The only oral HMA with equivalent systemic exposure to IV decitabine1,2
INQOVI in the ASCERTAIN Phase 3 study
The ASCERTAIN crossover trial was designed to assess systemic decitabine exposure, demethylation activity, and safety between IV decitabine and INQOVI tablets in a broad range of patients with cytogenetic risks, including poor (24%-25%), intermediate (20%-28%), and better (39%-45%). 35% of patients had TP53 mutations, a hallmark of treatment-resistant MDS. The trial allowed for intrapatient comparison in the first 2 randomized treatment cycles, then assessment of the long-term efficacy and safety of INQOVI as a single arm.1-4
The Phase 3 crossover trial had a median follow-up of approximately 2.6 years.1,2
Study design & endpoints
Phase 3 crossover design1,2
Open-label, randomized, 2-cycle, 2-sequence, crossover clinical trial in treatment-experienced or treatment-naïve patients with MDS, including CMML (IPSS intermediate-1, -2, or high-risk). Patients were allowed to have 1 prior cycle of decitabine or azacitidine, and there was no limit for body weight or surface area.
Patients were randomized 1:1 to INQOVI (decitabine 35 mg/cedazuridine 100 mg) or IV decitabine 20 mg/m² daily from Day 1 through Day 5 of each 28-day cycle
In Cycle 1, patients received one agent and then crossed over to receive the other agent in Cycle 2
After Cycle 2, all patients received INQOVI and treatment continued until disease progression or unacceptable toxicity
Phase 3 (N=133)1,2
Phase 3 long-term follow-up (N=133)2
Primary endpoint
5-day area under the curve (AUC) between oral decitabine-cedazuridine and IV decitabine for Cycles 1 and 2
5-day area under the curve (AUC) between oral decitabine-cedazuridine and IV decitabine for Cycles 1 and 2
Key secondary endpoints
Complete response
Rate of conversion from transfusion dependence to transfusion independence
Clinical response, transfusion independence, median overall and leukemia-free survival (LFS), safety, and pharmacodynamics
Other endpoints
Median duration of complete response and best response
Median time to complete response
Median duration of complete response and best response. Median time to first response
The only oral HMA with equivalent systemic exposure to IV decitabine1,2
99% ratio of oral to IV 5-day decitabine AUC (indicating equivalent pharmacokinetic exposure) (90% CI: 93, 106)*
This ratio is the geometric mean of the 5-day cumulative decitabine AUC between INQOVI (decitabine and cedazuridine) tablets and IV‑administered decitabine when administered once daily for 5 consecutive days1
*Excludes data from some participants due to data confidence or quality issues.
Secondary endpoints
Clinical response
70% of MDS patients experienced a clinical response, showing improvements like complete or partial response, complete marrow response, and hematological improvement.2 (Evaluable participants: 82 of 117) (95% CI: 50, 69)†
†Based on International Working Group 2006 myelodysplastic syndromes response criteria.
