has served on advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, Celgene-BMS, Macrogenics,
`Agios and Gilead; receives research funding from Novartis, AbbVie, Servier, Celgene-BMS, Astra Zeneca and Amgen; serves on
`speaker’s bureaus for AbbVie, Novartis and Celgene; and receives royalty payments from the Walter and Eliza Hall Institute of Med-
`ical Research related to venetoclax. The authors have no other relevant affiliations or financial involvement with any organization
`or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from
`those disclosed.
`No writing assistance was utilized in the production of this manuscript.
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`Executive summary
`
`Pharmacokinetic properties, optimal dose & toxicity of CC-486
`• CC-486 has low bioavailability (∼20% compared with subcutaneous exposure) due to rapid clearance by the
`enzyme CDA, and is therefore not bioequivalent to parenteral azacitidine.
`• Oral administration provides a cumulative azacitidine exposure of 38–57% of that seen with the parenteral
`formulation.
`• The optimal dose is 300 mg daily.
`• The most common adverse events are gastrointestinal (GI). These are mostly mild (grade 1–2).
`Pharmacodynamic properties of CC-486
`• CC-486 causes less DNA demethylation than the subcutaneous formulation.
`• Nonetheless, extended dosing schedules of CC-486 result in sustained demethylation throughout the treatment
`cycle, with maximal demethylation at 22 days.
`• CC-486 exposure is significantly correlated with the extent of DNA demethylation.
`CC-486 in lower risk myelodysplastic syndromes
`• CC-486 has an overall response rate of 30–40% in patients with lower risk myelodysplastic syndromes (MDS).
`• Approximately 30% of patients with lower-risk MDS and transfusion-dependent anemia achieve red cell
`transfusion independence.
`• Extended dosing schedules are effective and feasible.
`Phase I study of CC-486 in acute myeloid leukemia
`• CC-486 showed a modest response rate in patients with acute myeloid leukemia (AML) treated in a small Phase I
`study.
`Phase III study of CC-486 as maintenance therapy in AML
`• The Phase III QUAZAR AML-001 study randomized 472 patients aged at least 55 years in a 1:1 ratio to CC-486,
`300 mg daily, or placebo for 14 days per 28-day cycle. The primary end point was OS.
`• The median overall survival from randomization was significantly improved with CC-486 versus placebo (24.7
`vs 14.8 months; p = 0.0009). The median relapse-free survival was also significantly prolonged with CC-486 (10.2
`vs 4.8 months; p = 0.0001).
`• Based on the positive efficacy outcome and tolerable safety profile, CC-486 received US FDA approval as a new
`maintenance therapy in AML.
`Oral maintenance therapy after allogeneic stem cell transplantation
`• A small Phase I/II study investigated the use of CC-486 maintenance after allogeneic hematopoietic cell
`transplantation. Azacitidine was well tolerated and resulted in favorable relapse and 1-year survival rates.
`• A large randomized controlled trial incorporating CC-486 as maintenance in the postallogeneic hematopoietic
`cell transplantation setting for AML is currently underway (ClinicalTrials.gov: NCT04173533).
`Oral hypomethylating agent therapy for MDS
`• Decitabine is also not readily bioavailable, due to rapid inactivation by CDA in the gut and liver.
`• Cedazuridine (CDZ) is an oral inhibitor of CDA and increases decitabine exposure.
`• Decitabine combined with cedazuridine (ASTX727) is associated with systemic exposure, pharmacodynamic
`activity and safety profile that are equivalent to those of intravenous decitabine.
`• ASTX727 has fewer GI side effects than CC-486.
`• In July 2020 ASTX727 was approved for the treatment of International Prognostic Scoring System intermediate-1
`or higher-risk MDS or chronic myelomonocytic leukemia.
`Conclusion
`• The pivotal QUAZAR AML-001 AML maintenance study has shown that CC-486 improves both relapse-free and
`overall survival in older pat