Complete response in patients with MDS or CMML1,2
Phase 3 (N=133)
Phase 3 long-term follow-up (N=133)
Median follow-up time
12.6 months (range: 9.3-20.5)
~32 months (IQR: ~30-35)
Patients who achieved CR (CI)a
21% (95% CI: 15, 29)
25% (95% CI: 17, 34)b
Median duration of CRc
7.5 months (range: 1.6-17.5)
14.1 months (range: 11.7-18.7)
Median time to CRa
4.3 months (range: 2.1-15.2)
4.5 months (range: 2.1-18.7)5
aComplete or partial response may take longer than 4 cycles.1
bOf the evaluable 117 participants, 25% (29/117) achieved a complete response (CR).2
cFrom start of CR until relapse or death.1
Rates of transfusion independence were consistent at the long-term follow-up
Phase 3 results (N=133)1
Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period
Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 48 (63%) remained transfusion independent during any 56-day post-baseline period
Phase 3 long-term follow-up results (N=133)2
Among the 54 patients who were RBC transfusion dependent at baseline, 28 (52%) achieved RBC transfusion independence during the study
Of the 12 patients who required platelet transfusions at baseline, 6 (50%) achieved platelet transfusion independence during the study
33% of patients in each category (RBC: 18/54; platelet: 4/12) who were transfusion dependent at baseline maintained transfusion independence for at least 112 consecutive days
Incidence of cytopenias was slightly higher in INQOVI tablets during Cycle 1 compared to IV decitabine1,6
In the pooled safety population of Phases 2 and 3, 61% of patients receiving INQOVI were exposed for ≥6 months and 24% were exposed for >1 year1
In the long-term follow-up, the adverse event profile was similar to what was observed in the pooled safety population1,2
The incidence of serious adverse reactions in Cycles 1 and 2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with IV decitabine
Adverse reactions in pooled safety population
Adverse reactions reported in ≥10% of patients in the pooled Phase 2 and Phase 3 safety population1
Adverse reactionsa
INQOVI Cycle 1 n=107
IV decitabine Cycle 1 n=106
INQOVI all cycles n=208c
All grades (%)
Grades 3‑4 (%)
All grades (%)
Grades 3‑4 (%)
All grades (%)
Grades 3‑4 (%)
General disorders and administration site conditions
Fatigueb
29
2
25
0
55
5
Hemorrhageb
24
2
17
0
43
3
Edemab
10
0
11
0
30
0.5
Pyrexia
7
0
7
0
19
1
Gastrointestinal disorders
Constipationb
20
0
23
0
44
0
Mucositisb
18
1
24
2
41
4
Nausea
25
0
16
0
40
0.5
Diarrheab
16
0
11
0
37
1
Transaminase increasedb
12
1
3
0
21
3
Abdominal painb
9
0
7
0
19
1
Vomiting
5
0
5
0
15
0
Musculoskeletal and connective tissue disorders
Myalgiab
9
2
16
1
42
3
Arthralgiab
9
1
13
1
40
3
Respiratory, thoracic, and mediastinal disorders
Dyspneab
17
3
9
3
38
6
Coughb
7
0
8
0
28
0
Blood and lymphatic system disorders
Febrile neutropenia
10
10
13
13
33
32
Skin and subcutaneous tissue disorders
Rashb
12
1
11
1
33
0.5
Nervous system disorders
Dizzinessb
16
1
11
0
33
2
Headacheb
22
0
13
0
30
0
Neuropathyb
4
0
8
0
13
0
Metabolism and nutritional disorders
Decreased appetite
10
1
6
0
24
2
Infections and infestations
Upper respiratory tract infectionb
6
0
3
0
23
1
Pneumoniab
7
7
7
5
21
15
Sepsisb
6
6
2
1
14
11
Cellulitisb
4
1
3
2
12
5
Investigations
Renal impairmentb
9
0
8
1
18
0
Weight decreased
5
0
3
0
10
1
Injury, poisoning, and procedural complications
Fall
4
0
1
0
12
1
Psychiatric disorders
Insomnia
6
0
2
0
12
0.5
Vascular disorders
Hypotensionb
4
0
6
1
11
2
Cardiac disorders
Arrhythmiab
3
0
2
0
11
1
aPlease see full Prescribing Information for complete list of adverse events occurring during all cycles.
bIncludes multiple adverse reaction terms.
cIncludes adverse reactions that occurred during all cycles, including during treatment with 1 cycle of intravenous decitabine.
Hematologic abnormalities in pooled safety population
Select hematologic lab abnormalities observed in >20% of the pooled safety population1
Lab parametera
INQOVI Cycle 1b
IV decitabine Cycle 1b
INQOVI all cyclesb
All grades (%)
Grades 3‑4 (%)
All grades (%)
Grades 3‑4 (%)
All grades (%)
Grades 3‑4 (%)
Hematology
Leukocytes decreased
79
65
77
59
87
81
Platelet count decreased
79
65
77
67
82
76
Neutrophil count decreased
70
65
62
59
73
71
Hemoglobin decreased
58
41
59
36
71
55
aIncludes any lab abnormalities that worsened by ≥1 grades. Grades 3 to 4 include any lab abnormalities that worsened to Grade 3 or Grade 4.
bThe denominator used to calculate the rate varied from 103 to 107 for INQOVI Cycle 1, from 102 to 106 for the IV decitabine cycle, and from 203 to 208 for INQOVI (all cycles) based on the number of patients with a baseline value and ≥1 post-treatment value.
Fatal adverse reactions occurred in 6% of patients1
These included sepsis (1%), pneumonia (1%), respiratory failure (1%), septic shock (1%), and 1 case each of cerebral hemorrhage and sudden death1
Also in the long-term follow-up, 11 (8%) of 133 participants had fatal treatment-emergent serious adverse reactions during the study. 5 of these deaths were deemed treatment related; 2 to oral therapy (sepsis and pneumonia) and 3 to IV treatment (septic shock [n=2] and pneumonia [n=1])2
5% of patients discontinued INQOVI due to an adverse reaction1
1 participant in each group discontinued treatment during the first 2 cycles due to an adverse reaction2
Overall treatment discontinuations due to an adverse reaction included 1 (out of 132) receiving IV decitabine and 2 (out of 130) receiving oral decitabine-cedazuridine2
The most frequent adverse reactions resulting in permanent discontinuation were febrile neutropenia (1%) and pneumonia (1%)1
The most common reason for treatment discontinuation was undergoing allogeneic HSCT (27 [20%])2
Dose interruptions due to an adverse reaction occurred in 41% of patients1
Adverse reactions requiring dose interruptions in >5% of INQOVI patients included neutropenia (18%), febrile neutropenia (8%), thrombocytopenia (6%), and anemia (5%)1
Dose reduction due to an adverse reaction occurred in 19% of patients1
Adverse reactions requiring dose reductions in >2% of patients included neutropenia (12%), anemia (3%), and thrombocytopenia (3%)1
Additional safety profile information
Clinically relevant adverse reactions in <10% of patients who received INQOVI tablets included: acute febrile neutrophilic dermatosis (Sweet's syndrome) (1%) and tumor lysis syndrome (0.5%)1
Serious adverse reactions occurred in 68% of patients who received INQOVI. Serious adverse reactions in >5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%)1
References:1. INQOVI [package insert]. Princeton, NJ: Taiho Oncology, Inc.; 2022.
2. Garcia-Manero G, McCloskey J, Griffiths EA, et al. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024;11(1):e15-e26.
3. Savona MR, McCloskey JK, Griffiths EA, et al. Prolonged survival in bi-allelic TP53-mutated (TP53mut) MDS subjects treated with oral decitabine/cedazuridine in the Ascertain trial (ASTX727-02). Blood. 2022;140(suppl 1):2066-2069.
4. Santini V, Stahl M, Sallman DA. TP53 mutations in acute leukemias and myelodysplastic syndromes: insights and treatment updates. Am Soc Clin Oncol Educ Book. 2024;44(3):e432650.
5. Data on file. Taiho Oncology Inc., Princeton, NJ.
6. Kim N, Norsworthy KJ, Subramaniam S, et al. FDA approval summary: decitabine and cedazuridine tablets for myelodysplastic syndromes. Clin Cancer Res. 2022;28(16):3411-3416.
Important Safety Information
Important Safety Information
Warnings and Precautions
Myelosuppression: Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.
Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.
Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.
Embryo-Fetal Toxicity: INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment and for 6 months (females) or 3 months (males) after last dose.
Adverse Reactions
Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.
The most common adverse reactions (≥ 20%) were fatigue (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and transaminase increased (21%). The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased (81%), platelet count decreased (76%), neutrophil count decreased (71%), and hemoglobin decreased (55%).
Use in Specific Populations
Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.
Renal Impairment: No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min).
